11th October 2018

Blood pressure

I have tended to avoid talking about blood pressure, because I am not entirely sure what I think about it as a cause of CVD. However, since more people now take blood pressure lowering medication than any other type of medication in the world, including statins, it wold be remiss of me not to at least mention it.

Another problem is that, whilst blood pressure may seem a very simple subject. Either it is high, or it is not, nothing could be further from the truth. It is immensely complicated, and fragments rapidly into thousands of different strands, looping and whirling in front of you.

For example, let us take an apparently simple question, what is a high blood pressure? Well, with almost every passing year, this changes. The experts and the guideline writers get together on a regular basis and decide that well, hey ho, we thought 140/90 was high, turns out we are wrong. It is 130/85 – or whatever. By the way, the definition of a ‘normal’ blood pressure always goes down – never up. On current trends we should hit 0/0mmHg by the year 2067. What happens after that is hard to say.

I suppose a question that may seem reasonable to ask is the following; is average normal. Not, not even slightly. In a similar fashion to blood cholesterol levels, average and normal do not even remotely match up. Last time I looked eighty-five per cent of the population in almost all Western countries had high cholesterol levels. I would suspect another eighty-five per cent have high blood pressure.

In fact, if you wish to stretch logic to its very boundaries it is possible to propose that 99.9% of the population has a high blood pressure level. How can this make any sort of sense, you may ask? Well, in a moment of ennui I opened the American College of Cardiology/American Heart Association (ACC/AHA) risk calculator. You can find it here. http://www.cvriskcalculator.com/

I put in all my risk factors, kept them all the same, apart from my blood pressure which I started moving up and down, as you do when there is nothing good on the TV. What I found was that, as I reduced my blood pressure on the calculator, my CV risk went down, and down, until I got to a systolic (upper figure) of 90mmHg. You cannot make your blood pressure go any lower than this on the calculator.

The reason why you cannot get your blood pressure below 90mmHg is that if you go below this figure, you will be diagnosed with hypotension. Hypo = low. So, we have the weird situation whereby at 90mmHg your blood pressure is perfect. Above this, your risk of CVD goes up, below this the pressure is dangerously low and should be raised.

Therefore, at exactly 90mmHg your blood pressure is ‘normal’. At any other pressure it is abnormal – in that it increases the risk of death. Which is the definition of any ‘abnormal’ clinical test. It must be said that this constitutes a pretty narrow range. A doctor should be trying to keep your systolic blood pressure between 90mmHg and 90mmHg. And good luck with that. A very delicate titration indeed.

Clearly this is nuts, and it is not based on any clinical data whatsoever. There has never been a study whereby the systolic blood pressure has been lowered to 90mmHg. Nor will there ever be one done. This, I can guarantee. The mortality rate would be catastrophic.

So, how is this figure arrived at?

It comes from a mathematical smoothing technique whereby you get all the points on a graph, then draw the ‘best fit’ line through them all. I include an example here, which is where someone (Zoe Harcombe actually) looked at the cholesterol levels and rate of death from CVD in every country in the world (these are the dots). As you can see everything is rather scattered. [Data taken from the World Health Organisation].

However, there is a trend here, and that trend can be worked out. In this case, you feed in all the data points and a formula works out the underlying association between cholesterol and CVD death. As you can see in this case, as cholesterol goes up – CVD deaths go down. If you half close your eyes (which gets rid of the outlying points) the association between the dots and the line seems clearer.

(Or maybe that is just me).

What does this prove? Well, it proves nothing very much, for certain. What it almost certainly disproves, however, is an association between raised cholesterol and CVD.

When it comes to blood pressure it cannot be denied that. as the blood pressure rises, the risk of CVD also rises. However, the association is non-linear. By this I mean that, if your blood pressure goes from 100mgHg to 110mmHg, the risk of CVD does rise (but not by a statistically significant amount]. It only rises very, very slightly.

From 110mmHg to 120mmHg another very slight rise

From 120mmHg to 130mmHg another very slight rise

It is only when you get to about 160mmHg that the risk suddenly starts to go up sharply. From then on, things become rapidly worse. So, if your systolic blood pressure is above 160mmHg you should probably do something about it. However, what is the risk for a systolic blood pressure below this? Here we must rely on mathematics.

A paper that I have mentioned a few times, because I think it is a belter is from the European Heart Journal – from the year 2000 (believe me nothing of significance has happened since then). It is entitled ‘There is non-linear relationship between mortality and blood pressure.’

It is worth quoting the first two paragraphs in full. Sorry, for those not of a scientific bent:

‘Stamler stated that the relationship of systolic blood pressure (SBP) to risk of death is continuous, graded, and strong, and there is no evidence of a threshold…’ The formulation of this ‘lower is better’ principle, in terms of the linear logistic model (often referred to simply as the linear model) is the paradigm for the relationship of all cardiovascular risks to blood pressure and form the foundation for the guidelines for hypertension [and still does].

But it is often forgotten that when a study reports a linear (or any other) relationship between two variables it is not the data itself, but the model used to interpret the data, that is yielding the relationship. Almost universally, studies that report a linear relationship of risk to blood pressure do so via the linear models, such as the Cox model, or the linear logistic model.

Formally that model can be applied to any bivariate data and, independently of the data will always show that there is a linear relationship between the two variables. Before one can have confidence that the stated linearity correctly reflects the behaviour of the data, and is not just an artefact of the model, it is necessary to carefully examine the data in relation to the proposed model. At a minimum, it must be demonstrated that the model actually ‘fits’ the data and that it does not ‘smooth away’ important features of the data.’ ¹

To paraphrase, your carefully constructed mathematical model may well be bollocks. In fact, it most probably is.

The statisticians who wrote this paper went back to the Framingham study – from whence all guidelines on blood pressure have since flowed, in all countries, everywhere – and found that the data ‘statistically rejected the model.’ They made the following statement ‘the paradigm MUST be false.’

I hate to say it, but the first person to recognise that the linear model ‘in terms of the relationship of overall and coronary heart disease death to blood pressure was unjustified.,’ was Ancel Keys. I am not sure what to make of that, as Keys is my number one medical historical villain. Still, he wasn’t stupid.

Anyway, the response to the European Heart Journal paper was…. Complete silence. Nothing. No counter arguments were proposed, nothing. “First they ignore you, then they laugh at you, then they fight you, then you win.” Gandhi. In this case we never got beyond ‘first they ignore you.’ Oh well, such is life.

None of this means that blood pressure has no role to play in CVD – or vice-versa – I just wanted to make it clear that that the whole area has become such a mess that it is very difficult to see through the forest of bias. What is a fact here? Frankly, sometimes, I have no real idea.

So, where does this leave us regarding blood pressure and CVD? It leaves us with only a few certainties. First, and most important, the only blood vessels in the body that normally develop atherosclerosis are the larger arteries. These blood vessels have a high blood pressure in them. Let us say around 120/70mmHg.

[120mmHg is equivalent to a column of water about three metres high. The units used to measure blood pressure are mmHg i.e., millimetres of mercury. Mercury was used to measure blood pressure, because it is many times denser than water. To measure blood pressure using a water sphygmomanometer would need a device more than three metres tall.]

On the other hand, the larger arteries in the lungs (pulmonary arteries) have an average blood pressure of around 20/6mmHg. In normal circumstances they never develop atherosclerosis. The veins have a blood pressure of about 6mmHg. It does not go up and down, because the pressure in the veins is unaffected by the pumping of the heart. The veins never develop atherosclerosis.

This makes it clear that the blood pressure, and turbulent blood flow, needs to reach a certain level before atherosclerosis can start. I sometimes liken this to a river flowing down a mountainside, with rushing and roaring and white water foaming and raging. That would be an artery. When the river reaches the plain below, the speed of water flow drops, the river widens and meanders. That would be a vein.

I think it is pretty clear that the lining of an artery is put under far more biomechanical stress than the lining of a vein – or a pulmonary artery. Which is why atherosclerotic plaques develop in [systemic] arteries, and nowhere else.

This idea is further supported by the fact that it is perfectly possible to get atherosclerotic plaques to develop pulmonary arteries, and veins. But only if you significantly raise the blood pressure. There is a condition known as pulmonary arterial hypertension (high blood pressure in lungs). There are many causes of this, and I am not going through them all here.

Let’s just say that people who suffer from pulmonary hypertension can, and do, develop atherosclerosis in the lungs. It should be pointed out that the pressure still gets nowhere near that in the rest of the body, perhaps 50/20mmHg, or suchlike. However, the blood vessels in the lungs were never designed to cope with high(er) blood pressure, and so damage will occur at a lower level.

When it comes to veins, if you take a vein from the leg, and use it as a coronary artery bypass graft (CABG), it will very rapidly develop atherosclerosis. Both of which prove that there is nothing inherently different about arteries and veins that normally protects veins and pulmonary arteries. It is all due to pressure.

Low pressure – no atherosclerosis

High pressure – atherosclerosis

So, surely the lower you get the blood pressure the better? Maybe, maybe not. There are many, many, other issues to be taken into account here – some of which I will discuss in the next blog.

1: Port S, et al: ‘There is a non-linear relationship between mortality and blood pressure.’ Eur Heart J, Vol 21, issue 20 October 2000

23rd September 2018

As you may know I am a member of an organisation known as The International Network of Cholesterol Sceptics (THINCS). When I say this, people always laugh. I suppose it is better than people shouting and screaming and slapping you repeatedly. The man who set it up was Uffe Ravnskov – our glorious leader.

He has done far better than me. His first book The Cholesterol Myths, was burnt, live on air, in a television studio in Finland. I am very jealous. Having your critics become so enraged, that the only thing they can think to do is burn your book, is a very great ‘sceptic’ honour. Although one must be slightly fearful that the mob doesn’t stop at burning your books.

Uffe has written many books and papers in this area, and from time to time I have been honoured to help him. Most recently we have battered away, trying to get a paper published on blood clotting factors in Familial Hypercholesterolaemia. Many rejections, and many years later. Hoorah.

The paper is called ‘Inborn coagulation factors are more important cardiovascular risk factors than high LDL-cholesterol in familial hypercholesterolemia.’ And you can see it here https://www.sciencedirect.com/science/article/pii/S0306987718304729.

We can provide fifty days free access to this paper, before the pay wall comes down. To make it free access forever would cost us thousands, and since none of us gets paid a bean for any of this work, this would be far too costly for a bunch of (in this area) independent researchers.

You need to be a major university, or a pharmaceutical company to make your papers free access. Although such are the costs that even these organisations are baulking. As Richard Smith– who edited the BMJ for many years –  said ‘The function of medical journals used to be to make research freely available to all. It is now to keep it hidden.’ Or words to that effect.

Anyway, a quick summary of this paper would be that it is not the raised LDL that causes an increased risk of CVD in familial hypercholesterolaemia (FH) – such as the risk may be, in some individuals. It is the fact that FH is also genetically linked to inborn areas of blood clotting abnormalities.

Which means that some of those with FH also have raised factor VIII and fibrinogen levels (there are also issues with the LDL receptor itself, which plays an important role in blood clotting – not covered in this paper). Our contention is that it is these factors that are important, not the LDL level. The data, as we analysed it, supports this contention.

