14th January 2022

A few months ago, I resolved not to write anything more about COVID19. I was having zero apparent effect on anything, or anybody, and I was just getting increasingly despondent at the destruction of science, debate, logic, humanity, personal freedoms … life.

However, my New Years resolution was to not have any more resolutions. Which lead to an almost inescapable logic loop from which I have only just managed to extricate myself.

In truth, I believe that I still have a few things left to say about COVID19 that may be useful in stopping some of the most egregious nonsense being repeated. [Fat chance, says the little man on my shoulder].

What I am about to write, I have written about before, in various different guises. However, I think it is worth going back over some old ground again. Hopefully in a more effective manner.

In this blog what I want to do is to look at how we think about a few things, primarily in medicine, and medical science. To try and highlight how some repeated flaws in thought have influenced the reaction to COVID19.

I hope that by doing this, it may help to prevent some us travelling down the terribly well-worn ‘paths of pointlessness’ again. Or, at least, to get people to stop and question how they are thinking, before throwing themselves into the fray.

To begin.

What I saw happening with COVID19 is a pattern that repeats in medicine over and over again:

• We have a serious illness – panic
• Something must be done – grab the pitchforks, run about screaming
• An influential person, or organisation, grabs the initiative – ‘‘experts’ move in.’
• I/We know what to do, you must follow me/us – simple idea + soothing paternalism
• Frightened people latch onto their ideas – two legs good, four legs bad
• A path is chosen – along the side of a cliff
• Momentum builds – the unstoppable charge of the light brigade
• Those who object to the path taken are crushed – 1984

Fast forward a few decades… ‘Oh, it seems that the thing we always do as standard medical practice… Turns out it does more harm than good.’ See under: removal of toxic colon, the radical mastectomy, strict bed rest following a heart attack, cutting teeth, use of radium water, plombage, mercury for syphilis, pre-frontal lobotomy etc.

Of course, this pattern is not true of every medical intervention, not by any manner of means. Sometimes the influential person, or organisation, promotes the best course of action. This has been known to happen from time to time… believe it or not. In addition, medical practice does eventually auto-correct – and ends up doing the right thing. Almost always. We no longer remove toxic colons to cure female neurosis.

But what never, ever, seems to happen is OODA. Defined as ‘a practical concept designed to function as the foundation of rational thinking in confusing or chaotic situation’.

OODA stands for. ‘Observe, Orient, Decide Act.’

It was developed by the Air Force Colonel, John Boyd.

What John Boyd taught was simple. If you don’t know what is going on, do not make immediate decisions. First, work out what is happening, then orientate yourself – before you decide what to do. That way you avoid most, if not all, stupid mistakes. For many years, without knowing anything of OODA my own medical strategy has tended towards ‘don’t just do something, stand there.’

Unfortunately, the medical profession has always battled ferociously against doing nothing. It has always greatly favoured the ‘You must do something, anything, I don’t care what it is so long as it sounds like a good idea. Chaaarge!’ Strategy.

This, the ‘do something strategy’, has always proven far more seductive, and almost always wins. It is easier to attract followers to do something, than to than to do nothing. Why not whack a hole in the skull and split the brain apart to cure various mental diseases? Why not… indeed. Ah yes, the good old pre-frontal lobotomy.

A.N. Other doctor: ‘If you do nothing people will surely die. You cannot just stand there doing nothing.’

Me:                             ‘But what if those things we do end up causing more damage, or killing more people?’

Many years ago, my father said to me. ‘You will always be blamed for failures of omission, rath than commission.’ At the time I was young,  I knew everything, and thought he was talking rubbish. In truth I didn’t really understand his point. Now that I know that… I know nothing, I fully understand how profound his comment was. I wish I had listened to him more.

Yes, doing something will always be looked on in a positive light. Effort has been made, decisions have been taken, activity carried out. In medicine this is reflected in a comment that I have had directed at me, from time to time. ‘At least you tried, doctor.’ Well, seeing as they are now dead, my efforts achieved very little. But thanks anyway.

In addition, if you do nothing, you can be accused of laziness, of being uncaring. You just stood there and watched them suffer, even die. You cruel swine. I see this overwhelming urge to do something, anything, in the person who cannot swim, jumping into a river to try and save their dog from drowning.

What exactly did they think they were going to achieve? Oh well, at least they tried, you may say. No… they were stupid. They drowned along with their dog. But who can stand on the riverbank watching their dog die?

Well, me, actually.

This also moves into the area of survival guilt. How am I still alive when others have died? Better to die trying than to have done nothing? It all further wraps round into it the almost irresistible urge to be seen to be doing something. I think it is hard-wired into our psyche. We must fight to protect those in our tribe and be seen to be doing it. Chop, chop, busy, busy, work, work, bang, bang ¹.  

I am, however, reminded of the philosophy behind recruitment to the German army in the good old days – as recounted to me. Men were divided in to four categories:

• Intelligent and lazy
• Intelligent and hardworking
• Stupid and lazy
• Stupid and hardworking

At which point

• Intelligent and lazy men were taken for officer training
• Intelligent and hardworking men were turned into NCOs (non-commissioned officers)
• Stupid and lazy men became privates – squaddies, to use the UK vernacular
• Those who were both stupid, and hardworking, were taken out and shot, before they could do too much damage

Doing things, doing things, doing things. We place great value on it. Too much.

As Kurt Vonnegut Jnr noted in Cat’s Cradle:

“We do, doodley do, doodley do, doodely do,
What we must, muddily must, muddily must, muddily must;
Muddily do, muddily do, muddily do, muddily do,
Until we bust, bodily bust, bodily bust, bodily bust.”

Of course, if there are things to be done, they should be done. But that does not mean we should rush around doing stuff, just because it seems better than doing nothing. Here is what Vinay Prasad has to say in his blog ‘Will science do better post COVID19?’

‘When faced with a pandemic, we re-treated to all the old delusions. Bioplausibilty was sacrosanct— that’s why #maskswork! We can’t run RCTs— these are parachutes. Doing something is always better than doing nothing! More is better than less! Keep boosting, young man!! Newer is better than older. Disease bad; treatments good. Bad people (John Ioannidis) are always wrong (never mind, that a year ago we all thought he was brilliant).’ ²

The additional problem with doing things is that, once you have started doing them, it becomes damned difficult to stop again. After you have decided to blow four hundred billion pounds on lockdown, or thereabouts, then you are pretty much stuck with it. Or else, you are going to look pretty stupid. ‘Sorry, ahem, I seem to have wasted a teensy bit of money. Sorry, my mistake.’

If everyone is ordered to wear a mask, on pain of death, you are stuck with that too. Back pedalling from instant decisions is very, very, difficult. For the scientists and politicians involved you cannot be seen to have been wrong. Reputations must be protected.

At which point, vast amounts of time and effort are expended in trying to batter down anyone who dares to suggest that we rushed into doing things that were completely pointless, even damaging. Science then becomes twisted and bent to justify the errors made. Those in power must retain power. The narrative must be supported:

• COVID19 is really, really deadly
• Lockdowns really, really, work
• Masks really, really, work

If you question these narratives, people will demand an answer to this rhetorical question. Do you want people to die! (That’s always an effective weapon). The correct answer to this question by the way, is usually no – although I am willing to make exceptions.

The other terrible flaw in thinking here, especially in medicine, was also mentioned by Vinay Prasad. It is Bioplausibility. Often closely associated with fast thinking a.k.a. jumping to conclusions, because they just seem right.

Masks, indeed, must surely work. Because? Because they prevent the virus from spreading. In fact, masks represent an almost perfect example of bioplausibility a.k.a. sheer common sense. No-one can argue against using them. If you do, your arguments must be pure sophistry, or simply nonsense. ’You do not understand science.’ That’s a good one, I get that a lot.

‘I think you will find it is not I that fails to understand science.’ I think to myself. But I don’t say it, because it makes you sound like a prat.

Let me remind you of a time when, after a heart attack you had to rest in bed doing nothing for six weeks. The heart has been damaged and must be given a chance to rest. Yes, perfect Bioplausibility, believed by virtually everyone. To question it was to be cast into the outer darkness.

It is now known that the worst thing you can possibly do is to enforce strict bed rest post heart attack. This advice, in place from 1912 to about 1960(ish), killed tens of millions. Maybe hundreds of millions.

As for masks – the sort of masks worn by almost everyone.

‘The use of cloth facemasks in community settings has become an accepted public policy response to decrease disease transmission during the COVID-19 pandemic. Yet evidence of facemask efficacy is based primarily on observational studies that are subject to confounding and on mechanistic studies that rely on surrogate endpoints (such as droplet dispersion) as proxies for disease transmission. The available clinical evidence of facemask efficacy is of low quality and the best available clinical evidence has mostly failed to show efficacy, with fourteen of sixteen identified randomized controlled trials comparing face masks to no mask controls failing to find statistically significant benefit in the intent‐​to‐​treat populations. Of sixteen quantitative meta‐​analyses, eight were equivocal or critical as to whether evidence supports a public recommendation of masks, and the remaining eight supported a public mask intervention on limited evidence primarily on the basis of the precautionary principle. Although weak evidence should not preclude precautionary actions in the face of unprecedented events such as the COVID-19 pandemic, ethical principles require that the strength of the evidence and best estimates of amount of benefit be truthfully communicated to the public.’³

How can masks possibly fail to work?

Well, unfortunately, our brains work one way, and the world often works in quite another way. As does, therefore, science. For centuries people thought that heavier than air flight would only be possible if you flapped things that looked very like wings. Why, because birds and bats were the only flying things people had ever seen flying [apart from lemmings] and they mostly flapped about like mad – using wings.

Except that, if you looked closely, they didn’t – not really. If you thought flapping was the key to flight, you were not really looking. An albatross can stay aloft for hours, gliding above the waves, using the wind and updrafts, and barely moving its wings at all.

Yet, and yet, no-one was able to see this. When I say ‘see’ this I mean – look beyond the obvious, in your face, flappy stuff. Observe properly, deeply, to really understand what you are looking at – in this case aerodynamics. Eventually, of course, some people did. Et voila, the Wright Brothers.

With masks… Yes, it is both true, and self-evident, that a mask stops droplets being catapulted across a room after a cough or sneeze, or suchlike. So, they must stop spread…mustn’t they? I mean, you can even see it working in slow motion videos. A man coughs in London, virus ends up in New York – or something. Ah, the dreaded Bioplausibility… that can also be visualised. Double bubble.

But a mask can also turn droplets into an aerosol by breaking the droplet down into far smaller particles. Particles will float in the air for longer, and thus be inhaled for longer. Possibly, probably⁴. You didn’t think of that, did you?

A mask can also become damp and keep viral particles viable for longer. Once discarded – as many masks are – they represent receptacles for viruses and can spread disease when picked up. What happens when masks are used and used, and re-used? As they often are. Superspreading here we come. Blowing viral particles out of a wet mask.

