26th August 2022

And so, after a great deal of faffing about, my article on cardiovascular disease ‘Assessing cardiovascular disease: looking beyond cholesterol’ has been made free to view.

Writing an article for a medical journal is not that difficult. Trying to submit it through Kafkaesque editorial systems, now, that is tricky. They seem incapable of understanding that I am not funded by anyone. Shock, horror, I do it simply for the love of science – or something of the sort.

As for allowing the article to be open access … don’t go there. I would rather fill in a US tax form, in triplicate and, yes, I have seen US tax forms in all their incomprehensible glory. I also spent considerable time trying to explain to the editorial team that the two risk calculators I discussed in the paper could not be referenced in the approved Vancouver style.

Vancouver style: required elements:

Author. Title [Type of medium]. Place of publication: Publisher; Date of publication [Date of update/revision; Date of citation]. Availability.

I could not use Vancouver style because there was no author, place or date of publication – to start with. They were both on-line tools used to assess cardiovascular risk. Helloooo… ever heard of the Internet. Thud!

Anyway, I was invited to write the article by Dr Eric Westman, who was the guest editor for this edition of ‘Current Opinion in Endocrinology, Diabetes and Obesity.’ In truth, I get about fifty invites a day to write articles. This is not a boast, anyone who has written almost anything that has been published in a medical journal is bombarded with such requests. New journals spring up like desert flowers after the rain.

Most of the requests are, essentially, vanity publishing. You spend ages putting together a paper that you then must pay to get published – you certainly have to pay a lot to allow open access. Usually thousands of dollars. The publisher meanwhile gains copyright. Then hardly anyone ever reads it. But, hey, you can send a copy to your mum – who will be very proud. If none the wiser what you are trying to say.

Thus, I do not respond to such requests normally. But in this case, I did. Eric Westman is a staunch ally in the crusade to look at different causal models of cardiovascular disease. Models not based on LDL/cholesterol levels.

For this edition he also invited others e.g., David Diamond to write other articles casting doubt on the LDL/cholesterol hypothesis – in the proper scientific manner. Dr Westman then paid to make them open access. A cost running into many thousands of dollars. Good man.

Anyway, here it is. https://journals.lww.com/co-endocrinology/Fulltext/9900/Assessing_cardiovascular_disease__looking_beyond.21.aspx

For those who have read my blog assiduously, or have read ‘The Clot Thickens’, none of this is new, or any surprise. However, I hope that it does add some more scientific credibility.  Here is the abstract.

Abstract

Purpose of review

The low-density lipoprotein (LDL)-cholesterol level is a weak predictor of developing cardiovascular (CV) disease and can only explain a small proportion of CV risk. It is not used to determine CV risk on either the atherosclerotic cardiovascular disease (ASCVD) calculator in the United States, or the Qrisk3 in the UK.

A study in JAMA in 2022 suggested that ‘the absolute benefits of statins are modest and may not be strongly mediated through the degree of LDL reduction’. Perhaps it is time to look beyond cholesterol to a different causal model – the ‘thrombogenic’ model of ASCVD.

Recent findings

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) pandemic demonstrated that infectious agents damage the endothelium and the glycocalyx – the glycoprotein layer protecting underlying endothelial cells. There are numerous other conditions leading to this kind of damage, which can trigger thrombus formation, causing strokes and myocardial infarctions.

Although these are acute events, they highlight a mechanism for the development of ASCVD which centres on endothelial damage and thrombus formation as both the primary causal mechanism for acute events, and the driver behind progression towards atherosclerotic plaque development.

Summary

The cholesterol hypothesis, that a raised LDL is directly causal for ASCVD, does not adequately explain cardiovascular risk in individuals, or populations. An alternative ‘thrombogenic’ hypothesis is proposed as a more valid causal model.

Here are the key points

KEY POINTS

• Low-density lipoprotein (LDL)-cholesterol is a weak predictor of cardiovascular risk
• Factors that drive endothelial damage and thrombus formation greatly increase atherosclerotic cardiovascular disease (ASCVD) risk.
• The thrombogenic can explain a number of causal risk factors that do not fit within the LDL-cholesterol hypothesis, including type II diabetes, smoking and systemic lupus erythematosus.
• The thrombogenic hypothesis, that endothelial damage and subsequent clot formation underlies the formation and growth of plaques, may represent a better model for ASCVD.
• There is a need to research the thrombogenic hypothesis in more depth.

Stripping away the scientific obfuscation which is now required of all scientific writing. If anyone understands what you are trying to say, you lose. The two points that I was trying to make were the following:

• The LDL/cholesterol hypothesis is most likely wrong. It is a weak predictor of risk, at best, and cannot explain how many factors known to increase the risk of cardiovascular disease, actually cause cardiovascular disease.
• There is an alternative hypothesis, the ‘thrombogenic’ hypothesis which can explain how, and why, many different, apparently unconnected factors actually do cause cardiovascular disease.

I hope that the readers of this blog can make as much noise about it as possible and share it as widely as possible. You may even want to read the entire paper. It is not very long, and it is not too technical. At least I don’t think so.

Thank you.

21st March 2022

Someone once said to me that I really must despise the pharmaceutical industry. There are certainly times when this is true, and my anger with them is sharp … and hot.

But yet, and yet, I know many people who work in the industry, and they all seem nice, concerned about the world, caring. Trying to do good. The industry itself has also produced some great innovations and medications. Without which the world would be a much scarier and more unpleasant place.

In truth, I find the industry is a bit like capitalism. Both fantastic and dreadful. Which is a bit like humanity itself. Both fantastic and dreadful. Capable of the most amazing things, yet the darker side can be very dark indeed. Dr Jekyll and Mr Hyde.

To be frank, my personal problems with the pharmaceutical industry have mainly centred around cholesterol lowering. Various companies have made billions, nay tens of billions, nay hundreds of billions, pushing LDL-Cholesterol reduction with all their might.

However, I have oft sat with my head in my hands in despair at such nonsense. Pfizer with Lipitor (atorvastatin) pushed the hardest and made the most … and horribly distorted the entire world of cardiovascular disease research in so doing.

However, thirty years ago, and purely by chance, the planets Pfizer and Kendrick were in a strange alignment. Briefly, I found myself on the same side as Pfizer when it came to cardiovascular disease.

How could this possibly be so? Well, gentle reader, let me take you back to a time when Pfizer had a very different drug to promote, called Doxazocin. It was a type of blood pressure lowering agent known as an Alpha-1 blocker. It was not selling terribly well, so they were looking for other angles in an attempt to boost sales.

I should mention that this was before Pfizer had a statin. A time that you could refer to as the ‘BS’ era. (Or maybe we are now in the true BS era – discuss). Then, in the year 2000, Pfizer took over Warner Lambert, which just happened to have a statin called atorvastatin (Lipitor). Yes, Pfizer didn’t actually develop atorvastatin. They just bought out the company that did. Nifty move.

Anyway, in 1992, Pfizer was not much interested in lowering LDL-Cholesterol, as they didn’t have a statin. Which meant they had other fish to fry with their cardiovascular drugs. They were more focussed on blood pressure lowering. But their Alpha-1 blocker for this, doxazocin (Cardura) was a bit rubbish.

So, what to do? What to do indeed. What they did was to use the tried and trusted mechanisms of looking at different effects that this drug might have.

To explain, almost all drugs when they are launched are marketed for one indication, and that indication only – the thing that will make the most money. Achieving marketing approval, for any indication e.g., blood pressure lowering, costs vast sums of money. Which means that companies must keep their focus tight, to drive the drug through the clinical trials process.

However, almost all drugs will do many other things, and you cannot run separate clinical trials on them all. To long, too complex, too costly.

There may be some ‘magic bullet’ drug that hits one target, and one alone, and spares everything else. Sniper fire. However, with most of them, you select automatic, raise the gun over your head from behind a sheltering wall, close your eyes, and spray bullets vaguely towards the target. Hoping you manage to hit the thing you’re aiming at.

Just to give a few well-known examples from history. Aspirin was initially found to reduce pain, inflammation and temperature. It was later discovered it helps to prevent platelets (small blood cells) sticking together. So, it was also an anti-coagulant – it reduced the risk of blood clots forming – and thus reduced the risk of dying of a heart attack. Now, it is being used to prevent cancer.

Sildenafil (Viagra) was initially developed as a drug for angina. The rest, as they say is history. It ended up being marketed for erectile dysfunction because it had an unknown, at the time, ‘off-target effect’ that had nothing, directly to do with angina at all. Or, at least, no-one could see the connection at the time.

Thalidomide was originally developed as a sedative. It was then sold for treating colds, flu, nausea and morning sickness. As everyone now knows, it caused horrible deformities in the unborn child.