Here is the abstract:

‘High low-density-lipoprotein cholesterol (LDL-C) is routinely described as the main cause of cardiovascular disease (CVD) in familial hypercholesterolemia (FH). However, numerous observations are in conflict with Bradford Hill’s criteria for causality: a) degree of atherosclerosis is not associated with LDL-C; b) on average the life span of people with FH is about the same as for other people; c) LDL-C of people with FH without CVD is almost as high as in FH patients of the same age with CVD; and d) questionable benefit or none at all have been achieved in the controlled, randomized cholesterol-lowering trials that have included FH individuals only. Obviously, those individuals with FH who suffer from CVD may have inherited other and more important risk factors of CVD than high LDL-C. In accordance, several studies of FH individuals have shown that various coagulation factors may cause CVD. Equally, some non-FH members of an FH kindred with early CVD, have been found to suffer from early CVD as well. The cholesterol-lowering trials have only been successful by using apheresis, a technique that also removes many coagulation factors, or in an animal experiment by using probucol, which has anticoagulant effects as well. We conclude that systematic studies of all kinds of risk factors among FH individuals are urgently required, because today millions of people with FH are treated with statins, the benefit of which in FH is unproven, and which have many serious side effects. We predict that treatment of FH individuals with elevated coagulation factors with anticoagulative drugs is more effective than statin treatment alone.’

Of course, this paper also supports my hypothesis that increased tendency to blood clotting (hypercoagulability) is one of the key processes in both accelerated atherosclerotic plaque formation, and the development of the final, fatal, blood clot.

17th September 2018

I have headed off into different areas from time to time, but to be frank I never thought I would start looking more closely at albumin. This is a substance that almost always ends up getting measured when you do a general blood screening test for patients – for some reason or other.

Albumin is a protein that floats about in the blood. It is made in the liver and, I suppose, it has some important functions in the body. Although I have never really quite known what. At medical school, silence. In medical journal, silence. It seems to be a ubiquitous substance, like nitrogen in the air. We all know it’s there, but we don’t know how it got there, or what it does.

About the only thing I know about albumin is that as the level drops, fluid leaks out of the blood into the abdominal cavity, due to a fall in osmotic pressure. This causes the stomach to swell up like a balloon and is known as ascites.

Small starving children in Africa have ‘pot bellies’ because they cannot make enough albumin. The syndrome is known as kwashiorkor a.k.a. oedematous malnutrition. Alcoholics often have ascites because their livers start to fail, and they cannot make enough albumin either, so fluid – sometimes many tens of litres – fills their abdominal cavity. I have happily drained bucket’s full from stomachs in my time. Just stick in a wide-bore needle and stand back. The pressure can be quite high.

Other than that, I knew nothing about albumin, apart from the fact that, whenever I request a blood test in the elderly, the albumin is almost always a bit low. I have no idea what to make of such a result, or what to do about it. ‘Tick and file – and forget’ represents my normal action.

However, after writing an article about the glycocalyx, and how important it was for arterial health, I wondered if having a low protein/albumin level in the blood might be a bad thing. In that the protein part of the glycocalyx might need to be replenished from somewhere. Perhaps by albumin? Therefore, a low albumin level might be a bad thing – from a cardiovascular disease perspective.

Following such thoughts, I found myself reading papers such as this one: ‘Degradation of the endothelial glycocalyx in clinical settings: searching for the sheddases.’ I definitely need to get out more. In fact, this paper was fascinating. It discusses the role of the glycocalyx, and things that can damage it. [jargon warning].

‘The endothelial glycocalyx has a profound influence at the vascular wall on the transmission of shear stress, on the maintenance of a selective permeability barrier and a low hydraulic conductivity, and on attenuating firm adhesion of blood leukocytes and platelets. Major constituents of the glycocalyx, including syndecans, heparan sulphates and hyaluronan, are shed from the endothelial surface under various acute and chronic clinical conditions, the best characterized being ischaemia and hypoxia, sepsis and inflammation, atherosclerosis, diabetes, renal disease and haemorrhagic viral infections.’¹

Which is pretty much what we already know. Many factors that increase the risk of CVD, damage the glycocalyx, and in atherosclerosis there is clear glycocalyx loss/dysfunction. The bit about haemorrhagic viral infections is fascinating and could be worth a future blog.

However, the information I was looking for was to find out if albumin really did help to maintain the glycocalyx and noticed this. ‘…plasma components, especially albumin, stabilize the glycocalyx and contribute to the endothelial surface layer.’ Something I would never have thought to pay the slightest attention to before now. Anyway, in short, yes, albumin does help to maintain the glycocalyx.

Next question. Is there any evidence that having a low albumin level contributes to CVD risk? Well, of course, there is. Here, in the paper ‘Critical appraisal of the role of serum albumin in cardiovascular disease.’ ²

When they looked at serum albumin levels and patients with stable coronary artery disease, the risk of a major adverse cardiovascular event was raised 368%, and the risk of overall mortality went up 681% (relative increase in risk). In their words…’This study unequivocally confirms the important association between SA (serum albumin) and individuals with chronic stable CAD’.

So, you may ask, can you do anything about your serum albumin level? I am not sure that you can do very much. A high protein diet may help, in that the more protein you eat, the more amino acids are available to make albumin from, and Kwashiorkor is due to a low protein diet – so this could do no harm.

At this point, however, the main point that I want to make here – again – is that, once you start to understand CVD as a process that is triggered by endothelial damage, you can start to look at the research on CVD in a completely different light. You can make associations where, using the LDL hypothesis, none exist. It also makes sense.

I find that it is also like freeing your mind from a tyranny. I find it refreshing, and exciting, and I hope that you do to. ‘The difficulty lies not so much in developing new ideas as in escaping from old ones.’ John Maynard Keynes.

Next, they just fired Peter Gotzsche from the Cochrane Collaboration. This is a bloody outrage.

1: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4574825/

2: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5681838/

31st August 2018

One of the greatest problems in researching possible causal factors for any disease in humans, is that if you want to do clinical studies, you run straight into a major ethical issue ‘first do no harm’.

For example, if you believe that vaping causes heart disease, it would be extremely difficult to get the go-ahead to find ten thousand people, ask them to start vaping, and see what happens. To confirm your hypothesis, you need a significant number of people to drop dead.

Which is why almost all clinical trials, at least on humans, are designed to study interventions that are supposed to make people better. Of course, ethically this is a good thing, but it does make it extremely difficult to prove causality – for sure. Which is probably why Bradford Hill, in one of his famous nine criteria for causation stated the following ‘Experiment’. Occasionally it is possible to appeal to experimental evidence. (More on Bradford Hill later)

In effect, when we try to study causal ‘risk factors’ for disease, we are normally forced to rely on epidemiological, or observational evidence. We can look at risk factors in populations, but we can’t touch. At least we can’t touch, if we are trying to create the disease we are studying. This is why you get so much conflicting advice on, just to pluck a topic from thin air, diet.

However, there are times when you get a chance to look at a causal agent in action, as with smoking. On other occasions, the window opens by accident. A drug is being used to treat condition X, and you find it triggers disease Y. This recently happened with Proton Pump Inhibitors (PPIs) such as omeprazole.

PPIs were recently found to interfere with NO synthesis¹. As readers of this blog know, NO is vitally important for endothelial cell health, preventing blood clots, and endothelial progenitor cell (EPC) production in the bone marrow. Knowing this, you would expect that PPIs would increase the risk of CVD. At least you would expect that, if you believe that lowering NO is likely to cause CVD.

As some of you know, I wrote a blog on this very issue and, yes, people prescribed PPIs have a significantly increased risk of CVD – almost a doubling of risk. Not that this has had the slightest impact on long-term omeprazole prescribing, anywhere.

Of course, you can argue that the data on PPIs did not come from an interventional clinical study, specifically designed to prove that PPIs cause CVD. You are never going to get one of those. However, in a world of imperfect evidence, this is the next best thing to experimental evidence. A drug that should, theoretically, cause CVD, causes CVD.

Moving beyond PPIS, there is another class of drug which could have a far greater impact on CVD. Before I get to it, I should remind everyone that the hypothesis I am outlining in this blog is that CVD is caused by three interlinked processes:

• Endothelial damage
• Clot formation at the site of damage
• Repair of the clot/damage.

These things are going on, all the time, in everybody. Atherosclerotic plaque growth – and potentially fatal blood clots – occur when damage > repair. Greater damage is caused by such things as: PPIs, or smoking, or air pollution, or raised blood glucose levels, or lead poisoning, or high blood pressure, or vitamin C deficiency, or sickle cell disease – and suchlike. However, you can also tip the balance towards plaque formation in the opposite way, by impairing the repair systems. Ensuring that: repair < damage.

One of the most important repair systems in the body consists of white blood cells, primarily monocytes and macrophages. These latch onto, engulf, and clear up the debris left by any assault of the body, including blood clots.

It is mainly the macrophages that do the heavy lifting. They destroy and digest any ‘alien’ material in the body. They start by firing a super-oxide burst at any junk in the body, which could be bacteria, or broken-down cells remnants, or what is left of blood clots. They engulf the ‘oxidised’ material, then they transport themselves to the nearest lymph nodes, where everything in them (and the macrophage itself) is broken down and, eventually excreted by the kidneys. [Or they get stuck, turn into foam cells, and die].

The other critical part of the repair system, following endothelial damage, are the Endothelial Progenitor Cells (EPCs) themselves. I have mentioned them many times in this blog. They are synthesized in the bone marrow. They cover areas of damage in blood vessels, and then mature and re-grow into a new layer of endothelial cells.

However, EPCs have another repair ‘trick’ up their sleeves. Because they are not mature cells, they can travel down other developmental pathways. Which means that they do not necessarily become mature endothelial cells, they can also transform into monocytes which, in turn, can further mature into macrophages.

Bringing all this together, if you find a drug that throws a spanner into EPC production – and thus macrophage development – whilst damaging NO synthesis and interfering with the growth of new endothelium, you will have found a drug that is almost perfectly designed to increase CVD risk.

And, yes, there is a class of drug that does exactly that and they are also, believe it or not, prescribed to humans. They are called vascular endothelial growth factor inhibitors. (VEGF-inhibitors). At one time is was thought that vascular endothelial growth factor (VEGF) was only active in the developing foetus, helping to stimulate EPCs, new endothelium growth, and driving the development of the entire vascular (blood vessel) system.

But it is now clear that VEGF still has a role in adults. It has a critical role in maintaining and helping to repair and re-grow the endothelium. Knowing this, you would expect that a drug specifically designed to inhibit VEGF could do some pretty serious damage to the cardiovascular system.

I have mentioned this class of drugs before, a few times, but I think it is worth highlighting them once more, as they provide almost perfect proof of the ‘three interlinked process’ hypothesis.

The most widely used VEGF-inhibitor is Avastin, the generic name is Bevacizumab. The mab at the end means it is a monoclonal antibody. It is an anti-cancer drug. Avastin works by inhibiting angiogenesis (‘angio’ = blood vessels, ‘genesis’ = new). Many cancers, as they grow, stimulate new blood vessel growth, which provides the tumour with the nutrients it needs. Cut the blood vessel production and the tumour shrivels and dies. This works. Avastin is an effective anti-cancer drug, and it is widely used.

Avastin is also used in macular degeneration where, in many cases, the growth of excess new blood vessels at the back of the eye (under the macula) is the problem, causing inexorably progressive blindness. With macular degeneration, Avastin is injected directly into the eyeball. (Yes, I know…ouch).

Avastin does not, as far as I can establish, seriously damage already existing endothelium – although I would imagine you would find that it does, if you looked hard enough. However, it seriously damages repair systems once the endothelium has been damaged. Therefore, it tips the scales heavily towards repair < damage. This effect has been directly studied in animals.

‘Systemic VEGF inhibition disrupts endothelial homeostasis and accelerates atherogenesis, suggesting that these events contribute to the clinical cardiovascular adverse events of VEGF-inhibiting therapies.²

That animal study was followed four years later, by a detailed review of all the clinical trials on Avastin, and the impact on ‘cardiovascular events.’. Some trials only went on for a few weeks, some were longer, lasting more than two years.