As a wise man also said. Using cloth masks to prevent viral spread it like trying to pick up sand with a tennis racket. Virus particle size ‘x’. Holes in mask size 1000x.

A mask can also mean that people stand closer to each other than they otherwise would. A mask may, simply, never had had a chance to work at all. After all, we breathe in and breathe out the same amount of air whilst wearing a mask than not.

If there is virus in floating in the air, we are still going to breathe it in, and out. Masks do not stop us breathing, and the air has to come from somewhere. Unless masks act as a type of black hole, trapping, then transporting viral particles from here into another universe… I’m not putting much money on that hypothesis.

Some months ago, I wrote about the last people to be infected with smallpox. In one hospital, in Germany, a patient with smallpox was being treated on the ground floor. The patient in the room above, and then the room above that, become infected. Which means that viral particles must have got out the window, drifted upwards and infected those above.

Which just gives you some idea of how few viral particles were needed to spread a disease that was, up to that time, not even believed to spread through the air. No droplets required.

Early on, with COVID19 it was noted that ferrets could be infected with the virus. So, researchers put one ferret in a cage, with another ferret above with a solid barrier between them. The one below was infected with COVD19.

The only route for COVID19 to travel from one ferret to the other was through a tube that bent through ninety degrees, bent again to go upwards through the barrier, then across, and back round through ninety degrees

In essence, this tube was specifically designed to ensure that droplet spread was impossible. As droplets cannot go round corners, travel upwards, turn another ninety degrees… and suchlike.

Despite this, all of the uninfected ferrets became, very rapidly, infected. Conclusion – COVID19 can travel and infect through aerosol spread. Secondary conclusion – masks cannot stop this. At least not the sort of masks that virtually everyone wears, and then re-uses.

Of course, there are masks that you can use to prevent the spread of viral particles. But they have to be airtight, they have to have filters. They are uncomfortable to wear for any length of time, and they need to be changed regularly. They also prevent a great deal of communication, as people hard of hearing will tell you. Oh yes, there are serious downsides to mask wearing.

I only focus on masks here to make the point that masks appear totally ‘Bioplausible’. If, that is, you don’t think about all the issues too deeply. Also, getting everyone to wear masks represents doing ‘something.’ Doing something, especially something visible, is always better than doing nothing.

Yes… doing something, anything, and Bioplausibility. Two bear traps in human thought. Traps that seem impossible to eradicate.

There is another, major trap, which is the urge to draw ourselves into tribes. Then attack and attempt destroy anyone who does not agree with us. Humiliate and silence. Turn the ‘other’ into someone with evil intent. I am not getting into this in any depth here. We have all seen too much of it. The terrible seductive pleasure of righteous anger. Which so easily flips into hatred.

As also mentioned by Vinay Prasad. Bad people (John Ioannidis) are always wrong (never mind, that a year ago we all thought he was brilliant).’

As we all know, it is not just Ioannidis who is attacked. Dare to breathe one word of caution about vaccines and you become ‘dirty anti-vaxxer scum. You deserve to lose your job. Ha!’

This is no way for humans to act towards each other. Crush debate, silence those who dare to think differently. Bring in the Spanish Inquisition a.k.a. fact checkers. All bought and paid for by those who have vested interests in obliterating the opposition, of course.

Question:     When is a fact checker not a fact checker?

Answer:        When they are called a fact checker. [Especially if they work for a company that used to begin with Face and ended in Book. Or Witterpedia]

Also Meta…as in, I meta  ‘n’ idiot – who think it’s okay to silence anyone they disagree with, and claim this is science. Spare me.

Anyway, what do we do next time? How do we do better? How do we think better? Well, I suppose that first of all you have to get those in power to accept that they made mistakes…. Ho hum.

Frankly, that ain’t going to happen. Therefore, we need new people in power. People who can understand that things are complicated. That the immediate Bioplausible and simplistic ‘answer’ is as likely to be wrong, as it is right. More likely in truth.

We really need people to think better:

‘We have a crisis in medicine when it comes to understanding and appraising science. We do not teach this explicitly in medical schools, and it gets short shrift to mechanistic science. Our overemphasis on molecular mechanisms fuels the cognitive distortion that a reductionistic view is superior to empiricism*’ ²

*empiricism is the view that all concepts originate in experience, that all concepts are about or applicable to things that can be experienced, or that all rationally acceptable beliefs or propositions are justifiable or knowable only through experience.

Were there any examples of doing things better from which we could learn? In Sweden they did things differently – at least from most of the rest of Europe. Anders Tegnell, the state epidemiologist (yes they have such a post) was the man who led the Swedish response. It was to bring in very few restrictions and make almost everything voluntary. Lockdown ‘lite’ if you like.

He was ruthlessly attacked from all directions, but remained superficially calm. Although I imagine he felt most terribly bruised and battered inside. TIME magazine ran a story about the Swedish response entitled ‘The Swedish COVID-19 Response Is a Disaster. It Shouldn’t Be a Model for the Rest of the World.’⁵

You don’t really need to read the article. The title makes it entirely clear what tone was adopted, and also what the conclusion was going to be. Sweden = death and mayhem, run for the hills. Frankly, I am amazed that the Swedish Government held firm in supporting him.

At one point even the Swedish King, Carl XVI Gustaf ‘Gustaf –  the eminent epidemiologist’ as I believe he is also known – had a pop at poor old Anders. But the Government did support Tegnell’s light touch strategy – mostly. They held their nerve.

What was Anders thinking, the mad mass murdering fool? As he calmly stated in the British Medical Journal, after COVID19 deaths in Sweden had settled into the lower half of European figures. Not as good as some, better than most:

… there is still disagreement among scientists about which measures are effective against the spread of infection. “This is what we are still struggling to understand: some measures work in some places, but it is difficult to see patterns.”

“Countries that went through lockdowns are not doing that much better,”⁶

Yes, he is describing his OODA journey. Anders is still observing and attempting to orientate, but he cannot see what to do. He still believes that the evidence for severe lockdowns, and mask wearing, simply does not exist. To put it another way, he cannot yet decide what should be done. So, he isn’t doing it.

Good man. We need far more like Anders Tegnell, and less of those like the members of SAGE in the UK. Screaming blue bloody murder with threats of hundreds of thousands dying if WE DO NOT ACT NOW! The sky is falling, the sky is falling. OMCIRON will kill us all… all I tell ee’. Beware the black spot Cap’n.

We also need more people to be sceptical. To look at the science and the evidence. We need, quite frankly, to learn to think… and grow up. Also, importantly, learn the incredibly difficult trick of doing nothing at all.

As they used to say in a UK advert. ‘Nothing acts faster than Anadin (a painkiller)’

Solution… take nothing

Nothing acts faster than a damn good lockdown

Solution…do nothing

Or, to quote the famous physician William Osler. ‘One of the first duties of the physician is to educate the masses not to take medicine.’ I shall now leave you with two things to consider. The first is an open letter, written by Professor Ehud Qimron, head of the Department of Microbiology and Immunology at Tel Aviv University and one of the leading Israeli immunologists:

I suppose I should say that the opinions of Professor Udi Qimron are not necessarily those of the senior management of this blog. I, in exactly the same way as Google and Facebook (Sorry, Alphabet and Meta. ‘As I was going to St Ives I meta man with seven wives’… how many idiots were going to St Ives), and suchlike, am merely the repository for information, and articles. A warehouse if you like. I have no editorial control over content, so you cannot sue me for anything written.

Unfortunately, I am not rich enough to employ Fact Checkers and unleash them upon anyone who disagrees with me. Yet. You have been warned.

The second thing, that I shall leave you with, is the fact that doing nothing can be very rewarding, and sometimes pretty hard work. As outlined by this article in The International Journal of Doing Very little:

‘We’re busy doin’ nothin’
Workin’ the whole day through
Tryin’ to find lots of things not to do
We’re busy goin’ nowhere
Isn’t it just a crime
We’d like to be unhappy, but
We never do have the time,’

‘I have to watch the river
To see that it doesn’t stop
And stick around the rosebuds
So they’ll know when to pop
And keep the crickets cheerful
They’re really a solemn bunch
Hustle, bustle
And only an hour for lunch.’

La-la-la-la-la-la
La-la-la-la-la-la-la-la-la-la
La-la-la-la-la-la
La-la-la-la-la-la-la-la-la-la

‘We’re busy doin’ nothin’
Workin’ the whole day through
Tryin’ to find lots of things not to do
We’re busy goin’ nowhere
Isn’t it just a crime
We’d like to be unhappy, but
We never do have the time.’

‘I have to wake the Sun up
He’s liable to sleep all day
And then inspect the rainbows
So they’ll be bright and gay
I must rehearse the songbirds
To see that they sing in key
Hustle, bustle
And never a moment free.’

‘We’re busy doin’ nothin’
Workin’ the whole day through
Tryin’ to find lots of things not to do
We’re busy going nowhere
Isn’t it just a crime
We’d like to be unhappy, but
We never do have the time.’

‘I have to meet a turtle
I’m teachin’ him how to swim
Then I have to shine the dewdrops
You know they’re looking rather dim
I told my friend, the robin
I’d buy him a brand-new vest

Hustle, bustle
We never do have
We never do have
We never do, never do
Never do, never do, never do have the time
Never do have the time.’⁸

And if that don’t cheer you up, nothing will. And follow my motto. ‘Don’t just do something stand there….’ Whilst observing and orientating of course. Think first, act later.

1: https://www.youtube.com/watch?v=2bnWLTI-QmE

2: https://vinayprasadmdmph.substack.com/p/will-science-do-a-better-post-covid19

3: https://www.cato.org/working-paper/evidence-community-cloth-face-masking-limit-spread-sars-cov-2-critical-review

4: https://www.nature.com/articles/s41598-020-72798-7

5: https://time.com/5899432/sweden-coronovirus-disaster/

6: https://www.bmj.com/content/375/bmj.n3081

7: It’s an open letter you can go and find it yourself

8: https://www.youtube.com/watch?v=1QxvPXK3Gv4

6th December 2021

Here I am on vitamins again. I don’t wish to give the impression that all I care about is vitamins. However, I have been thinking about them recently for various reasons.

The first thing to say is that I do find it slightly strange that we have substances which are absolutely essential for life, that we must eat., because our bodies cannot make them. It seems a design flaw. I want my money back.

Added to this absolute reliance on them, we do not get any hint that we are running out. If we become dehydrated, we feel thirsty, and we drink. If our energy supplies are running down, we feel hungry and we eat.

On the other hand, if our Vitamin B₁₂ supplies are becoming perilously low – we might end up feeling bloody awful. In the final stages we could end up paralyzed, then dead, without knowing why. Vitamin B₁₂ is essential for the health of neurones (amongst other things). But there is nothing that triggers our desire to forage around for foodstuffs rich in vitamin B₁₂. Supposing we knew what they were anyway.