Coincidentally, it was discovered the very same mechanism that led to the terrible deformities, also meant it was pretty good at treating a whole series of different diseases, such as multiple myeloma and leprosy. It is now prescribed as Thalomid – it has many different names. But certainly not thalidomide.

Last time I bothered counting, statins had thirty-four off-target effects. These are sometimes called ‘pleiotropic’ effects. I suppose this makes them sound more scientific. I am only surprised that statins have not yet been repurposed as anti COVID19 drugs. Probably because they are all off-patent, thus cannot make vast sums of money.

In an attempt to pull all these strands together, if your drug is not selling that well, have a closer look at all the other things it may do. The off-target effects, the ‘pleiotropics’. It has already reached market, at great cost, and whilst you are not allowed advertise it for ‘off-label’ benefits i.e., benefits not studied in the clinical trials, you can hold educational meetings and produce educational booklets to promote these additional things.

You can, effectively, launch it again as ‘Cardura two point one’. Ladies and Gentlemen …. drum roll. ‘A new era in cardiovascular disease prevention has begun.’ Dun, dun, duuuuuuuuun!’

At which point you can purchase a few off the shelf cardiology opinion leaders to push Cardura two point one with great enthusiasm. Throw a few million – carefully labelled – free pens, sticky pads, and BP cuffs around as an appreciative gift to doctors. Take them to a free lunch, sorry, educational meeting. Bore them for ten minutes, then reward them with a prawn sandwich. Feed the sea-lions.

And lo it came to pass that Pfizer scrutinised Cardura in greater detail, and found that it, like aspirin, helped to stop platelets sticking together. Platelets are small cells that float around in the bloodstream and play the key role in blood clotting. They have been described as the conductors of the clotting orchestra.

If you stop platelets sticking together, you can reduce the risk of cardiovascular disease, as was discovered with aspirin. Aha! So, not only does Cardura lower blood pressure, but it also has ‘anti-coagulant’ properties. Even better, it reduced fibrinogen, and PAI-1 and increased TPa activity. These are all ‘good’ in reducing the formation and increasing the breakdown of blood clots. As Pfizer stated:

‘These recent studies suggest that doxazosin may have a range of significant antithrombotic effects in many patients…’

Unfortunately, in 1992 doctors had already been under heavy and continuous bombardment with the message that lowering cholesterol and blood pressure were, by far, the most important things you could possibly do to prevent cardiovascular disease.

Blood clotting? Well, aspirin was used, a bit. But this was mainly to help with the final event. The big blood clot that blocked a major artery. No-one was suggesting that blood clotting had anything to do with atherosclerosis itself.

After all, how can blood clotting possibly cause atherosclerotic plaques to develop? As everyone had already been told, and told, and told … and told, and then told some more, atherosclerotic plaques (the entities that gradually grow and narrow down arteries) were full of cholesterol. Not the remnants of blood clots.

Love and marriage may go together like a horse and carriage, but platelet aggregation and atherosclerotic plaques …. You certainly cannot get a rhyme out of that – go on, I challenge you. Ergo, it must be wrong.

It was certainly a big mountain to climb. ‘You know that stuff about cholesterol…. Sorry. Turns out we should have been looking at Platelets and blood clotting instead.’ Here from a booklet on Cardura in 1992:

Platelets and atherosclerosis progression

Several features of mature plaques, such as their multi-layered pattern, suggest that platelet aggregation and thrombus formation are key elements in the progression of atherosclerosis. Platelets are also known to provide a rich source of growth factors, with can stimulate plaque development.

Given the insidious nature of atherosclerosis, it is vital to consider the role of platelets and thrombosis in this process, and the serious events that may be triggered once plaques are already present.

Goodness me. Who said all this? Why, of course it was Pfizer … Pfizer, Pfizer, Pfizer.

However, they didn’t get very far with this story. Merck were hammering away with simvastatin (Zocor) and Bristol Myers Squibb were also promoting pravastatin (Pravachol) with relentless fervour. The world of cardiovascular disease prevention was moving even more firmly in the direction of cholesterol lowering and statins.

As King Cnut (Canute to you and me) once demonstrated, once the tide starts to come in, not even a king can stop it. And the statin wave was very powerful. On the basis that, if you can’t beat them, join them, Pfizer decided to ride that wave. So, they went out and bought a large part of it, then bought the surf-boards and the tinnies.

To their (money making) credit, they then rode the cholesterol wave exceptionally well. To be frank you would buy a used car from Pfizer. I don’t know how they got so brilliant at spraying bull-shit with yellow paint, to make it look like one-hundred per-cent gold bullion, but there is no doubt they are the masters of pharmaceutical marketing.

At which point the Kendrick and Pfizer, planets were no longer in alignment. We span off on different orbits. I was still slowly plodding along the ‘platelets and atherosclerosis progression’ path, trying to make sense of it all.

Pfizer, to flip my analogies, firmly jumped on the ‘all singing, all dancing’ cholesterol lowering bandwagon.’ Complete with dancing girls in fancy costumes, a brass band, champagne, hundreds of balloons – and all the key opinion leaders in cardiology singing ‘We’re in the money.’

We’re in the money

We’re in the money

We’ve got a lot of what it takes to get along

We’re in the money

The sky is sunny

Old man depression, you are through you done us wrong, oh

We never see a headline

‘Bout a breadline today

And when we see the landlord

We can look that guy right in the eye

Oh, We’re in the money

Come, on my honey

Let’s lend it, spend it, send it rolling around…

And lo it came to pass that Pfizer and I were no longer friends. But there was a time when I like to think we could have danced all night, and still have begged for more. I could have spread my wings, and done a thousand things, I’ve never done before. Yes, my bandwagon would have been much better. Better music too. John Martyn, Fleetwood Mac, Randy Newman, The Pretenders, Jools Holland ….

Yes, it’s a little bit funny that Pfizer knew, thirty years ago, that blood clotting and atherosclerosis were intimately connected. They had seen the research. They knew:

‘Important evidence is now emerging that the selective alpha-1 inhibitor, doxazosin, in addition to its beneficial effects on elevated blood pressure and the serum lipid profile, may help to intervene in the evolution of thrombosis, a key component of atherosclerosis.’

In my recent book The Clot Thickens, I said I would put up the Pfizer booklet for all to see. It proved a bit more of a technical challenge than I thought, but here it is. And when people tell me that atherosclerotic cardiovascular disease (ASCVD) is all due to raised cholesterol I can say, not even Pfizer believes that. Not really. Not deep in their hearts …. They have a ghost in the machine that still stalks the corridors of Pfizer HQ. And if it doesn’t, it should.

They knew, oh yes once upon a time, they knew. It’s just not very profitable for them to admit it. To quote John Martyn:

‘Half the lies I tell you are not true.’

Introduction

To date, most of our attempts to prevent atherosclerosis have centered on the control of hypertension and hyperlipidaemia, as well as lifestyle factors . However, recent insights into the pathology of coronary heart disease have sharpened our focus on the natural history of atheroma and its relentless progression to acute cardiac events.

Platelets and atherosclerosis progression

Several features of mature plaques, such as their multi-layered pattern, suggest that platelet aggregation and thrombus formation are key elements in the progression of atherosclerosis. Platelets are also known to provide a rich source of growth factors which can stimulate plaque development.

Given the insidious nature of atherosclerosis, it is vital to consider the role of platelets and thrombosis in this process, and the serious events that may be triggered once plaques are already present.

Fibrinolysis

If fibrinolysis is incomplete, thrombus may become incorporated into the plaque, and may cause severe stenosis. Alternatively, any residual thrombus can act as a powerful stimulant to further platelet aggregation. The growing mass of fibrin, platelets and enmeshed red cells may become solid enough to cause complete vessel obstruction.

It is significant to note that complete obstruction and myocardial infarction often develops from mild lesion initially causing less than 50% stenosis. Rupture of these plaques and the cascade of events that leads to thrombosis can occur rapidly and it now recognized as a common and major precipitant of unstable angina, myocardial infarction and sudden cardiac death. Studies suggest that thrombotic events may account for up to 90% of acute myocardial infarction.

Triggering factors in thrombosis

Hypertensive patients are known to have greater platelet adhesiveness and aggregability, which could increase clot formation at the site of plaque injury. In addition, thrombolysis is often defective in hypertension and hyperlipidaemia, which may result in an impaired ability to dissolved clots in the presence of atherosclerosis.

Clot propagation

Any residual thrombus can act as a powerful stimulant to further platelet aggregation. The growing mass of fibbing, platelets and enmeshed red-cells may become solid enough to cause complete vessel obstruction.