In this paper, the cardiovascular events themselves were listed in the strangest way I have ever come across. For example, we have, ‘arterial adverse events’ including arterial hypertension… is there any other sort?

‘Arterial adverse events’ were then further subdivided into one of the following: myocardial ischemia or infarction, cerebral infarction, cerebrovascular accident, cerebral ischemia, ischemic stroke, and peripheral or visceral arterial thrombotic events. Basically, it boils down to heart attacks and/or strokes – with a couple of other things thrown in.

Because I did not want to edit the results, I have listed them below, exactly as described in the paper. A risk of 2.40 means a two-point four times increase in the risk of something happening. This number could also be expressed as a 140% increase in risk.

The number 12.39 represents a twelve point three nine times increase in risk. Which can also be expressed as a one thousand, one hundred, and thirty-nine per cent (1,139%) increase in risk [These are relative risks].

INCREASE IN CARDIOVASCULAR EVENTS WITH AVASTIN³

Arterial adverse events                                  2.40 (1.64–3.52), P<0.001

Cardiac ischemia (heart attack)                      5.16 (0.91–29.33), P=0.06

Cerebral ischemia (stroke)                              12.39 (1.62–94.49), P=0.02

Venous adverse events                                 1.37 (1.11–1.68), P=0.03

Bleeding                                                          2.96 (2.46–3.56), P<0.001

Arterial hypertension                                      4.81 (3.10–7.46), P=0.001

If you read the paper in more detail you will note that the longer the trials went on for, the greater the increased risk of an arterial adverse event.

At this point I think it is time to introduce you to the full set of Bradford Hills cannons/criteria for causation. Bradford Hill was a famous epidemiologist who worked with Richard Doll to ‘prove’ that smoking causes lung cancer. Within a certain arcane world, Bradford Hill’s cannons for causation are revered. I have listed them out below, having copied this version from Wikipedia.

What you may notice is that nothing in Hill’s list is black and white. He was wise enough to know that absolute proof in something as complex as disease causation, is very tricky. Very tricky indeed. There are often contradictions, and gaps, in the knowledge. However, with Avastin, every single one of his criteria are fulfilled.

Strength (effect size): A small association does not mean that there is not a causal effect, though the larger the association, the more likely it is causal. [Avastin can cause a 1,139% increase in stroke risk in less than two years]

Consistency (reproducibility): Consistent findings observed by different persons in different places with different samples strengthens the likelihood of an effect. [Every study on Avastin has shown the same thing, to a greater or lesser extent]

Specificity: Causation is likely if there is a very specific population at a specific site and disease with no other likely explanation. The more specific an association between a factor and an effect is, the bigger the probability of a causal relationship. [We have a very specific connection here, with no other obvious explanation]

Temporality: The effect has to occur after the cause (and if there is an expected delay between the cause and expected effect, then the effect must occur after that delay). [There is a clear delay with Avastin, the problems only occur after the drug is given]

Biological gradient: Greater exposure should generally lead to greater incidence of the effect. However, in some cases, the mere presence of the factor can trigger the effect. In other cases, an inverse proportion is observed: greater exposure leads to lower incidence. [With Avastin we have a clear biological gradient]

Plausibility: A plausible mechanism between cause and effect is helpful (but Hill noted that knowledge of the mechanism is limited by current knowledge). [The mechanism of endothelial damage is well identified, and plausible, with Avastin]

Coherence: Coherence between epidemiological and laboratory findings increases the likelihood of an effect. However, Hill noted that “… lack of such [laboratory] evidence cannot nullify the epidemiological effect on associations”. [Almost perfect coherence with Avastin]

Experiment: “Occasionally it is possible to appeal to experimental evidence”. [The experiment, albeit inadvertently, has been done]

Analogy: The effect of similar factors may be considered. [Other agents that interfere with NO, e.g. omeprazole, steroids, have the same effect]

Now, whilst I am reluctant to keep harping back to the LDL hypothesis, I think it is worth asking the question. Can the LDL hypothesis explain the increase in CVD with Avastin? Answer, no it cannot. Because Avastin has no impact on LDL.

Of course, as you might expect, Avastin does increase the blood pressure (BP). If you significantly lower NO synthesis, then the blood pressure will inevitably rise. So, the classical risk factors do have something to say about Avastin – if not a great deal.

ACE-Inhibitors, such as enalapril, or perindopril, are used to keep the BP down when people are prescribed Avastin. This works, primarily because ACE-inhibitors raise NO synthesis. [Although, to be frank, I do not know if anyone involved in treating the raised BP caused by Avastin has the faintest idea that is how they work, in this case].

Anyway, if you have a hypothesis that CVD is caused by three interlinked processes:

• Endothelial damage
• Clot formation at the site of damage
• Repair of the clot/damage.

Or, to be more accurate CVD is caused by any factor, or factors, that can

• Increase endothelial damage
• Create bigger and more difficult to shift blood clots
• Interfere with the repair systems.

Then, your attention is bound to turn to drugs that can do one of these three things. PPIs are one, VEGF-inhibitors are another. Whilst few things are absolute in human research, the evidence linking VEGF-inhibitors to a ‘three process’ hypothesis is, I believe, compelling.

It is certainly true to say the VEGF-inhibitors are sufficient, to cause CVD, by themselves. No need for any other risk factor to be present. Does this mean that they are THE cause of CVD? Of course not, but they are A cause of CVD, and their impact cannot be explained by any of the other traditional risk factors for CVD.

What does this mean? It means we have a black swan on our hands. The blackest of black swans. An agent, that is perfectly designed to create endothelial mayhem, causes CVD, with no explanation available within the LDL/cholesterol hypothesis.

Not only that, the data on VEGR-inhibitors fits every single one of Bradford Hills cannons for causation, and that is a rare thing indeed. You might even argue that VEGF-Inhibitors have allowed us a direct and uninterrupted view of the true ‘cause’ of CVD.

1: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4864131 /

2: https://www.sciencedirect.com/science/article/pii/S0167527313004282

3: http://jaha.ahajournals.org/content/6/8/e006278

21st August 2018

One of the most common diseases in the world is type II diabetes, and it seems to be increasing inexorably. I feel I should quickly mention that I have a problem with calling a high blood sugar measurement a ‘disease’ but that is an issue for another time. Anyway, because type II diabetes also greatly increases the risk of CVD (by around 300 – 500% depending on which study you read) then I could hardly continue ignoring it, in a blog primarily focussed on CVD.

At present, the increase in CVD risk in diabetes is not explained by the widely accepted risk factors.

‘Patients with diabetes have increased vascular vulnerability to atherogenic insults, leading to accelerated atherogenesis. Although atherogenesis is in part due to the increased prevalence of traditional cardiovascular risk factors, these factors cannot fully explain the propensity toward vascular complications in diabetic patients.’¹

This, in some ways, is a rather bizarre concept. Type II diabetes is a traditional risk factor for CVD. So why do we need to explain why a risk factor cannot be explained by other risk factors? Which, if you try to chase down the logic, provides a perfect example of the incoherence around the thinking on CVD.

Anyway, what is really meant here is that, whilst other conventional risk factors, such as blood pressure, are raised in diabetes (although not necessarily) most other ‘traditional’ risk factors are unchanged. LDL is certainly not raised, although there is usually a high VLDL/triglyceride level and a low HDL level. However, in my opinion – and the opinion of many others – the high VLDL and low HDL is a result of insulin resistance in the liver. It is not a cause of, anything².

So, what causes the greatly increased risk of CVD in type II diabetes? What is the mechanism, or process going on here? You may be thinking to yourself, a high blood sugar must be damaging. Now that may well be true (although it could well be that a high insulin level is damaging, because you rarely find one without the other). But if a high blood sugar is damaging, how does it do the damage?

At this point I shall introduce you to the glycocalyx – never mentioned before on this blog. Not, I hasten to add, because I had never heard of it, but because it added another complication to the discussion so far. A complication that I felt was not needed. Now it is. Because you cannot explain how diabetes increases CVD risk without looking at the glycocalyx.

If you have ever tried to pick up a fish, you will find that it slips through your fingers. This is due to the slippery slimy layer that lies on top of the scales. This is glycocalyx, or at least the fish version of glycocalyx. It allows fish to swim faster, because the glycocalyx is almost frictionless.

Inside your blood vessels, and lining endothelial cells, we humans have a slippery, slimy layer that, under a powerful microscope looks like a billion tiny hairs. This is our glycocalyx. A slippery forest. It does many, many, different things. Yes, I know, the human body is just mind-bogglingly complicated.

What are these ‘hairs’? They are usually referred to as proteoglycans. Basically, long strands of protein and sugars bound together. You can look them up on Google images, if you wish. Lots of pictures to see.

Perhaps the best paper to read in this area is, the following: ‘Loss of Endothelial Glycocalyx during acute hyperglycemia coincides with endothelial dysfunction and coagulation activation in vivo.’ ³

Main functions of the glycocalyx:

• Protects the underlying endothelium from damage
• Maintains the endothelial barrier function
• Acts as a mechanical sensor for stress/shear stress
• Mediates nitric oxide (NO) release
• Anticoagulant (stops blood clotting) – many anticoagulant factors live here, including NO
• Prevents adhesion of white blood cells and platelets.

It should come as no surprise, therefore, that if you damage the glycocalyx, a number of very bad things are going to happen. Damage to the underlying endothelium, adhesion of platelets, loss of anticoagulation, severe disruption to nitric oxide synthesis etc. etc. And a high blood sugar level does ALL of these things.⁴

So, there you go. Diabetes/raised blood glucose greatly increases the risk of CVD by causing damage to the glycocalyx/endothelium, and a parallel increase in the risk of blood clotting. Which, as you may have noticed, is exactly the mechanism of action that I have been outlining on this blog for the last three years. And if you think it cannot be that simple. Well, it is.

1: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4127581/

2: https://www.medscape.com/viewarticle/584885_2

3: http://diabetes.diabetesjournals.org/content/55/2/480

4: http://diabetes.diabetesjournals.org/content/55/4/1127

16th August 2018

Having talked about the end, I shall now talk about the beginning of cardiovascular disease (CVD). Or, to be more precise, the beginning of atherosclerotic plaque development.

The problem that I always had with the LDL/cholesterol hypothesis was that it relied on a mechanism of action that sounded reasonable – if you didn’t think about it in any great depth. However, once you started looking at it closely, it become more and more unlikely. Namely, the idea that it is possible for low density lipoprotein to simply “leak” into artery walls, triggering the development of atherosclerotic plaques.

Whilst everyone, and I mean everyone (apart from about a hundred flat-earthers), confidently states that leakage of LDL in the artery wall is the first step in atherosclerotic plaque development, the pattern of atherosclerosis around the body is impossible to reconcile with this hypothesis.

Lets just start with a short list of problems. It may not look short, but it is. Just don’t get me started on ‘oxidised LDL’ and LDL particle size, and inflammation, and suchlike:

One: If LDL is leaking into artery walls, by active transport, or down a concentration gradient, or through any other mechanism you can come up with, why doesn’t it leak into all artery walls at exactly the same rate? Or, to put this another way, why are some arteries devoid of atherosclerotic plaques, when other arteries, in the same person, are highly atherosclerotic?

In the same way, how can you have a discrete area of plaque in an artery wall, when the rest of the artery wall, even the opposite side of the artery wall, is plaque free. Or, to put this another way, why does LDL leak through only in certain places, and not others?

If your answer is that LDL can only leak through in areas of arterial/endothelial damage then I would say, fine, reasonable argument. However, it means that the starting point for atherosclerosis is arterial/endothelial damage – not LDL leaking into the artery wall. And once you have damage to the arterial wall, you have moved into a completely different ball game. The ball game of endothelial damage and clot formation. Which means that you are now in my world. My rules, I win.

