What causes heart disease part 66

5th October 2019

How does lead cause CVD?

Following my last blog, several people asked the question. How does lead cause CVD – or atherosclerotic plaques? What is the mechanism of action? It’s a good question, one that I think I have answered before, at least in part. However, I think there is real value in going over it again.

First, I want to highlight some of the more general thinking about causes of CVD, I believe this is important as well, in order to see how lead fits in, and where my interest in lead came from.

For many, many, years now I have been trying to create a unified hypothesis about cardiovascular disease. A journey I thought I would never finish. Mainly, I now realise, because I kept coming across ever more ‘factors’ that had a role in CVD. This meant that – although I couldn’t quite work out why at first – I was running into the impossible, and unsolvable, problem.

246 factorial

The unsolvable problem is a direct result of the number of possible interactions between all the risk factors that have been identified.

To try and explain this further, I shall start with the latest UK risk factor calculator which is called Qrisk3. The previous one was Qrisk2. Qrisk3 can be found on-line here https://qrisk.org/three/ You can play with it to your heart’s content. Qrisk3 has moved on considerably from Qrisk1 and 2. It now incorporates twenty different factors.  If you strip them out of the algorithm they are, in no particular order:

  • Age
  • Sex
  • Smoking
  • Diabetes
  • Total cholesterol/HDL ratio
  • Raised blood pressure
  • Variation in two blood pressure readings
  • BMI
  • Chronic kidney disease
  • Rheumatoid arthritis
  • Systemic Lupus Erythematosus (SLE)
  • History of migraines
  • Severe mental illness
  • On atypical antipsychotic medication
  • Using steroid tablets
  • Atrial fibrillation
  • Diagnosis of erectile dysfunction
  • Angina, or heart attack in first degree relative under the age of 60
  • Ethnicity
  • Postcode

As a quick side-track, it amuses me that LDL is not in there – yet HDL is.

Now, you may think that this appears to be a relatively short list. At first sight it does not appear a complex task to fit these factors together into a coherent model. A twenty-piece jigsaw puzzle – at most?

Not so. The reality is that, if you view the model of CVD as twenty independent and unconnected risk factors, the number of possible interactions, or pieces, you need to analyse becomes mind-boggling.

Just to give you an idea of the scale of the maths involved here. You have twenty different risk factors, and you do not know how the connections between them work. Every risk factor can, potentially, interact with all the others – independently. This means that the possible combinations you must analyse is twenty factorial.

Calculating factorials is, on one hand, very straightforward. You simply multiply each factor, by all of the other factors, in turn. Thus, twenty factorial = 20 x 19 x 18 x 17 x 16 etc.

The result of multiplying 20 x 19 x 18 x 17 x 16 etc. is you end up with the following number: 432,902,008,176,640,000. Which is the number of different possible combinations between twenty factors. Rounding this figure up slightly, that equates to four hundred and thirty-three quadrillion. Which is a lot. And it gets far worse than that.

As far back as 1981, a paper was published outlining 246 different risk factors involved in CVD 1. Today, there would be far more, several thousand at least. However, even by 1981 the number of possible combinations was already incomprehensibly huge. I say this because 246 factorial is:


Yes, to my amazement, there is a website which will calculate factorials for you. You don’t think I worked that out myself do you? I would have definitely got bored and made several mistakes on the way. Therefore, I have no idea if this figure is right or wrong, but it seems to be in the right sort of ballpark.

There is no way to even describe a number that big, and it would certainly make for some jigsaw puzzle. In truth what we have here represents a figure so huge that you cannot possibly do anything with it. It has fifty-seven zeros before you even get to another number. At least I think it is fifty-seven, I may have lost count.

How long would it take to feed in the data on all these risk factors, run the combinations, and see if you can establish how they all fit together? That would take as close to an infinite amount of time as makes no practicable difference. Even with the latest Google quantum computer.

Thinking about things in this way, I came to realise that unearthing risk factor, after risk factor, after risk factor, was not going to make it easier to work out the cause of CVD. It was making it impossible.

The other word for impossible, I came to realise, is ‘multifactorial’.

Multifactorial = a word commonly used by cardiologists to prevent any discussion as to the real causes of CVD. In conversation on this issue, I silently change the word multifactorial to ‘246-factorial’, just to remind myself what a stupid concept it is to call a disease multifactorial. Then to believe that, by doing so, you have explained anything. ‘So, how do the factors all fit together?’ I mutter, imaging a number so vast that it is beyond comprehension.

Then I may quote Poincaré at them.

Science is built up of facts, as a house is built of stones; but an accumulation of facts is no more a science than a heap of stones is a house.’ Henri Poincaré.

Because multifactorial also effectively = a pile of stones. Well done, you have found thousands of stones, and carefully piled them ever higher, but this gets no nearer to constructing a house. To build a house you need to know how all the stones join up. You need a plan my friend.

Which starts to bring me, in a roundabout way, back to lead.

As regular readers of this blog will know, I ripped up the multifactorial model of CVD and tried to replace it with a process model. The plan of the house, if you like. I was no longer interested in finding endless risk factors, then chucking them on the pile. I wanted to know the process – or processes – involved.

In the end I stripped it down to three main elements. Basement, walls, roof.

  • Endothelial damage (damage to the lining of artery walls)
  • Formation of a blood clot
  • Repair

Or at least I stripped it down to three main processes – going wrong. Because this triad is all quite normal, and healthy. It is only when endothelial damage and clot formation accelerate, or repair is sub-optimal, that CVD/atherosclerosis will develop.

So, the simplest possible model is: rate of damage > rate of repair = CVD

Using the three-process model I began a different search. Starting with things that could damage the endothelium. I cast the net far and wide. Of course, it is more difficult to do the searching this way. Where do I begin? Do you just start thinking of things that might be damaging, and hope for the best? You will find yourself wandering all over the place. At least I did. Although it is quite an interesting journey – for a geek.

Bringing some structure into my search strategy, I decided that heavy metals were something that could not be doing any good to the human body. Mercury, lead, cadmium, and suchlike. Gold? Gold doesn’t seem to do much, one way or another. It was used to treat rheumatoid arthritis at one time. As for the others – not great. Lots of damage to health.

But do they damage the endothelial lining of the artery wall? Well, yes, they do. Looking at lead, here is a passage from the paper: ‘Mechanisms of lead-induced hypertension and cardiovascular disease.’

I admit that it is far too jargon heavy for most people. But I enjoyed it and I reproduced it in full because, what we have here, is the perfect storm. Many mechanisms I have previously mentioned in my long and winding series on what causes heart disease can be found here. Including many I did not mention because they were just too technical. I have put in bold some of the more important mechanisms:

‘Lead is a ubiquitous environmental toxin that is capable of causing numerous acute and chronic illnesses. Population studies have demonstrated a link between lead exposure and subsequent development of hypertension (HTN) and cardiovascular disease. In vivo and in vitro studies have shown that chronic lead exposure causes HTN and cardiovascular disease by promoting oxidative stress, limiting nitric oxide availability, impairing nitric oxide signaling, augmenting adrenergic activity, increasing endothelin production, altering the renin-angiotensin system, raising vasoconstrictor prostaglandins, lowering vasodilator prostaglandins, promoting inflammation, disturbing vascular smooth muscle Ca2+ signaling, diminishing endothelium-dependent vasorelaxation, and modifying the vascular response to vasoactive agonists. Moreover, lead has been shown to cause endothelial injury, impede endothelial repair, inhibit angiogenesis, reduce endothelial cell growth, suppress proteoglycan production, stimulate vascular smooth muscle cell proliferation and phenotypic transformation, reduce tissue plasminogen activator, and raise plasminogen activator inhibitor-1 production.’ 2

So, there you go. Not just one mechanism of action, but twenty-one different processes that lead can cause CVD. Fifteen ways of damaging the endothelium, four that inhibit repair, and two mechanisms for making blood clots more difficult to get rid of, as highlighted in the final passage… reduce tissue plasminogen activator, and raise plasminogen activator inhibitor-1 production.’

Tissue plasminogen activator (TPa) is the enzyme that activates the breakdown of blood clots. TPa converts plasminogen to plasmin, and plasmin then chops fibrin to bits, thus shaving down blood clots. Plasminogen activator inhibitor-1 is a substance that inhibits the action of tissue plasminogen activator (TPa = the clot buster, often given to patients after a heart attack or stroke).

Clearly, if you reduce TPa, and increase TPa inhibition, you end up with a blood clot that is very difficult to get rid of and is thus more damaging.

So, when people ask, have you got a mechanism of action to explain how lead causes CVD I say (rather smugly), no, I have got twenty-one. In truth, I have found quite a few more, but twenty-one is probably enough to be getting on with. One thing I have found is that once you start looking at all the potential processes, there seems almost no end to this stuff. It stretches in all directions.

Big fleas have little fleas upon their backs to bite ’em,

And little fleas have lesser fleas, and so, ad infinitum.

And the great fleas, themselves, in turn, have greater fleas to go on;

While these again have greater still, and greater still, and so on

Anyway, getting back on track, I started to look for factors, causal agents, whatever is the best name for them, that can impact on one of three processes:

  • Endothelial damage (damage to the lining of artery walls)
  • Formation of a blood clot
  • Repair

This is how I got to lead, only to discover that there was a huge body of research linking lead to CVD… that I had been completely unaware of. My analogy was that of a round the world sailor bumping into Australia and wondering why no-one had bothered to tell him it was there. ‘It’s pretty big, you know.’

Looking at things, by starting with one of the three processes, is also how I came across the evidence on sickle cell disease (SCD). I reasoned that sharp pointy red blood cells (sickled cells) hammering through the blood vessels would create serious damage to endothelial cells.

When I started looking, I found that, in some studies, SCD increases the (relative risk) of CVD by fifty thousand per cent. Yes, you did read that right. Fifty thousand per cent. With none of the other ‘established’ risk factors present.