It is significant to not that complete obstruction and myocardial infarction often develops form mild lesions initially causing less than 50% stenosis. Rupture of these plaques and the cascade of events that leads to thrombosis can occur rapidly and it now recognized as a common and major precipitant of unstable angina, myocardial infarction and sudden cardiac deaths. Studies suggest that thrombotic events may account for up to 90% of acute myocardial infarctions.

The atherosclerotic process begins with infiltration of low-density lipoproteins or LDL into the arterial intima to create lipid-rich foam cells which form the basis of the ‘fatty streak.’ This early lesion contains large amounts of cholesterol, but its development to atherosclerosis is not inevitable. Progression appears to depend critically upon endothelial injury, caused by oxidation of LDL by the shearing forces of hypertension and by smoking.

Conclusion

With each decade, new insight is gained into how drug therapy can reduce the risk of coronary heart disease and stroke, the primary goal in the management of the hypertensive patient.
Important evidence is now emerging that the selective alpha-1 inhibitor, doxazosin, in addition to its beneficial effects on elevated blood pressure and the serum lipid profile, may help to intervene in the evolution of thrombosis, a key component of atherosclerosis.

The Document is called Pathological Triggers ‘New Insights into Cardiovascular Risk.’

Produced by Medi Cine Inc
488 Madison Avenue
New York
NY 10022

For Pfizer Inc
New York
NY 10017 Copyright 1992 Pfizer Inc. All rights reserved.

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

The Clot Thickens is available in paperback and eBook.

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9th February 2020

The good thing about having different ideas about diet, obesity, diabetes and heart disease and suchlike, is that you get to meet with such interesting people. Steve Bennett is one such. He set up successful businesses, that have nothing whatsoever to do with health, and only came to diet and health from his own interest and passion.

He then established a brand called Primal Living, based on eating food that we used to eat in the past. Woolly mammoths and suchlike and avoiding processed foods and carbs. In addition taking supplements that have been removed from our diet by the mass food manufacturing industry. It has improved his own health, and the health of many others.

He is, essentially, on the same pathway as Aseem Malhotra, Tim Noakes, Ivor Cummins, Zoe Harcombe, Gary Taubes, David Unwin – and anyone else who has looked at diet, and health, and possess a fully functioning brain.

They have all – we have all – recognised that the current dietary guidelines are complete dangerous bunk, doing harm rather than providing benefit.

He was also good enough to allow me to outline my ideas on CVD, and the process of CVD, which his team has put together into a podcast. It can now be seen here https://podcasts.apple.com/gb/podcast/fat-furious/id1495158540

As always, I feel I have not really explained things as well as I can, but I hope you find it interesting, and I would welcome feedback and constructive criticism. I would further recommend looking at the other podcasts under the ‘Fat and Furious’ banner.

17th January 2020

I thought I should write a blog on coronary artery calcification (CAC), as it has become the latest hot topic. CAC scans, and CAC scoring are now increasingly popular, and the results are worrying lots of people who wonder what they mean, and exactly how worried they should be. I get many e-mails on this issue from people who have been scared witless, or another word ending in***tless, by having a high CAC score.

What is coronary artery calcification

Coronary artery calcification (CAC) is the deposition of calcium in artery walls. It represents the final stages in the life cycle of some/many/most atherosclerotic plaques. At the risk of oversimplification, it is generally accepted that atherosclerotic plaques go through four stages

• Small
• Bigger
• Vulnerable
• Calcified

Forget small and bigger. The important ones are vulnerable and calcified. What is a vulnerable plaque? It is a plaque that reaches a certain size (undefined) containing an almost liquid core, with a thin cap. If this thin cap ruptures, it exposes the liquid core to the bloodstream triggering a major blood clot than can fully block a coronary artery and cause a myocardial infarction.

This is generally described as plaque rupture. If it happens in an artery in the neck, a carotid artery, the clot will normally not be big enough to block the artery. But it can break off and head up into the brain, causing a stroke.

Which means that it is these ‘vulnerable’ plaques that are dangerous, and these are often not calcified, and therefore cannot be seen on a CAC scan.

Over time, assuming the vulnerable plaques do not rupture and kill you, some of them (all of them?) shrink down in size, become more solid and start to calcify. At which point they are less likely to rupture and may be considered relatively benign.

Calcification of areas of damage in the body is not restricted to atherosclerotic plaques. Almost any damaged area in the body, that is not perfectly repaired, is likely to calcify to some extent or another. Scars tend to be white, and the white is calcium.

At the extreme end of calcification is a condition called myositis ossificans, whereby almost any damage ends up becoming bone. With damaged muscle turning into bone. This does not end well.

Anyway, assuming you have plaques developing and growing in your arteries, they will in time calcify. Or at least some of them will. Are some people genetically more likely to get calcification than others? Almost certainly.

Some things are known to increase the rate of calcification. Statins, for example. Here from the Cleveland clinic:

• Patients with coronary artery disease (CAD) who are treated with statins experience an increase in coronary calcification, an effect that is independent of plaque progression or regression.
• Paradoxically, high-intensity statin therapy is associated with the largest increases in coronary calcification despite promoting atheroma regression ¹

With statins the plaques get smaller and the calcium load gets bigger.

Another drug that whacks up the rate of calcification is warfarin (often called coumadin in the US).

‘The vitamin K antagonist, warfarin, is the most commonly prescribed oral anticoagulant. Use of warfarin is associated with an increase in systemic calcification, including in the coronary and peripheral vasculature. This increase in vascular calcification is due to inhibition of the enzyme matrix gamma-carboxyglutamate Gla protein (MGP). MGP is a vitamin K-dependent protein that ordinarily prevents systemic calcification by scavenging calcium phosphate in the tissues.’ ²

High intensity exercise also stimulates CAC.

‘Emerging evidence from epidemiological studies and observations in cohorts of endurance athletes suggest that potentially adverse cardiovascular manifestations may occur following high-volume and/or high-intensity long-term exercise training, which may attenuate the health benefits of a physically active lifestyle. Accelerated coronary artery calcification, exercise-induced cardiac biomarker release, myocardial fibrosis, atrial fibrillation, and even higher risk of sudden cardiac death have been reported in athletes.’ ³

An interesting mix, I think.

• Statins increase calcification
• Warfarin increases calcification
• Intense exercise increases calcification

Yet, all three reduce the risk of dying of cardiovascular disease. Yes, even statins – a bit.

But, let’s turn this around for a second. If you have no calcification in your arteries, you have a greatly reduced risk of dying of cardiovascular disease. Which means that calcification can be both good, and bad? Yes, you are right, this area is not straightforward at all.

Even if you look at non-calcified atherosclerosis, or pre-calcified atherosclerosis, the picture is complex.

For many years I have studied the Masai villagers, on and off. They are fascinating because, amongst Masai males, the diet almost entirely consists of cholesterol and saturated fat – or at least it did. Nowadays, I believe it is more McDonalds and Subway.

Despite their previous super-high saturated fat and cholesterol diet, their cholesterol levels were the lowest of any population studied. However, they developed atherosclerosis at around the same rate as any Western male of the same age.

Added to this, and just to make things even more complicated, there were no recorded cases of any male Masai villagers dying of CVD. Which made me think, at one time, that atherosclerosis and death from CVD must be unrelated phenomenon.

You think not? Here, for example, is a study on the Masai from 1971 by George Mann (who helped to set up the Framingham Study and then became a trenchant critic of the cholesterol hypothesis).

Atherosclerosis in the Masai

‘Do the Masai not develop atherosclerosis or do they have it but remain immune to occlusive disease because of some other protective circumstances? The question was answered with autopsy material collected over a five-year period. The Masai do have atherosclerosis but they are almost immune to occlusive disease.’ ⁴

Now, if we bring these facts together, what do they tell us. At the risk of running the thinking too fast, these facts tell us that atherosclerosis, calcified or not, is necessary for someone to die from CVD. However, it is not sufficient, by itself, to cause death from occlusive disease.

In epidemiology this is the well-recognised concept of ‘necessary but not sufficient’. It actually applies to many/most diseases. For example, you cannot get TB, or die of TB, without infection with the tuberculous bacillus. However, you can be exposed to the bacillus and not have TB.

Why, because your immune system fought it off. Which means that the tuberculous bacillus is necessary but not sufficient, to cause infection and death from TB. As a slight aside, one sign of TB is calcified nodes in the lungs. Which can mean that you have active TB. Alternatively, it can mean that you had active TB, which has now been cleared out, leaving only calcification.