Two: Why does LDL never leak into vein walls? Again, if your hypothesis is that LDL can get past endothelial cells and then move straight into the artery wall, then why cannot it do this in veins? Veins and arteries have exactly the same basic structure. Arteries are somewhat thicker, with more smooth muscle and suchlike, but otherwise all is the same, and the endothelial cells lining both arteries and veins are identical in structure and function.

And no, the high blood pressure in an artery cannot force LDL into the artery wall. Whilst pressure may be involved in damaging the artery wall, pressure alone cannot be the answer. For pressure to force LDL into the artery wall, you would first have to breach the endothelial layer, at which point everything else in the bloodstream would flood into the artery wall at the same time. Then you are into the ‘damage to the blood vessels’ discussion again. My rules, I win.

Three: The arteries, at least those where atherosclerosis develops, have their own blood supply. Yes, bigger blood vessels (both arteries and veins) have their own blood vessels to provide them with the nutrients they require – the vasa vasorum, literally ‘blood vessels of the blood vessels.’

LDL molecules can freely move out of the vasa vasorum, and into the surrounding artery wall – then back again. Therefore, the concentration of LDL in the artery wall, and the bloodstream, is identical. So, for one thing, there can be no concentration gradient between the LDL in the blood flowing through the artery, and within the artery wall itself.

Equally, even if LDL did enter the artery wall by passing through the endothelial layer and then, against all the laws of physics, the concentration of LDL in the artery wall managed to rise above that in the bloodstream, it would simply be absorbed back into the vasa vasorum to be taken back into the blood circulating around the body.

To put this another way, there is nothing to stop LDL entering the artery wall, and vein walls, via the vasa vasorum. So, why does LDL entering the artery wall from the blood, that is flowing through the artery, cause damage, when the LDL entering the artery wall (and vein walls) from the vasa vasorum does no harm? Same LDL, same rules.

Four: The intact/healthy endothelial layer is impermeable to LDL, no matter what the concentration in the blood. We know this because the brain has to manufacture its own cholesterol because, in turn, LDL cannot force entry through the endothelial cells that line the blood vessels.

In the brain all endothelial cells, even in the smallest blood vessels (capillaries) remain tightly locked together, which is the ‘structure’ that creates the blood brain barrier (BBB).

‘The BBB is defined as the ‘microvasculature’ of the brain and is formed by a continuous layer of capillary endothelium joined by tight junctions that are generally impermeable (except by active transport) to most large molecules, including antibodies and other proteins.’¹

In the rest of the body, when you reach the level of capillaries, these minute blood vessels are loosely bound, with gaps between the endothelial cells. There are also holes (fenestrations) in the endothelial cells themselves. Which is why LDL can move in and out of the vasa vasorum quite easily. This is not the case in the brain, or the larger blood vessels, where tight junctions are the rule.

In short, an intact endothelial layer, with the cells locked together by protein bridges – as found in the BBB and in all large arteries – cannot be penetrated by LDL. Indeed, if it were possible for LDL to simply force entry into, and then pass straight though endothelial cells, you would not need LDL receptors to get LDL into cells, and you do.

This is why, in familial hypercholesterolaemia (FH) the level of LDL rises very high. It rises very high because there are fewer LDL receptors on cells, so the LDL remains trapped in the bloodstream. Somewhat ironically, FH provides powerful proof that the LDL/cholesterol hypothesis must be wrong, because it proves that LDL cannot enter cells unless the cell has an LDL receptor. At least it disproves the idea that LDL can simply move through endothelial cells.

As for the idea that LDL can slip through the gaps between endothelial cells. This too, is impossible. Endothelial cells, in larger arteries, and in the BBB, are locked together very tightly indeed. I quote here from Wikipedia. If you don’t like Wikipedia, then go to Google and look up “IMAGES” ‘tight junctions between endothelial cells.’ You will see how impossible it is for LDL to pass between endothelial cells that line artery walls.

‘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.’² Wikipedia ‘tight junction’.

Yes, there is not enough of a gap for ions (charged atoms) to pass between endothelial cells. Which means the idea that an LDL molecule, which is tens of thousands of times bigger – probably hundreds of thousands – can slip between cells is quite clearly, nonsense. It is like suggesting a super-tanker can slip through a gap that a rowing boat cannot.

Five: The only possible way that LDL could leak past or through the undamaged endothelium is if the endothelium wants it to get past. That would require active transport through endothelial cells. Now active transport exists – it is called transcytosis. A substance is absorbed into the cell on one side, it is then transported through the cell, and pops out the other side. [Transcytosis is clearly not possible with LDL, as we already know that it cannot cross the blood brain barrier BBB]

However, transcytosis only happens if the cell has a reason to transcytose a molecule. It is tightly controlled and highly complex process. It does not happen by chance, It is unaffected by any concentration gradient. It is the action of a living entity. In this case, an endothelial cell [other cells are just as clever].

The idea that an endothelial cell would be programmed to absorb LDL from the bloodstream, then actively transport it through itself, then deposit it in the artery wall behind – for no reason whatsoever – defies all laws of biology and physiology – and any other natural laws that you can think of. Especially when the artery wall can get any and all the LDL it requires from the vasa vasorum.

Now, there are more problems than this, but I am not taking it any further at present, as that is enough to be going on with. The counter argument has always been, well you do find LDL in atherosclerotic plaques, so it must have got there by passing through the endothelium.

Hmmmm. Well, as pointed out in the last blog, you can find red blood cells in atherosclerotic plaques too, and we know for an absolute certainty that red blood cells cannot penetrate the undamaged endothelium. Simply finding a substance in an atherosclerotic plaque does not mean it caused the plaque in the first place.

Having said all of this, the alterative ‘blood clotting’ hypothesis appears to immediately run into an alternative problem. When you look at early stage atherosclerotic plaques, they do not obviously look anything like a blood clot. In fact, they are often referred to as ‘fatty streaks.’ No sign of a blood clot there (at least, so it is almost universally believed).

I don’t refer to them as fatty streaks, because that immediately sets your thinking off down the fat/cholesterol LDL pathway, from where it can never again emerge. I prefer to call early stage plaques “fibrous streaks” which is far more descriptive of what they are, and what they look like.

However, that is slightly jumping ahead of myself. What I am going to do now, is to take you back in time to the 1960s and 1970s. A time when researchers were actually trying to work out exactly what was going on with CVD. Rather than now, when the LDL hypothesis is just accepted as an inarguable fact. Which means that no-one researches plaque growth any more, in any meaningful way. Or at least, they can only research it by accepting that, whatever else you see, LDL is the cause.

So, let us begin by looking at the fatty streak in more detail, as described in the book ‘Factors in Formation and Regression of the Atherosclerotic Plaque.’

‘Juvenile-type fatty streaks are the earliest lesions that can be recognized by macroscopic inspection of aortas of children. They characteristically appear as small yellow/white dots most frequently in longitudinal lines between the intercostal branches (places where arteries that travel around the chest branch out from the aorta. Intercostal means, between ribs). They stain brilliantly red with macroscopic Sudan staining, and Holman reported that they were already present in all children aged more than 3, increased rapidly in area between ages 8 – 15, and reached a maximum age 20.’

So, yes, there are such things as fatty streaks. Sorry to scare you, but they start in infancy, and every single child has them by the age of three. They reach their maximum level at age 20 (when no-one has a heart attack). However, most importantly, fatty streaks do not become atherosclerotic plaques:

‘For many years it was widely believed that they (fatty streaks) were the precursors of fibrous plaques, and it was postulated that the fat-filled cells disintegrated, releasing sclerotic organic lipid that stimulated proliferation of SMCs (smooth muscle cells) and collagen. However, there is now evidence from many different sources that suggests that fatty streaks and fibrous plaques develop by separate and independent pathways.’

‘Separate and independent pathways’. Today, if you read anything on atherosclerosis, any textbook, any research paper on atherosclerosis, it will inform you that atherosclerotic plaques start as fatty streaks which gradually grow larger and turn into atherosclerotic plaques – somehow or another. This is just an accepted fact, never challenged, constantly quoted. But it is, as with most facts in the world of CVD, wrong.

In the 1970s, a couple called the Velicans undertook a painstaking review of arteries at all ages, from those who had died of accidental causes. Children to adults. Two of their key findings are worth highlighting. The first, again, is that fatty streaks do not turn into plaques. The second is the association of microthrombi with plaque formation:

‘They, (the Velicans), record many significant morphological observations. They did not observe conversion of fatty streak into atherosclerotic plaques and concluded that the two types of lesion developed as unrelated pathological processes. ‘Advanced’ fatty streaks exhibiting cell disintegration and accumulation of extracellular lipid were first encountered in the 26 – 30 age group and increased fairly rapidly over the next decade, but again they did not observe ‘further transitional stages between advanced fatty streaks and atherosclerotic plaques.

In the third decade lipid became abundant in the plaques (the plaques, not the fatty streaks) in the form of foam cells which were particularly associated with areas of insudation. (insudation is the accumulation of a substance derived from the blood), and small pools of extracellular lipid: there was also ‘progressive involvement of microthrombi in the early steps of plaque formation.‘

What does this mean? At the risk of repeating myself to death. It means that fatty streaks exist, but these ‘lesions’ are not the things that become atherosclerotic plaques. Plaques form in a completely different way.

And, when you examine early stage plaques closely, they contain microthrombi (small blood clots) and other material derived from the blood – insudation. The Velicans did not know what caused plaques, but they observed that they began life as small fibrous streaks – not fatty streaks, with progressive involvement of microthrombi.

What is the most ‘fibrous’ material in the body? It is, of course, fibrin. Fibrin is the long string of protein the body uses to bind blood clots together. Sticky fishing line, if you will. It is formed with blood clots, as part of blood clots, and it is always found in high concentrations in and around atherosclerotic plaques.

What is important to note here is the fact that everyone believes about the growth and natural history of atherosclerotic plaques – is wrong. Fatty streaks have nothing whatsoever to do with atherosclerotic plaque development. On the other hand, fibrous streaks, fibrin and microthrombi do!

Which takes us way back in time to Karl von Rokitansky, who was studying plaques in the arteries of people who had died of accidents in the 1850s. Rokitansky noted that plaques looked very much like blood clots – in various stages of repair. He then proposed that atherosclerosis begins in the intima (the bit lying just beneath endothelial cells), with deposition of thrombus (blood clot) and its subsequent organisation by the infiltration of fibroblasts and secondary lipid deposition. ‘The Encrustation Theory.’

However, what Rokitansky could not do, the Velicans could not do, and Russell Ross and Elspeth Smith and Duguid could not do – explain the following:

How can a blood clot form under the endothelium?

The answer, as readers of this blog now know, is that the blood clot formed when the endothelium was not there. It had been damaged, and/or stripped away, at which point a blood clot formed on that area and then, once the blood clot stabilised, and most of it was broken down, apart from the fibrin and a few other bits and pieces (including Lp(a)), the endothelium simply re-grew on top of it. Like all magic tricks, it is simple once you know how it’s done.

However, the existence of endothelial progenitor cells (EPCs), that could stick to, then re-grow, on top of a blood clot, was unknown until the mid-nineteen nineties. So, prior to this time, anyone suggesting the encrustation theory, or any variant thereof, could be easily dismissed. Just as Virchow dismissed Rokitansky in 1852. ‘Do not talk nonsense Rokitansky, blood clots cannot form under the endothelium – I win.’

Because of this, with no other hypothesis to challenge it, the LDL hypothesis gained such a powerful grip, that no-one was the least interested in the Encrustation theory. The time to strike had passed, the battle had been lost. The warriors grew old and withdrew from the battlefield, and then simply died of old age. Their names forgotten, ghosts in the machine.