Which makes SCD a ‘sufficient’ cause of CVD. In fact, it is the only sufficient cause I have ever found – in that it can lead to atherosclerosis in the blood vessels in the lungs, where the blood pressure is pretty low.

Which means that, with SCD, you don’t even need a high blood pressure. SCD can cause CVD all by itself. If you can find any other factor that can do that – let me know. For a more in-depth discussion on causation, and the concept of ‘sufficient’ see this article: https://jech.bmj.com/content/55/12/905.long

Then, I thought, what else causes damage to the endothelium. I ended up looking at a group of diseases known as ‘vasculitis’. Itis means, inflammation, as in tonsillitis, appendicitis. So, vasculitis means inflammation of the vascular system, by which I mean inflammation of the lining of the blood vessels. By which I mean, damage (and repair) to the lining of the blood vessels. Remember, inflammation = repair.

There are many different forms of vasculitis, most of which are not really thought of as being ‘vasculitis.’ For example, Rheumatoid arthritis, and Systemic Lupus Erythematosus. These conditions cause inflammation in many different places, but they also cause vasculitis. You may have noticed that both also appear on the Qrisk3 calculator.

Other forms of vasculitis, or diseases where vasculitis is an important part of the spectrum of abnormalities include:

  • Scleroderma
  • Sjogren’s
  • Erythema nodosum
  • Takayasu’s arteritis
  • Kawasaki’s disease

I think they all have great, evocative names:

All these forms of vasculitis are associated with a greatly increased risk of CVD. You can look this up yourself, if you want. In fact, children who suffer Kawasaki’s can die of myocardial infarctions (MIs), aged five. They have a brief, super-accelerated, form of endothelial damage that lasts a few weeks. Some can then end up with large aneurysms (balloon-like swellings) in their coronary arteries. These can burst, causing a MI.

So, not an entirely conventional MI. Nor conventional atherosclerosis. However, if you think of an aneurysm as a late stage abnormality in atherosclerosis [which most are] then in Kawasaki’s we can get from endothelial damage, to an aneurysm, in a month. Something that normally takes about sixty years to develop.

Three stones to make a wall

Lead, sickle cell disease, vasculitis.

In one sense it could be said that I have been discussing three completely unrelated things here. Lead, sickle cell disease, vasculitis. In another sense I hope you can see that these three ‘factors’ are related to CVD. Not by what they are, but by what they do. The damage they cause… the process.

They all fit very neatly into the walls of the house that are called ‘endothelial damage’. How else can you explain how three such disparate things can possibly cause exactly the same disease.

I must admit that this breakthrough in my thinking, from causes to process, was not mine. It was entirely due to one man. Professor Paul Rosch. We were discussing stress (strain) and CVD and he was critiquing a presentation I had given.

I shall paraphrase his comment. ‘Very good, you have given us the what, but not the how.’ Yes, very simple, when you think of it that way. What he was really asking was, what is the process? Since then, I have often wondered why have others not gone down this route?

I then realised that the problem, the great problem in all research into CVD, is that very early on it was decreed that LDL/cholesterol causes CVD. Therefore, all thinking, and any hypothesis on CVD required that LDL sat at the centre.

To my mind this is like opening a two-thousand-piece jigsaw puzzle and deciding, straight away, that one big piece – LDL/cholesterol – sits at the centre, and the other pieces must be made to fit around it.

Well, perhaps it does have a (small role) to play in CVD, but it most certainly does not sit and the centre. But if you keep it there, you distort the entire puzzle and make it impossible to complete. The pieces must be forced into place. Hammered down, or twisted into extreme shapes.

This, though, is where CVD research currently sits. Thousands of pieces are lying about the board. A few of them have been fitted together, here and there. As for the whole puzzle, it is doomed to failure, because the wrong piece is taking up the key position. Unfortunately, if you are a ‘serious’ CVD researcher, who wants to get grants for research, you can’t move it.

What I found if that you chuck that piece away, and start again, then everything becomes clear. The puzzle can be made to fit into one of these three processes:

  • Endothelial damage (damage to the lining of artery walls)
  • Formation of a blood clot
  • Repair

Lead, for example. Lead makes no sense as a significant risk factor using conventional thinking. It doesn’t raise BP, it doesn’t raise LDL, it doesn’t cause diabetes, it simply does not fit. So, it has become, essentially, ignored. But how can you ignore something that may be responsible for four hundred thousand deaths per year, in the US alone? Most of them CVD deaths?

The answer is that you cannot.

1: https://www.atherosclerosis-journal.com/article/0021-9150(81)90122-2/abstract

2: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2519216/

155 thoughts on “What causes heart disease part 66

  1. Jonathan Bacon-Sandwich

    Has anyone researched levels of lead in CHD pts? That would be interesting. Meanwhile I’m in with the multifactorial. To extend the metaphor, the walls of a house can be damaged by many different agents, but to blame the mortar that is used to patch them up seems silly.

  2. judefossett

    Hi,I’ve read something recently that homocystein  is the culprit?  And all else is the repair mechanism. Homocystein issues are caused by an imbalance in B2, folic acid and riboflavin?Kind regards,Jude FossettSent from my Samsung Galaxy smartphone.

    1. BobM

      I often have “high” Homocysteine, though not too high (from 10.2 to 13.6 umol/L), but I have a zero CAC (coronary arterial calcification) scan score.


    I’ve been following this for as long as it remains valid and true…question: Where are we getting our lead from? Old water pipes, bullet factories, putty manipulation? I like the endothelial damage, clot formation, repair, as an acute inflammatory process whereby chronic would mean trouble, but where is the villain? leaded fuel and the exhaust thereof?

    1. Bob Niland

      re: Where are we getting our lead from?

      Food needs a look. In the US, standards for heavy metals in foods are a bit lax, resulting in independent watchdog sites like ConsumerLab. This page of theirs directly addresses your question, and appears to be open to non-subscribers (although not all its links are):

      CL’s most recent test of cacao powders, for example, rejected EVERY product they tested, due to Pb and Cd; with brand, organic, country of origin, price and process providing no protection. One brand, rather than put a California Prop.65 warning on the package, simply discontinued the product. My guess is they wanted to fix it instead, and found they couldn’t.

  4. Micki Jacobs

    Lead directly ‘dinks’ with calcium as both a signaling molecule and replaces the calcium in hydroxyapatite-laden tissues.
    Lead dysregulates calcium.
    Microcalcifications are what mess with and damage the endothelium – they are ubiquitous in plaques (and the fatty, non-calcified plaques are benign, which is why CAC is so predictive of risk) – and recent technology allows us to see these microcalcifications when they are too small to see with CT.
    Clotting is calcium regulation via K-dependent proteins – just consider warfarin, how it works, how it increases CAC.
    CAC is super accurate in describing risk of death by all causes, so lets understand it.
    Repair… not sure, but calcium likely has a role.
    Look at calcium regulation and what impairs it and the many, many factors we have embraced in supplements, food, medicine, consumer products that all impair proper calcium regulation.
    Do they cause heart disease/CAC?
    It appears so:
    * Calcium supplements (alone or with D)
    * Bunches of food additives including inorganic phosphorus, man-made emulsifiers, etc
    * So-called ‘trans fats’ which are made by hydrogenating high vitamin K1 oils creates an aberrant form of the vitamin – dihydrophylloquinone – which cannot act as normal vitamin K, a player in calcium regulation
    * Loss of dietary K2 due to misguided dietary guidelines, making for widespread subclinical insufficiency of K, and thus, suboptimal calcium regulation
    * Statins, bisphosphonates, warfarin, maybe antidepressants
    * Water fluoridation, widespread F in consumer products

    Seriously, calcium dysregulation appears to be a unifying mechanism of our common chronic diseases.

    1. James DownUnder

      Micki, Thou shalt not criticize the Holy Ones, $tatins, biphosphonate$ and Dietary Guidelines lest thy enemies curse thee as a “Denier”.

    2. Soul

      I’m reading a book about chelation. The author mentions their favorite chelating substance for improving circulation and health overall is best known for removing excess calcium.

      It had me thinking that possibly we consume more calcium than we need. There are a few books on this idea. Also possibly it explains why in part sun exposure is beneficial. Vitamin D and other substances made in our body from sun exposure could help place calcium into bones and not into soft tissue.

  5. errett


    discarded electronic appliances such as mobile phones, computers, and televisions.

    Lead (Pb) and polycyclic aromatic hydrocarbon (PAH) exposure is positively associated with cardiovascular disease (CVD), and the possible potential mechanism may be caused by damage to the endothelium by modulation of inflammatory processes. No comprehensive research shows co-exposure of Pb and PAH on cardiovascular endothelial inflammation in electronic waste (e-waste) exposed populations. Given this, the aim of this study is to provide evidence for a relationship between Pb and PAH co-exposure and cardiovascular endothelial inflammation, in an e-waste-exposed population, to delineate the link between a potential mechanism for CVD and environmental exposure.

    Our results indicate that children with elevated exposure levels of Pb and PAHs have exacerbated vascular endothelial inflammation, which may indicate future CVD risk in e-waste recycling areas.

  6. Robert Bramel

    Great article! As always! I got a chuckle, more of a groan, thinking of the size and significance of twenty factorial. Seems that recently the explanation for those of us with truly extreme LDL (and of course, terrible TC/HDL) but no plaque has entered a modern phase. It can’t possibly be that LDL isn’t a risk; no, the new buzzword for people like me is “polygenic protective factors”. Twenty factorial??!! your number is a pittance compared to the factorials available using DNA. And with so many possibilities to work with it is child’s play to find some combinations of genes that exceed a mere 95% confidence. Another pesky problem is solved.

    1. Frederica Huxley

      And how many of the inorganic phosphorus additives in foods are GRAS, and have never been tested in the US by the FDA? The EU may have different standards, but I doubt it.