Turning back to atherosclerosis, and using the Masai as one example, it is clear that you can get atherosclerosis, and calcified atherosclerosis, and not die of CVD, or even have an increased risk of CVD. Why, because other factors are required to kill you. Which is why it can be said that atherosclerosis is necessary, but not sufficient, to cause heart attacks and strokes.

To put this another way, you are exceedingly unlikely to die from an acute blockage to an artery without any atherosclerosis [or at least this is vanishingly rare], but just having atherosclerosis is not sufficient to cause heart attacks and strokes.

Which means that for example, if your atherosclerosis is (only) caused by intense exercise you are at no significant increased risk of dying CVD. In this case your calcified atherosclerosis is not sufficient to cause CVD.

‘A new study of mostly middle-aged men in JAMA Cardiology found the most avid exercisers—averaging eight hours per week of vigorous exercise—did indeed show greater levels of coronary artery calcium (CAC). Nevertheless, they were less prone to dying over the average follow-up period of 10.4 years compared to men who exercised less, suggesting they can safely continue their workout regimens.’ ⁵

However, if your CAC score has gone through the roof because of say: diabetes, smoking, steroid use, air pollution, heavy metal toxicity, high Lp(a), lack of various nutrients etc. then you are at great risk of dying of CVD, and you need to do something about it.

Further complications

At one time atherosclerosis was defined as either athero…sclerosis, or arterio…sclerosis, in acknowledgement that there seem to be two distinct and different type of …sclerosis in your arteries. This concept seems to have fallen by the wayside.

This may be a mistake. Some years ago, the AHA tried to define all the different types of lesion* that could be found in arteries. The report was so big, that it got split in two ^6.7. Then it got ever bigger, and then they gave the project up. The reports are long, and mind splittingly boring. One of them was a ‘twenty cups of coffee’ read. Followed by three Red Bulls.

(*lesion = abnormal thing)

What I learned, I think, in the moments when I was still conscious, was that atherosclerotic plaques are most certainly not all the same. Which lead me to think that we should attempt to bring back arteriosclerosis as a concept.

By which I mean the idea that some plaques develop, primarily, in response to biomechanical stress – such as is caused by physical exercise. On the other hand, some plaques develop in response to factors that independently damage the endothelium – such as a high blood sugar level, or smoking. With the addition of high clotting factors.

Whilst all plaques are now called atherosclerotic plaques, they do not all look the same, and they probably do not act the same. The arteriosclerotic lesions are thinner and more fibrous, they have no real lipid core and are very unlikely to rupture. They are, still, sometimes called fibroatheroma.

On the other hand atherosclerotic lesions are thicker, have a lipid core, more likely to narrow the artery and are also more likely to rupture, causing an occlusive blockage – leading to a stroke and/or heart attack.

Which is why the Masai (the most heavily exercising population on the planet – at the time) had …sclerosis yet remained ‘almost immune to occlusive disease’. Which is also why people who exercise intensely can develop …sclerosis and calcification but are not at an increased risk of dying of CVD.

However, both arterio and athero… sclerosis can calcify. So, they (probably) look much the same on the CAC san.

Moving on, again.

Sensitivity and specificity

Getting back to the CAC test, and what it means. The next issue is one that plagues all screening tests. Namely, what is the sensitivity, and what is the specificity? Something I always get the wrong way around in my head, then I must go back and look it up, to get it clear again.

To explain. A perfect screening test is one that is 100% sensitive and 100% specific. No test has ever achieved that, and I doubt any test ever will.

Sensitivity means, how good is the test at picking up that someone with the disease is identified as having the disease. Specificity means, how good is the test at making sure that people who do not have the disease are accurately told that they do not.

If we look at breast cancer, the first sign of breast cancer can often be that a woman feels a lump in her breast. However, many things that are not breast cancer, can cause a lump in the breast. Let us say 50% of palpable lumps are not breast cancer. If this is true, then the specificity of manual examination of the breast, in detecting breast cancer, would be 50%.

What of mammography? While it is clearly much better than manual palpation (from a sensitivity point of view) many cancers that cannot be felt, can still be seen on a scan, but it is actually worse from a specificity point of view.

This is because many/most ‘abnormal’ things seen on a mammogram will turn out to be benign. Sensitivity and specificity are often inversely related.

Some things sit in an intermediate area. In breast cancer screening a lot of women are told they may have breast cancer, but what has been detected is an abnormality called ductal carcinoma in situ (DCIS). This is something that may, or far more likely may not, progress to become a significant breast cancer. Should it be treated, or not?

The specificity problem is a problem for almost all screening tests. You have managed to find something abnormal on your test. Is it really abnormal? Does it need treatment? Would it have been better not to have found this ‘abnormality’ at all.

This is not a simple argument. Although it is usually presented in the most black and white terms if you question the breast cancer screening programmes. ‘Do you want women to die of breast cancer?’ Is a statement I have often heard from the pro-screening side. How does one answer this? ‘Well, of course I do. I see it as my role, as a doctor, to ensure that as many women as possible die from breast cancer.’

The real debate, of course, is far more complex and nuanced. Do the harms of finding benign abnormalities (with all the anxiety, further investigations, possible mastectomies etc. that this causes) outweigh the benefits of finding breast cancer at an early stage? Currently, the answer seems to be … yes.

If you want a far more detailed review of this area, you could buy the book ‘Mammography Screening’ by Peter Gøtzsche.

‘If Peter Gøtzsche did not exist, there would be a need to invent him … It may still take time for the limitations and harms of screening to be properly acknowledged and for women to be enabled to make adequately informed decisions. When this happens, it will almost entirely due to the intellectual rigour and determination of Peter Gøtzsche.’ Iona Health President RCGP (Royal College of General Practitioners)

Screening and scanning always seems a fantastic idea. Pick up a disease early, then you can treat it, even cure it. Presented in this, the simplest form, who could argue against it?

But it is not simple, in medicine very few things are. Breast cancer screening – in fact most cancer screening programmes – are far from black and white. You can argue for them, you can argue against them.

And, at present, cancer screening programmes are much better than CAC screening, for many other reasons. I will only deal with the most important one. Which is that… We don’t know what to do about the finding!

If you find a small, early stage, not yet spread anywhere, breast cancer you can remove it. It is gone, never to return. But what are you going to do with calcified plaques? You certainly can’t remove them. You do not know if they are going to rupture. They probably won’t. If you manage to stop the calcification getting worse, are you doing any good. Who knows? What caused them in the first place?

It is not even the calcified plaque that is the problem. The calcified plaque is only really a marker for earlier stage vulnerable plaques. If these start to calcify, this is probably a good thing, but whilst calcification is going on, the CAC score will be getting worse – while your risk of suffering a myocardial infarction is falling.

Sensitivity and specificity, false positives – and CAC scans (Pandora’s box)

My first general comment here is that you should never start screening and scanning until you are extremely certain, based on strong evidence, that you understand the natural history of the disease you are screening for.

Also, that you fully understand what the results of your test mean. And that you have an effective treatment for any abnormality you find.

These criteria are all missing with CAC scans.

Yes, a negative scan – no calcium detected – has reassurance value. If you have no calcium in your arteries, you almost certainly do not have any type of …sclerosis in your arteries. So, your risk of CVD is low.

However, positive scans, like positive mammograms, will include a very high number of false positives. Then what? You have been told you have significant calcification in your arteries. But it is ‘good’ calcification, or ‘bad’ calcification. Are you at increased risk, or not? This, no-one can tell you, for sure.

Equally, if you have calcification in your arteries, what are you going to do about it? Take statins… that makes it worse. Do more exercise…. that makes it worse. If you don’t know why you have calcification in the first place, it becomes impossible to take steps to do anything about it.

This is somewhat analogous to having a genetic test to discover if you have Huntington’s Chorea – if one of your parents had it. Do you want to find out that you have a disease – which will kill you – that you can do absolutely nothing about?

In a similar way should you have a test for Alzheimer’s, to find out if you are going to get the disease. Do you really want to know that you are going to have a terrible and devastating disease, and that there is nothing that can be done to prevent it?

In fact, CAC scans meet most of my criteria for ‘a bloody awful test that should not be done.’ It may or may not mean anything, there is no clear guidance as to what you can do about it if it is positive, and it spreads fear and anxiety in many, many, people. I should know, my inbox is stuffed with e-mails from people terrified by their CAC score.

Recommendations

My first recommendation is that, if you have not had a CAC scan, do not have one.

My second recommendation is that, if you have had a CAC scan, and it shows no calcification, good. Do not have another one.

If, however, you have had a CAC scan and it shows significant calcification. What then? What then indeed? You may want to read this paper: ‘Non-invasive vulnerable plaque imaging: how do we know that treatment works?’