‘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 system are involved: not only in the acute occlusive event, but also in all stages of atherosclerotic plaque development from the initiation of atherogenesis and growth of large plaques.

Infusion of recombinant tissue plasminogen activator (rt-PA) into healthy men with no evidence of thrombotic events of predisposing conditions elicited significant production of crosslinked fibrin fragment D-dimer. Thus, in apparently healthy human subjects there appears to be a significant amount of fibrin deposited within arteries, and this should give pause for thought about the possible relationship between clotting and atherosclerosis. It also provided in vivo biochemical support for the numerous morphological studies in which mural fibrin and microthrombi have been observed adherent to both apparently normal intima and atherosclerotic lesions.

In 1852 Rokitansky discussed the ‘atheromatous process’ and asked ‘in what consists the nature of the disease.’ He suggested. ‘The deposit is an endogenous product derived from the blood, and for the most part from the fibrin of arterial blood.’ One hundred years later Duguid demonstrated fibrin within, and fibrin encrustations on fibrous plaque, and small fibrin deposits on the intima of apparently normal arteries.

These observations have been amply confirmed but, regrettably the emphasis on cholesterol and lipoproteins was so overwhelming that it was another 40 years before Duguid’s observations had a significant influence on epidemiological or interventional studies of haemostatic factors in coronary heart disease.’³

Those words were written almost thirty years ago by Dr Elspeth Smith, who once taught me at Aberdeen University. I should have listened more closely, it would have saved me twenty-nine years of research. Those words too, have now been forgotten, whilst LDL and statins bestride the world.

Silence has once again descended on this area. But when you look at it through fresh eyes, and you know of the existence of EPCs, these researchers had the answer, right there, in the palm of their hands. So close they could almost smell it. They just couldn’t quite join all the dots. They couldn’t explain how massive molecules that are normally found in the bloodstream, could get inside the artery wall. So, they were defeated by the facile, impossible, ridiculous, LDL hypothesis.

A great pity, because the encrustation theory explains what the LDL hypothesis cannot. Why do plaques form where they do, why do they not form in veins? Why do they contain substances that you can only find in blood clots? Why do so many grow in layers, like tree trunks? In fact, they all grow this way, it is just that – over time – the plaque can lose structure and turn to mush.

Why does smoking and air pollution increase the risk of CVD. How does avastin increase the risk of CVD by 1,200%? How do Rheumatoid Arthritis and Systemic Lupus erythematosus vastly increase the risk of CVD? It is because they all damage the endothelium and increase the risk of blood clotting at that point of damage. I could go on listing factor after factor. Using the encrustation theory everything can be explained, simply, quickly. There is no need to distort the evidence, no need to explain away paradoxes.

Statins, for example, which are held up as inarguable proof of the LDL hypothesis. How do they actually work to reduce the risk of CVD? It is because they increase nitric oxide synthesis in endothelial cells, and nitric oxide protects the endothelium, stimulates the growth of endothelial progenitor cells, and is also the most powerful anticoagulant agent known to nature.

‘Statins have pleiotropic effects on the expression and activity of endothelial nitric oxide synthase (eNOS) and lead to improved NO bioavailability. NO plays an important role in the effects of statins on neovascularization. In this review, we focus on the effects of statins on neovascularization and highlight specific novel targets, such as endothelial progenitor cells and NO.’⁴

Blood clots, blood clots. All the way down. Rokitansky was right, as were Ross, Duguid and Smith (and many others). They had worked it out, and they knew what was going on. They simply failed to convince the world. My role is to resurrect these forgotten scientific heroes and place them where they should always have been. The scientists who discovered what really causes CVD.

1: https://www.researchgate.net/figure/Schematic-diagram-of-the-structure-of-the-blood-brain-barrier-BBB-The-BBB-is-created_fig1_259386351

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

3: https://www.sciencedirect.com/science/article/pii/0049384894900493

4: https://www.ncbi.nlm.nih.gov/pubmed/16614729

6th August 2018

One of the most difficult issues in discussing cardiovascular disease is that it is generally considered to consist of two completely different processes. The first of which is the development of atherosclerosis, or atherosclerosis plaques, which are thickenings that can grow, narrow, and block arteries over years or decades.

The second process is thrombosis (a blood clot) that forms on top of the plaque. Often thought to be due to plaque rupture – something like a boil bursting – which exposes the blood to the inner plaque material. This, in turn, triggers a sudden blood clot (thrombus) to form, which fully blocks the artery causing a heart attack. Now that, anyway, is the current mainstream view.

Or, perhaps like a volcano? The pressure from the magma builds up and up, until the ‘plug’ at the top gives way and the whole things goes off bang. I am not sure if I like that analogy, but it may capture the concept of something slowly, slowly, building up, before the sudden catastrophe occurs.

You may see nothing wrong with this model, but it creates massive and complex issues when looking for potential causes of cardiovascular disease. Because it states that we have two completely different processes here, which could have completely different causes, and how do you know which one is more important, or which one to target? Or which one to blame?

So, for instance, we know that heart attacks are more common on a Monday morning than any other time of the week¹. Clearly, this is not due to the sudden growth of atherosclerotic plaques overnight on a Sunday. If it is due to anything, it is due to the early morning rise of cortisol which, in turn, makes it more likely for a blood clot to form – because cortisol is ‘pro-coagulant.’

Equally, after you have suffered a heart attack, almost all of the treatment that takes place is to do with breaking down blood clots, removing them, or prizing them apart. At its simplest, you can give an aspirin to try and dissolve the clot. Or you could give a ‘clot buster’, such as tissue plasminogen activator – (TPa).

More commonly nowadays, a catheter is inserted into the coronary artery blocked by a blood clot, to reach the clot, push through it, and open up a metal stent to hold open the blocked area. So, in one way, the acute treatment of heart attacks could simply be described as blood clot management. As could the treatment of the majority of strokes where a clot breaks off from the carotid artery (artery in the neck) before travelling into the brain and getting stuck.

So, clearly, you cannot dismiss the importance of blood clotting in causing death from cardiovascular disease. In fact, if you never had a blood clot, you would never die of a heart attack or a stroke. No matter how much atherosclerosis you had. [I am not entirely sure if this statement is correct, but it is very nearly correct].

Now, you may rather like this dual model of ‘Athero-thombosis’. However, I do not. Indeed, I hate it. For one thing I do not like having to invoke two completely essentially unrelated processes to explain a single disease. Mainly though, even if it wasn’t deliberately designed to protect the ‘LDL-hypothesis,’ that is exactly what it does.

Primarily because the idea of athero-thrombosis firmly places blood clotting, in the aetiology (causal chain) of CVD right at the end, where it can then have nothing to do with the development and growth of plaques. Which means that you can dismiss any and all associations between plaque formation and blood clotting, no matter how strong. ‘Yes well, of course, things that make the blood less likely to clot will protect against cardiovascular disease, and vice-versa. But it has nothing do with atherosclerotic plaque formation, that is all to do with LDL.’ End of discussion.

Yet, and here is a thing, not often commented on – if at all. Most atherosclerotic plaques contain cholesterol crystals. In fact, the early researchers, when they found cholesterol in plaques must have been looking at cholesterol crystals, or they would have had no idea what they were looking at.

Why is this important? Because you cannot make cholesterol crystals from the cholesterol found in LDL molecules. Why not? Because the cholesterol in LDL is primarily bound to fatty acids (call them fats), thus creating a cholesterol ‘ester’, a.k.a. ‘esterified cholesterol.’ And cholesterol esters do not, indeed cannot, turn into cholesterol crystals. The only substance in the body containing enough pure cholesterol to form cholesterol crystals, are the membranes of red blood cells (RBCs).

Next question, how do you get a red blood cell into a plaque?

The only possible way is for there to have been some form of bleeding/haemorrhage into the artery wall. Of course, once you have had a haemorrhage, you end up with a blood clot. At which point you have enough RBCs kicking about for cholesterol crystals to form. As made clear in the NEJM paper: ‘Intraplaque Hemorrhage and Progression of Coronary Atheroma.’²

‘The aim of this study was to demonstrate erythrocyte membranes within the necrotic cores of human atherosclerotic plaques, even those without recent hemorrhages, and relate them to the progression and instability of the lesions. We also examined the fate of erythrocytes in established plaques in atherosclerotic rabbits to provide a model of hemorrhage-induced progression of lesions. Establishment of a link between intraplaque hemorrhage and the expansion of the lesions would provide another potential mechanism of plaque progression and vulnerability.’

‘The finding that intramural hemorrhage in an experimental atherosclerotic lesion induces the formation of cholesterol crystals with the recruitment of macrophages supports our hypothesis that erythrocyte membranes in the necrotic core of human coronary lesions can cause an abrupt increase in the levels of free cholesterol, resulting in expansion of the necrotic core and the potential for the destabilization of plaque’

Okay, what does that all mean? Basically, red blood cells that end up in plaques cause an abrupt increase in cholesterol in the plaque, leading to destabilisation of the plaque – which is the underlying cause of heart attacks and strokes. Or, to put this another way. Repeated blood clotting occurs first, followed by intra-plaque rupture. Which is the exact opposite way round to the current athero-thrombosis model. Which means that it should really be called the ‘thrombo-atherosclerosis’ model.

The observation of blood clots going off all over the place, narrowing an artery, shortly to be followed by heart attack is outlined very clearly in this paper. ‘Unstable angina with fatal outcome: dynamic coronary thrombosis leading to infarction and/or sudden death. Autopsy evidence of recurrent mural thrombosis with peripheral embolization culminating in total vascular occlusion.’

Now, that is a lot of jargon for one title … of any paper. So, I shall translate. Unstable angina is a condition whereby the attacks of angina become more and more frequent, triggering almost all the time. It is usually the harbinger of a final, fatal Myocardial Infarction. So, yes, in one way we are looking at the end process of CVD. However, in the situation we have an opportunity to see rapid atherosclerotic development with clots forming, one on top of another which, eventually completely block the artery. That is the ‘recurrent mural thrombosis’ bit.

Here is the abstract. If you are not medically trained, you are not going to get much of this. However, what it describes is exactly what I am talking about. Repeated blood clots creating layered blood clots, one sitting on top of another, causing the artery to narrow. This is, in effect, super-accelerated thrombo-atherosclerosis.

I include this unchanged, because I want people to know that I am not interpreting what is said here to suit my argument. What the authors are describing is, exactly, what I have been banging about for years. Namely that atherosclerotic plaques are blood clots, in different stage of development and breakdown. Good luck:

‘Extensive microscopic examination of epicardial arteries and myocardium was performed in 25 cases of sudden death due to acute coronary thrombosis. Eighty-one percent of the thrombi had a layered structure with thrombus material of differing age, indicating that they were formed successively by repeated mural deposits that caused progressive luminal narrowing over an extended period of time. This episodic growth of the thrombus was accompanied by intermittent fragmentation of thrombus in 73% of the cases, with peripheral embolization causing microembolic occlusion of small intramyocardial arteries associated with microinfarcts. The period of unstable angina before the final heart attack was, in all but one of 15 patients, characterized by such an ongoing thrombotic process in a major coronary artery where recurrent mural thrombus formation seemed to have alternated with intermittent thrombus fragmentation. The culmination of this “dynamic” thrombotic process in total vascular occlusion caused the final infarction and/or sudden death.’³

Clot after clot after clot, building up a layered structure of clots one of top of another. Followed by the ‘big one’, the clot that killed them.

Another condition where you get very rapid atherosclerosis development is following a heart transplant – sad to say. The process in such patients is exactly the same as in unstable/crescendo angina, if far slower. Namely, repeated thrombus formation, leading to the rapid growth of atherosclerotic plaques. Here from the European Heart Journal: ‘Repeated episodes of thrombosis as a potential mechanism of plaque progression in cardiac allograft vasculopathy.’