      1. Micki Jacobs

        Actually, these additives are a debacle…and GRAS, even though they are not.
        They are absorbed 100% while the P in food is more like 40%, which shows a fundamental difference, but not considered by powers that be.
        If you search, you will find that the CKD folks, who must tightly control intake of phosphorus, are mostly discussed, since there are no requirements for declaring P-added amount in foods on labels.
        This means that the ever-increasing phosphorus additives are an unquantified threat to them, but also everyone.
        ‘High normal’ serum levels in regular folks are related to increased heart risk (and other bad endpoints).
        Intake determines serum levels.
        Concern about this uncontrolled increase in P intake are occasionally voiced, but no one seems to be addressing this as we chase the usual suspects.
        Yet P based food additives, which will increase CAC are GRAS.


        Note how messed up and/or excessive P dysregulates calcium.
        And I claim that that – dysregulated calcium – is a result of many things, but is a fundamental and shared etiological factor in all the common chronic diseases.
        I guess you could say dysregulated calcium is multifactorial. 😉

  7. qofmiwok

    Is a standard blood test adequate to check lead levels, or is lead like mercury which is difficult to measure correctly because it is stored in tissues?

    1. andy

      qofmiwok: re. lead and mercury
      Will check with GP and request test for lead. A long tie ago when working for a company that had dental coverage a dentist replaced all dental amalgam with fresh ones. Assume that mercury and lead has had an impact on my health. Found a detox plan today. Need help with the garlic part.

      “How to Rid Your Body of Mercury and Other Heavy Metals: A 3-Step Plan to Recover Your Health
      I will provide you with a clear, three-step plan to help you detoxify from mercury and other heavy metals and recover your health. I have used this plan successfully and safely with patients over the last 10 years.
      ByMark Hyman, MD, Contributor”

  8. qofmiwok

    Is a standard blood test adequate for assessing lead levels, or is it like mercury which is difficult to measure correctly because it is stored in tissues?

    1. JDPatten

      Yes, iwok – This simple question needs answering! Gotta know to worry. Or not to. (Worry is a risk factor to add to . . . . Oh. Nevermind.)

      1. JDPatten

        OK. There are tests of blood, urine, or hair.
        What nuances of information does each afford? (Google not so helpful!)

  9. Marjorie Daw

    Another protoplasmic poison with adverse effects on the cardiovascular system is fluoride. Fluoride is even more toxic than lead and we are dosed with it daily from drinking water, toothpaste, mouthwashes, dental treatments pesticides and pharmaceuticals. Probably fewer studies on fluoride and cardiovascular disease because artificial water fluoridation is a sacred cow and a profitable way to dispose of industrial pollution.


    1. Janet

      You’re absolutely correct, water flouridation is so ingrained, one of those “obvious truths”… that honest researchers are loathe to risk career etc by asking too many questions.

        1. AhNotepad

          Anyone in the UK should look at https://www.gov.uk/government/consultations/advancing-our-health-prevention-in-the-2020s/advancing-our-health-prevention-in-the-2020s-consultation-document.

          It has something on fluoride, apparently with a bias in favour of water adulteration, oops, I meant treatment. No doubt there will be other things such as mandatory vaccinations and any number of forced procedures in the name of “prevention”. Another result of corporate lobbying?

          You have to get views in by 14 October.

          You might have noticed the “hidden in plain sight” intention of the consultation. “………advancing-our-health-prevention……………..”.

  10. Jean Humphreys

    Thank you. Remembering an incident in my childhood – Dad was melting lead on a camping stove in his shed, to cast fishing weights. He showed me, as a matter of interest, that the flashpoint of celluloid is lower than the melting poin of lead, by pushing a bar of celluloid in and seeing it burst into flames.
    He always made his own weights – yes and he did have heart disease. But it was thirty years from the first MI to everything else failing.

  11. Göran Sjöberg


    It has struck me as a “hammer blow” , the overwhelming complexity of our physiology – and the relation to what we are externally exposed to. That is also why I myself for precaution avoid all possible external “contaminations”.

    1. James DownUnder

      ‘Complexity’ is an understatement, though this has been understood by the Ancients far better than Modern Man. Good example would be my (ex…) cardiologist who asserted that a year of constant stre… er, ‘strain’ and deep depression…. contributed nothing to my arteries occluding…
      I reckon Solomon in Proverbs Ch 15 understood the autonomic nervous system better than he did !

      “A glad heart makes a cheerful face,
      but by sorrow of heart the spirit is crushed.”
      – Fits perfectly with Dr Kendricks’ comments on the fall of Soviet Union, and earthquakes in Greece.

      Not to mention yet another personal (multi…) Factor… I worked for decades in a letterpress printing factory, – the various Printer’s metals ranging from 76 to 84% lead.

  12. Jennifer

    Thanks once again Dr K. Having been intrigued by ‘factorial’ since 6th form maths, I see why I had to learn about it…because your explanation illustrates the complexities of what influences CVD, or, indeed most disease processes.
    Of course, more research adds more numbers to an unimaginable exponential curve. I am so pleased that you have whittled down to the essential processes that I can better understand now. In the meantime, us patients rely on thoughtful medics to do what’s good for us. Being on the verge of commencing anti-hypertensive medication, I feel better informed than ever before. Many thanks.

    1. Jerome Savage

      Jennifet – from the Doctor’s November 2018 release part 58
      “What I do recommend to patients is:
      Increase potassium consumption
      Go on a high fat, low carb diet
      Use relaxation techniques: mindfulness, yoga, whatever floats your boat
      Take exercise
      Get out in the sun – this stimulates NO synthesis
      Try L-arginine and L-citrulline – as above
      Increase magnesium consumption
      This will often, if not always, do the trick.
      If you must take medication, I was a very strong supporter of ACE-inhibitors”
      Just got similar advice.

      1. Jennifer

        Jerome. I so much appreciate your response to me. My endocrinologist (for 6 years) has now advised I introduce a low dose of ramapril to protect my kidneys. I am more than happy to comply as I have complete confidence in him.
        Many years ago I was unable to tolerate Captopril, and was commenced on a high dose of Amias in its place. As time passed by I was on buckets full of meds, and getting more unwell into the bargain, so I questioned the reasons why, especially as I was 65 and had had no medication review for years. I was referred to the said endocrinolist for advice. He said the Amias, Pioglitasone, Sitagliptin, Metformin and Simvastatin were excessive, so all (and other meds(!)) were discontinued with no ill effects. As you can see, I had been caught up in the Big Pharma merry-go-round, and it took courage on my behalf, and that of my hubby, (who supported me), to turn my back on the monthly repeat-prescription malarkey. The new advice to commence Ramapril coincides with much that I have gleaned from reading this wonderful blog, and doing some elementary research myself…..and being a good few years older, with age-related failing eyesight.
        I am not a stubborn, non-compliant individual, as was intimated to me 7 years ago, and fortunately I was referred to a great endocrinologist who agreed that I was right to question things. I acknowledge that health matters can change for the worse as the years go by. But, I contend that the loads of meds I was being prescribed from my mid-fifties, were inappropriate, and possibly unhealthy.
        As you mention other positive interventions, I do follow them. I try my best to do ‘what’s right’ and it gets me down when the media jump on the bandwagon of the “over weight, slothful, junk-eating individuals ” causing their “self-induced ill health”. It plays into the hands of a Government which chooses to be blinkered about cause and effect, preferring to blame the individual.
        There I go again….Politics!

  13. jbarnesbaker

    A Canadian private researcher has discovered what may be the missing piece of the puzzle that has been hiding in plain sight for over 100 years. It is a fascinating story. I’d love to hear your opinions about his theories, Dr. Kendrick, and I’m sure held be happy to discuss them with you. My intro to his work is here: https://www.carbwarscookbooks.com/eureka

    1. Göran Sjöberg

      Interesting to read about vitamin – A as a health culprit – this was new to me. (

      (BTW I am taking very large doses of natural vitamin – E to successfully keep my angina at bay – but no vitamin – A supplements. Could i be question about natural versus synthetic vitamins?)

      Though Vitamin – A poisoning has been a concern for 100 of years (?) especially among arctic explorers. However Whiljalmur Stefansson tells in his books how the eskimo hunter groups feasted on raw seal liver on the spot after they had successfully pulled the seal through the hole in the ice. The liver was considered as an almost holy piece of meat and when you look at a list nutrients for liver it is rather impressive. Perhaps it is as you indicate that it is the “overfill” of stored vitamin A which is causing the health problems.

      1. James DownUnder

        … and I just ordered months of a vitamin A supplement. 😦
        – Would have been safer to take more of my Wife’s excellent Pumpkin soup instead. ! ( very rich in beta-carotene)
        On another note, this quote -of-a-quote I lifted from the Mercola site, is saying the same thing Dr Kendrick said some time ago, how/why social connection is so vital.

        “…We always think of diet, exercise and genetics … [but] the biggest factor is your social life and how engaged you are in the world — the number of close friends you have, social integration. How many people have you talked to throughout the day? Did you say hi to the mailman? Did you talk or chat with people at the gym? That’s got a massive influence on your immune system.

        When you’re lonely, you have this sort of corrosive inflammatory response. But when you’re not lonely, your immune system has a more targeted response. Inflammation, as we know, is the root cause of so many cardiovascular disease, cancer and so many chronic diseases.

        That’s kind of why these blue zones get so much attention. That’s the constant variable … People are connected and they’re surrounded by each other all the time. [The blue zones] is where you have … 10 times the number of centenarians than you do in North America.”

      2. Tom Welsh

        I have no medical or scientific qualifications, so all I know is what I have read.

        That said, my understanding is that A and D work together, and an excess of either (alone) can create an artificial scarcity of the other. But if you take balanced A and D, large amounts of both are safe. (Cod-liver oil is a good source, I believe).

        You also need magnesium to balance the calcium which is so plentiful in most modern diets. (Dairy, meat, etc.) You can get some magnesium from plants, fruit, nuts, etc.; but a supplement might be advisable as well.