‘Atherosclerosis is an inflammatory disorder that can evolve into an acute clinical event by plaque development, rupture, and thrombosis. Plaque vulnerability represents the susceptibility of a plaque to rupture and to result in an acute cardiovascular event. Nevertheless, plaque vulnerability is not an established medical diagnosis, but rather an evolving concept that has gained attention to improve risk prediction. The availability of high-resolution imaging modalities has significantly facilitated the possibility of performing in vivo regression studies and documenting serial changes in plaque stability. This review summarizes the currently available non-invasive methods to identify vulnerable plaques and to evaluate the effects of the current cardiovascular treatments on plaque evolution.’ ⁸

It will, at least, give you some idea of the other forms of investigation that are available.

Or, you might want to read this one: ‘New methods to image unstable atherosclerotic plaques.’

‘Atherosclerotic plaque rupture is the primary mechanism responsible for myocardial infarction and stroke, the top two killers worldwide. Despite being potentially fatal, the ubiquitous prevalence of atherosclerosis amongst the middle aged and elderly renders individual events relatively rare. This makes the accurate prediction of MI and stroke challenging. Advances in imaging techniques now allow detailed assessments of plaque morphology and disease activity.

Both CT and MR can identify certain unstable plaque characteristics thought to be associated with an increased risk of rupture and events. PET imaging allows the activity of distinct pathological processes associated with atherosclerosis to be measured, differentiating patients with inactive and active disease states. Hybrid integration of PET with CT or MR now allows for an accurate assessment of not only plaque burden and morphology but plaque biology too.

In this review, we discuss how these advanced imaging techniques hold promise in redefining our understanding of stable and unstable coronary artery disease beyond symptomatic status, and how they may refine patient risk-prediction and the rationing of expensive novel therapies.’ ⁹

The key words in that abstract are ‘hold promise.’

My final recommendation is that we should NOT be doing CAC scans, until it can be proved in a well conducted clinical trial, that we can do something positive and beneficial about the findings.

Yes, a ‘negative’ CAC is reassuring. This, however, must be set aside against the psychological damage caused by a ‘positive’ CAC scan. At present we are playing a form of psychological Russian Roulette. Half the population walks away reassured, half the population reels away, scared witless.

Also, often puzzled and disappointed. I have lost count of the number of people who have written to me saying that they: don’t smoke, exercise regularly, are not overweight, have low cholesterol levels, do not have high blood pressure, do not have high blood sugar levels, etc. etc. yet they have a terrifyingly high CAC score. What should they do?

Well, what can they do?

I don’t know. Because I don’t know what the test means. Not for sure. Not enough to provide any advice that I can be certain is right. Some boxes are better left unopened, however tempting it may be to peek inside.

Just because you can do something does not mean that you should.

1: https://consultqd.clevelandclinic.org/plaque-paradox-statins-increase-calcium-in-coronary-atheromas-even-while-shrinking-them/

2: https://www.amjmed.com/article/S0002-9343(15)30031-0/pdf

3: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6132728/

4: https://thescienceofnutrition.files.wordpress.com/2014/03/atherosclerosis-in-the-masai.pdf

5: https://www.cardiovascularbusiness.com/topics/lipids-metabolic/intense-exercise-protective-even-cac

6: https://pdfs.semanticscholar.org/cff1/77c1afc2cd00f6db27cf498cb1d05933ec55.pdf

7: https://www.ahajournals.org/doi/full/10.1161/01.CIR.92.5.1355

8: https://academic.oup.com/ehjcimaging/article/15/11/1194/2399586

9: https://www.atherosclerosis-journal.com/article/S0021-9150(18)30135-7/pdf

23rd December 2019

Another new study

Question: If a tree falls in the forest, and there’s nobody around to hear, does it make a sound?

This is a philosophical question that has been around for some time. I shall change it slightly to the following: “If a journal publishes a study, and it doesn’t make a noise, can it make a difference?”

A couple of weeks ago the Lancet published a ridiculous study with the snappy title:

‘Application of non-HDL cholesterol for population-based cardiovascular risk stratification: results from the Multinational Cardiovascular Risk Consortium.’

Which created headlines around the world – most of which failed to understand the difference between LDL (‘bad’ cholesterol) and non-HDL cholesterol. Which may, or may not, have been deliberately done.

This study was reported as saying that twenty-five-year olds should get their cholesterol checked, because raised cholesterol is far more damaging, at a young age, than previously thought. All based on, pretty much nothing at all. I critiqued it in my last blog. It was, to use a word I rather like … bilge!

Then another study came out last week to which I was pointed by a reader of this blog… thanks. It had the even snappier title:

‘Association between hyperlipidaemia and mortality after incident acute myocardial infarction or acute decompensated heart failure: a propensity score matched cohort study and a meta-analysis.’ ¹

You know that title really does not scream ‘READ ME!’ What is it about medical journals, and medical writing, which demands all enthusiasm and interest is sucked out, leaving only the driest, of dry, husks. I call it mummified prose.

What I first noticed was that it did not appear to make any headlines, anywhere, at all. Of course, making enough noise to be heard, in today’s jittery, overloaded information world, takes a lot of money and effort. Which is why the Lancet study got blanket coverage. Someone, somewhere, will have been paid a lot of money to ensure that it happened.

The money was paid because there are people who stand to make billions and billions from increased cholesterol testing, including younger people, and suggesting that “raised” cholesterol must be ‘treated’ from an ever-younger age. Perhaps you would like to guess who those people may be.

On the other hand, the study ‘Association between hyperlipidaemia and mortality after incident acute myocardial infarction or acute decompensated heart failure: a propensity score matched cohort study and a meta-analysis.’ could result in the loss of billions and billions.

Because what they found, was that, after an acute myocardial infarction (AMI), and in people with acute decompensated heart failure (ADHF) – normally caused by a previous MI – the higher the LDL level, the lower the overall mortality. They called a higher LDL level hyperlipidaemia (HLP), but it was a high LDL a.k.a. ‘bad’ cholesterol.

The ‘association’ of which they spoke, is in the exact opposite direction to that in the Lancet study. Just to repeat their main finding. Those with higher LDL levels lived the longest. Full stop, exclamation mark.

They set the study up to consider the following questions – I make no excuses for the jargon here:

‘We postulated that if a diagnosis of HLP [Hyperlipidaemia] decreases the mortality after AMI or HF [Heart Failure], then, it also lessens the magnitude of mortality risks associated with other competing comorbidities.

We tested this hypothesis, separately, in large cohorts of patients hospitalised for incident AMI and acute decompensated HF (ADHF). To compare patients with and with no HLP, we assembled 1:1 balanced groups using propensity score-matching for each study condition.

Our objectives were three-fold:

(1) to estimate the association of HLP with all-cause mortality among patients with AMI or ADHF,

(2) to determine the extent to which the association between other competing comorbidities and mortality is modified by HLP

(3) and to provide risk estimates for mortality associated with HLP after incident AMI or HF through systematic review and meta-analyses of published and current study data to place the current findings in the context of published literature.’

Here were the main results. First for those diagnosed with AMI:

• In matched patients, mortality was significantly lower among patients with Hyperlipidaemia (HLP) versus those with no Hyperlipidaemia (HLP)
• Overall mortality 2182 (50.2%) vs 2718 (62.5%)
• 5.9 vs 8.6 deaths/100 person-years of follow-up, p<0.0001.

Next for those diagnosed with acute decompensated heart failure (ADHF):

• In matched patients, mortality was significantly lower among patients with HLP versus those with no HLP
• Overall mortality 1687 (58.6%) vs 1948 (67.7%)
• 12.4 vs 16.3 deaths/100 person-years of follow-up, p<0.0001.

You may have noted that the mortality rate in these patients was very high. For those with ADHF, and lower cholesterol levels (LDL levels), the mortality rate was 16.3 deaths per 100 person years. That is a sixteen point three per-cent death rate per year. One in six.

This, therefore, is a super, exceptionally high-risk population. It is also a super exceptionally high-risk secondary CV prevention population. The exact group where statins are purported to do the most good – through the specific action of lowering LDL levels.

At this point, a short detour. I know any cardiologist reading this will be thinking – or has been taught to think: “Yes, but low cholesterol is a sign of other serious conditions, such as cancer. Ergo, it is not the low cholesterol that is damaging, it is the other underlying conditions”.

This ‘fact’ been stated for many years – without a single scrap of evidence to support it.

It was Stamler who first came up with this ‘apologia’ for much contradictory evidence about low LDL levels and increased mortality. Like many things in medicine it is universally believed, without any supportive evidence. It is true that in a very few cases, late stage terminal cancer, and late stage liver failure, the LDL levels can drop. Otherwise … nothing.

