Category Archives: Cardiovascular Disease

What causes heart disease part 52

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.





What causes heart disease part 51 – ‘Athero-thrombosis’.

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.


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.





What causes heart disease – part fifty

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 alllook, 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:

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 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

Why saturated fat cannot raise cholesterol levels (LDL levels)

3rd July 2018

“Explanations exist; they have existed for all time; there is always a well-known solution to every human problem — neat, plausible, and wrong.’ H.L. Mencken.

Of all the flaws of the human mind, the number one must be the overwhelming desire to find simple, easy to understand answers – to everything. I think this is why my favourite film of all time is Twelve Angry Men. It was a stage play first.

A black youth is accused of killing his father. The evidence that is presented by the prosecution seems utterly overwhelming. A unique knife is used for the murder, one that the youth was known to carry. He was seen leaving the apartment after shouting ‘I’ll kill you’ and suchlike. Most importantly, however, he was a young black youth, and young black youths are widely considered to be the sort of person who do such things.

In the film, prejudice presses down heavily on most of the jurors. Some of them, it is hinted, would have found him guilty no matter if there had been any evidence, or not. Here we have all the worst aspects of human decision making on show. Confirmation bias, prejudice, gathering together only the evidence that supports a case, the desire to ‘get on with it’ and not hang about listening to people who just want to make things complicated.

In my mind, for many years, I have changed ‘black youth’, into the word ‘cholesterol’ as I watch the ‘heart disease jurors’ in action. A suspect was found, fitted up, put on trial and found guilty by people who were just desperate to get on with it. At the very first congressional meetings on dietary guidelines, any attempts to wait until there was sufficient evidence, were railroaded.

When the US government introduced “Dietary Goals for the United States”, they did not have unanimous support. The guidelines, which urged the public to cut saturated fat from their diet, were challenged by a number of scientists in a Congressional hearing. The findings were not based on sufficient evidence, they argued.

They were ignored. Dr. Robert Olson recounts an exchange he had with Senator George McGovern, in which he said: “I plead in my report and will plead again orally here for more research on the problem before we make announcements to the American public.” McGovern replied: “Senators don’t have the luxury that the research scientist does of waiting until every last shred of evidence is in.’1

Senator McGovern might as well have said. ‘Listen son, we know that saturated fat raises cholesterol and causes heart disease, we don’t need any damned evidence.’ Of course, they didn’t have any evidence at all. None. But they still managed to find saturated fat and cholesterol guilty. Some people would call this proper leadership. Make a decision and go with it.

I would call it monumental stupidity.

As you can see I am stepping back in this blog to look at saturated fat – again. Because I am going to share some thinking with you, which I have not really shared before. Some of you will know that I am a ‘first principles’ kind of guy. I take very little at face value, and I am certainly highly critical of accepted wisdom: I usually translate it, in my mind, into accepted stupidity.

So, I am going to try and explain to you that saturated fat cannot raise blood cholesterol levels. By which I mean low density lipoprotein levels (LDLs) as this is the substance which someone or another ended up calling ‘bad’ cholesterol. It is the lipoprotein that is thought to cause CVD.

However, LDL is not cholesterol, it never was. We do not have a blood cholesterol level – but we are seemingly stuck with this hopelessly inaccurate terminology for all time.

Anyway, the idea that saturated fat raised cholesterol was driven by Ancel Keys in the late nineteen forties. The first point to make here is that, when Keys first started his anti-fat crusade, no-one knew that there was such a thing as LDL. You took a blood test, gathered together all the lipoproteins you could find (good, bad, and indifferent) and measured them all. Quite what they were measuring is a good question.

Despite this rather important gap in his knowledge, Ancel Keys was able to create an equation to exactly predict the effect of saturated and polyunsaturated fatty acids in the diet on serum cholesterol levels.

Change in serum cholesterol concentration (mmol/l) = 0.031(2Dsf − Dpuf) + 1.5√Dch

[Where Dsf is the change in percentage of dietary energy from saturated fats, Dpuf is the change in percentage of dietary energy from polyunsaturated fats, and Dch is the change in intake of dietary cholesterol].