I presume this means that whilst we were evolving from the primeval soup, there were plenty of vitamins (and minerals) about. We had no need to seek them out specifically, because they were always present in the things we ate. In ample supply? Always …? Of course, it is not just vitamins, there are minerals we need too.

Magnesium

Most people are probably blissfully unaware they need magnesium. If you don’t have enough, how would you know? The first recognisable symptom may be … suddenly dropping dead.

Israel gives us a stark warning of what happens when magnesium goes missing, with no-one noticing. For many years, most of the water supply in Israel has been provided by desalination. This process does not just get rid of salt (NaCl), it also removes the other salts, and minerals, at the same time.

In normal circumstances people get most of the magnesium they need from drinking water. Which means there was clearly a potential for a major deficiency problem building up in Israel. As most of their water contained nothing but pure H₂0.

Did anyone notice? As in, did anyone say, ‘golly I feel low in magnesium today, I must go and eat a substance high in magnesium…’ Nope. Did anyone die. Yup, they did. As outlined in the paper ‘Association between exposure to desalinated sea water and ischemic heart disease, diabetes mellitus and colorectal cancer; A population-based study in Israel.’ ¹

 There were possibly as many as 4,000 deaths a year:

‘An estimated 4,000 Israelis die in an average year due to an inadequate amount of magnesium in their bodies – and the amount they get from natural potable water sources is increasingly declining due to the growing desalination of sea water. The figure is 10-fold the death toll from road accidents.’ ²

The population of Israel is just over nine million. The equivalent death rate in the UK would be 30,000 deaths a year, or 180,000 in the US. A silent killer indeed.

Anyway, yes, magnesium is critical stuff. It is extremely important for health, especially heart health. It is required for the correct functioning of the electrical system in your heart, and a low level increases the risk of atrial fibrillation. Here from the paper ‘Low serum magnesium and the development of atrial fibrillation in the community: the Framingham Heart Study.’

‘…individuals in the lowest quartile of serum magnesium were ~50% more likely to develop AF…compared with those in the upper quartiles.’ ³

Unfortunately, despite its importance, we don’t feel magnesium depleted. We do not crave magnesium rich foods – as if we would have any idea what they might be … I certainly don’t. The symptoms of severe deficiency are also non-specific. The first symptom might be that your heart decides to stop beating.

It’s not just Israel. Here from the paper: ‘Subclinical magnesium deficiency: a principal driver of cardiovascular disease and a public health crisis.’

‘Furthermore, because of chronic diseases, medications, decreases in food crop magnesium contents, and the availability of refined and processed foods, the vast majority of people in modern societies are at risk for magnesium deficiency.’ ⁴

Have you ever heard of any of this? Did you even know you had magnesium in your body – or that it did anything important? I suspect not. However, from the same paper:

‘…magnesium deficiency can lead to serious morbidity and mortality and has been implicated in multiple cardiovascular diseases such as hypertension, cardiomyopathy, cardiac arrhythmia, atherosclerosis, dyslipidaemia and diabetes. Unfortunately, the western diet is often low in magnesium due to the refining and processing of foods, and hypomagnesaemia is often underdiagnosed in hospitalised patients.’⁴

My advice, take a supplement. Especially if you live in an area with ‘soft’ water – which generally means not many minerals. Doubly especially if you have atrial fibrillation. It might just go away. How much do you need to take? Around 400mg a day is fine.

Back to vitamins – in this case, Vitamin(s) B

The reason for the detour is that I really wanted to make it clear that it is certainly not a given that we routinely get all the essential micro-nutrients we need from our diet.

Modern living, modern food production and farming, modern food processing … have all have a significant impact on what our food, and water, contains.

The lazy mainstream assumption that micronutrient deficiencies simply do not exist is, therefore, wrong. Try looking at Iodine deficiency in Switzerland sometime. In addition, I am extremely dubious that we truly know what the optimal intake of micronutrients may be. The research in this area is sketchy, to say the least.

This, eventually, takes us onto vitamins, more specifically, the B vitamins. There are many of them – eight, in fact.

• B1 (thiamine)
• B2 (riboflavin)
• B3 (niacin)
• B5 (pantothenic acid)
• B6 (pyridoxine)
• B7 (biotin)
• B9 (folate ak.a. folic acid)
• B12 (cobalamin)

The first question that springs to mind is the following. Where are numbers four, eight, ten and eleven? What happened to them? It’s a bit like clotting factors. We have VII, VIII, IX etc. But there is no factor one, or two. Who gets to name things in medicine anyway?

Moving on. My main interest in the B vitamins is that, if you are low in three of them, maybe four of them: three, six, nine and twelve, this can lead to an increased level of a protein in the blood called homocysteine. [I think B6 is more important than B3, but we shall let this go for now].

The reason why this is important is if you have a high level of homocysteine then this is strongly associated with an increased risk of cardiovascular disease. The mechanism of action appears to be that homocysteine is toxic to endothelial cells.

‘Elevated homocysteine (Hc) levels have a well-established and clear causal relationship to epithelial damage leading to coronary artery disease.’ ⁵

On the other hand, low levels of homocysteine are associated with a lower risk:

‘In observational studies, lower homocysteine levels are associated with lower rates of coronary heart disease and stroke. Folic acid and vitamins B6 and B12 lower homocysteine levels.’[i]

As you may have gathered from that short quote, if you have a high homocysteine level, and you take B vitamins, your homocysteine levels will fall. As confirmed in a study in the American Journal of Clinical Nutrition:

‘Elevated levels of homocysteine is an indication of inadequate folate and vitamin B-12 in the diet, writes lead author Giovanni Ravaglia, a researcher with University Hospital S. Orsola-Malpighi in Bologna, Italy. His paper appears in the March American Journal of Clinical Nutrition….High homocysteine levels can be treated very easily with vitamins, including folate, niacin, and B-12.’ ⁶

I think the connection between B vitamins, and homocysteine, were first noted by Kilmer McCully. He studied the area in detail at Harvard University. At least he did so for a while, before he was unceremoniously booted out for carrying out research that threatened to undermine the almighty cholesterol hypothesis. A sorry tale, as reported in the New York Times:

‘Thomas N. James, a cardiologist and president of the University of Texas Medical Branch who was also the president of the American Heart Association in 1979 and ’80, is even harsher [regarding the treatment of McCully]. ”It was worse than that you couldn’t get ideas funded that went in other directions than cholesterol,” he says. ”You were intentionally discouraged from pursuing alternative questions. I’ve never dealt with a subject in my life that elicited such an immediate hostile response.”

It took two years for McCully to find a new research job. His children were reaching college age; he and his wife refinanced their house and borrowed from her parents. McCully says that his job search developed a pattern: he would hear of an opening, go for interviews and then the process would grind to a stop. Finally, he heard rumors of what he calls ”poison phone calls” from Harvard. ”It smelled to high heaven,” he says.’

McCully says that when he was interviewed on Canadian television after he left Harvard, he received a call from the public-affairs director of Mass. General. ”He told me to shut up,” McCully recalls. ”He said he didn’t want the names of Harvard and Mass. General associated with my theories.’ ⁷

And you wonder why researchers are wary of questioning the cholesterol hypothesis? Yes, crushing scientific debate has a long and inglorious history, starting long before COVID19 first appeared over the horizon. In the world of cholesterol, it has been going on for well over sixty years.

Homocysteine, B vitamins and dementia

Now, dear reader, having just focussed on B vitamins, homocysteine and cardiovascular disease, I am going to abruptly change tack. I shall now move away from heart disease to Alzheimer’s disease. The reason for this is straightforward.

As I began to research this area in more detail, it become increasingly clear that there was a worrying association between raised homocysteine, brain damage, and dementia. This certainly attracted my attention. Because I like my brain, and I want to keep it healthy for a long as possible.

I came across papers such as this: ‘Plasma Homocysteine as a Risk Factor for Dementia and Alzheimer’s Disease.’

‘An increased plasma homocysteine level is a strong, independent risk factor for the development of dementia and Alzheimer’s disease.’ ⁸

There were many more such papers, but you probably get the general idea. Raised homocysteine … Bad.

At this point I already knew that the B vitamins can lower the homocysteine level – if it is high. In addition, B vitamins are well known to have vital functions in the central and peripheral nervous system.

Here, from the paper: ‘B Vitamins in the nervous system: Current knowledge of the biochemical modes of action and synergies of thiamine, pyridoxine, and cobalamin.’

Neurotropic B vitamins play crucial roles as coenzymes and beyond in the nervous system. Particularly vitamin B1 (thiamine), B6 (pyridoxine), and B12 (cobalamin) contribute essentially to the maintenance of a healthy nervous system. Their importance is highlighted by many neurological diseases related to deficiencies in one or more of these vitamins, but they can improve certain neurological conditions even without a (proven) deficiency.’ ⁹

So, not only do certain B vitamins lower homocysteine levels. A number of them play a critical role in the growth and support of nerve cells, and suchlike.

None of this is exactly news. It has been known for centuries that excess alcohol consumption – which blocks Vitamin B1 absorption from the gut – can cause a specific form of dementia called Korsakoff’s dementia. Because of this, people with alcohol problems are often prescribed high dose vitamin B1 (Thiamine).

Which means that it was never a stretch to suggest that giving people B vitamins might be an extremely good thing if you want to prevent, or delay, the progression of Alzheimer’s/brain shrinkage. Either through the benefits on lowering raised homocysteine, or via the critical functions of B vitamins on the structure and function of the brain.

That, anyway, was the underlying science. But does giving B vitamins actually work? Well researchers at Cambridge University certainly believed it was a splendid idea:

‘In an initial, randomized controlled study on elderly subjects with increased dementia risk, we showed that high-dose B-vitamin treatment (folic acid 0.8 mg, vitamin B6 20 mg, vitamin B12 0.5 mg) slowed shrinkage of the whole brain volume over 2 years.’ ¹⁰

In a follow-up study, this group of researchers then found that, in people with raised homocysteine levels, who already had signs of dementia, B-vitamins reduced brain destruction and slowed, even halted, the progression of Alzheimer’s. In their own words, from the paper ‘Preventing Alzheimer’s disease-related gray matter atrophy by B-vitamin treatment’:

‘….we showed that high-dose B-vitamin treatment (folic acid 0.8 mg, vitamin B6 20 mg, vitamin B12 0.5 mg) slowed shrinkage of the whole brain volume over 2 years. Here, we go further by demonstrating that B-vitamin treatment reduces, by as much as seven-fold, the cerebral atrophy in those gray matter (GM) regions specifically vulnerable to the AD (Alzheimer’s Disease) process, including the medial temporal lobe. In the placebo group, higher homocysteine levels at baseline are associated with faster GM atrophy, but this deleterious effect is largely prevented by B-vitamin treatment. We additionally show that the beneficial effect of B vitamins is confined to participants with high homocysteine.’ ¹¹

Yes, it was all looking quite good. By the way, this study came out in 2013.