However, these researchers made sure they adjusted for this, non-existent, factor anyway.

‘Our findings were adjusted for cancer and numerous other Clinical Conditions.’

What were the conclusions of this study? Well, they were exceptionally carefully worded.

‘The findings of this study, if validated, should reinforce the importance of HLP in predicting long-term mortality after index AMI or ADHF and potentially provide guidance for subsequent management. HLP can readily be diagnosed and help recognise AMI and HF patients with lower long-term mortality.

In these patients, clinical care should not focus on certain lipid targets; rather evidence based secondary prevention strategies should be initiated.

Conversely, patients with AMI and ADHF without HLP may be considered to have increased risk for early mortality and potentially alert providers for close monitoring during hospitalisation and after discharge. Both categories of patients would profit from thoughtful tailored programme with distinctive goals of care for existing CCs.’

Let me cut to the key comment in that passage. That is, the comment regarding those patients who had HLP:

Clinical care should not focus on certain lipid targets

Clinical care should not focus on certain lipid targets

Clinical care should not focus on certain lipid targets

I thought it was so good, I should say it thrice, for that makes it true. According to Lewis Carroll anyway.

“Just the place for a Snark!” the Bellman cried,

   As he landed his crew with care;

Supporting each man on the top of the tide

   By a finger entwined in his hair.

“Just the place for a Snark! I have said it twice:

   That alone should encourage the crew.

Just the place for a Snark! I have said it thrice:

   What I tell you three times is true.”

Of course, the comment is couched in such diplomatic language that I am not absolutely sure what is meant by it, although I am pretty sure.

On that basis, I shall wind up the emotion of the language somewhat. ‘These poor people, who are dreadfully ill, who have suffered the agony of a heart attack, or severe heart failure, fare so much better when they have a high LDL level. So, for pity’s sake, I beseech thee in the name of God, do not try to lower their LDL level you mad fools. Aaaaaarrrrrrrrggggghhhhh! Gasp, bonk.’

Maybe a touch too emotive? Oh well – after reading too many clinical papers, the temptation to shout become irresistible. Creeping around in the grey and lifeless world of the passive voice is not really my style. Science should not be a place of hushed diplomacy. Science should be lively and stimulating, nay argumentative. If you’ve got something to say, shout it out. Fight for it and debate it properly.

Anyway, my original question was the following. ‘If a journal publishes a study, and it doesn’t make a noise, can it make a difference?’ The answer is, almost certainly, no. Hopefully, however, I have now made a bit of noise, and maybe this study can make a bit of difference.

1: https://bmjopen.bmj.com/content/bmjopen/9/12/e028638.full.pdf

10th November 2019

The Blood Brain Barrier

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

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

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

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

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

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

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

This is a headline that I must have missed.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Strange…

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

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

So, deep breath.

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

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

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

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

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

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

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

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

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

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

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

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

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

Next time, why LDL also cannot damage the endothelium.

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

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

9th October 2019

But not by me

Following a podcast by Ivor Cummings, where I bored him for an hour and a half on what causes CVD*, a journalist that I know well, Jerome Burne, had a go at summarising the ‘thrombogenic’ hypothesis. I thought this was brave of him. I consider him a friend and an ally.

Of course, this is the Readers Digest version and, by necessity, misses out a great deal of the detail. However, I would be grateful if readers of this blog, go have a look on Jerome’s site and see what you think. Leave comments if you feel the urge.

I told him that I could not really comment on it, because I know this whole are so well that I cannot look at it the way a naïve reader could. Or, to put it another way, does it make any sense to an interested and intelligent reader coming across these ideas for the first time.

The blog can be found here: http://healthinsightuk.org/2019/10/08/cholesterol-is-innocent-how-the-real-killers-were-tracked-down/

*Ivor Cummings/Fat emperor podcast:

Or you can view it on Ivor’s site here

5th October 2019

How does lead cause CVD?

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

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

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

246 factorial

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

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

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

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

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

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

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

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

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

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

980360372638941007038951797078339359751464353463061342202811188548638347461066010066193275864531994024640834549254693776854464608509281547718518965382728677985343589672835884994580815417004715718468026937051493675623385569404900262441027874255428340399091926993707625233667755768320823071062785275404107485450075779940944580451919726756974354635829128751944137276448671023801110260206915547825809239994946405007360000000000000000000000000000000000000000000000000000000000

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

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

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

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

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

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

Then I may quote Poincaré at them.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

I think they all have great, evocative names:

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

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

Three stones to make a wall

Lead, sickle cell disease, vasculitis.

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

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

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

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

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

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

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

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

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

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

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

The answer is that you cannot.

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

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

23 September 2019

Lead again

I am returning to lead, the heavy metal. Not the verb to lead, or a noun – such as a dog lead. Yes, English is complicated, with the same word meaning several different things, which can lead to confusion.

I am indebted to Leon Vd Berg for bringing my attention to another paper about lead that I had missed. Which is slightly surprising as I tend to look for such papers. However, such is the daily avalanche of medical publications that it is literally, impossible to keep up.

There are several things about the paper that I found fascinating. However, the first thing that I noticed was that…. it hadn’t been noticed. It slipped by in a virtual media blackout. It was published in 2018, and I heard nothing.

This is in direct contrast to almost anything published about diet. We are literally bombarded with stories about red meat causing cancer and sausages causing cancer and heart disease, and veganism being protective against heart disease and cancer, and on and on. Dietary articles often end up on the front page on national newspapers.

Here is one such headline from the Daily Mail 7^th August 2019

‘Eating chicken instead of steak, lamb or sausages ‘slashes a woman’s risk of developing breast cancer by 28%’

Mind you, here is another headline from the Daily Mail 8^th Sept 2019

‘Chicken ’causes cancer’: Oxford University scientists say people who eat poultry are at increased risk of developing deadly disease.’

Tricky thing eating chicken. It can cause and prevent cancer simultaneously. You read it here first.

However, the point I wish to make is not so much the utter nonsense and constant contradictions of dietary studies. Nor is it the fact that the increased, and decreased risk in such studies, is minute. Sitting well within the boundaries of reasonable chance. Which is why you keep getting contradictory studies.

Researcher one:      ‘I just threw a head – all throws of a coin must be heads.’

Researcher two:       ‘No, sorry, I just threw two tails – most throws of a coin end up tails

Researcher one:      ‘Hold on, forget your tails, I just go four more heads – in a row – most throws end up heads, not tails.’

The correct term for this is idiot research, and those who do it are – primarily – idiots. However, none of this nonsense is really important. The point I am trying to make here is that this type of dietary research hogs the limelight.

It seems that whatever else Ancel Keys did not achieve – scientific truth and accuracy, for starters – he most certainly did manage to convince almost everyone in the World that diet is the single most critical important factor for health.

In years gone by, people ate food because they enjoyed eating it. This still happens in France. Imagine that. Nowadays every meal comes with implied fearmongering, and high-level criticism. Are you destroying the world or not – you evil scum.

‘Hold on, it’s only a bacon sandwich. With a fried egg and a bit of cheese grated on top…. Yes, I suppose you’re right, I am personally responsible for the destruction of the Amazonian rain forest. Forgive me father, for I have sinned.’

Destruction of the planet is only one aspect of eating, it’s also destruction of your health – with added moral judgement. If you go to Slimming World, you can eat various tasteless stuff, but you are allowed ‘sins.’ A sin would be something you really like eating, but it is so deadly, that it is a sin to eat it. Chocolate, for example. Get thee behind me Satan.

I don’t understand how anyone manages to eat anything nowadays. I have almost given up eating salads because someone will always remark ‘Oooooh, that’s healthy.’

My reply used to be. ‘I am not eating it because it is healthy, I am eating it, because I enjoy it.’ Nowadays I just grunt in a vaguely non-threatening way. I do not say. ‘No, a healthy meal would be a full English breakfast with bacon, eggs, sausages, fried bread. a few more sausages and a bit of lard melted on top.’

I do not say this because, in truth, almost all diets are perfectly healthy. Vegetarian, paleo, keto, vegan (with a few essentially nutrients thrown in, so you don’t die), HFLC, etc. In fact, the only non-healthy diet would be the one recommended by all the experts around the world.

Namely, High carb, low fat (HCLF). The ‘eat well plate’, ‘the food pyramid’ – whatever it is now called. Stay away from that, and you will be fine.

Rule one of diet.       Everything the ‘experts’ recommend, is wrong.