This became the accepted wisdom. You could believe, given the apparent precision of this equation, that he did some proper research to prove it was true. Frankly, it seems bloody unlikely, as the equation contains the ‘change in dietary cholesterol’ as a key factor in raised blood cholesterol levels. It is now accepted that cholesterol in the diet has no significant impact on blood cholesterol levels. Keys even knew this himself.

To quote him from a paper in 1956:

‘In the adult man the serum cholesterol level is essentially independent of the cholesterol intake over the whole range of human diets.’

In 1997 Keys wrote this:

“There’s no connection whatsoever between cholesterol in food and cholesterol in blood. And we’ve known that all along. Cholesterol in the diet doesn’t matter at all unless you happen to be a chicken or a rabbit.” Ancel Keys, Ph.D., professor emeritus at the University of Minnesota 1997.

More recently, the fact that cholesterol in the diet has no impact on ‘cholesterol levels’ or CVD was reaffirmed. In 2015, the Dietary Guidelines Advisory Committee in the US, having reviewed all the evidence made this statement:

“Cholesterol is not considered a nutrient of concern for overconsumption.” 2

This was even supported by the likes of Walter Willet and Steven Nissen:

‘Nutrition experts like Dr. Walter C. Willett, chair of the Department of Nutrition at Harvard School of Public Health, called the plan a reasonable move. Dr. Steven Nissen, chair of cardiovascular medicine at the Cleveland Clinic, told USA Today “It’s the right decision. We got the dietary guidelines wrong.3

Anyway, Keys had started out with a hypothesis that cholesterol in the diet raised cholesterol levels in the blood but discarded it after feeding eggs to volunteers (eggs contain more cholesterol than any other food) and finding that their cholesterol level remained stubbornly unchanged.

Undaunted, he did what no scientist should ever do. He simply changed the hypothesis. The nutrient of concern was no longer cholesterol, it was saturated fat. So, what is it about saturated fat that can raise LDL? I wanted to know the exact, proven, mechanism.

We start with the certain knowledge that the body is exceptionally good at keeping all substances in the blood under strict control. If the level of something rises too high, mechanisms are triggered to bring them back under down, and vice-versa. The entire system is known as homeostasis.

Thus, if saturated fat intake really does cause LDL levels to reach damaging levels, it must be overcoming homeostasis, and breaking metabolic and physiological systems. How does it do this?

To try to answer this question we should look at what happens to saturated fat when we eat it. The first step is that it binds to bile salts in the bowel. Bile salts are a form of mildly adapted cholesterol, synthesized in the liver and released from the gall bladder. Without bile, fat cannot be absorbed well, if at all, and simply passes through the guts and out the other end.

The absorbed saturated fat is then packed into a very large lipoprotein (known as a chylomicron). Once a chylomicron is formed it travels up a special tube, called the thoracic duct, and is released directly into the blood stream. It does not, and this is important, pass through the liver.

Chylomicrons then travel around the body and are stripped of their fat, shrinking down until they become about the size of an LDL. At which point they are called chylomicron remnants. These are absorbed back into the liver – using LDL receptors – and are then broken down into their constituent parts

Therefore, a small amount of fat that you eat will end up in the liver. However, the vast, vast, majority will go straight from the guts to fat cells (adipose tissue). Whereupon they are stored away for later use.

In fact, this is the fate of all types of fat: saturated, polyunsaturated, or monounsaturated. There is nothing unique about saturated fat in the way that it is absorbed and transported around the body. Anyway, as you may have noticed, none of this has anything to do with LDL whatsoever. Nothing. Ergo the consumption of saturated fat, or any fat, can have no direct impact on LDL levels.

I suppose the next question to ask is simple. Where does LDL come from? LDL is created when VLDLs (very low-density lipoproteins) shrink down in size. VLDLs are the type of lipoproteins that are synthesized in the liver, then released into the bloodstream. They contain fat and cholesterol and, as they travel around the body, they lose fat and become smaller and smaller, until they become an LDL -which contains proportionately more cholesterol.