        Lastly, K2. Food sources are rare, though dairy from cows that have been eating new grass in spring or autumn is a good source. (Butter that has a rich yellow colour *without artificial colourings*). I have been taking K2 pills for a while with my magnesium and D. (I don’t take A supplements, preferring the occasional liver, chocolate, etc).

      3. jbarnesbaker

        Goran, natural vitamin A is certainly deadly after you exceed your ability to safely store it. I doubt that synthetic is any safer. Stefansson also said that the Inuit typical died at 70 years of age, which was 10 years younger than Europeans at the time. Their diet may have been healthful for them, but they may have reached their maximum tolerance earlier because of the high amount of vit. A. The 2nd part of my post is here: https://www.carbwarscookbooks.com/eureka-part-2/

      4. jbarnesbaker

        A few more observations about the Inuit. They were hunters; they had a natural rhythm of feast and famine. Stefansson tells of extreme hunger during his time living with them. Fasting depletes vitamin A stores. Also, they had a special diet for pregnant women to insure that they produced “perfect babies.” It included the intestines of herbivores with the fermented plant matter inside, as I recall. They probably found out by experience about the horrific birth defects caused by Retinoic Acid. Look at the insert that comes with prescriptions for Accutane to read the side effects of the drug (which is really just pure retinoic Acid). They are like those of Thalidomide, the drug for morning sickness, that caused babies to be born without limbs. Accutane patients are required to sign a pledge that they will take two kinds of birth control while taking it. Here is a quote from the iPledge brochure: “There is an extremely high risk that severe birth defects will result if pregnancy occurs while taking isotretinoin in any amount, even for a short period of time.”

        Vitamin A is in a class by itself among so-called, “vitamins.” It is not really a “vitamin” at all. The definition of “vitamin” is that it is something that is essential to life that the body cannot make. The early researchers who discovered vitamin A made a serious mistake. They thought they were giving their animals a zero-vitamin A diet when they were really poisoning them with Retinoic Acid that killed them in a matter of weeks. Later scientists who attempted to verify the findings used the same animal feed. (Retinoic acid, the final metabolite of vitamin A, had not been discovered yet, and they had no way to test for it. They spoke of an “unknown toxic factor” but they didn’t know what it was.) Grant Genereoux duplicated the studies, but using a truly zero-A diet. His animals lived normal, healthy lives. https://ggenereux.blog/wp-content/uploads/2018/09/PoisoningForProfits.pdf

      1. Gary Ogden

        Angelica Nelson: Agreed. Some people may accumulate excess vitamin A, but I suspect vitamin A deficiency is more common. Additionally, not everyone coverts beta carotene to retinol well. Chris Masterjohn has written at length on this subject, showing that vitamins A and D function synergistically in the body, and that toxicity in one of them only occurs in the relative absence of the other. As I recall, vitamin K2 is part of this synergy, too.

        1. Angelica Nelson

          My experience of secondary vitamin A and D deficiency is that Celiac can mess them both up. My body doesn’t convert very well now. All my deficiencies are secondary to years of undiagnosed Celiac. I only have one of the two genes for it, so I suspect the process for me was not very textbook. Also I had kidney damage on one side when I was young so that adds to the conversion issues with Vitamin D. I notice that Magnesium is a key nutrient for me which makes all the other vitamins work better. Once I switched to preformed vitamin A and focused my foods on it, a lot of things improved, but only if I was also focusing on eating greens every day and in my case I seem to need Magnesium and Choline boosters from supplements. I also eat liver regularly now and that makes the biggest difference so if someone can’t afford supplements the habit of eating liver may be the way to go. I haven’t felt any toxic effects from vitamin A even though I’ve tried to find an upper limit for myself. It certainly happens to some people or there wouldn’t be so many symptoms identified for it, but in general I am guessing that chronically ill people need more of the right kind, meaning, not beta carotene.

          For a while I had the bizarre effect that my skin wouldn’t burn or tan, even after a considerable time in the sun. That didn’t fix itself until I got enough of the fat based vitamins in active form, strongly supported by dietary habits.

      2. jbarnesbaker

        Is it vilifying it to say that it was never really a “vitamin” (essential to life) at all? It is the huge mistake made by the early researchers that is partly responsible for our multiple epidemics of autoimmune diseases, including obesity, diabetes, CVD, osteoporosis, cancer, and many, many more. I can testify from my own experience that NONE of the side effects attributed to a lack of vitamin A are real. I have been on a zero-A diet for about 10 months now and I can report marvelous effects that I can only describe as aging backwards.

        Grant Generoux has been on a zero-A diet for over 5 years and he continues to see improvements in his health. He decided to risk all the dire consequences he was told to expect because he was already so miserable with head-to-toe eczema, fatigue, and diabetes, and he had been diagnosed with a fatal kidney disease. I hope you will at least read my posts and his e-books and blog with an open mind. You have nothing to lose. You don’t have to take anything, or buy anything, or do anything. All you have to do is stop doing one thing.


        1. Angelica Nelson

          Actually that would mean stopping several habits that make me healthier and reduce pain for me. So I think we should avoid blanket statements. If it worked for someone that’s great and I think there’s something to learn from it, but I don’t know what we’re learning from it. And I’m not ready to call the discovery of vitamin A a huge mistake just based on that.

      3. Craig E

        @jbarnesbaker I’m intrigued as to what led early researchers to conclude that Vitamin A was essential and why/how they made the ‘mistake’ (ie what’s come to light since that proves Vitamin A is non-essential)?

        1. Angelica

          This is very belated, but a lot of what leads me to need vitamin A (not beta carotene), choline, and B12, plus glutathione from whole food liver, is due to the specific genetic situation I have which is a rare MTRR mutation that causes homocysteine to build up. I didn’t know that until I uploaded the raw file from my DNA analysis to another company that finally told me. They should’ve told me a long time ago. I already knew liver was helping me, but not why.

      4. jbarnesbaker

        Craig E. The scientists who “discovered” and named vitamin A, which was the first of all the vitamins, did animal testing back in the 20s and 30s. I don’t know why they originally thought it was essential. Grant Genereoux goes into a lot of detail about the history of their experiments and how they went wrong in his free e-book “Poisoning for Profit”, https://ggenereux.blog/wp-content/uploads/2018/09/PoisoningForProfits.pdf He also offers ample proof that they mistook the symptoms of vitamin A poisoning for a vitamin A deficiency.
        There is actually a lot of science on vitamin A that has accumulated in the last 90 years and much of it contains serious warnings about its dangers. It is one of those situations where something has been considered “settled science” for so long that nobody questions it and nobody wants to rock the boat. If you read the test results carefully, you can often understand what the research really showed in spite of the way it is interpreted. (If the results don’t agree with their biased expectations, it often says, “more study needed.”
        Here’s a report from the NIH that shows the conclusion from one of their studies: “The acute and chronic effects of vitamin A toxicity are well documented in the literature. Emerging evidence suggests that sub-toxicity without clinical signs of toxicity may be a growing concern, because intake from preformed sources of vitamin A often exceeds the recommended dietary allowances (RDA) for adults, especially in developed countries. Osteoporosis and hip fracture are associated with preformed vitamin A intakes that are only twice the current RDA…” Ncbi.nlm.nih.gov
        The RDA for vitamin-A for adult males is 900 mcgs and the RDA for women is 700 mcgs. A single three-ounce serving of cooked beef liver has 6,582 mcgs or 22,175 IUs (International Units), which is 731% of the RDA for an adult male. Is it any surprise we have epidemics of autoimmune diseases? Read more on my blog at http://www.carbwarscookbooks.com/eureka
        and https://www.carbwarscookbooks.com/eureka-part-2/

        1. Angelica Nelson

          I don’t doubt that the RDAs are messed up, for several vitamins, but you’ve referenced a blog to support the theory that there was a mistake made in the original research. Nevertheless, I don’t dismiss these things out of hand. So I went and read parts of both ebooks. The author makes a case for a single study called the Rothman study and references only a NYT article about it. At no time did the article talk about any mistake made in the original science. it points out that taking more than 10,000 IU Vitamin A from food or supplements can lead to a higher rate of birth defects according to one study. Then the ebook goes on to question why later other research was conducted to find more detail and often mistakes this new research for attempts to discredit “the Rothman study.” The so called Rothman study was making a case for using beta carotene in supplements instead of preformed vitamin A. Nothing about a so called “original mistake” in the science of vitamin A is noted in the article quoted in the ebook. Vitamin toxicity affects more than just vitamin A. And disease processes can cause a deficiency. Only deficiency is treated with doses like you describe, taken daily. A person who simply likes vitamin A because it helps them, isn’t going to eat liver daily, believe me I’ve tried, it’s boring.

          But it’s really harmful to tell people that dietary habits that help them are somehow “bad.” It’s more appropriate to say “just be careful of overdose” instead of “avoid it.” I strongly object to your absolutist tone which implies that eating preformed vitamin A is always dangerous. That kind of health message can truly harm people.

          I was vegan and vegetarian for over 12 years. I assure you, my problem is lack of vitamin A, not the reverse, also lack of several other things. This article describes my situation better than I could. I think the vegan diet triggered full blown Celiac for me, after first disabling my thyroid. I ended up with liver malfunctions that I can feel as physical pain if I don’t eat liver regularly. But obviously not every day. https://butternutrition.com/10-vegan-diet-dangers/

          1. Gary Ogden

            Angelica Nelson: And the healthiest and most robust and physically beautiful people Dr. Weston A. Price found on his extensive worldwide travels ate liver, and they ate it raw. This was in East Africa. As for me, I eat 2-4 oz of beef liver once a week, lightly cooked, with mustard, although I’ve had it raw. I also eat about the same portion of beef or pork heart weekly.