Rule two:                   Eat food you enjoy – and enjoy eating

Rule three:                Eat food that looks like food

Rule four:                   Cook your own meals – when possible

Rule five:                   Try fasting from time to time

Rule six:                     That’s it

Where was I? Oh yes, lead. The heavy metal. The thing that, unlike diet, makes no headlines whatsoever, the thing that everyone ignores. Here is one top-line fact from that study on lead, that I missed:

‘Our findings suggest that, of 2·3 million deaths every year in the USA, about 400 000 are attributable to lead exposure, an estimate that is about ten times larger than the current one.’ ¹

Yes, according to this study, one in six deaths is due to lead exposure. I shall repeat that. One in six. Eighteen per cent to be exact, which is nearer a fifth really.

Of course, this study is observational, with all the usual caveats associated with such studies. Indeed, many people commenting on this blog have stated that correlation [found in such studies] does not mean causation. I think you will find that this does not include me – although I may have said it by mistake. It is true that correlation does not mean causation, up to a point. However, once that point has been reached, causation can be considered proven.

For example, in observational studies, smokers were found to have fifteen times the risk of lung cancer. That is a powerful enough correlation to prove causation – beyond any reasonable doubt. There is no point in setting up a controlled clinical trial to prove this. In fact, any such trial would be completely unethical.

The question is, at what level of increased risk/correlation can causality be accepted. There is no absolute clear-cut answer to this Life ain’t black and white. However, most epidemiologists will tell you that unless the odds ratio (OR) is above two, you cannot attempt to claim causality. Too much noise, too many possible confounders.

Which means (deep breath, waiting for statisticians to attack this mercilessly) you need to find that a ‘factor’ is associated with at least a doubling of risk, before you do not simply crumple up the published paper and throw it in the bin.

Most dietary studies get absolutely nowhere near two. We have risks such as one point one (1.10), or one point three. One point three (1.3) is a thirty per-cent increase in risk. Here for instance is a review of red meat and colo-rectal cancer

‘As a summary, it seems that red and processed meats significantly but moderately increase CRC risk by 20-30% according to these meta-analyses.’  ²

Figures like this, from an observational study, mean only one thing. Crumple, throw, bin. Remember also, they are only looking at one form of disease colo-rectal cancer (CRC).  The impact on overall mortality (the risk of dying of anything) would be minuscule, if it could even be found to exist at all. Of course, overall mortality is not mentioned in that CRC paper. Negative findings never are.

So, on one side, we have papers (that make headlines around the world) shouting about the risk of red meat and cancer. Yet the association is observational, tiny, and would almost certainly disappear in a randomised controlled trial, and thus mean nothing.

On the other we have a substance that could be responsible for one sixth of all deaths, the vast majority of those CVD deaths. The odds ratio, highest vs lowest lead exposure, by the way, depending on age and other factors, was a maximum of 5.30 [unadjusted].

Another study in the US found the following

‘Cumulative lead exposure, as reflected by bone lead, and cardiovascular events have been studied in the Veterans’ Normative Aging Study, a longitudinal study among community-based male veterans in the greater Boston area enrolled in 1963. Patients had a single measurement of tibial and patellar bone lead between 1991 and 1999. The HR for ischemic heart disease mortality comparing patellar lead >35 to <22 μg/g was 8.37 (95% CI: 1.29 to 54.4).’ ³

HR = Hazard Ratio, which is similar, if not the same to OR = Odds Ratio. A Hazard Ratio of 8.37, means (essentially) a 737% increase in risk (Relative Risk).

Anyway, I shall repeat that finding a bit more loudly. A higher level of lead in the body leads to a seven hundred and thirty-seven per cent increase in death from heart disease. This is, in my opinion, correlation proving causation.

Looking at this from another angle, it is true that smoking causes a much greater risk of lung cancer (and a lesser but significant increase in CVD), but not everyone smokes. Therefore, the overall damage to health from smoking is far less than the damage caused by lead toxicity.

Yet no-one seems remotely interested. Which is, in itself, very interesting.

It is true that most Governments have made efforts to reduce lead exposure. Levels of lead in the children dropped five-fold between the mid-sixties and the late nineties. ⁴ Indeed, once the oil industry stopped blowing six hundred thousand tons of lead into the atmosphere from vehicle exhausts things further improved. Lead has also been removed from water pipes, paint, and suchlike.

However, it takes a long old time from lead to be removed from the human body. It usually lingers for a lifetime. Equally, trying to get rid of lead is not easy, that’s for sure. Having said this, chelation therapy has been tried, and does seem to work.

‘On November 4, 2012, the TACT (Trial to Assess Chelation Therapy) investigators reported publicly the first large, randomized, placebo-controlled trial evidence that edetate disodium (disodium ethylenediaminetetraacetic acid) chelation therapy significantly reduced cardiac events in stable post–myocardial infarction (MI) patients. These results were so unexpected that many in the cardiology community greeted the report initially with either skepticism (it is probably wrong) or outright disbelief (it is definitely wrong).’ ³

Cardiologists, it seems from the above quotes, know almost nothing about the subject in which they claim to be experts. Just try mentioning glycocalyx to them… ‘the what?’

Apart from a few brave souls battling to remove lead from the body, widely derided and dismissed by the mainstream world of cardiology, nothing else is done. Nothing at all. We spend trillions on cholesterol lowering, and trillions on blood pressure lowering, and more trillions on diet. On the other hand, we do nothing active to try and change a risk factor that kicks all the others – in terms of numbers killed – into touch.

Funny old world. Is it not?

Next time, back to diet, because everyone knows how important diet is…. Only joking.

1: https://www.thelancet.com/journals/lanpub/article/PIIS2468-2667(18)30025-2/fulltext

2: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4698595/

3: https://www.sciencedirect.com/science/article/pii/S0735109716015989

4: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1240871/pdf/ehp0110-000563.pdf

19th January 2019

I suppose it is gratifying to see things I write very strongly supported a few days later. After telling everyone that a high cholesterol level is not a risk for stroke, out comes a study almost straight away, demonstrating that a low cholesterol level increases mortality in patients who have already had a stroke.

This was in a population – and I would highlight this fact – in a population who have high grade carotid artery stenosis. Which mean a high degree of atherosclerosis on the carotid arteries (supplying blood to the brain). The paper is called:

‘Lower cholesterol tied to increased mortality in ischaemic stroke patients with carotid artery stenosis.’

Takeaway

In patients with acute, first-ever ischaemic stroke with high-grade internal carotid artery (ICA) stenosis and post-stroke functional dependence, lower total cholesterol level was associated with increased risk for 5-year mortality.

Why this matters:

Recent treatment guidelines of hyperlipidaemia suggest more aggressive treatment for reducing risk for atherosclerotic cardiovascular diseases and ischaemic stroke.

However, these findings suggest a careful consideration of aggressive treatment of hyperlipidaemia in patients with acute, first-ever ischaemic stroke with high-grade ICA stenosis and post-stroke functional dependence.

Study design:

Study prospectively evaluated 196 patients with acute ischaemic stroke with high-grade ICA stenosis and modified Rankin Scale score ≥3.

Patients were divided into 2 groups based on total cholesterol level at admission: ≥200 or <200 mg/dL.

Patients were followed-up for 5 years after initial assessment.

Key results:

After adjusting for established clinical predictors of adverse outcomes, lower total cholesterol level (aHR, 1.88; 95% CI, 1.09-3.23; P=.023) was a significant risk factor for 5-year all-cause mortality.

The prevalence of diabetes mellitus (P=.013) was significantly higher and that of atrial fibrillation (P=.011) was significantly lower in patients with high vs low total cholesterol level.

Patients with lower cholesterol level had significantly lower value of haemoglobin (P=.001), whereas glycohaemoglobin was significantly higher in patients with higher total cholesterol level (P=.001).

Funding: None.

Four most annoying words in the English language. ‘I told you so.’

Of course, this study will be dismissed out of hand. “We should still be prescribing statins to people who have had ischaemic strokes” we will be told. “Studies like this are purely observational” we will be told. “A high cholesterol level still needs to be lowered” we will be told. Nothing to see here, please move along!

I do become increasingly weary of finding evidence that directly and absolutely contradicts the cholesterol hypothesis. It never makes the slightest difference – to anything. Hopefully a few people are out there listening, whose minds are not made of reinforced concrete.

1: https://www.univadis.co.uk/viewarticle/lower-cholesterol-tied-to-increased-mortality-in-ischaemic-stroke-patients-with-carotid-artery-stenosis-651463

Lung YJ, Weng WC, Wu CL, Huang WY. Association Between Total Cholesterol and 5 year Mortality in Patients with Carotid Artery Stenosis and Poststroke Functional D ependence. J Stroke Cerebrovasc Dis. 2019 Jan 11 [Epub ahead of print]. doi: 10.1016/j.jstrokecerebrovasdis.2018.12.030. PMID: 30642665

15th January 2019

In this never-ending story on heart disease, I have tended to use the terms “heart disease” and “cardiovascular disease” almost interchangeably. Well, everyone else does it, so why not me? However, in this blog I shall be splitting cardiovascular disease into its two main components, heart attacks and strokes, and concentrating mainly on strokes.