But then we need to factor in the knowledge that B vitamins are very cheap. Very cheap indeed. In addition, they cannot be patented. Which makes it extremely difficult for any pharmaceutical company to make money from them. You can, of course sell them for a small profit, but pharmaceutical companies need billions to feed the machine. They require unique, patentable, blockbuster drugs. Drugs my precious.

Had any drug shown such a significant effect on brain shrinkage, I am one hundred per cent certain that the finding would have been shouted from the rooftops. We would be looking at a massive blockbuster. Probably the biggest selling drug in the world – ever.

As it was, the research from Cambridge was passed over in virtual silence … I suspect you never heard anything about it. Then, with a certain inevitability, the findings were, effectively squashed.

How was this done?

It was done through the power of the meta-analysis. A meta-analysis is a fancy term describing an attempt to bring together all the relevant trials that have been done in a therapeutic area. In order to construct a ‘meta’ study, or meta-analysis.

They can be a very useful way to bring together all of the relevant research, where there have been a large number of different studies done. In an attempt to establish the definitive answer to a medical question. Does drug x, or intervention y, actually work. If so, what are the true benefits? Assuming that the trials have all showed subtle, or not so subtle, differences in their effects.

Meta-analyses are often treated as though they are the very pinnacle of medical research. Tablets of stone handed down by Gods. In realty, they need to be treated with a very large pinch of salt, and a healthy dose of scepticism.

This is because meta-analyses often ram together studies with very different populations, using different doses of drugs, or vitamins. Or completely different drugs or vitamins, for different lengths of time.

Just to add to the potential messiness, studies can be included that have completely unrelated outcomes. You end up comparing apples and bananas, in order to decide if pomegranates actually work. In computing it would be called garbage in, garbage out – GIGO.

Moving on, in 2014, the year after the Cambridge study, a whole number of different studies on B-vitamins were brought together in a ‘meta-analysis.’ I use the term meta-analysis very loosely here. It was called: ‘Effects of homocysteine lowering with B vitamins on cognitive aging: meta-analysis of 11 trials with cognitive data on 22,000 individuals.’ ¹²

Sounds good, so far. In fact, the total number of individuals they looked at was 20,431 – which is a lot nearer to twenty thousand than twenty-two thousand. But, hey ho, what’s sixteen hundred or so people between friends? Having said this deliberate figure inflation is an important indication of researchers trying to ‘big up’ their findings – in my book.

Here’s another thing. A number of the studies had absolutely nothing to do with cognitive function … at all. One of the studies included was HOPE-2. Here is the background to the study.

‘In observational studies, lower homocysteine levels are associated with lower rates of coronary heart disease and stroke. Folic acid and vitamins B6 and B12 lower homocysteine levels. We assessed whether supplementation reduced the risk of major cardiovascular events in patients with vascular disease.’ ¹³

Yes HOPE-2 was a study on cardiovascular disease. It has absolutely nothing to do with Alzheimer’s, or any other form of dementia. The title of HOPE-2 was ‘Homocysteine Lowering with Folic Acid and B Vitamins in Vascular Disease.’ Cognition, or brain function, was not measured. Yet, it was still included in a meta-analysis of ‘11 trials with cognitive data on 22,000 individuals.’ [20,431 individuals, actually].

Moving on, and this is perhaps more mission critical. In only just over seven thousand of the individuals studied did anyone measure cognitive function at the start of the trial and then again, at the end. Leaving aside such studies as HOPE-2 where it was not measured at all. Which, straight off, means that the vast bulk of this meta-analysis is utterly meaningless.

How can you possibly know what happened to anyone’s cognitive state, if you only measured it once? Did it improve, did it worsen – not the faintest. In two thirds of the individuals included in this meta-analysis we have no idea what happened to cognitive function – at all.

It doesn’t stop here. There were others who felt that this was not meta-analyses finest hour:

‘First and foremost, this meta-analysis excluded trials on mild cognitive impairment (MCI) and Alzheimer’s disease. As a possible consequence, most of the trials included in this meta-analysis either did not see any significant cognitive change (between the start and the end of the trial) in the placebo group or did not look at such change. ¹⁴

Yes, they specifically excluded people with existing cognitive impairment, or Alzheimer’s, which would be, by far, most important group to study. As they actually have the condition you are interested in.

Which leads on to the next obvious problem:

… people included in these trials included in the meta-analysis were healthy and did not show any cognitive decline, whether they received B-vitamin treatment or not. So, B-vitamins could hardly prevent or slow down something not happening in the first place.’ ¹⁴

Just to make this point a little clearer, in the minority of studies, where they bothered to measure cognitive function at the start, and also at the end, they found that almost no individuals developed any degree of cognitive impairment – in either group. Not in the treatment group, or the placebo groups. As virtually nothing happened to anyone, nothing could have been proved one way or another.

Attempting to study the progress of dementia, in people who do not have dementia, and who may never get dementia, nor have any signs of cognitive decline … is like doing a blood pressure lowering study on people who do not have a raised blood pressure.

Then, on finding there was no difference in cardiovascular event in either arm of the trial, you proceed to claim that blood pressure lowering does not work. Because there was no difference between those given the drug, and those taking the placebo. Do you think this makes any sense? Answers on a postcard, that should be sent to the Willie Wonka chocolate factory. Care of A.N. Idiot.

Despite begin riddled with fatal flaws, this analysis was greeted as though it was the definitive study. B-vitamins have no effect on cognitive decline, end of. This is what the head of Alzheimer’s Research UK had to say:

‘Although one trial in 2010 showed that for people with high homocysteine, B vitamins had some beneficial effect on the rate of brain shrinkage, this comprehensive review of several trials shows that B vitamins have not been able to slow mental decline as we age, nor are they likely to prevent Alzheimer’s. While the outcome of this new and far-reaching analysis is not what we hoped for, it does underline the need for larger studies to improve certainty around the effects of any treatment.

New and far-reaching analysis. Comprehensive review … ho hum. If I were given the job of marking this meta-analysis, I would hand it back in a rather grumpy fashion. ‘I asked you to look at the benefit of lowering homocysteine, using B-vitamins, in people with cognitive problems, or early-stage Alzheimer’s. Yet, you have not even bothered to look at these groups. In fact, you deliberately excluded them.

In addition, you included trials where the researchers failed to measure mental decline. Added to this, in most of these trials, no-one even had a high homocysteine level to start with, so they cannot – by definition – have had low levels of B-vitamins. So, how could vitamin B supplementation possible have been of any benefit … I am most disappointed. Please try again, and this time READ the brief.’

One of the trials lasted for four months, another for six months. What measurable different in cognitive function can anyone possibly expect to see in those timescales… This was not a flawed meta-analysis. It was simply gibberish.

There was a time when I would have questioned my own sanity in reading a meta-analysis such as this. Surely, I had got it wrong. Researchers would never put together such a steaming pile. If they did, then no-one would publish it. Nowadays I find myself far more in agreement with Drummond Rennie: deputy editor of the Journal of the American Medical Association:

‘There seems to be no study too fragmented, no hypothesis too trivial, no literature citation too biased or too egotistical, no design too warped, no methodology too bungled, no presentation of results too inaccurate, too obscure, and too contradictory, no analysis too self-serving, no argument too circular, no conclusions too trifling or too unjustified, and no grammar and syntax too offensive for a paper to end up in print.’ ¹⁵

A famous quote… in certain circles.

As it turns out, this analysis was done by exactly the same people who rule the research world of cholesterol lowering, known as the Cholesterol Treatment Triallists Collaboration (CTT) in Oxford. This paper came under the banner of the ‘B-vitamin treatment triallists collaboration’. Who knew such a group existed? One wonders exactly why they exist? Does the world really require such an organisation?

They sure as hell slammed the door shut on vitamin B/homocysteine research in cognitive function. Which was, some may say, possibly whey they were set up in the first place.

In my opinion, you can either believe the B-vitamin treatment triallists collaboration from Oxford with their meta-analysis. Which some would call complete and utter rubbish. Not me, of course. Personally, I have never seen a more detailed and error free research paper. I can hardly praise it highly enough.

Or, you can believe the Cambridge researchers, who demonstrated a seven-fold reduction in cerebral atrophy with B-vitamins – in those with raised homocysteine levels. The choice is entirely up to you.

1: https://pubmed.ncbi.nlm.nih.gov/29982150/

2: https://www.jpost.com/business-and-innovation/health-and-science/4000-israelis-die-annually-due-to-lack-of-magnesium-479184

3: https://pubmed.ncbi.nlm.nih.gov/23172839/

4: https://openheart.bmj.com/content/5/1/e000668

5: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5359933/#:~:text=Elevated%20homocysteine%20(Hc)%20levels%20have,II%20diabetes%20mellitus%20(T2DM)

6: https://www.webmd.com/alzheimers/news/20030228/elderly-dementia-linked-to-homocysteine#:~:text=A%20new%20study%20suggests%20that,researcher%20with%20University%20Hospital%20S

7: https://www.nytimes.com/1997/08/10/magazine/the-fall-and-rise-of-kilmer-mccully.html

8: https://www.nejm.org/doi/full/10.1056/nejmoa011613

9: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930825/

10: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3677457/

11: https://pubmed.ncbi.nlm.nih.gov/23690582/

12: https://academic.oup.com/ajcn/article/100/2/657/4576556

13: https://www.nejm.org/doi/full/10.1056/nejmoa060900

14: https://www.alzheimersresearchuk.org/blog/b-vitamins-and-alzheimers-disease/

15: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3005733/

4th November 2021

And so, after only thirty short years of research, my book on heart disease is finally finished, and is published today. Up to now my books, and blogs, have mainly consisted of telling people what does not cause heart disease. Or to be slightly more accurate, cardiovascular disease.

Hint, it is not cholesterol, or LDL, or LDL/cholesterol, or the good cholesterol/bad cholesterol ratio – or whichever term is in favour today.

So, what does cause cardiovascular disease? Those few, those happy few, who have read this blog over the years may already know a great deal of what is in the book. For others this will be a new and, hopefully, fascinating foray into a completely different way of thinking.

The first point I want to make, then emphasize, then re-emphasize, is that there is no ‘the’ cause of cardiovascular disease. By which I mean that there is not, and never has been, any one single factor that can be considered to be ‘the’ cause. Instead, there are many. They can work by themselves or combine with others.

So you can say that, for example, diabetes is ‘a’ cause of cardiovascular disease. But you cannot say that it is ‘the’ cause. Yes ‘a’ cause but not ‘the’ cause. This is not purely semantics. Whilst the difference may seem subtle, it is critical. A table, or the table. A man, or the man. An answer, or the answer.