      5. jbarnesbaker

        Angelica and Gary:
        I ate liver and a lot of vitamin A rich foods too for many years and thought it was good for me. And it probably was–until it wasn’t. Most people on a vitamin A elimination diet go back to eating a regular diet after they have lowered their storage level. The diet is a cure, so you get to start over. Personally, I will not go back to eating liver, even if I can, because It is so high in V A–you will have all you have accumulated in your own life plus all the animals accumulated in their lives and it is very hard to get rid of it. (It takes about 2 years to empty your stored A, and that is if you have zero intake.)
        According to the WHO, there is no vitamin A deficiency in industrialized countries and yet most of us a supplementing with it whether we know it or not because it is added to our food. I looked up the foods that are highest in V A and was shocked to find that most of the foods at the top of the list were breakfast cereals and baby formula! We are started our kids out with a huge overload very early. It’s not surprising that we now have babies on drugs for depression and other autoimmune conditions.
        Genereux covers a lot more than one study. Keep reading his material.

        1. Gary Ogden

          jbarnesbaker: I agree that the fortification of foods with vitamins can be a bad idea. One of those is folic acid, when it is methyl folate, as found in foods, which we need. Folic acid is cheaper to produce. But like laws and vaccines; once given the stamp of approval, they never go away.

      1. Gary Ogden

        jbarnesbaker: Your blog post is very well done, but the evidence that you give for avoiding vitamin A-rich foods is too slim to be of value to me. For some people the cautions you give are likely to improve their health, but I think for the majority, this is not the case. I do agree about cod liver oil, for several reasons, and wouldn’t recommend it to anyone, and Dr. Price was very cautious in his recommendations for its use. I was very much involved in the kerfluffle four years ago about FCLO, and left WAPF over it. Taken as a whole, I think that the message of Nutrition and Physical Degeneration is that traditional foods in their great variety which provided excellent health among traditional cultures are what we should be eating for most of our meals, and these most certainly included vitamin A-rich items.

      2. Jerome Savage

        As an 8 year user of CLO your comments prompted me to do some research. From what I can see, the only issue (apparently no longer) was with FCLO. European CLO is extracted immediately, so the issue of rancidity never arises. (The US version might have been called PLO as Alaskan Pollock liver had been used.)
        CLO was suggested to me by my GP after identified hip cartilage damage. LD running had by all accounts compounded an old motorbike injury. To me, and I hav some trust in my GP, this was her thinking outside the box. No money or kudos in it for the good GP and no script so I paid particular attention.
        I remain unaware of any side effects.

        1. Gary Ogden

          Jerome Savage: CLO from the Atlantic Cod properly extracted, handled, and stored can be a very good thing to take, in small doses. In the U.S. there are a number of different brands available, none of which I would recommend, except Rosita. They do it properly. I was just so horrified by the FCLO (which WAPF still recommends) fiasco that I have sworn off all CLO as unnecessary.

      3. jbarnesbaker

        Gary Ogden and Jerome Savage: I also trusted my doctor who followed the WAP protocol. Big mistake! Even after I was too sick to get out of bed, she continued to believe that I needed a mega dose of vitamin A. I’m pretty sure I’d be dead by now if I had taken it much longer. I’m working on a third post about vitamin A. The title is “To everything there is a season..” Some things that serve a purpose at one time of your life, may be deadly at another. In fact in my first post, http://www.carbwarscookbook.com/eureka , I speculated that the accumulation of vitamin A may be the signal that causes us to die of old age. Be sure you know the symptoms so you can stop before you cross that line.

      4. jbarnesbaker

        Gary Ogden: thanks for the conversation! I’m still working on my 3rd post on the subject, but my website went down 3 days ago. I have a tech guy working on it but it is a mess. He said it had been infected with malware since 2016! I hope I’ll be back in business soon. Not sure what I’ll do if he can’t get it back up

  14. Gary Ogden

    Thank you for this, Dr. Kendrick, and for quoting the above paragraph in full. I think we’ve all been at this long enough to understand it well. I’m no genius, but I had no difficulty with it. Best to avoid lead like the plague, and eat lots of garlic and cilantro. Thinking of CVD as a process. Brilliant. Mistake to think of disease as a simple cause/effect relationship. How many genes have been found which directly cause specific diseases? Some, to be sure, but not many. Yet gazillions are spent each year looking for genetic causes of specific diseases. On another note, my potassium supplier (Prescribed for Life, in Texas) now has Potassium Citrate (officially TriPotassium Citrate Monohydrate), and I’ve switched to it. Supposed to be able to ward off kidney stones from oxalates, and tastes better than the bicarbonate. Not yet certain of the dose, but the proportion of K is about the same as in the bicarbonate (36% vs. 38%). I remember Phil informing us that 1/4 tsp (1 mL) is about 0.7-0.8 g, so I’m taking this twice a day. The package suggests 275 mg/day, but we know the clinical trial used 2 g/day, and it is likely our foods contain less than they once did.

      1. Gary Ogden

        AhNotepad: Yes, I have always taken the potassium supplement dissolved in either beet kvass or mineral water. If you use potassium chloride, a sort of fake salt, then you sprinkle it on food, I suppose, but I don’t remember buying it except in the dim recesses of time. All I know about potassium supplementation comes from Dr. Kendrick’s 2014 potassium post and its discussion thread, and some of the discussion threads on subsequent CVD posts. The Scottish Heart Study is a ringing endorsement of the protective effect of increased urinary K excretion, a marker for increased consumption.

      2. pamojja

        Potassium salts apparently can damage the stomach wall with too high a concentration. Well desolved in water it can’t. All the case reports of potassium adverse events come from concentrated pills or capsules, the high dose slow-release prescription forms.

  15. Derek

    Err – my maths package says the number you quoted is 241!, whereas 246! is as below (remove the backslashes):


    Calculated using ‘bc’ at the terminal on a mac:

    derek$ bc
    bc 1.06
    Copyright 1991-1994, 1997, 1998, 2000 Free Software Foundation, Inc.
    This is free software with ABSOLUTELY NO WARRANTY.
    For details type `warranty’.
    define f (x) {
    if (x <= 1) return (1);
    return (f(x-1) * x);

    1. David Bailey

      Drat, you beat me to it, I was going to quote the number you quoted for 246! Malcolm made a serious error by quoting a number which was 8 x 10^11 times too small! I used the free algebra system, SymPy to perform the calculation.

      1. Gary Ogden

        David Bailey: In any case, Dr. Kendrick deserves a round of applause for counting all those zeros at the end.

      2. Martin Back

        Not to mention 20! is 2.43 billion billion, to three significant figures.
        His answer needs to be multiplied by 5.62.
        My diagnosis: finger trouble.

  16. Craig

    Thank you Malcolm.

    I think that even with the simple set of twenty factors, the possibilities far exceed 20! since most if those 20 factors are not simple binary, present/absent occurrences. They have a continuum of values. I don’t even know how to begin working that out. There are big rocks and small grains but all can grow and shrink.

    WikiP. describes the wide range of harm via lead poisoning: “Lead has no known physiologically relevant role in the body,[42][78] and its harmful effects are myriad. Lead and other heavy metals create reactive radicals which damage cell structures including DNA and cell membranes.[145] Lead also interferes with DNA transcription, enzymes that help in the synthesis of vitamin D, and enzymes that maintain the integrity of the cell membrane.[24] “

  17. AhNotepad

    I never knew lead was such a problem. As at least one of its actions appears to be oxidative, does vitamin C provide some level of remedy?

  18. johnplatinumgoss

    I don’t doubt that lead, other heavy metals and other substances can have a deleterious effect on the cardiovascular system. Many other risk factors must similarly play a part. And some people are more resilient to risk effects (like the smoker who lives into his/her nineties).

    Your style makes easy reading and your efforts to make your articles interesting and understandable to the layman are a credit to you. Thank you. This blog taught me where CVD is concerned there are two major contributory influences of which you are in total agreement with mainstream medical opinion. Smoking is bad. Exercise is good.

    2 factors I can handle. Permutations of large numbers of factors make it a complex issue. As I haven’t smoked for more than forty years I concentrate on exercise. The advice is sound and seems to work.

    1. AnnieLaurie Burke

      The problem with all the multifactorial nonsense is, despite the protestations of researchers to the contrary, the change in risk for many of said factors is not statistically significant. This or that will “raise (or lower) your risk” by 11%, or 13%, or some such. I think I recall that Dr. K, in one of his previous blogs, quoted an eminent statistician as saying that, unless the effect is at least doubled, there are too many confounding factors to enable one to sift out a change that small from the statistical noise. And much research into factors is based on observation of trends — and sometimes, observations of trends that don’t even actually exist, but, the researchers assert, WOULD exist if they could but do the experiment. No, really….

      1. James DownUnder

        Annie, have a heart… ‘researchers’ have to be employed, and need to be seen as being, well,

    1. Janet

      I feel the greater your age, the more right you have to vary and modify diet to suit YOUR tastes, as did Peter at Hyperlipid (above)
      Or, so much for the ‘vegan’ dietary religion !

      1. andy

        Hi mikeezeem, not “worried well” more like “concerned well”. I must confess that I am addicted to learning about health issues. Having lived through the leaded petrol era in an urban environment I was a bit concerned about my lead exposure. Took lead off the concerned about list since learning that Vit C, garlic, cilantro, and saunas are useful for excreting lead and other toxins.

      2. Jennifer

        It’s because, as you put it, he seems to belong in the category of ‘ ‘worried well’ that he has reached a wonderful age. Most comments ‘jamming up this blog’, add to the big picture to help us understand what is good, bad, or indifferent to us keeping well. So let’s discard that awful description, and instead use the term ‘informed well’. I, for one, are much healthier since reading these blogs because I am better informed.
        Everything in moderation, I say, and then we just might be able to ward off ill effects of known toxic elements such as lead. Over indulgence in anything, including beneficial nutrients, might just as easily upset the applecart too.
        Language can be hurtful, and I think Andy made a good point.

  19. Big Mac

    Love your very rational and entertaining posts.