The first thing to say is that there are three main causes of strokes.

• Atrial Fibrillation (ischaemic)
• A burst blood vessel in the brain (haemorrhagic)
• A blood clot (ischaemic)

[There are also cryptogenic strokes (no known cause), strokes due to a hole in the heart, strokes due to antiphospholipid syndrome, strokes due to sickle cell disease etc. etc.)

Atrial Fibrillation (AF) is a condition where the upper chambers of the heart (atria) do not contract and relax smoothly every second or so. Primarily because there is a disruption in the electrical conduction system, causing the atria to spasm and twitch in a highly irregular fashion.

When this happens, blood clots can form in the left atrium then break off and head up into the brain and get stuck. Causing a stroke. They can also travel elsewhere in the body causing a blockage to an artery in the kidneys, the leg, the arm and suchlike. If they form in the right atrium, they will end up stuck in the lungs.

These clots are usually quite small, about the size of a large grain of rice, but this is still big enough to do quite considerable damage. The treatment for AF is either to try and reverse the fibrillation or, if this does not work, to give anticoagulants such as warfarin to stop the clots forming.

A haemorrhagic stroke is when a blood vessel in the brain bursts. Blood is then forced into the brain and causes a lot of damage – leading to a stroke. Haemorrhagic strokes are usually quite severe, as you can imagine. The treatment is to NOT give an anti-coagulant of any sort. Haemorrhagic strokes are often/usually caused by a thinning of the artery wall, causing a ballooned area (aneurysm), which then bursts.

An interesting question, and I have seen different views on this is whether a small blood clot travels to the brain where it gets stuck, but does not completely block the artery, so it does not cause a stroke, but it creates an area of damage – which is then repaired – that leaves a weakness in the artery that balloons out – an aneurysm.

Anyway, the most common cause of a stroke is that large atherosclerotic plaques form in the main arteries that supply blood to the brain (carotid arteries). These plaques usually form around the base of the neck. A blood clot then forms on top of the plaque, then breaks off and travels to the brain, where it gets stuck – as with atrial fibrillation – causing a stroke. The effect is the same as with AF, but the underlying causing is completely different.

According to the American Stroke Association 87% of strokes are ischaemic.

Which means that the vast majority of strokes are caused by atherosclerotic plaques in the neck. Just as the vast majority of heart attacks are caused by atherosclerotic plaques in the coronary arteries. Therefore, you would expect that the risk factors for stroke would be exactly the same as the risk factors for heart attacks, as the underlying process is the same.

Well, many of the standard risk factors are the same. Smoking, diabetes, high blood pressure and suchlike. However, a raised LDL most certainly is not. There is a research study called the Simon Broome registry, started in the UK, that tracks the health outcomes of people diagnosed with familial hypercholesterolaemia (FH).

It is a fascinating resource which, if you decide to interpret their data through a different prism, virtually rules out the raised LDL in familial hypercholesterolaemia as a cause of CVD. One of the earlier papers in the BMJ, on the findings of the Simon Broome registry, found that:

‘Familial hypercholesterolaemia is associated with a substantial excess mortality from coronary heart disease in young adults but may not be associated with a substantial excess mortality in older patients.’¹

For ‘may not be’, replace, ‘is not’. In fact, what the Simon Broome registry has found repeatedly is that, after the age of, about fifty, FH does not increase the risk of coronary heart. Thus LDL is a risk factor before the age of fifty, and not after? Which means that it cannot be a risk factor at all [the thing that kills young people with FH before the age of fifty is clotting factor abnormalities – not raised LDL]

Which is something covered in the magnificent and insightful paper: ‘Inborn coagulation factors are more important cardiovascular risk factors than high LDL-cholesterol in familial hypercholesterolemia.’² Yes, as you may have guessed, I was a co-author.

However, if we move away from heart disease, to strokes. FH has never been found to be a risk factor for stroke – at any age. Here, for example is a study done in Norway, and published in the Journal Stroke. It was called ‘Risk of ischaemic stroke and total cerebrovascular disease in familial hypercholesterolaemia.’

A total of 46 cases (19 women and 27 men) of cerebrovascular disease were observed in the cohort of people with FH, with no increased risk of cerebrovascular disease compared with the general population (standardized incidence ratio, 1.0; 95% CI, 0.8–1.4). Total number of ischemic strokes in the cohort of people with FH was 26 (9 women and 17 men), with no increased risk compared with the general population (standardized incidence ratio, 1.0; 95% CI, 0.7–1.5).³

In 2010 the Lancet published a major study looking at risk factor for stroke in the non-FH population³. They used the term population attributable risk factors (PAF), which ‘weights’ the factors, depending on how prevalent they are (i.e., how many people have got the various risk factors). Their list of PARs for stroke was as follows:

• 51.8% – Hypertension (self-reported history of hypertension or blood pressure >160/90mmHg)
• 18.9% – Smoking status
• 26.5% – Waist-to-hip ratio
• 18.8% – Diet risk score
• 28.5% – Regular physical activity
• 5% – Diabetes mellitus
• 3.8% – Alcohol intake
• 4.6% – Psychosocial stress
• 5.2% – Depression
• 6.7% – Cardiac causes (atrial fibrillation, previous MI, rheumatic valve disease, prosthetic heart valve)
• 24.9% – Ratio of ApoB to ApoA (reflecting cholesterol levels)

You will see that LDL is not in that list. The ratio of ApoB to ApoA is. However, this is primarily the ratio of VLDL (triglycerides) to HDL (‘good’ cholesterol), which is an accurate reflection of ‘insulin resistance’ and bears no relationship to LDL. As I always say to people who ask me for advice on reviewing clinical research…’the most important thing to focus on is not what is there, it is what is not there.’

Any study on CVD will be examining LDL levels very closely. If a relationship were found it would be shouted from the rooftops. The fact that you hear nothing about LDL in this paper means that there was no correlation – at all.

You can, if you wish, try to find some evidence that the risk of stroke is increased by a raised LDL level. I must warn you that you will look for a long time, because there is no evidence, anywhere – at all. It has interested me for many years that this issue is simply swept under the carpet.

Now, write out one hundred times:

• Raised LDL is not a risk factor for stroke
• Raised LDL is not a risk factor for stroke
• Raised LDL is not a risk factor for stroke….

Then, ask yourself the question. How can a raised LDL be a risk factor for heart disease and not stroke – as the two conditions are, essentially, the same condition? Atherosclerotic plaques in medium sized arteries with the critical/final event being the formation of a blood clot – on top of the plaque.

Then, ask yourself another question. If a raised LDL is not a risk factor for stroke, how can lowering the LDL level provide any benefit? The correct answer is that… it cannot. Yet statins do provide benefit in stroke (Usual proviso here. Not by a great amount in absolute terms, but the benefit does appear to exist).

‘A meta-analysis of randomized trials of statins in combination with other preventive strategies, involving 165,792 individuals, showed that each 1-mmol/l (39 mg/dl) decrease in LDL-cholesterol equates to a reduction in relative risk for stroke of 21.1 (95% CI: 6.3-33.5; p = 0.009)’ ⁴

Just to repeat the main point here. A raised LDL is not, and has never been, a risk factor for stroke. Yet it is claimed that lowering the LDL level reduces the risk of stroke? In reality, the evidence from the statin trials prove, beyond any doubt, that any benefit achieved by statins cannot be through lowering the LDL level.

The logic stripped down is, as follows:

• A raised level of factor A does not cause disease B
• Thus lowering factor A cannot reduce the risk of disease B
• Thus, you cannot claim that lowering factor A can have any possible effect on disease B

However, every single cardiovascular expert seems delighted to inform us, in all seriousness, that lowering factor A does, indeed, reduce the risk of disease B. Despite this breaking the very fabric of logic in two.

“Alice laughed: “There’s no use trying,” she said; “one can’t believe impossible things.”

“I daresay you haven’t had much practice,” said the Queen. “When I was younger, I always did it for half an hour a day. Why, sometimes I’ve believed as many as six impossible things before breakfast.” Alice in Wonderland.

1: https://www.bmj.com/content/303/6807/893

2: https://www.ncbi.nlm.nih.gov/pubmed/30396495

3: https://www.ahajournals.org/doi/10.1161/STROKEAHA.118.023456

4: https://www.ncbi.nlm.nih.gov/pubmed/19814666