If there is no ‘the’ cause, what does this mean in practice? It means that many different things, or factors, or whatever term you use to describe them, can lead to exactly the same disease. You may then ask; can they all be described as causes? Boy, oh boy, it all gets very complicated. I have found that the language used here has become perhaps the greatest barrier to understanding.

Laying that admittedly complex issue to one side for the moment, and trying to keep things concrete, rather than abstract, the inescapable fact is that many, many, different factors can increase the risk of/cause cardiovascular disease. So, how can they all be fitted together into a unified theory?  

It has been tricky, very tricky.

Mainstream medicine has effectively stuck its fingers in its ears, yelled ‘la, la, la, I’m not listening,’ and run away from this entire issue. The current position is simply to state that cardiovascular disease is multifactorial. No need to think beyond that. Just find the important risk factors, then deal with each one separately. This works up to a point. Stop smoking, keep the blood pressure down, control diabetes and the risks will fall. I can’t argue with any of these actions, but they only get you so far.

In the end, you cannot just bring a whole bunch of wildly different factors together, declare that cardiovascular disease is ‘multifactorial’, and everything is now, officially, sorted. No need to look further. Move on, nothing to see here.

Many years ago, the French mathematician and science philosopher Henri Poincaré stated the following, which I find describes the situation almost perfectly. ‘Science is built of facts, as a house is with stone. But a collection of facts is no more a science than a heap of stones is a house.’

In the same way, calling cardiovascular disease “multifactorial” is just a clever sounding way of describing a pile of stones. There is no structure, no understanding, no hypothesis.

Below, for example, is a list of factors that are closely associated with an increased risk of cardiovascular disease. It comes from the latest UK cardiovascular risk factor calculator, called Qrisk3, which you can see here https://qrisk.org/three/

You input your personal data e.g., age, sex, diabetes, blood pressure and suchlike, it then purports to calculate your risk of a cardiovascular event in the next ten years. In truth, not that accurately.

I deconstructed the Qrisk3 factors and put them into a list:

• 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

Fine…ish. It is true that all these things are associated with an increased risk of cardiovascular disease, in the UK, at present. However, to create a coherent hypothesis, you have to explain how they fit together. Where’s the house?

For example, you need to link a ‘history of migraines’ together with smoking. Then explain how they both lead to exactly the same disease. Or diabetes and severe mental illness. Or ethnicity and chronic kidney disease. Someone, anyone. Good luck.

As a quick aside, you may notice that the low-density lipoprotein level plays no part in this list of ‘most important’ risk factors in Qrisk3. None. Instead, we have the total cholesterol/HDL ratio – which is a very different thing indeed. It is only very indirectly related to the low-density lipoprotein level, if at all.

Moving on, the more I studied cardiovascular disease, the more I became aware of an inescapable fact. Which was that, in order to claim that I understood it, I had to establish how such very disparate factors can all lead to exactly the same disease.

This, in turn, meant giving up on the causal model. Because all that the causal model had produced was an ever-growing pile of ‘stones.’ Beneath which, the structure of an underlying house was becoming increasingly difficult to discern.

The process model

What I had to do, as pointed out to me by the late, great, Paul Rosch, was to turn my attention to the disease process. As in, what is actually going on? What is cardiovascular disease? What are we looking at?

What became very clear to me, very early on, is that what we cannot be looking at LDL molecules leaking through artery walls – or to be more exact, the endothelial cells that line all artery walls – then gradually building up into cholesterol plaques/thickenings.

This blog is not long enough to describe in any great detail why this ‘LDL leaking through’ process makes no sense. There is a great deal of information to be covered. Most of which is described, in some detail, in the book.

However, just to give you a couple of thoughts to consider. All blood vessels are lined by cells called endothelial cells. These cells, and indeed all cells in the body, have enormously complex mechanisms in place to regulate what gets into them, and what can then escape from them.

This regulation can control the movement of the largest molecule, down to the very smallest. Including tight control of the entrance, and exit, of single atoms e.g., sodium, or potassium, or calcium (in truth, in the body, these atoms exist as ions – which is just the name for a charged atom).

In short, nothing can gain entry to a cell unless the cell grants entry. Nothing [Unless you are a virus e.g., COVID19, whereby you hijack a receptor to sneak in – the cunning little devils]. For anything to gain entry, the cell must open a channel of some sort i.e., an ion channel. Or it has to manufacture a receptor. The receptor will then lock onto the substance floating in the bloodstream and drag it through the cell membrane and into the cell.

Just to pluck an example from the air. In order to get low-density lipoprotein into a cell, the cell must first synthesize a low-density lipoprotein (LDL) receptor. It then transports the receptor to the cell membrane. Once in place, it locks on to a passing LDL molecule, and then drags the entire LDL/receptor complex back inside – before breaking it down. Without this machinery getting to work, there is no way to get LDL into a cell. None.

Just to repeat this, from a slightly different direction. Cells can control the movement of single ions/atoms through their cell membranes. An LDL molecule is massive in comparison to an ion. Think rowing boat vs. super tanker.

Yet, if we are to accept the LDL hypothesis, we are supposed to believe that cell membranes simply step aside, or part like the red sea, to wave through a super-tanker sized molecule.

It all gets more unlikely. The cell must then allow the LDL molecule to propel itself from one cell membrane to the other. A very clever trick for an inanimate molecule, with no means of propulsion. Looked at from a human scale, if I were an LDL molecule, a cell would be about half a mile across.

Even if the LDL managed this, once it reached the other side of the cell, the LDL would need to pop back out of the cell and into the artery wall behind – using an inside-out LDL receptor perhaps?

Some people have therefore suggested the LDL molecules simply sneak between endothelial cells. But this, too, is impossible. Endothelial cells are tightly bound to each other, with a whole series of protein bridges a.k.a. ‘tight junctions.’ These too, can prevent the passage of single ions. Which means that nothing can get from the blood and into the artery wall though a side entrance either:

‘Tight junctions prevent the passage of molecules and ions through the space between plasma membranes of adjacent cells, so materials must actually enter the cells, in order to pass through the tissue.’¹

If this were not the case, if the ‘endothelium’ did not represent a perfect barrier, we would all die immediately. To quote from a paper in the journal ‘Tissue Barriers’ yes indeed, there is such a journal:

‘Physiological barriers provide the framework for a boundary between circulating blood and interstitial fluid, a pre-requisite for mammalian life.’²

So, yes, there is simply no way for LDL to sneak between cells either.

Just to give you one example of what happens if you loosen the tight junctions between cells, we can look at the Ebola virus. This virus opens up the tight junctions between endothelial cells. At which point the endothelial barrier function is critically compromised, and blood can now escape into the tissues, and organs.

This leakage is the reason why Ebola is also known as a form of haemorrhagic fever. Blood appears in the cornea, so your eyes become bloodshot. You cough up the blood that that has escaped into your lungs. Your tongue falls off. Your urine is filled with blood from your kidneys, your bowel motions turn black, and then…. Bang, dead, from massive fluid loss and vascular collapse.

Ebola demonstrates very clearly the critical importance of tight junctions between cells. Open them up… and you die. How did you think Ebola actually kills you? I imagine that you, like me, before I started looking at this area in detail, probably never really thought much about it. You just vowed never to catch it:

‘Ebola patients experience a breakdown in endothelial barrier integrity that leads to massive fluid losses and vascular collapse.’³ 

That would be where the ‘pre-requisite for mammalian life’ comes in.

Anyway, forgetting about that for the moment. Let me take you back to think about an alternative process model. To ask, so what is the disease process that allows you link smoking to, say, systemic lupus erythematosus? Because both things are most certainly causal. ‘A’ cause, rather than ‘the’ cause, of course.

And what of the many, many, other factors, not mentioned in Qrisk3? This is a very long list indeed. For example: cocaine use, antiphospholipid syndrome, Avastin, use of steroids, periodontitis, Sjogren’s syndrome, sickle cell disease, high fibrinogen levels. I could go on… for a few pages.

The harder you look, the more stones you unearth. In the end I had this massive pile of stones which became my two-thousand-piece jigsaw puzzle – just to change metaphors abruptly. A puzzle that didn’t even have a box to go with it, so I didn’t know what the picture was supposed to look like once I fitted all the pieces together. Was it a cow, or a lake, or a mountain scene?

At this point, you may get some insight as to why I called the book ‘the enduring mystery of heart disease’. Admit defeat …me? Well, usually, I am quite good at chucking in the towel. If at first you don’t succeed, give up, why make an idiot of yourself. But for some reason I did not, could not.

This bloody thing kept nagging away. I would lie awake at night considering the morphology (structure) of plaques. I contemplated the blood clotting system in all of its massively complex detail. I read papers outlining the thirty-two different types of HDL (good cholesterol). I discussed plaques with cardiologists and pathologists. I stumbled across entirely new entire worlds of research that I didn’t know existed. There were few rabbit holes down which I did not disappear.

The answer, when it finally lodged in my brain, was surprisingly simple. Not only was it simple, but it has also been kicking around for very nearly one hundred and seventy years. In 1852 Karl von Rokitansky published his ‘encrustation hypothesis.’ Describing what he saw when he closely examined atherosclerotic plaques.

‘Rokitansky proposed that the disease is the result of an excessive intimal deposition of blood components (blood clots) including fibrin. He maintained that localized thickening, atheromatous changes and calcification of the arterial wall are due to the repeated deposition of blood elements and their subsequent metamorphosis and degeneration on the lining membrane of the vascular wall.

There you go, that’s it. Blood clots, blood clots… and more blood clots.

In fact, I am being slightly disingenuous here. I had been thinking about blood clots for many years, but in a rather uninformed and directionless way. Many moons ago, when I was a medical student at Aberdeen, I was briefly taught cardiology by Dr Elspeth Smith. In a small group tutorial, she mentioned to us fresh faced students that LDL cannot penetrate the endothelium. Bing!

This was almost an off the cuff remark. Almost… but the way she said it… I knew that there was something critical here. A secret never to be told. Or, it was like a good murder mystery, where a chance remark represents the most important clue. My antennae pricked up at that moment and have not stopped twitching since.

She also wrote this over forty years ago:

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

Yes, she knew what causes cardiovascular disease. I now know, for sure, that she knew. She never knew that I knew she knew. I was daft and did not take the opportunity to discuss things with her. Too much ego, I suppose. I also went off in other daft directions for many years. Looking for ‘the’ cause: the lost chord, the Ark of the Covenant, the Holy Grail. Of course, I never found ‘the’ cause, because it does not exist. Oh, well.

It was only when I was directed to return to process, that I came to fully recognise her genius – and the genius of others. I only hope that this book will help to raise her status up to where it belongs. Along with Rokitansky, Duguid, Ross and all those who pursued the blood clotting route over the decades, nay, centuries now.