    Since your goal is to identify what casues CVD, and not just who it is likely to happen to, perhaps the factors need to be separated into potentially causative and merely indicative, with the idncative ones beinig ignored as causes. This reduces your combiinations considerably, altoough there are still a lot.

    For example, high blood pressure could be causative, while post code may be associated with some causative factor/s due to local diet/pollution/etc but is not itself causative.

    Perhaps something like this …

    Maybe Causative: (may cause CVD but some could just be symptoms not causes)
    Total cholesterol/HDL ratio
    Raised blood pressure
    Chronic kidney disease
    Rheumatoid arthritis
    Systemic Lupus Erythematosus (SLE)
    Using steroid tablets
    Atrial fibrillation
    Angina, or heart attack in first degree relative under the age of 60

    Maybe Indicative: (Associated with CVD but not causing CVD)
    Variation in two blood pressure readings
    History of migraines
    Severe mental illness
    On atypical antipsychotic medication
    Diagnosis of erectile dysfunction

  20. foodnstuff

    Brilliant! Simplifying the process down to 3 sub-processes makes it so much more easy to understand. I hope all these blog posts are going to be collected into a book at some stage!

  21. Karl

    I looked at various papers over the years linking polyphenol consumption with improvements in CAD. They didn’t make sense to me – polyphenols are not absorbed. Then reading about lead and chelation – I find that they are a poor man’s chelator – possibly they pass right through – keeping some metals attached for the ride.



    One of the things that screws with the Glycocalx is high BG – and the group that had the most benefit from chelation were diabetic.

    That lead generated ROS is damaging to the glycocalx is not a surprise – see https://www.sciencedirect.com/science/article/abs/pii/S0891584912000421 ( it is about glycocalx in the liver – but appears to apply).

    I’m in ’the damage and clot happens first’ camp – and if I understand the Lancet paper – several of the leading causes of death are lead related. Ask your doctor what caused the increase in heart disease in the 1900’s – I bet he doesn’t mention lead exposure.

    If you are focused on LDL you might miss this paper https://www.ahajournals.org/doi/full/10.1161/01.HYP.37.2.223

    Leading causes of death:
    Heart disease.
    Chronic lower respiratory diseases.
    Alzheimer’s disease.

    But not just CAD – Strokes and cancer are near the top of the list as well – so if we reorganize the list not by the actual disease, but what likely causes these diseases – we find lead, and cigarettes.

    There is a link between gycocalx and chronic respiratory disease as well

  22. lunaticfringe01

    I think what bothers e is that you mentioned in an earlier post that heart attacks can occur without a clot blocking an artery. I think that would make endothelial dysfunction a promising but incomplete answer to what causes MI’s.

    I ran across this post a while ago and I think it explains why there is no clot found in a lot of MI’s and the chronic stress aspect of it falls in line with risk factors you’ve noted in the past. Might be something to think about.


  23. AnnieLaurie Burke

    Thank you, Dr. K, for this most interesting addition to the series. Perhaps most medical researchers do not think in terms of “processes” because this would be more of an “engineering” approach. Since I’m an environmental engineer/scientist (now retired), the process approach seems logical to me, and this blog, since it involves lead (a ubiquitous environmental toxin I had to deal with in my active career), it was doubly interesting.

  24. Jessie

    I found it interesting that at least some of the risk factors for CVD were autoimmune diseases, i.e. Rheumatoid arthritis and Lupus. Autoimmune diseases are now on the rise, estimated to be around 3 times higher than they were several years ago and it is estimated that all autoimmune diseases combined is the 2nd most common cause of chronic illness in US, probably the same in the UK.

    According to the British Heart Foundation Heart disease fatalities are rising for the first time in 50 years.

    I was reading some while back now, about the metabolism of lead in the body. Absorbed lead that is not excreted is exchanged primarily among three compartments:-
    (1) blood (2) mineralizing tissues (Bones and teeth) which typically contain the vast majority of the lead body burden and (3) soft tissue (liver, kidneys, lungs, brain, spleen, muscles and heart).
    The chemical form of lead compounds entering the body is also a factor for the absorption and biological fate of lead:- (1) Inorganic lead, the most common form of lead, is not metabolized in the liver (2) Nearly all organic lead that is ingested is absorbed (3) Organic lead compounds (those found in petrol and additives) are metabolized in the liver.

    Blood levels do not accurately measure the total body burden of lead, they are more reflective of recent ongoing exposure. Inert components of lead is stored for decades, however, under certain conditions this inert lead can leave the bones and re-enter the blood and soft tissues. Lead mobilization can increase during periods of:- broken bones, chronic disease, hyperthyroidism, immobilisation (bedridden), kidney disease, menopause and physiological stress etc. Calcium deficiency exacerbates, or worsens, bone-to-blood mobilisation in all of the above instances.

    Anyway, to get to the point, is it possible that the rise in chronic illness (autoimmune disease etc), and the seemingly unrelated rise in heart disease, a result of the mobilisation of bone-to-blood lead. In addition, the liver does a good job in ridding toxic substances, but it can only do this if it has a good supply of minerals, so are we back to diet?

    1. andy

      Jessie: some thoughts about lead accumulation and excretion.

      Lead effect on mitochondria: more ROS produced and less ATP. Vitamin C or other antioxidants can mitigate ROS damage. Mitophagy will eventually eliminate a severely dysfunctional mitochondrion. The Pb atom will be recycled into another mitochondrion. The cell can still function but be less efficient.

      Effect on cells: Autophagy will recycle a severely affected cell. The Pb atoms could then enter the plasma. This is when chelation and elimination is possible. Kidneys and skin would be main routes of excretion. Being hydrated and taking frequent saunas could be beneficial.

      Lead can poison any cell, that is why there are many possible symptoms. Ingestion and absorption of lead is diet related. Green tea has lead and polyphenols, net effect might be beneficial.

      1. Jerome Savage

        “Green tea has lead and polyphenols, net effect might be beneficial”
        I find two surprises here, that;
        1. Green tea has lead and
        2 that net effect might be beneficial with polyphenols

        1. andy

          Jerome Savage: There appears to be very little information how to reduce Pb absorption and excretion. Glyphosate chelates heavy metals and everyone gets a daily dose. Maybe that is another reason for drop in CVD.
          Another possibility for reducing Pb:
          “The management of lead (Pb) exposure and toxicity remains a major public health priority worldwide. In our previous study, the probiotic strain Lactobacillus plantarum CCFM8661 prevented Pb absorption in mice via intestinal sequestration.”

  25. Jan Dawe

    Well all heavy metals are a problem because they mess with the bodily processes in various ways. Don’t forget about gadolinium, used as a contrast agent in MRI’s. It is toxic and some of it is retained post scan. It is not all excreted in the first one or two days. I can attest to that, after being poisoned from several MRI’s. It messes with calcium and interferes with nitric oxide production and causes fibrosis. It is at this stage not easily chelated out of the body.

    1. mmec7

      In the same position here Jan Dawe – 2013, following two MRAs with contrast suffered a severe Iatrogenic lipodermatosclerosis, was hospitalised, and am advised that the residual damage will be permanent : lower limbs still scaley, discoloured, swollen, often painful (as though ‘in’ the bone).
      Three Gd contrast dyes have been removed from the market place – was four in France, but pharma made a huge fuss and uproar, so much so that one was brought back !
      Am now facing a diagnosis for MS, whether that ‘may’ be linked to MS I don’t know, but it might have been a trigger as MS is found in my paternal family. Have yet to follow up that possibility. Ho-Hum !

  26. andy

    The time has come to update risk factors for most diseases:
    1- insulin resistance
    2- polyunsaturated Omega-6 seed oils
    3- plant anti-nutrients: lectins, oxalates, leading to leaky gut and autoimmune diseases
    4- heavy metals
    5- pharmaceuticals
    6- food additives, msg, polysorbate-80, etc
    7- stress
    8- depression: could result from above factors

  27. Charles Gale


    Your comments about:

    (1) your ex cardiologist dismissing the impact of “constant stre…er, ‘strain’ and deep depression” on your arteries exactly describes my experience too – my cardiologist is an ex cardiologist for the same reasons and

    (2) the importance of social life. This reminds me of an article in the Times a few Saturdays ago. According to the article 1/5 of men have no close friends and are more likely to lead solitary lives.

    Author Henning Mankell wrote the Wallander detective novels and he wrote for the ageing process – Wallander was at retirement age in the last novel. There is a comment in the final novel about the phone ringing less, less visitors as we age and I can relate to this: there is no comparison now to my social life at 18.

    I’m not sure this applies to everyone, but it is often true. Check out the demographics in the pubs on a Friday night.

      1. James DownUnder

        … Not what I felt he deserved ! 😦

        His replacement couldn’t be more opposite, and a Doctorate of Philosophy has pride of place on his wall.

        1. Gary Ogden

          James DownUnder: I’ve been thinking ever since about your comment concerning leaded type and CVD. My father was a printer, and I suspect he frequently handled leaded type, breathed fumes, and so forth. Fatal MI at 32; autopsy showed arteries of an 80-year-old. I’ve long suspected the strain from the war (he was in the hospital corps in the ETO, so saw blood and gore every day) was the major factor, but now I wonder of lead exposure was just as, or more important a factor. His father, born in 1884, lived nearly to 88. Lucky enough to miss all the wars in his lifetime he was.

    1. chris c

      When my mother died, aged 95, and I was trying to organise the funeral I discovered that her address book was full of dead people.

      I’ve lost a lot of friends and neighbours, mostly from seventies to 108 1/2, but a couple were 23 and 51, both cancer. Since I don’t expect to be around for much longer I’m tending to disconnect from people for their own good, but I make up for it by talking to strangers

    2. Angelica Nelson

      I can attest to the social life slows down after a certain age thing. It’s picking up again now with my grandson’s birth. I’ve noticed it’s really helpful to keep track of people’s birthdays and remember them with cards, calls, etc. It might be a Victorian sensibility but it’s nonetheless fun.