[Cardiac allograft vasculopathy = degeneration of the blood vessels in transplanted heart. I don’t know why they don’t just call it atherosclerosis, but they don’t.] Now, here comes some more proper jargon from the paper If it is too dense for you, what it describes are repeated blood clots on the arterial wall (mural thrombosis), leading to the development and growth of atherosclerotic plaques.

Discussion

The current serial IVUS (intravenous ultrasound scan) study demonstrated that a substantial number of asymptomatic HTx (Heart transplant) recipients had lesions (plaques) with complex lesion morphology, such as multiple layers, intraluminal thrombi, and plaque ruptures. Furthermore, this study implies that recurrent episodes of coronary thrombosis, presenting as ML(multi-layered) appearance, may mediate the progression of CAV (Coronary allograft vasculopathy).

Multiple layers are often indicative of repetitive, periodically occurring asymptomatic thrombus formation. Post-mortem studies for native atherosclerosis demonstrated healed plaque ruptures and erosions with multiple layers of distinct tissue components.12 ML appearance identified by cross-sectional IVUS imaging has been interpreted as mural thrombus. To our knowledge, this is the first longitudinal IVUS study, demonstrating multiple layers not only at a single time point (ML appearance) but also longitudinally (ML formation). The present serial IVUS study demonstrated that lesions with ML formation exhibited new inner layers with distinct echogenicity overlaying pre-existing outer layers. This observation could be highly indicative of repeated episodes of mural thrombosis.’ ⁴

Yes, ladies and gentlemen. Thrombo-atherosclerosis. Not athero-thrombosis. Blood clotting is not simply the final event in the CVD. It is the only event, and it is how atherosclerosis starts, grows and eventually kills you. Or, to put it another way, there are not two processes in cardiovascular disease, there is only one.

You heard it here first.

1: https://www.ncbi.nlm.nih.gov/pubmed/7925507

2: https://www.nejm.org/doi/full/10.1056/NEJMoa035655

3: http://circ.ahajournals.org/content/71/4/699?ijkey=7c374f414cfa07f8668551aba66604e81cc54adc&keytype2=tf_ipsecsha

4: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3787274/

23rd July 2018

Trying to work out what causes any disease is tricky, very tricky, although in some cases it has been relatively straightforward – at least in retrospect. Scurvy, for example, has a single cause. A lack of vitamin C. If you replace the vitamin C, all the signs and symptoms of scurvy will disappear.

Equally, tuberculosis, is caused by the single pathogen, or microorganism, the tuberculous bacillus. The discovery of the bacillus was made by Robert Koch in 1882 using his meticulous scientific technique, based on his famous postulates:

• The microorganism must be found in abundance in all organisms suffering from the disease but should not be found in healthy organisms.
• The microorganism must be isolated from a diseased organism and grown in pure culture.
• The cultured microorganism should cause disease when introduced into a healthy organism.
• The microorganism must be re-isolated from the inoculated, diseased experimental host and identified as being identical to the original specific causative agent.

Koch didn’t just stumble across a bacteria in someone with TB and announce to the world that this was the cause of TB. He knew that if you look in any sample from diseased lungs, you will find hundreds of different bugs kicking about. Which of them is the true cause?

To find out, you need to isolate one, find a culture where it can multiply, then stick it in another animal to see if it develops the same disease. You take that microorganism back out of the newly diseased animal and check it is the same bacteria that you isolated in the first place. Then, and only then, can you claim you found the causal agent.

Good stuff, sounds complicated. In truth, that was simple.

Things become far more difficult when, for example, you cannot find a single causal agent. Or you find that you have found a likely agent, but many people exposed to it do not get the disease. Or, you find that people who have not been exposed to your proposed causal agent can also get the same disease.

Smoking, for example. You have a hypothesis that smoking causes lung cancer, but most people who smoke do not get lung cancer. Equally, many people who have never smoked can suffer from lung cancer. Given this, you could argue that it is not actually smoking that causes lung cancer, but something else. An argument used for decades by the tobacco industry to establish that smoking was perfectly healthy.

Recognising these difficulties, in 1965 the English statistician Sir Austin Bradford Hill proposed a set of nine criteria, known as ‘Bradford Hills cannons of causation’. They were designed to provide a model for epidemiologic evidence of a causal relationship between a presumed cause and an observed effect. It was Hill and Richard Doll who demonstrated the connection between cigarette smoking and lung cancer. The list of the criteria, or cannons, is as follows:

Strength: (effect size): A small association does not mean that there is not a causal effect, though the larger the association, the more likely that it is causal.

Consistency: (reproducibility): Consistent findings observed by different persons in different places with different samples strengthens the likelihood of an effect.

Specificity: Causation is likely if there is a very specific population at a specific site and disease with no other likely explanation. The more specific an association between a factor and an effect is, the bigger the probability of a causal relationship.

Temporality: The effect has to occur after the cause (and if there is an expected delay between the cause and expected effect, then the effect must occur after that delay).

Biological gradient: Greater exposure should generally lead to greater incidence of the effect. However, in some cases, the mere presence of the factor can trigger the effect. In other cases, an inverse proportion is observed: greater exposure leads to lower incidence.

Plausibility: A plausible mechanism between cause and effect is helpful (but Hill noted that knowledge of the mechanism is limited by current knowledge).

Coherence: Coherence between epidemiological and laboratory findings increases the likelihood of an effect. However, Hill noted that “… lack of such [laboratory] evidence cannot nullify the epidemiological effect on associations”.

Experiment: “Occasionally it is possible to appeal to experimental evidence”.

Analogy: The effect of similar factors may be considered.

You may have noted that these cannons are not remotely black and white. There are many shades of grey here. Even so, I can confidently assure you that if you take any of the current risk factors for heart disease, they fail to meet some, many, or indeed any, of Bradford Hills cannons for causation.

For some time, I looked at Koch’s postulates, changing the word microorganism to pathogen. I reviewed the Cannons for causation and repeatedly tried to apply them to possible causes of cardiovascular disease, but I found that they are of little practical use. Things got very complicated very quickly and trying to pull all the necessary strands of thought together was well beyond my mental capacity.

I began to realise that when it comes to cardiovascular disease we do NOT have any single causal agent, or factor, or even a remotely coherent causal model. Something noted over twenty years ago.

‘Our poor understanding of the nature of coronary heart disease explains why we lack a clearly expressed paradigm to explain it. All diseases are explained on the basis of a paradigm, or model, which is an expression of present understanding even though it might be incomplete or wrong. Being able to develop a paradigm, to construct a model, implies a certain level of understanding; the absence of such a paradigm which would include most if not all known risk indicators, implies very little understanding.

In practice there is what can be regarded as a ‘flat paradigm’ for the development of coronary heart disease, in that it is thought to be due to the addition of a wide range of risk indicators. The flat paradigm of CHD means that it might appear to be due to genetic influences in one person, cigarette smoking in another, a faulty diet in another, a metabolic abnormality in another etc.. This contravenes traditional pathological teaching that a given disease has a specific cause, although a variety of factors might influence the natural history of the disease. In fact, the flat paradigm is simply a summation of observations and make no attempt to explain how the various factors might interact.’¹

In that article, Grimes uses the term ‘flat paradigm’ which I rather like, but have never seen used before, or since. Others commonly describe CVD as being multifactorial, as though this helps in any way. ‘Yes, CVD is multifactorial.’ In reality, the use of this term is basically an admission of failure. ‘We don’t really know what causes CVD, but here is a list of things that we think might have something to do with it, in some people, but not all… look, stop asking difficult questions.’

This lack of any coherent model is reflected in the latest CVD risk calculator developed in the UK. It is called Qrisk3. There were two earlier models Qrisk1 and 2. You can bring up the calculator on-line and input all your ‘risk factors’. It will then work out your risk of having a cardiovascular ‘event’ in the next ten years – allegedly. It can be found here:https://qrisk.org/three/

It has twenty variable factors. These are

• Age
• Sex
• Smoking
• Diabetes
• Total cholesterol/HDL ratio
• 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

There is an alternative calculator used in the US. It only uses ten factors. It can be found here http://www.cvriskcalculator.com/ As an aside, neither of them use LDL to calculate risk. Interesting? [Both calculators greatly overestimate risk].

Looking at the UK version, what does it all mean? Does this list imply understanding? No, it is just a mis-mash of the most common things that have found to increase your risk of CVD. Some of the items on the list can only be associations e.g.:

• Age
• Sex
• Ethnicity
• Postcode (Zipcode)
• Angina, or heart attack in first degree relative under the age of 60

You may say that age clearly does cause CVD – it is certainly the most powerfully weighted factor on the list. I would counter that, if you have no other identified risk factors for CVD, why should getting older be a problem? What is the mechanism?

At least three items on the list are caused by CVD

• Variation in two blood pressure readings
• Erectile dysfunction
• Chronic kidney disease

One of them sits completely alone

• Atrial Fibrillation

As for the others:

• Smoking
• Diabetes
• Blood pressure
• Total cholesterol/HDL ratio
• BMI
• Rheumatoid arthritis
• Systemic Lupus Erythematosus
• History of migraines
• Severe mental illness
• On atypical antipsychotic medication
• Using steroids tablets

Here we have ten causes? But can these extremely disparate things all cause the same disease, and in the same way. History of migraines, and smoking, for example – what links them. Or, severe mental illness and rheumatoid arthritis. Go on, try and fit them together, with the LDL hypothesis, and see if you can end up with a coherent model.

Therein lay the challenge that I set myself many years ago. Of course, I could easily add many other items to Qrisk3. Antiphospholipid syndrome, sickle cell disease, Kawasaki’s, air pollution, magnesium deficiency, Avastin, proton pump inhibitors and on and on.

The reality is that, when you analyse Qrisk3, it is immediately apparent that there is no single necessary and sufficient causal agent to be found here. One alternative would be to suggest that there are several hundred different varieties of CVD, all with their own specific cause, and all leading to the same pathophysiology [a term used to describe the disordered physiological processes associated with disease or injury.]

To put this another way, the classical causal models were never going to work for CVD. Koch’s postulates, Bradford Hills cannons for causation represent a paradigm that is not suitable for understanidng CVD. For starters it is impossible to establish how they can all fit together as independent factors.

Even if you restrict yourself to the twenty different variables on Qrisk3, the possible combinations between them is twenty factorial. Which is twenty times nineteen, times eighteen, times seventeen etc. That is 2,432,902,008,176,640,000 possible interactions. Two-point four sextillion. Go on, design a clinical trial to explore that.

What I came to realise, eventually, is that you cannot understand CVD by studyng hundreds and hundreds of different risk factors that could be causal, could be associations, could be coincidence. The only possibly way to understand this disease, was to stop looking for causes and start looking at the process. This is something that I have said many times before, but it bears almost endless repetition, for it is key to everything.

If you cannot explain why, and more importantly how such things as: postcode, rheumatoid arthritis, smoking, steroids and history of migraines can lead to an increased risk of CVD you are just making lists and explaining nothing. So, having got that off my chest, again, I shall return to process in the next instalment.

1: Grimes D, Hindle E, Dyer T: ‘Respiratory infection and coronary heart disease: progression of a paradigm.’ Q J Med 2000: 93:375-383

15th June 2018

Many years ago, whilst I was at University, a doctor called Elspeth Smith was giving a small group tutorial on cardiovascular disease. I did not know it at the time, but she was doing detailed research into the process of atherosclerosis itself. During the tutorial she made this statement ‘cholesterol cannot get past the endothelium.’