Yes, I know this probably sounds very simple, and possibly completely wrong. There is no way you are going to believe straightaway that atherosclerotic plaques are just blood clots, ‘in various stages of metamorphosis and degeneration’. How can this possibly be true?

The reason why it can be true, is because it fits all the known facts about cardiovascular disease, and atherosclerotic plaques, and heart attacks, and strokes, and suchlike. Yes, everything.

For example. It is widely known, and accepted, that the single most common ‘final’ event in cardiovascular disease is the formation of a large blood clot – almost inevitably on top of an existing plaque. This can fully block an artery, leading to downstream mayhem.

It is also widely accepted that thrombus formation, on top of an already existing plaque, can make plaques suddenly jump in size. Here, for example, is a passage from a paper in the journal Atherosclerosis. This is about as mainstream a publication as you can get in cardiovascular disease research. The paper was called: ‘The role of plaque rupture and thrombosis in coronary artery disease.’

‘In addition, plaque rupture and subsequent healing is recognized to be a major cause of further rapid plaque progression.’ ⁴

I could find a million quotes confirming this mechanism, without even breaking sweat.

In short, it is not remotely controversial to say that blood clots represent the final event, the thing that kills you. Nor is it controversial to say that plaques grow through the deposition of a new clot on top of an existing plaque. I would get very little argument from any cardiologist about this sequence of events. I know, I have had many such discussions.

But what is not accepted, will simply not be accepted, is that the arrival of a blood clot on the ‘healthy’ arterial wall is what initiates atherosclerotic plaque formation. Instead, it is almost universally accepted that it is LDL that does this, and LDL alone. Therefore, current conventional wisdom is that we have a three-step process:

• The plaque starts – due to LDL leaking through the artery wall
• The plaque grows – due to deposition of new blood clots on top of the existing plaque (which has become a point of clotting vulnerability)
• A ‘final’ obstructive blood clot forms on the already grown plaque, causing a heart attack, or stroke – due to a blood clot

In one way, all I have done in this book is to make it clear that, yes, we do have a three-stage process. However, low-density lipoprotein plays no part in it. It is entirely driven by blood clots, from start to finish. Which means that the first step is not:

• The plaque starts – due to LDL leaking through the artery wall

The first step is that:

• The plaque starts, due to endothelial damage, and resultant clot formation (creating the ‘focus’ for further plaque growth)

Then, everything else follows, as described earlier by Elspeth Smith:

It is increasingly clear that all aspects of the haemostatic [blood clotting] system are involved: not only in the acute occlusive event, but also in all stages of atherosclerotic plaque development from the initiation of atherogenesis to the expansion and growth of large plaques.

Yes indeed, the Clot Thickens.

In truth, this is not a major leap in thinking? All I actually needed to do was remove low density lipoprotein from the picture. Once I did that, the jigsaw actually fitted together. Leave it in, and you cannot create a coherent hypothesis. Everything is distorted, nothing works, the picture is a mess. Take it out and it all makes sense.

I hope this brief foray into the process of cardiovascular disease has left you suitably enthused to buy the book, read it, and find out in much greater detail what is really going on here. And also, what you can do to prevent heart disease. It has been my life’s work. I hope I am right. I hope you can learn from it and enjoy it.

1: https://en.wikipedia.org/wiki/Tight_junction

2: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4836485/

3: https://www.sciencedirect.com/science/article/pii/S120197121500106X 4: https://www.sciencedirect.com/science/article/pii/S0021915099004797

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22nd October 2021

Studying cardiovascular disease for over thirty years can take you to some very interesting and seemingly strange places. Places where I never expected to find myself. Connections appear where you least thought they would be, and entirely new worlds of research open up. Very often, into places where mainstream medical thinking simply does not go.

The fascinating thing is how so many things end up looping back round, in ways that you would never have considered. One of those places is within the world of vitamins. Vital…amines, and the connections to cardiovascular disease.

Unfortunately, mainstream medicine has firmly locked vitamins into a tightly constrained box. Yes, it is accepted that vitamins are vital, because you die without them – that is where the ‘vital’, in vitamins, comes from after all.

However, it is universally believed that the exact requirements for all vitamins – known as the recommended daily allowance (RDA) – which were established decades ago. It is also universally believed that everyone gets sufficient vitamin intake from their diet, so there is absolutely no need for supplementation.

But how true are these comfortable assumptions? At one point I looked into Vitamin B12 deficiency. Even mainstream medicine agrees that this can, and does, occur and can lead to very serious medical problems. Irreversible nerve damage and paralysis, for example.

The normal range for Vitamin B12 in the UK varies from 190 to 950 picograms/ml (pg/ml).  [A picogram (pg) is one trillionth of a gram]. This at least is the normal range, in some laboratories… in some places the UK. In truth, it is almost impossible to find a consistent figure.

This ‘normal’ range also varies enormously from country to country. In Japan, for example, it is 500 – 1300 pg/ml. Thus, the lower range is nearly three times higher in Japan than the UK¹. If you went to your GP in the UK with a level of four hundred and said you were Vitamin B12 deficient they would point you to the door. In Japan, they would treat you.

Another thing to note here is that the range is almost always ridiculously wide. It can vary by a factor of five! This alone suggests that people are pretty much guessing at what “is” normal. Despite this, most doctors remain perfectly content that a normal/healthy level has been well established and is based on robust science. There is no need to look again.

This is not the case, not even remotely. Here, for example, are the first three key recommendations on determining what constitutes Vitamin B12 ‘deficiency’ from the British Society for Haematology – with some of the highly technical text removed. They use the term cobalamin here, not Vitamin B12, although it is (basically) the same thing [Cobalamin (Vitamin B12) comes in several different formulations e.g., hydroxycobalamin, methylcobalamin, cyanocobalamin]

• The clinical picture is the most important factor in assessing the significance of test results assessing cobalamin status because there is no ‘gold standard’ test to define deficiency

• Serum cobalamin currently remains the first‐line test… Serum holotranscobalamin has the potential as a first‐line test, but an indeterminate ‘grey area’ may still exist.

• Definitive cut‐off points to define clinical and subclinical deficiency states are not possible, given the variety of methodologies used and technical issues, and local reference ranges should be established²

There you are, clear…. as mud. What the British Haematology Society informs us is that: there is no gold standard test for vitamin B12 deficiency, there are also ‘grey’ areas, and ‘definitive cut-off points to define deficiency states are not possible.’

As with almost all areas of medical research, the more you dig down, the more uncertain things become. The authors of the report are not even sure if you should be measuring cobalamin, or holotranscobalamin – whatever that may be. It sounds like something from Star Trek.

When it comes to vitamin D there is a similar lack of clarity. In the UK, recent guidelines on vitamin D suggested more people should take supplements… finally. However, the NHS advice on vitamin D then goes on to make this statement:

‘…although roughly one in five people has low vitamin D levels, this is not the same as a vitamin D deficiency. It is not accurate to say that millions of people are at risk of deficiency.’³

So, according to the NHS, a low level is not a deficiency. However, a low level cannot, by definition, be normal. For, if it were normal, you could not call it “low”! So, what is it? Here is where words really start tripping over each other. Low, deficient, normal…optimal, inadequate, sub-optimal? Trying to pin any clear definition down is, I can assure you, like trying to pick up mercury using your fingertips.

In the same article it is stated that a blood level of 20nmol/l is ‘sufficient’. Again, what does sufficient mean? Is it the same thing as normal, or is it optimal? Is this really the level we should be aiming for? The National Institutes of Health in the US provides completely different figures for vitamin D deficiency. Or, as they choose to call it – ‘inadequacy.’

‘Some people are potentially at risk of inadequacy at 30 to 50 nmol/L (12–20 ng/mL). Levels of 50 nmol/L (20 ng/mL) or more are sufficient for most people. In contrast, the Endocrine Society stated that, for clinical practice, a serum 25(OH)D concentration of more than 75 nmol/L (30 ng/mL) is necessary to maximize the effect of vitamin D on calcium, bone, and muscle metabolism.’

The truth is that, wherever you look the figures are all over the place. Made more complicated by the fact that the US uses different units of measurement to everyone in the civilised world, by which I mean Europe… of course. When they say seventy-five, they really mean thirty. ‘You say nanograms per millimole, I say nanomoles per litre – let’s call the whole thing off.’

So, should you be aiming for 20nmol/l? Or is it thirty or forty, or fifty? If in doubt aiming higher would be my advice, better safe than sorry. After all, it has been found that the majority of people with cancer have ‘low’, if not ‘deficient’ levels of Vitamin D.

‘More than three-fourths of people with a variety of cancers have low levels of vitamin D, and the lowest levels are associated with more advanced cancers, a new study suggests.’⁴

If having a low level of Vitamin D means you are more likely to get cancer, then I would certainly define this as deficient, not low, and I would certainly want to do something about it.

And it is not just cancer. There are studies linking low vitamin D to many other diseases, such as kidney disease and, more importantly for the sake of this article, diabetes, and cardiovascular disease. As highlighted in this paper: ‘Vitamin D deficiency increases risk of nephropathy and cardiovascular diseases in Type 2 diabetes mellitus patients.’

‘Vitamin D (VD) deficiency is associated with insulin function and secretion. It is linked with diabetes mellitus (DM) progression, and complications were also recorded…The evidence from this study suggest that patients with Type 2 diabetes with vitamin D deficiency are at higher risk for developing CVD and nephropathy [kidney damage].’ ⁵

Additionally, a low Vitamin D level can be a factor that drives obesity and diabetes in the first place. Here, from the study: ‘Vitamin D deficiency is a risk factor for obesity and diabetes type 2 in women at late reproductive age.’

‘Our results showed that vitamin D insufficiency is highly prevalent in the population of healthy women. Low 25(OH)D [a form of vitamin D] levels correlated with high body fat, glucose levels and decreased insulin sensitivity. We conclude that vitamin D deficiency is a potential risk factor for obesity and development of insulin resistance leading to diabetes type 2. ⁶  

If you choose to look, the evidence for the potential harms of low… deficient… inadequate…insufficient… suboptimal Vitamin D stretch on, and on, and on. Cancer, diabetes, obesity, kidney failure, cardiovascular disease. In the era of COVID19, there are also significant benefits from vitamin D in boosting of the immune system and reducing the risk of infection.⁷

Cutting to the chase, most doctors are eager to dismiss the benefits of Vitamin D on, pretty much, anything. However, I think the evidence for benefits on overall, and cardiovascular health are overwhelming.

Of equal importance is the fact that vitamin D is incredibly safe to take. It is true that toxicity has been seen in a few people, very few. However, it took sixty thousand units a day for several months to reach this point.

‘Taking 60,000 international units (IU) a day of vitamin D for several months has been shown to cause toxicity.^{8 ‘}

Frankly, taking that dose would be nuts, and would not be required by anyone, ever. Personally, I take nine thousand units a day from October to March. I am l looking to get my levels above 50nmol/l, and keeping them there, if possible.