  28. pamojja

    Quote: When I started looking, I found that, in some studies, SCD increases the (relative risk) of CVD by fifty thousand per cent.

    Anyone knows what is the absolute risk?

  29. Angelica Nelson

    Aren’t heavy metals a cause for CKD? If the kidneys get messed up, isn’t that going to lead to some of the typical risk factors like blood pressure changes? I tried to find links from heavy metals in general, to diabetes, but to my untrained eye, it looks vague at best. I mean, Cr has good effects on diabetes. Probably less good if it’s part of a pesticide though.

    I went looking for where people get lead from, landed on an article vilifying cigarettes (again), and then looked for why cigs would have lead, answer: pesticide use. So the main input for humans would then be conventional foods (instead of bio/organic). Seems like one of the reasons nobody is pointing fingers at lead is because it would hurt chemical sales for conventional farming. I would be very amused to see a warning like this on conventional foods: “this food is known to contain heavy metals residues.”

    Note that I have no interest in entering into the “are organic cigarettes safer” argument. That’s a beehive and I have no interest in disturbing it.

    1. Anna M

      Obviously organic cigarettes are safer if they use pesticides and they have lead. Doesn’t mean cigarettes are good! But where does the lead in pesticides come from? I mean, surely they aren’t allowed to put lead into pesticides?

        1. AhNotepad

          andy, thanks for the link. It does make ne wonder about the possible damage being done by using the current pesticides. The claims are they provide benefits, while mentioning nothing of the dangers. How wonderful are these chemicals? There are almost nothing of the flying insects we used t find covering the front of cars in the summer. Did we wipe them out by driving into them? Or is something else going on. It’s not only the ones we used to collect on cars that have disappeared.

          1. Gary Ogden

            AhNotepad: Yes, insects appear to have disappeared. More shocking are birds. What was once an every-morning cacophony has been replaced by silence. The mourning dove, ubiquitous everywhere in large numbers, is only rarely to be seen. I still see plenty of jays and crows, and the occasional junco or sparrow, but I haven’t seen a sapsucker or woodpecker at all, except in the Sierra, for a couple of years. This is an ominous development. The disappearance of the mourning dove cannot be blamed on the disappearance of insects (or Trump or global warming), since they are ground-feeders, eating mainly seeds. Agricultural chemicals it must be.

      1. Angelica Nelson

        Potato beetle pesticide contains lead and arsenic. I don’t know if rice would have it too, I know the pesticide used in rice ag contains arsenic or did contain it until recently because there are papers written about how to mitigate the arsenic in rice. Rice will pull heavy metals out of the ground, so if someone has land that contains lead from previous applications of pesticide, the assumption that “no till” will not disturb the lead is wrong. Not to be too scaremongering, one easy way to reduce the effects of rice pulling metals from the ground is to eat white, not brown rice. Of course, many gluten free pastas are based on rice bran so that’s a serious issue in the Celiac community. I would like to see a lot more Organic farming in the world, but even with the three year transition, that won’t remove the lead from the soil if it was sprayed with it previously. A specific cleanup has to take place. Which, I assume is done, because soil testing is required, but all regulations are enforced in a spotty way. I’m a realist about that, but I still buy as much Organic as possible.

  30. Kevin O'Connell

    Many thanks Dr K for this excellent post. I may be needing some of this info because I have just had a change of ‘médecin traitant’ (French GP) following retirement of one who could almost have qualified for THINCS by one who has qualified rather recently!

    Incidentally, your reference to Henri Poincarré comes from La Science et l’hypothèse (1908) (see https://dicocitations.lemonde.fr/citations/citation-99523.php : “On fait la science avec des faits, comme on fait une maison avec des pierres; mais une accumulation de faits n’est pas plus une science qu’un tas de pierres n’est une maison.”

  31. Martin Back

    Big clots have fibrin; plasmin will dissolve it:
    Plasmin from fibrinogen; should TPa evolve it.
    But plasminogen activator inhibitor-1
    Puts a stop to the process. All good work undone!

    Have I got it right? It’s complicated!

      1. AhNotepad

        I agree. The MSM seem to only publish the narrative dictated by the corporatist lobby. Facts and public interest are not on the agenda.

  32. Anna M

    While ever-learning what might be useful in cancer, I came across a lecture in which the interviewee suspects that sulfur/sulfate deficiency may be a factor in cancer, and then went to search for ways to eat more sulfur, and it turns out that we really need to get sun exposure. It seems that the making of sulfates in the body is very similar to the making of vitamin D and that it might be quite pertinent to heart disease as well.


    1. AhNotepad

      Sasha, I wonder if people will take any more notice of the findings of this study than they did of the work of Jungblut, Klenner et al. I also wonder if others will try and replicate the study using lower doses of vit C, then claim the tests were a failure.

      Meanwhile when they find vaccines don’t seem to work, they instantly respond with a call for more vaccinations. If that doesn’t work, they make vaccines mandatory

      1. Sasha

        Who knows? The article said that this therapy “should improve financial health of hospitals” as it cuts hospital stay in ICU by about 7 days, lowers absolute risk of mortality by 15%, etc.
        But I think it’s having it backwards. In the US, at least, if you are a hospital and you are getting paid for your services, you are incentivized to keep your patients in ICU for longer, not shorter periods. It is a cynical way to look at it but I don’t see how to see it differently, at least from the standpoint of a hospital.

  33. Soul

    Saw yesterday Humana released a study report saying around 1 trillion dollars was being spend on health care fraud and waste in America each year. I don’t know how they came to that figure of 1 trillion dollars. They provide some information in their report of course but I have to admit I didn’t read the details. It just another report of many on this area of waste and fraud that will be ignored. I’m guessing they didn’t take into account the lack of success with the cholesterol theory and other questionable areas of health care spending. So maybe 2 trillion dollars annual wasteful spending is more accurate. Maybe lead poisoning testing would be more beneficial and helpful to patients. Basically 1 trillion dollars is thrown away every year according to Humana by the American medical system. It’s an unreal enormous number.

      1. Soul

        That’s what I often think also. I tell myself that a few bags with a million or two dollars worth of questionable health care spending could be left off at my front door, please. i wouldn’t mind, not a peep of complaint from me if that happened. (I say that jokingly of course)

        I think though that money can be spent better else where in the economy.

        I recall last week that it was reported health care was believed to cost the average family around $20,000 a year. There has been talk of stagnant wage growth in America this election cycle. I can imagine that stagnant growth is due in part to run away health care costs.

        “The cost of employer-provided health insurance for a family now tops $20,000 a year”


        1. Sasha

          I agree about that money being better spent elsewhere but there seems to be a lack of political will. And when you have such a large and powerful sector of economy as healthcare, there’s lots of lobbying to ensure that things don’t change. My view is that because the medical-industrial complex has gotten so big (possibly the biggest sector of the US economy), it siphons the vast amounts of money out of everywhere else. There’s a great transfer of wealth happening every year, with money going from the pockets or regular citizens into the coffers of the medical-industrial complex.

      2. Jerome Savage

        2019 US federal Budget
        Pensions inc. SoSec $1.46 trillion
        Health care $1.71 trillion
        Education $1.14 trillion
        Defense $0.94 trillion
        Welfare $0.46 trillion
        Protection $0.3 trillion
        Transportation $0.36 trillion
        Gen. Government $0.2 trillion
        Other Spending $0.57 trillion
        Interest $0.5 trillion
        TOTAL Spending $7.63 trillion

        You were close. Health is 2nd.

        1. Sasha

          Jerome, this is just the federal budget, the stats you give don’t include private insurance. If you look at the totality of health expenditures, in 2017, for example, US spent 3.5 trillion dollars on healthcare. Thus, making it the largest business known to mankind. Whatever is being wasted there is going to someone’s pocket…

      3. Jerome Savage

        Amazing and incredible.
        The figures are so big that we somehow can’t connect and make any kind of rational comment. Bonkers does seem apt tho.
        Having said that, I find here that the US does seem to be the destiny for treatment for rare or difficult conditions. Local fund raising at times will garher very significant sums for such treatment. We might be forgiven for thinking therefore that the US provides stare of the art med services. It’s never Russia, Cuba or any other major economy – occasionally Germany. I hav heard of Poland for a particular treatment which escapes me right now.

        1. Sasha

          It depends on who you ask. Israel, Russia, and India, to give just a few examples, have some excellent doctors and medical centers. As does most of Western Europe, Germany in particular. Eastern Europe has had for centuries very effective treatments that are only now becoming popular in the West. Look up Karlovi Vary in Czech republic, for example.

      4. Jerome Savage

        There is a suggestion that the French system is the best, tho am unaware if it excels in any area of medicine. Neither am I aware of any treatments attracting custom from this neck of the woods.

        1. Sasha

          I have heard that one of the best systems is the one in Singapore but it places restrictions on the system that no American lobby would go for, in my opinion.

    1. andy

      Soul: eliminating waste could have consequences.

      Rural Hospitals in the US Are Closing at an Alarming Rate

      I have stopped worrying about a bit of lead in common foods. Discovered that green tea contains lead, therefore bad. But then green tea also contains oxalates and flavonoids that can bind toxic metals. Therefore I will not stop drinking green tea. Berries also contain oxalates and flavonoids. Excessive consumption of healthy foods is the problem.

      Oxalate content and calcium binding capacity of tea and herbal teas.

      “All brewed teas contained lead with 73% of teas brewed for 3 minutes and 83% brewed for 15 minutes having lead levels considered unsafe for consumption during pregnancy and lactation.”

      Click to access d1337a409cdb0246f4ffc768f7a50f7d2645.pdf

      “Flavonoids can be effective drugs because of their potent chelating or neuroprotective, radical scavenging and anti-inflammatory properties.”


  34. Gary Ogden

    We now have a gram scale, and I have determined that 1/4 tsp. of potassium citrate equals about 630 mg potassium. 1.75 g X 0.36 (36% K). Not certain the calculation is correct, but pretty sure.