At the time I had no idea what the endothelium was, and in truth, not much idea about cholesterol. However, those six words changed my life. At least my medical life. It was as if a door had opened onto a hidden world. No-one else in the group reacted, but I knew from the way those words were spoken that this was someone who was thinking something very differently. Very differently indeed.

Here is the conclusion of one of her talks, reproduced in the book: ‘Factors in formation and regression of the atherosclerotic plaque.’ Yes, the usual jargon filled stuff, but the bit at the end is most interesting.

‘In this talk I have concentrated mainly on the factors that may be involved in the progression of the early, low-lipid gelatinous lesion into the typical fibrous plaque with lipid-rich centre that is generally accepted as the significant lesion in occlusive vascular disease and have tried to emphasize the key role that may be played by fibrin.’

Fibrin, the key component of blood clots. How strange, how completely whacky. Is this woman mad. In the tutorial, she moved on quickly, almost as if being caught in an act of disloyalty. Which, I have come to realise, she was.

I now believe that, if she had been bolder, Dr Smith would have got it. The answer as to what really causes cardiovascular disease. I have since read many of her papers, and her contributions to various books. To my mind she was right over the target, looking straight down at the answer – bomb doors open.

Unfortunately, to fit in with mainstream consensus whereby everything must rotate around cholesterol (LDL/cholesterol), she kept looping back to cholesterol, and LDL, constantly trying to crowbar them into her research. Where they did not, and do not, fit.

She also made it too complicated, falling into the trap of ultra-reductionism. A trap that becomes almost impossible to avoid if you travel down and down, further and further, into biological systems. A point will be reached whereby, as physiological systems become smaller, they also multiply endlessly in all directions, and it becomes virtually impossible to see how they link together to create disease.

If you want to see the bigger picture, you must keep moving up and down between the levels. Just as a work of art cannot be understood by an analysis of the molecular structure of the paint, human physiology cannot be understood by tracking down individual biochemical pathways looking for the tiny, essential, lever that starts it all. The single snowflake that triggers an avalanche.

Anyway, getting back to her comment ‘cholesterol cannot get past the endothelium.’ Once you come to recognise that this is true, you are forced to accept that the cholesterol hypothesis, or LDL hypothesis is wrong, because it makes no sense. This does not necessarily mean that LDL does not have any role to play, but it cannot be the necessary factor. The ‘if and only if’ factor.

Which means that, if you want to understand cardiovascular disease, you must strip everything apart and start looking at the whole thing again. If not LDL, then what? Unfortunately, the moment you do this, a number of different problems emerge. The trickiest one is trying to find absolutely agreed facts to build a hypothesis on. Which is far more difficult than you would imagine.

Some facts may seem like bedrock, but when you start to press down on them, they can begin to crack and splinter, and turn to quicksand. For example, the fact that – at a younger age – women have a lower mortality rate from cardiovascular disease than men. This ‘fact’ is quoted endlessly but is it true? Not universally. Younger Brazilian women have an almost identical rate of death from heart disease as the men. At least it was, last time I looked

So, do women really have a lower rate of cardiovascular disease due to a biological difference? Or it is all to do with environmental differences, or psychological differences, or something else?

[By the way I am not referencing much of this blog, this time. You can simply Google most of this stuff yourself. I hope by now readers of this blog will accept that when I make a statement it is not plucked from thin air].

So, do we actually know? Really and truly know? Where are the foundation facts? At one point I reached a little island of despondency where I felt that there was no fact that I could rely on. It seemed that there was nothing that could not be contradicted.

For example, heart attacks are caused by blood clots in the coronary arteries. Surely that is certain? Well, I can find you solid evidence to contradict this, and several people I communicate with will argue that the blood clot follows the heart attack/myocardial inflation (MI). Not the other way around. You think this is mad?

What is certain is that you can find people who suffer from myocardial infarctions with no evidence of any blood clot, in any coronary artery, anywhere. It even has a name. Myocardial Infarction With Nonobstructive Coronary Arteries (MINOCA). To quote from an article in Circulation:

‘Myocardial infarction with nonobstructive coronary arteries (MINOCA) is clinically defined by the presence of the universal acute myocardial infarction (AMI) criteria, absence of obstructive coronary artery disease (≥50% stenosis), and no overt cause for the clinical presentation at the time of angiography (eg, classic features for takotsubo cardiomyopathy)’

This, I should add, is not rare. Maybe 25% of all heart attacks.

Yet, and yet. If you give drugs designed to break down blood clots (clots busters) you can reduce the risk of death from a myocardial infarction (MI). So, clearly, many myocardial infarctions are caused by blood clots. Equally if you use a device to clear out an obstruction from the coronary artery and put in a stent to keep the artery open this does reduce the risk of death following an MI.

Which means that you can – on the face of it – have MIs caused by blood clots, and MIs not caused by blood clots. Apart from the missing blood clot, they are both the same thing, with damaged heart muscle, raised cardiac enzymes and suchlike. So, what the bloody hell is going on?

Equally, you can find people who die of an MI and when you examine their coronary arteries you can find that a blood clot had formed days, or weeks, before the MI occurred. So, again, what the bloody hell is going on here? The blood clot did, or did not cause the MI? Surely not if there is a gap in time, of weeks, between the clot and the MI.

At which point you find yourself asking, or at least I did, how many people have the classic MI. By which I mean a blood clot forms in a coronary artery, then the person gets immediate central crushing chest pain and a myocardial infarction. More than half, less than half? In truth I do not know, and nor does anyone else.

In fact, just to throw more confusion into the ring, it is clear that the vast majority of MIs do not actually cause any symptoms at all. Or at least not symptoms that make anyone think they were having a heart attack.

Deep coal miners in Russia die the very earliest from heart attacks, at least I am pretty sure that they do. Average age of death is less than fifty. If you examine the hearts of these coal miners they will have had, on average, six previous MIs before the final one that got them. None of which were identified at the time. So, why do some MIs cause terrific pain whilst others do not? I have no idea. Nor, as far as I can ascertain, does anyone else.

Perhaps you now have some idea of my difficulty in trying to study CVD. At times it is like trying to pick mercury up off a flat table top. Or, asking questions of someone who will only answer your questions with another question. Frustrating.

I came to realise, eventually, that I could not rely on evidence, then work backwards. Instead I had to look at the metabolism, the physiology, the anatomy and suchlike, and attempt to work out what was going on. Then create a working hypothesis and see if facts fitted into it. Alternatively, find facts that completely blow it out of the water.

So, here we go, again. My working hypothesis as to the cause of CVD is, currently, the following:

• The first step in the development of atherosclerosis is damage to the endothelium (layer of cells that lines all blood vessels). No damage to the endothelium = no atherosclerosis.
• After the endothelium has been damaged a blood clot forms over the area
• The blood clot is mainly broken down and removed – on site
• Any remaining blood clot is covered over by new endothelial cells, effectively drawing the clot into the artery wall.
• Further repair systems, such as macrophages, then break up and remove any blood clot remnants, so nothing remains….

Unless.

Unless clots form more rapidly than they can be got rid of, at which point a plaque starts to develop, and grow. When it reaches a critical point, the final deadly blood clot occurs. [I will deal with the issues of MINOCA and suchlike, in the future].

Essentially, therefore, we are looking at a dynamic process whereby, if damage > repair, problems occur. However, if repair > damage, all is well. My analogy is with road repairs. [A major issue in the UK at the moment]. All roads are being damaged by car tyres, rain, ice and suchlike, all the time. If they are regularly repaired, then potholes will not form. However, if the damage outstrips repair, you end up with potholes all over the place.

In a similar sort of way if damage > repair in our arteries we develop atherosclerotic plaques. There are three things that can lead to accelerated atherosclerotic plaque development:

• Increased rate of endothelial damage
• Bigger, and more difficult to remove, blood clots forming
• Impaired healing systems

What this ‘three stage process’ hypothesis can immediately explain is why atherosclerotic plaques never develop in veins. The blood flow in veins in much slower, the blood pressure is around thirty times lower, and the biomechanical strain is much lower. Ergo, the endothelial cells in veins have a lot less ‘strain’ to deal with in their day to day lives. So, there is less endothelial damage going on.

It also explains why, if you take a vein, and use it in a coronary artery bypass (CABG) atherosclerosis very rapidly develops. It further explains why atherosclerosis never develops in the blood vessels in the lungs (pulmonary blood vessels). The blood pressure here is, again, far lower. Although, people with pulmonary hypertension (high blood pressure in the lungs) can develop plaques.

What else does it explain? Well, it explains how smoking increases the risk of CVD. Smoking has no impact on the classic risk factors such as LDL levels, or blood pressure, or diabetes. However, smoking does cause rapid and significant damage to endothelial cells.

Smoking a single cigarette causes mayhem. Endothelial cells die, as measured by a rise in endothelial microparticles in the blood, Endothelial Progenitor cells (EPCs) are released from the bone marrow to repair the damage. At the same time platelets (the key component of all blood clots) are activated. In fact, all hell breaks loose.¹

When you look at the damage smoking does, it amazes me that anyone who smokes lasts longer than a week. But they do. Which just demonstrates that the repair systems in the body are extremely efficient.

Anyway, what is clear is that smoking causes CVD through endothelial damage. Precisely the same thing happens with air pollution. It is increasingly recognised that air pollution increases the risk of CV death, and that the primary mechanism is endothelial damage.

‘In healthy, non-smoking, young adults, episodic exposure to PM2.5 [fine particulate air pollution] was associated with elevated circulating endothelial microparticles, indicative of endothelial cell apoptosis [cell death] and endothelial injury’. ²

Sorry, I did reference those two. I thought they might be difficult to find.

In fact, if you look for any ‘factor’ that damages the endothelium, you will find that it increases the risk of CVD. Below is a list of some of the things that I have been looking at, in some detail. Many of which you will never have heard of, but try not to let that put you off:

• Systemic Lupus Erythematosus
• Sickle Cell Disease
• Lead (the heavy metal)
• Mercury
• Bacterial infections
• Kawasaki’s disease
• Avastin (and any other VEGF inhibitor (vascular endothelial growth factor)
• Rheumatoid arthritis
• Proton Pump Inhibitors (used for ulcers and suchlike e.g. omeprazole)
• Scleroderma
• Smoking
• Air pollution
• Chronic Kidney Disease
• Vitamin C deficiency
• Erythema Nodosum
• Cocaine use
• Migraine
• Diabetes

That list is probably long enough for now. On the face of it, most of these factors may seem completely unrelated. But the simple fact is that they all cause significant endothelial damage, and they all greatly increase the risk of CVD. From 100% in the case of omeprazole, to 50,000% in the case of sickle cell disease.

You may be wondering how the hell does Sickle Cell Disease damage the endothelium. Well, sickle cells are sharp, sickle shaped red blood cells (erythrocytes) – that is where the name comes from. It should come as no great leap of the imagination to propose that having sharp sickle shaped red blood cells hammering through your arteries may be rather likely to damage them.

‘A recent study of spleens* resected from Sickle Cell Disease (SCD) patients… has shown that there was consistent vascular lesions affecting large arteries. The same finding was also shown in studies of brains from SCD patients who developed cerebrovascular accidents (strokes). These lesions were attributed to the rigidity of sickled erythrocytes causing mechanical injury to the endothelial cells. The widespread distribution of the lesions was also suspected in other studies, in which it was suggested that the sickled erythrocyte-endothelial adhesion seen in the microvasculature could be occurring in large arteries and contribute to large vessel endothelial injury, vascular intimal hyperplasia and thrombosis.’³

*spleens are often removed from those with sickle cell disease because they become enlarged and liable to rupture

And here, from the paper referenced above, is the case of a fourteen-year-old boy with sickle cell disease. Much jargon, but important jargon.