And why on earth would you not?  Vitamin D is remarkably safe, and cheap. In the summer you don’t need to take any at all. You can get all you need by going out in the sun when it shines and, shock, horror, exposing your skin for an hour or so. Even more if you like.

Why do doctors dislike vitamins so much? It is complicated, but primarily driven by the pharmaceutical industry, who absolutely hate the idea of people buying ‘health’ products that they cannot make any money from. So, they make wild claims about vitamins damaging health, and suchlike. They are simply trying to take out the opposition, usual tactics. For example:

‘….a USA TODAY investigation finds that a wide array of dietary supplement companies caught with drug-spiked products are run by people with criminal backgrounds and regulatory run-ins. Consumers buying products from these firms are in some cases entrusting their health and safety to people with rap sheets for crimes involving barbiturates, crack cocaine, Ecstasy and other narcotics, as well as arrests for selling or possessing steroids and human growth hormone. Other supplement company executives have records of fraud, theft, assault, weapons offenses, money laundering or other offenses, the investigation shows.⁹’

Blah de blah. I amuse myself by reading the title of the book by Peter Gøtzsche: ‘Deadly Medicines and Organised Crime. How big pharma has corrupted healthcare.’ As he says. ‘If you don’t think the system is out of control, please email me and explain why drugs are the third leading cause of death… If such a hugely lethal epidemic had been caused by a new bacterium or a virus, or even one-hundredth of it, we would have done everything we could to get it under control…’

Something reinforced by Richard Smith (previous long-time editor of the British Medical Journal) in the foreword to Gøtzsche’s book:

‘It is scary how many similarities there are between this industry (the pharmaceutical industry) and the mob. The mob makes obscene amounts of money, as does this industry. The side effects of organised crime are killings and death, and the side effects are the same in this industry. The mob bribes politicians and others, and so does the drug industry.’

Just in case you think Gøtzsche and Smith are over-reacting, here is what Harvard University states:

‘Few know that systematic reviews of hospital charts found that even properly prescribed drugs (aside from misprescribing, overdosing, or self-prescribing) cause about 1.9 million hospitalizations a year. Another 840,000 hospitalized patients are given drugs that cause serious adverse reactions for a total of 2.74 million serious adverse drug reactions. About 128,000 people die from drugs prescribed to them. This makes prescription drugs a major health risk, ranking 4th with stroke as a leading cause of death. The European Commission estimates that adverse reactions from prescription drugs cause 200,000 deaths; so together, about 328,000 patients in the U.S. and Europe die from prescription drugs each year. The FDA does not acknowledge these facts and instead gathers a small fraction of the cases.¹⁰’

Ouch. And there are those who think I am highly critical of the pharmaceutical industry. I’m a pussy cat in comparison. How many deaths have there been from vitamins? Last time I looked; it was one, over a ten-year period. I think a large crate of vitamin D fell off a lorry and squashed someone… (joke).

Anyway, yes, as you may have noticed, I have not yet talked about C… Vitamin C. I have just been setting the scene. Rearranging the mental furniture. So, now to vitamin C. How much do you need? What good does it do?

I find it somewhat strange that almost all animals can synthesize their own Vitamin C, but we cannot. Along with a few great apes, a couple of fruit bats and guinea pigs. Animals synthesize it from glucose, in four steps.

Humans have retained the first three steps but lack the fourth. We lost this fourth step about forty million years ago. Perhaps because we learned to re-cycle vitamin C within our red blood cells, so we need far less of it. The ‘electron transfer hypothesis.’ If making Vitamin C uses up resources that we need for other things… why bother. Just eat it, there is plenty about¹¹.

Anyway, for whatever the exact reason, we lost the ability to make vitamin C. So, we now have to eat it. Mostly from fruit and plants. Tricky if you are Inuit. However, animal meat does contain enough vitamin C to keep the Inuit going.

There is a hypothesis that the Inuit ensure that they eat the adrenal glands of various animals they kill, because this is where there is the highest concentration of vitamin C lies. I don’t think I have seen this proven. Anyway, how could the Inuit possibly have known where vitamin C was concentrated? A clever trick indeed. Do they have secret biochemical labs hidden within glaciers?

Moving on. What happens if you do not eat enough vitamin C? Well, a whole lot of different things. But the most serious problem is that vitamin C is required to create collagen. Think of collagen as being like the steel bars in concrete, providing support and strength for tissues around the body. Without collagen, things can start to break apart quite dramatically.

Blood vessels, for example, need a lot of collagen, as they have to withstand a lot of pressure, and squeezing and bending and suchlike. So, one of the first clinical signs of scurvy (Vitamin C deficiency) is often bleeding gums. Followed by bleeding everything else. Followed by bleeding to death. Not recommended.

What is both pertinent, and fascinating at this point in the vitamin C story, is that evolution came up with a plug to reduce the risk of bleeding to death in vitamin C deficiency. Until enough vitamin C could be found and consumed again, and collagen synthesis got back to normal.

This plug is called Lipoprotein(a). Or Lp(a).

If blood vessels start to crack, this action attracts a Lp(a) to the scene. It then flings itself at the cracks, to form a plug that is highly resistant to being broken apart. More so, than any other part of a blood clot. It achieves this resistance by using a very clever trick, which is that it blocks the activation of the enzyme specifically designed to break down blood clots.

At this point I need to explain a bit more about blood clots… So, off we go once more, on a detour.

The enzyme designed to break clots apart is plasmin, which does the job of slicing apart strands of fibrin. Fibrin is the very tough strand of protein that wraps around all blood clots, then binds them together, then tightens up the entire clot up and makes it very tough and difficult to ‘lyse’ i.e. slice apart.

Fibrin is constructed when smaller pieces of protein, called fibrinogen are linked up, end to end, to form the much longer fibrin strand. This is the final step of the monstrously complex ‘clotting cascade’. [You could not allow long strands of fibrin to float about freely in the blood. They would just end getting tangled around everything else and getting stuck in various vital places.]

So, whilst fibrin has a critical function in blood clot formation, if you cannot break it down – once the bleeding has stopped, and repair has started – then you cannot break apart the blood clot either – at least not easily. And if you cannot break apart blood clots, then they are going to hang around – almost forever. Which is not a good thing, as you can probably imagine.

Which is where the enzyme known as plasmin comes in. Once bleeding has stopped, plasmin is ‘activated’ to slice – or lyse – the clot apart, and then it is gone.

How do you activate plasmin? Well, this process starts with another protein called plasminogen – which is incorporated into all blood clots as they form. Plasminogen then sits there doing nothing much. However, you can convert plasminogen into plasmin using another enzyme called tissue plasminogen activator (TPa).

TPa + plasminogen → plasmin → fibrin sliced apart ‘lysed’

Yes, step after step… after step. Tissue plasminogen activator is now made commercially and is colloquially known as a ‘clotbuster’. It is often given to people having a stroke to ‘bust’ the clot apart. [Unless you are having a stroke due to a bleed, not a clot, at which point given TPa would not be a great idea].

So, and keep holding on here, because I am going to get back to Vitamin C in a bit… so, what if you could not break up clots? At least, not so easily. Well, whilst this is a good thing if your blood vessels are cracking due to a lack of collagen, as the blood clot ‘plugs’ will need to last for a long time. At least until Vitamin C intake goes up, and collagen can be made.

However, if you do not have scurvy, having blood clots that resist lysis is a bad thing, because these clots are more likely going to hang around for ages. They will be stuck to blood vessel walls for quite a long time. Which means that they can become the focus for atherosclerotic plaques. [At least this is what happen if you believe in the thrombogenic hypothesis – which I do].

Now, getting back to Lp(a). How does it stop clots being broken down? Well, the(a) in Lp(a) stands for apolipoprotein(a). This protein is almost identical to plasminogen – the protein that is incorporated into all blood clots as they form. However, apolipoprotein(a) cannot be converted to plasmin by tissue plasminogen activator. Instead, it acts as a tissue plasminogen activator inhibitor. It jams up the active site of TPa.

So, deep breath. If you have a lot of Lp(a) around, you are in danger of creating difficult to shift blood clots. As outlined in the paper ‘Lipoprotein(a) as a modifier of fibrin clot permeability and susceptibility to lysis.’

‘We here provide the first evidence that elevated plasma Lp(a) levels correlate with decreased fibrin clot permeation and impaired susceptibility to fibrinolysis both in apparently healthy subjects and patients with advanced coronary artery disease. The relationship between Lp(a) and clots …are associated with extremely unfavourable clot properties¹².’

Therefore, if you have a lot of Lp(a) in you blood, you will have blood clots with ‘extremely unfavourable clot properties.’ And so, you may end up dying of cardiovascular disease. Here is an article from the New York Times:

‘To millions of Americans, Bob Harper was the picture of health, a celebrity fitness trainer who whipped people into shape each week on the hit TV show “The Biggest Loser.”

But last February, Mr. Harper, 52, suffered a massive heart attack at a New York City gym and went into cardiac arrest. He was saved by a bystander who administered CPR and a team of paramedics who rushed him to a hospital, where he spent two days in a coma.

When he awoke, Mr. Harper was baffled, as were his doctors. His annual medical checkups had indicated he was in excellent health. How could this have happened to someone seemingly so healthy?

The culprit, it turned out, was a fatty particle in the blood called lipoprotein(a). While doctors routinely test for other lipoproteins like HDL and LDL cholesterol, few test for lipoprotein(a), also known as lp(a), high levels of which triple the risk of having a heart attack or stroke at an early age.’

You may think, why have I never heard of Lp(a). Fear not, you are not alone, as most doctors have never heard of it either. The surprising fact is that, although you may think you have never heard of Lp(a) you have. Because it is actually….

Drum roll, great suspense…

It is…. Low Density Lipoprotein (LDL). Yes, it is ‘bad cholesterol’ itself. The evil substance of doom itself. What a remarkable coincidence…

You think I am pulling your leg. I am, but only slightly. In fact, to be fully accurate, Lp(a) is actually low-density lipoprotein (LDL), with an extra strand of protein attached to it. And that protein is apolipoprotein(a).

Yes, apolipoprotein(a), the very protein that pretends to be plasminogen. The protein that inhibits blood clots from being broken apart. This is all a bit like a Sherlock Holmes story. Ladies and Gentlemen, I give you…

‘The tragic case of mistaken identity.’

‘I put it to you sir, that when you looked at atherosclerotic plaques and saw LDL within them, you were actually looking at Lp(a) molecules, but you did not recognise them. Because you miserably failed to look for the apolipoprotein(a).’

Or, to switch metaphors in a heavy-handed manner to Cluedo.

‘It was Lp(a) wot done it, in the left anterior descending artery, with an apolipoprotein(a) molecule.’