  35. David Bailey


    Is it possible to estimate what percentage of CHD is the result of lead poisoning?

    For example, are there reasons why the French, or the Japanese would have picked up less lead, or why the Russians might have picked up more lead? If lead explains some of the medical paradoxes, it might be a big factor.

  36. Martin Back

    A question: where do plasmin, fibrinogen, TPa, etc originate from? As they get used up something must sense their concentration in the blood is getting low and manufacture more of them. Is it a gland, or stem cells, or arterial lining cells, or what?

  37. Don

    So the big, bad wolf of heart disease is easy to beat, using Dr. Kendrick’s formula of rate of damage> rate of repair= cvd. Avoid or minimize those lifestyle, dietary, toxic things that contribute to endothelial damage or inhibit the repair process and do those lifestyle and dietary things that aid and increase the repair process. I have 100% faith in this and am going to begin looking at what increases the rate of repair. Perhaps you will start another blog Dr. Kendrick? “What helps heart disease”. I’ll be looking forward to that!

    1. Gary Ogden

      Don: Dr. Kendrick has addressed this well, about ten blogs ago or so, and in Chapter 21 in “A Statin Nation.” I highly recommend reading all three of his books.

      1. Sasha

        Another endorsement of time-restricted eating: I have a friend who leads a regular life. Does not exercise, doesn’t always watch what she eats, smokes, and drinks alcohol in the evening in front of a TV. As the result she has symptoms: hypertension, insomnia, BG dysregulation (wakes up every couple of hours to eat, otherwise unable to fall back asleep). She manages it all (except BG) with pills.
        I suggested to her that she can keep everything about her life except one thing: all of her calories must come within a 9 hour window of 24 hours. At first she tried to argue that alcohol in the evenings should not count but finally relented. In 3 weeks she lost 6 kg, falls asleep naturally and stays asleep through the night, has more energy, etc.

  38. errett


    Scientists at the University of Hawaii have uncovered a computer glitch that brings into question the findings of over 100 academic research papers.

    “This simple glitch in the original script calls into question the conclusions of a significant number of papers on a wide range of topics in a way that cannot be easily resolved from published information because the operating system is rarely mentioned,” the authors wrote in the update. “Authors who used these scripts should certainly double-check their results and any relevant conclusions using the modified scripts in the [supplementary information].”

  39. errett

    Six rules: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1182327/

    Corollary 1: The smaller the studies conducted in a scientific field, the less likely the research findings are to be true. Small sample size means smaller power and, for all functions above, the PPV for a true research finding decreases as power decreases towards 1 − β = 0.05. Thus, other factors being equal, research findings are more likely true in scientific fields that undertake large studies, such as randomized controlled trials in cardiology (several thousand subjects randomized) [14] than in scientific fields with small studies, such as most research of molecular predictors (sample sizes 100-fold smaller) [15].

    Corollary 2: The smaller the effect sizes in a scientific field, the less likely the research findings are to be true. Power is also related to the effect size. Thus research findings are more likely true in scientific fields with large effects, such as the impact of smoking on cancer or cardiovascular disease (relative risks 3–20), than in scientific fields where postulated effects are small, such as genetic risk factors for multigenetic diseases (relative risks 1.1–1.5) [7]. Modern epidemiology is increasingly obliged to target smaller effect sizes [16]. Consequently, the proportion of true research findings is expected to decrease. In the same line of thinking, if the true effect sizes are very small in a scientific field, this field is likely to be plagued by almost ubiquitous false positive claims. For example, if the majority of true genetic or nutritional determinants of complex diseases confer relative risks less than 1.05, genetic or nutritional epidemiology would be largely utopian endeavors.

    Corollary 3: The greater the number and the lesser the selection of tested relationships in a scientific field, the less likely the research findings are to be true. As shown above, the post-study probability that a finding is true (PPV) depends a lot on the pre-study odds (R). Thus, research findings are more likely true in confirmatory designs, such as large phase III randomized controlled trials, or meta-analyses thereof, than in hypothesis-generating experiments. Fields considered highly informative and creative given the wealth of the assembled and tested information, such as microarrays and other high-throughput discovery-oriented research [4,8,17], should have extremely low PPV.

    Corollary 4: The greater the flexibility in designs, definitions, outcomes, and analytical modes in a scientific field, the less likely the research findings are to be true. Flexibility increases the potential for transforming what would be “negative” results into “positive” results, i.e., bias, u. For several research designs, e.g., randomized controlled trials [18–20] or meta-analyses [21,22], there have been efforts to standardize their conduct and reporting. Adherence to common standards is likely to increase the proportion of true findings. The same applies to outcomes. True findings may be more common when outcomes are unequivocal and universally agreed (e.g., death) rather than when multifarious outcomes are devised (e.g., scales for schizophrenia outcomes) [23]. Similarly, fields that use commonly agreed, stereotyped analytical methods (e.g., Kaplan-Meier plots and the log-rank test) [24] may yield a larger proportion of true findings than fields where analytical methods are still under experimentation (e.g., artificial intelligence methods) and only “best” results are reported. Regardless, even in the most stringent research designs, bias seems to be a major problem. For example, there is strong evidence that selective outcome reporting, with manipulation of the outcomes and analyses reported, is a common problem even for randomized trails [25]. Simply abolishing selective publication would not make this problem go away.

    Corollary 5: The greater the financial and other interests and prejudices in a scientific field, the less likely the research findings are to be true. Conflicts of interest and prejudice may increase bias, u. Conflicts of interest are very common in biomedical research [26], and typically they are inadequately and sparsely reported [26,27]. Prejudice may not necessarily have financial roots. Scientists in a given field may be prejudiced purely because of their belief in a scientific theory or commitment to their own findings. Many otherwise seemingly independent, university-based studies may be conducted for no other reason than to give physicians and researchers qualifications for promotion or tenure. Such nonfinancial conflicts may also lead to distorted reported results and interpretations. Prestigious investigators may suppress via the peer review process the appearance and dissemination of findings that refute their findings, thus condemning their field to perpetuate false dogma. Empirical evidence on expert opinion shows that it is extremely unreliable [28].

    Corollary 6: The hotter a scientific field (with more scientific teams involved), the less likely the research findings are to be true. This seemingly paradoxical corollary follows because, as stated above, the PPV of isolated findings decreases when many teams of investigators are involved in the same field. This may explain why we occasionally see major excitement followed rapidly by severe disappointments in fields that draw wide attention. With many teams working on the same field and with massive experimental data being produced, timing is of the essence in beating competition. Thus, each team may prioritize on pursuing and disseminating its most impressive “positive” results. “Negative” results may become attractive for dissemination only if some other team has found a “positive” association on the same question. In that case, it may be attractive to refute a claim made in some prestigious journal. The term Proteus phenomenon has been coined to describe this phenomenon of rapidly alternating extreme research claims and extremely opposite refutations [29]. Empirical evidence suggests that this sequence of extreme opposites is very common in molecular genetics [29].

    1. Dr. Malcolm Kendrick Post author

      I agree with most of this, but I am not sure about number one. In my opinion, if you need thousands of people in a trial, the effect you are looking for is likely so small that it isn’t worth looking for. On the the hand, very large effects can be ‘proven’ in small populations. The use of parachutes in saving lives after jumping out of a plane for example. Or, to be less ridiculous, the use of insulin in type I diabetes. In this case, you could prove insulin was effective in one patient. Without it, death was certain. With it, people lived for many years. Huge trials are needed for marketing drugs.

  40. Lisa ONeill Wright

    I don’t know enough about the brain/genes/Alzheimer’s to have a clue what this means, but having followed your work for ages, I was struck by the passing reference to high cholesterol in the last sentence of the excerpts I pulled (see below). Made me wonder if high cholesterol might turn out to be protective (re: Alzheimer’s). I gather high cholesterol is often present in people who also have a lot of beta-amyloid plaques, long associated with Alzheimer’s – but the research on this woman suggests “a very clear dissociation of amyloid accumulation from tau pathology, neurodegeneration and even cognitive decline.” Anyway, have a look if you are curious …

    From the article:

    “APOE is important in general-population Alzheimer’s. It has three variants. One, APOE4, greatly increases risk and is present in 40 percent of people with Alzheimer’s.

    The Colombian woman has two copies of APOE3, the variant that most people are born with — but both copies have a mutation called Christchurch (for the New Zealand city where it was discovered). The Christchurch mutation is extremely rare, but several years ago, Dr. Reiman’s daughter Rebecca, a technologist, helped determine that a handful of Colombian family members have that mutation on one of their APOE genes. They developed Alzheimer’s as early as their family members typically did.

    “The fact that she had two copies, not just one, really kind of sealed the deal,” Dr. Arboleda-Velasquez said.

    The woman’s mutation is in an area of the gene that binds with a sugar-protein compound that is involved in spreading tau in Alzheimer’s disease. In laboratory experiments, the researchers found that the less a variant of APOE binds to that compound, the less it is linked to Alzheimer’s. With the Christchurch mutation, there was barely any binding.

    … Dr. Reiman, who led another newly published study showing that APOE has a bigger effect on a person’s risk of getting Alzheimer’s than previously thought, said potential treatments could try to reduce or even silence APOE activity in the brain. People born without APOE appear to have no cognitive problems, but they do have very high cholesterol that requires treatment.

    https://www.nytimes.com/2019/11/04/health/alzheimers-treatment-genetics.html?action=click&module=Top%20Stories&pgtype=Homepage [https://static01.nyt.com/images/2019/11/04/science/04ALZHEIMERS1/04ALZHEIMERS1-facebookJumbo.jpg] Why Didn’t She Get Alzheimer’s? The Answer Could Hold a Key to Fighting the Disease – The New York Times The woman’s genetic profile showed she would develop Alzheimer’s by the time she turned 50. A member of the world’s largest family to suffer from Alzheimer’s, she, like generations of her … http://www.nytimes.com



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