‘A 14 year-old boy was referred to our vascular unit, with gangrene of the right foot. The condition started about one year prior to this referral with ulceration of the foot which was treated conservatively. The condition of the foot deteriorated until development of gangrene of most of the foot. The boy is a known patient of SCD. His past medical history revealed right sided stroke when he was 8 years old. His parents have SCD. His brother had also SCD and died suddenly at the age of 5 years.

There were no identifiable risk factors for atherosclerosis.

On examination, there were no palpable pulses [no pulses could be felt]. He was found to have heavily calcified femoral and brachial arteries [main arteries of arms and legs]. Plain x ray of both arms showed extensive calcifications of brachial, femoral and popliteal arteries. An X ray of his right foot showed infarction and osteomyelitis of most of the bones [infection in the bones].

Plain CT [detailed x-ray] of the abdomen and pelvis showed calcification of splenic artery and calcifications of both iliacs and inferior mesenteric artery [arteries branching from the aorta, main arteries of legs and artery supplying the bowel]. Digital subtraction angiography [too complicated to explain here] showed occlusion of right external iliac artery and both superficial femoral arteries with extensive collaterals. MRI & MRA of the brain showed left parietal wedge area of infarction with total occlusion of the supraclinioid segment of left internal carotid artery [important bit of the brain] and multiple collaterals. The patient had a right below knee amputation and was discharged home on antiplatelets.’³

This fourteen-year-old boy had calcified atherosclerosis in virtually every artery in his body. With, and this should be highlighted again no identifiable risk factors for atherosclerosis.

Now, you can look at every single current hypothesis as to the cause(s) of CVD, and NONE of them can explain why this fourteen-year-old boy has widespread and overwhelming atherosclerotic plaque development. He represents the classic black swan.

On the other hand, if you believe that endothelial damage is the primary driver of CVD, this case history makes perfect sense. It also explains how the other fourteen things on my list increase the risk of CVD, whereas the current ‘LDL hypothesis’ can explain precisely NONE of them.

Which makes it – fourteen-nil to the endothelial damage hypothesis, and we have not even reached half time. Russell Ross – who first proposed the ‘response to injury’ hypothesis would be pleased with this result. As would, I hope, Elspeth Smith. Unfortunately, they are both now dead. But I hope to see that they get the posthumous recognition that they deserve.

They were telling us what truly does cause CVD, but no-one was listening. Everyone else was content to blindly follow the ‘cholesterol hypothesis’ waving flags, cheering, and raking in the money.

1: http://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0090314&type=printable

2: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5215745/

3: https://www.sciencedirect.com/science/article/pii/S1533316707000192

22nd March 2018

A year ago, I wrote a blog suggesting that lead – as in the element – could have caused/causes a great deal of cardiovascular disease. I went further, to propose that the removal of lead as an additive in petrol (gasoline) may have been responsible for a significant percentage of the decline in cardiovascular disease in the Western World, over the last forty or fifty years.

Last week a paper was published suggesting that excess lead was responsible for as many deaths as smoking ¹. So, there you go, it turns out I was right. Once again. Yes, yes, I know, Nobel prize on the way. Or perhaps not.

In fact, what cheered me most about this study is that my hypothesis that endothelial damage is the trigger for CVD, was strongly supported. Some time ago I set about looking for factors/things that were capable of damaging the endothelial cells that line arteries. I tend to do this by going to Google and typing in the words endothelial damage ‘and’ copper, or lead, or mercury, or glucose, or smoking, or sickle cell anaemia etc. etc.

Then I see what pops up. At which point I switch to PubMed to look for the associated papers in the area. As it turned out when you hit lead and endothelial damage there was not a great deal, but it is fascinating, and it is clear that lead does damage endothelial cells, in various ways. It also damages many other things in the body – but that is another story.

This relatively unstructured searching system is how I ended up looking at chelation therapy. This form of treatment is/was supposed to remove heavy metals, such as lead, from the body. I had written it off as ‘woo-woo medicine’ (a phrase I actually hate, but I thought it was appropriate here). So, you use drain cleaner in arteries and this makes you better. Yes, right, pull the other one. Bong, next.

Oh well, you live and learn. Turns out that chelation actually works².

The second thing about the latest paper demonstrating the impact of lead on CVD is that the endothelial damage conjecture had proven ‘predictive’. The best scientific hypotheses are those you can use to predict what is going to happen in the future or better explain the facts of what happened in the past.

As an example of a good predictive hypothesis, we know that if we stand in a specific place, at a specific time, we will see an eclipse of the sun. We know this because we have been told that it will happen by people, who get this right 100% of the time.

If, on the other hand, someone says global temperature will rise by two degrees in the next twenty years, and it does not, we should be rightly sceptical that the scientists predicting this have got their ideas properly nailed down. We should also be sceptical when people alter their hypothesis to fit the facts. Global Warming has become Climate Change. Which some, like me, would say has changed their hypothesis from one that can be disproven, to one that cannot. ‘We predicted the Climate would change, and look it has. Told you so.’

‘Well gee whizz that was just so extremely helpful. Thanks.’

Anyway, to get back to endothelial damage. My conjecture is that, if you can find a factor that damages the endothelium, you will find that it increases the risk of CVD. It is not enough to say that most things that damage the endothelium increase the risk of CVD, or that almost everything that damages the endothelium increases the risk of CVD. It has to be everything.

There are, of course, provisos. We know that smoking increases the risk of lung cancer. We also know that some people who smoke never get lung cancer. So, on an individual basis, there can be protective things going on. Ergo, I would not expect everything that causes endothelial damage to cause CVD, in everyone.

Equally, we know that the tuberculous bacillus causes TB. However, not everyone that is exposed to the bacillus gets TB. We also know that people who carry the gene for CCR5 delta 32 mutation cannot be infected with HIV or Ebola. Why not? Because their cells do not code for the protein that allows these viruses to gain entry to cells. Just thought I would throw that one in. I am not just interested in CVD, you know.

In reality, there is almost nothing that is both necessary and sufficient to cause disease, or death – in everybody. Some people have survived falling out of aeroplanes without a parachute. Not many, but it has happened. Ebola kills up to 80% of those it infects, but some survive.

So, what I spend a lot of time doing is attempting to establish is whether or not endothelial damage is ‘necessary’ for CVD to develop [not that it is sufficient in everyone]. Or as someone told me on the blog ‘If and only if.’ As in, CVD will develop if, and only if, endothelial damage has occurred.

So, are there contradictions to the endothelial damage hypothesis? Well, if there are, I have yet to find them. Which does not mean that they do not exist. The closest I have come to a contradiction is with thalidomide. Everyone has heard of this drug, and the terrible malformations it caused. I suspect not many people know why it caused limb malformations.

It is because it interferes with the production and growth of endothelial cells. Because these cells did not grow and develop, blood vessels did not develop and grow in the unborn child, so there was no blood supply to support limb growth. So, the limbs were terribly shortened. I suspect that if thalidomide had been given at an earlier stage of the pregnancy the heart, brain, lungs etc. would have failed to develop and the foetus would have been non-viable – with spontaneous abortion.

Because thalidomide interferes with the formation of new blood vessels (angiogenesis) it is now used to treat cancer, and leprosy, and a few other things as well. Cancers need their own blood supply to grow, and if you stop them triggering new blood vessel growth and development the shrivel up and die. At least, that is the plan.

Other drugs have been developed to stop angiogenesis. One of the first was Avastin. Technically, it is a Vascular Endothelial Growth Factor (VEGF) inhibitor. It inhibits the growth of new endothelial cells. It is also widely used in macular degeneration, where the growth of new blood vessels in and around the macula (the main bit of the retina you use to see with), destroys the vision.

Unfortunately, Avastin has a significant adverse effect. You can probably guess what it is. Yes, it increases atherosclerotic plaque growth, and significantly increases the risk of death from CVD. In high doses, over two years, up to a 1,200% increase in heart attacks³.

Now thalidomide is not exactly the same as Avastin, but it definitely has a negative impact on endothelial cells in some way. But I can find no evidence for thalidomide increasing CVD risk. I can find evidence that, if you give thalidomide to pregnant animals, they too demonstrated limb deformity in offspring. However, if you give Viagra this eliminates the deformity. So, we know that inhibition of nitric oxide (NO) must be a key mechanism of endothelial dysfunction with thalidomide.

Therefore, it should increase CVD risk. Does it, or does it not? Well, you can read this paper ‘Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications.’⁴ And try to decide if it does, or it does not. Personally, I cannot figure it out at all. I am kind of hoping that it does, or else my theory is in danger of hitting the waste bin.

Until next time.

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

2: https://universityhealthnews.com/daily/heart-health/the-therapy-nobody-wants-you-to-know-about-found-to-successfully-treat-heart-disease

3: https://www.sciencedirect.com/science/article/pii/S0167527313004282

4: http://www.bloodjournal.org/content/99/12/4525.full

13th March 2018

Before putting cardiovascular disease to bed for a while and talking about other things – such as diabetes – I thought I should highlight a fact that is almost never remarked upon yet is extremely important. At least it is, if you trying to bring down the cholesterol hypothesis. The fact is this. A raised cholesterol level, or LDL level, is not a risk factor for stroke. Not even in familial hypercholesterolaemia (FH) is a raised cholesterol level a risk factor for stroke.

Here, I am quoting from a study published in the Lancet called ‘Cholesterol, diastolic blood pressure, and stroke: 13,000 strokes in 450,000 people in 45 prospective cohorts. Prospective studies collaboration.’

‘After standardization for age, there was no association between blood cholesterol and stroke except, perhaps, in those under 45 years of age when screened. This lack of association was not influenced by adjustment for sex, diastolic blood pressure, history of coronary disease, or ethnicity (Asian or non-Asian).’ ¹

I think that this was a big enough study to demonstrate that, if there is any effect, it can only be tiny. Yes, the study is over twenty years old, but it was done before statins came along to distort the entire area. By which I mean after the mid-nineties, a large number of people with raised cholesterol were being put on statins, thus making any interpretation of the impact of different cholesterol levels, on stroke, almost impossible.

As for Familial Hypercholesterolaemia. The findings of the Simon Broome registry (set up in the UK to study the health impact of FH) were, as follows

‘The data also confirm our earlier findings that FH patients are not at a higher risk of fatal stroke.’ ²

Thus, a raised cholesterol level is not a risk factor for stroke, even at very high levels found in FH – even in homozygous FH (where both the subject’s genes are faulty so leading to more severe FH). Yet, and yet, statins reduce the risk of stroke. Not by much, and not to the extent that I consider the benefits to outweigh the harms, but they do. Here, plucked from a million possible articles is something from the American Heart Association

‘Millions more people worldwide may benefit from cholesterol-lowering statins after a global study showed the drugs help reduce heart attacks and strokes in people at moderate risk. The risk fell slightly further when patients also took blood pressure drugs.’ ³

The absolute figures wobble about, depending of which of the myriad studies and meta-analyses you choose to look at, but the reduction in stroke risk is about the same as the reduction in the risk of heart attacks/myocardial infarctions.

When I see facts like this, I try to use logic. The logic, in this case, goes something like this:

• Factor A (raised LDL) is not a risk factor for disease B (stroke)
• However, if you lower factor A, the risk of disease B falls

Conclusion. Something other than the lowering of Factor A is causing the reduction in the risk of disease B. If you take this thought one step further, the beneficial effect of statins on the risk of stroke, flatly contradicts the cholesterol hypothesis.

1: https://www.ncbi.nlm.nih.gov/pubmed/8551820

2: https://academic.oup.com/eurheartj/article/29/21/2625/530400/Reductions-in-all-cause-cancer-and-coronary

3: https://news.heart.org/statins-lower-heart-attack-stroke-risk-in-people-at-average-risk/