Or, to put it more technical speak, from the paper ‘Quantification of apo[a] and apoB in human atherosclerotic lesions.’:

‘These results suggest that Lp[a] accumulates preferentially to LDL in plaques, and that plaque apo[a] is directly associated with plasma apo[a] levels and is in a form that is less easily removable than most of the apo B. This preferential accumulation of apo[a] as a tightly bound fraction in lesions, could be responsible for the independent association of Lp[a] with cardiovascular disease in humans¹³.’  

Oh, my goodness, it is all so very complicated, is it not? Well, it is both complicated, and fascinating. You start looking at Vitamin C, and you end up comparing the molecular structure of plasminogen and apolipoprotein(a). Then you find that Lp(a) is, to all intents and purposes, LDL.

Now, let me see. Where does vitamin C properly fit into this tale?

Well, if you don’t have enough vitamin C, then you are more likely to end up with cracks in your blood vessels. These cracks will then be plugged by small blood clots, containing a lot of Lp(a). If you have a high Lp(a) level, then these small blood clots will be even bigger, and even more difficult to remove.

Which means that if you have a high Lp(a) level, it would be a splendid idea to ensure that you never become vitamin C deficient. Indeed, even if you do not have a high Lp(a) level it would be a splendid idea to ensure that you do not become vitamin C deficient. Because cracks in blood vessel walls are never a good thing. Ending up, potentially, as the focus for atherosclerotic plaques.

Linus Pauling, a famous double Nobel Prize winner, believed that ‘sub-clinical’ Vitamin C deficiency was ‘the’ cause of cardiovascular disease. He also believed that if everyone took enough vitamin C, cardiovascular disease would disappear.

Personally, I do not think it is ‘the’ cause of cardiovascular disease, but I do think that it is ‘a’ cause. That is, whether or not you have a high Lp(a) level. Of course, a high Lp(a) level is likely to make things far worse, were you to end up vitamin C deficient.

However, the vitamin C, cardiovascular disease story does not end here. Because vitamin C has many other critical functions that link back to cardiovascular disease in one way, or another. For example, it has a more general function in protecting endothelial cells from harm, and supports the integrity of the vascular system. Here, from the paper ‘Role of Vitamin C in the function of the vascular endothelium’:

‘Vitamin C, or ascorbic acid, has long been known to participate in several important functions in the vascular bed in support of endothelial cells. These functions include increasing the synthesis and deposition of type IV collagen in the basement membrane, stimulating endothelial proliferation, inhibiting apoptosis (endothelial cell death), scavenging radical species, and sparing endothelial cell-derived nitric oxide to help modulate blood flow. Although ascorbate may not be able to reverse inflammatory vascular diseases such as atherosclerosis, it may well play a role in preventing the endothelial dysfunction that is the earliest sign of many such diseases.’

Supplementation to upper normal plasma ascorbate levels is clearly indicated in most diseases and conditions in which ascorbate is depleted. However, it is seldom a priority, because patients, physicians, and health authorities are unaware of the increasing evidence for multiple potentially important functions of ascorbate. With regard to the endothelium, it is worth emphasizing observations made more than 50 years ago that early scurvy generates endothelial disruption in guinea pigs, which resembles atherosclerosis and is fully and rapidly reversible with ascorbate repletion.¹⁴’

Yes, with regard to the last part about guinea pigs. Many years ago, a researcher deliberately made guinea pigs ‘scorbutic’ – the medical term for the state of vitamin C deficiency, a.k.a. scurvy. At which point they developed atherosclerotic plaques.

When the vitamin C was added back into their diet, the atherosclerotic plaque disappeared. [Unless you left it too long, in which case, the plaques remained]. Best animal experiment on atherosclerosis ever done – never repeated.

Having just said all of this. I do not believe that most of us, most of the time, are lacking vitamin C – to any degree. At least I do not think so. However, if we become infected – with almost anything – the requirement for vitamin C shoots up. Because Vitamin C gets burned up protecting the endothelium, and it also supports the immune system

‘The role of vitamin C in lymphocytes is less clear, but it has been shown to enhance differentiation and proliferation of B- and T-cells, likely due to its gene regulating effects. Vitamin C deficiency results in impaired immunity and higher susceptibility to infections. In turn, infections significantly impact on vitamin C levels due to enhanced inflammation and metabolic requirements.¹⁵’

Another key thing to know about vitamin C, again closely related, is that people with type II diabetes, and people who smoke, have reduced circulating levels of Vitamin C.

‘Although T2DM [type II diabetes mellitus] is not traditionally considered a risk factor for vitamin C deficiency, our research indicates that those with prediabetes or T2DM are more likely to have inadequate or deficient plasma vitamin C concentrations. This did not appear to be due to a lower dietary vitamin C intake, so dietary advice needs to emphasise the importance of consuming high vitamin C foods.¹⁶’

What links smoking, type II diabetes, and vitamin C? Here I am hypothesizing a little. What links them is that with smoking, and type II diabetes, the endothelium is under ‘attack’. High blood sugar levels damage the glycocalyx (the protective lining of endothelium), and so do the nanoparticles that enter the bloodstream if you smoke.

Here is a quote from the paper: ‘Loss of endothelial glycocalyx during acute hyperglycemia coincides with endothelial dysfunction and coagulation activation in vivo.’ (In vivo means in a real live person, not just in vitro – in a test tube). Jargon alert:

‘Hyperglycemia is associated with increased susceptibility to atherothrombotic stimuli. The glycocalyx, a layer of proteoglycans covering the endothelium, is involved in the protective capacity of the vessel wall. We therefore evaluated whether hyperglycemia affects the glycocalyx, thereby increasing vascular vulnerability…

In the present study, we showed that the glycocalyx constitutes a large intravascular compartment in healthy volunteers that can be estimated in a reproducible fashion in vivo. More importantly, we showed that hyperglycemic clamping elicits a profound reduction in glycocalyx volume that coincides with increased circulating plasma levels of glycocalyx constituents like hyaluronan, an observation that is consistent with the release of glycocalyx constituents into the circulation¹⁷.’

Looking specifically at smoking:

‘Vascular dysfunction induced by smoking is initiated by reduced nitric oxide (NO) bioavailability and further by the increased expression of adhesion molecules and subsequent endothelial dysfunction. Smoking-induced increased adherence of platelets and macrophages provokes the development of a procoagulant and inflammatory environment.¹⁸’ 

Essentially, smoking and high blood glucose both damage the endothelium, which results in low vitamin C levels, as the endothelial cells burn through Vitamin C to maintain themselves. Ergo, fi you have type II diabetes, or smoke, you need more Vitamin C to maintain healthy levels….

Now, before I introduce you to far too many new and difference concepts – I did mention everything starts linking back together in completely unexpected ways – it is time to draw our little tale of Vitamin C together.

The first thing to say about vitamin C is that it is vital. I have only covered a few of the essential functions that it has in the human body. Those most closely related to cardiovascular disease. Importantly, it is almost impossible to cause harm by overconsumption. It is just about as safe to take, as anything can possibly be.

The next thing to say is that most of us, most of the time, probably have sufficient vitamin C intake, and require no supplements.

However, if you have a high Lp(a) level, then any damage caused by a lack of vitamin C will be amplified, dure the fact that Lp(a) sticks very tightly to areas of endothelial damage, making the resultant blood clot very difficult to remove. So, for those with high Lp(a) levels, I would recommend one gram of vitamin C a day – forever.

If you smoke, or have diabetes, the lining of your artery walls (glycocalyx and endothelium) are under constant attack from nasty substances – smoke nanoparticles and high blood glucose. This, too, will create ‘cracks’ in blood vessels.

In both situations Vitamin C is also used up more rapidly, trying to protect against this damage. So your vitamin C level is likely to be low. Which means that you too, should take one gram of vitamin C a day – forever. [Or you could try stopping smoking]

In addition, in many infections, the endothelium is under severe attack. Either directly from the microorganisms entering and killing endothelial cells (see under COVID19), or from the exotoxins (toxic waste products) released by any bacteria in the bloodstream.

The most severe endothelial attack occurs in sepsis (infection of the blood), where the exotoxins strip away the endothelium, resulting in widespread blood clotting (disseminated intravascular coagulation DIC). Which is the thing that, primarily, kills you with sepsis.

Whilst sepsis represents an extreme situation, it is still the case that if you are suffering from an infection, of any sort (gingivitis or periodontal disease) your requirement for vitamin C will shoot up. Which means that you should take as much Vitamin C as you can tolerate. Up to ten grams a day. I cannot take this amount due to the impact it has on my gastrointestinal tract. Loose, is the word. Very loose. Looser than loose.

But if you can tolerate it, Vitamin C will help to protect your endothelium. It will also boost the functioning of your immune system.

So, there we are then, vitamin C. My second favourite vitamin, after vitamin D. In the winter I take a gram a day. Along with my nine thousand units of vitamin D. Almost all medics will instantly dismiss this as ‘woo woo’ nonsense. I would tend to argue that this is because they know absolutely nothing about vitamins, or their critical roles in human physiology, and have never bothered to find out.

Pop quiz for your doctor, next time you see them. Ask them how a lack of vitamin C causes scurvy. What is the primary disease process? Watch them scrabble to bring up a Google search. Then ask them about Lp(a). What it is, what it does… I guarantee that silence will be the stern reply.

1: https://advances.augusta.edu/1014#:~:text=Interestingly%2C%20in%20Japan%20the%20reference,methylmalonate%20levels%20are%20not%20checked.

2: https://onlinelibrary.wiley.com/doi/full/10.1111/bjh.12959

3: https://www.nhs.uk/news/food-and-diet/the-new-guidelines-on-vitamin-d-what-you-need-to-know/

4: https://www.webmd.com/cancer/news/20111004/low-vitamin-d-levels-linked-to-advanced-cancers#1

5: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6540771/

6: https://pubmed.ncbi.nlm.nih.gov/23924693/

7: https://vitamindforall.org/letter.html

8: https://www.mayoclinic.org/healthy-lifestyle/nutrition-and-healthy-eating/expert-answers/vitamin-d-toxicity/faq-20058108#:~:text=Advertisement&text=The%20main%20consequence%20of%20vitamin,the%20formation%20of%20calcium%20stones.

9: https://eu.usatoday.com/story/news/nation/2013/12/19/dietary-supplements-executives-criminal-records-spiked/4114451/

10: https://ethics.harvard.edu/blog/new-prescription-drugs-major-health-risk-few-offsetting-advantages

11: https://academic.oup.com/emph/article/2019/1/221/5556105

12: https://onlinelibrary.wiley.com/doi/full/10.1111/j.1538-7836.2006.01903.x

13: http://www.jlr.org/content/32/2/317.full.pdf

14: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3869438/

15: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5707683/

16: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5622757/

17: https://diabetes.diabetesjournals.org/content/55/2/480

18: https://www.ncbi.nlm.nih.gov/pubmed/24554606