Almost all LDL molecules are removed from the circulation by LDL receptors in the liver. They are then broken down and the contents used again. Some LDL continues to circulate in the blood, and cells that need more cholesterol synthesize an LDL receptor to bind to LDL molecules and bring the entire LDL/LDL receptor complex into the cells.

Just to re-cap. Saturated fat (any fat) is absorbed from the gut and packed into chylomicrons. These travel around the body, losing fat, and shrink down to a chylomicron remnant – which is then absorbed by the liver. There is no connection between chylomicrons and LDL.

Instead LDL comes from VLDL. VLDLs are made in the liver, they contain fat and cholesterol. VLDLs leave the liver, travel around the body and lose fat, shrinking down to become an LDL.

As the only source of LDL is VLDL, this leads to the next obvious question. What makes VLDL levels rise? Well, it sure as hell isn’t fat in the diet. What causes VLDL levels to rise is eating carbohydrates. The next quote is a bit jargon heavy but worth including.

De novo lipogenesis is the biological process by which the precursors of acetyl-CoA are synthesized into fatty acids [fats]. In human subjects consuming diets higher in fat (> 30 % energy), lipogenesis is down regulated and extremely low; typically < 10 % of the fatty acids secreted by the liver. This percentage will increase when dietary fat is reduced and replaced by carbohydrate.’4

To simplify this as much as possible. If you eat more carbohydrates than your body needs, or can store, the liver converts the excess (primarily fructose and glucose) into fat in the liver. This process is called de novo lipogenesis (DNL) The fats that are synthesized are saturated fats, and only saturated fats. Once synthesized they are then packed into VLDLs and sent out of the liver.

In short, if you eat fat, the VLDL level falls. If you eat carbohydrates the VLDL level rises. Which is pretty much what you would expect to see.

Moving the discussion on, as VLDLs are the only source of LDL. you now have a conundrum to solve. How can you connect saturated fat intake to a rise in LDL levels, when saturated fat consumption reduces VLDL synthesis? What is the mechanism? The mechanism does not exist!

You could counter by saying, what of the many studies that have shown a fall in LDL when saturated fats are replaced by polyunsaturated fats? Well, this seems to have been shown often enough for me to believe it may even be true.

The explanation for this finding is most likely the fact that, in these studies, saturated fats were replaced by polyunsaturated fats, from plant oils. Plant oils contains stanols (the plant equivalent of cholesterol).

Stanols are known to lower LDL levels, see under Benecol and other suchlike ‘low fat’ spreads. Because stanols compete with cholesterol for absorption there is an impact on the ‘measured’ LDL levels. What this means, in turn, is that the studies that demonstrate a lower LDL, with a reduction in saturated fat consumption, fall foul of the two variables problem.

Namely, if you change two variables in an experiment at the same time, you cannot say which of the variables was responsible for the effect you have seen. Was it the reduction in saturated fats, or the increase in plant stanols, that lowers LDL?

This is all tacitly accepted in this Medscape article – again heavy on jargon: ‘Saturated Fat and Coronary Artery Disease (CAD): It’s Complicated.’

‘In a meta-analysis of over 60 trials, higher intakes of saturated fat were associated with increases in both LDL-C and high-density lipoprotein cholesterol (HDL-C) and decreases in triglyceride levels [VLDL}, for a net neutral effect on the ratio of total cholesterol to HDL cholesterol.

Although saturated fats increase LDL-C, they reduce the LDL particle number. Total LDL particle number quantifies the concentration of LDL particles in various lipid subfractions and is considered a stronger indicator of CV risk than traditional lipoprotein measures.

As for stearic acid, the allegedly non-cholesterol-raising fat, while it appears to lower LDL-C relative to other SFAs, one analysis concluded that it raised LDL-C, lowered HDL-C, and increased the ratio of total to HDL cholesterol in comparison with unsaturated fatty acids. And this is one of the confounders of much nutrition research—observations about a given nutrient are highly dependent on what you compare it to.’5

Which is a long-winded way of saying that everything we have been told about saturated fat, its impact on LDL, and its impact on CVD is – frankly – complete bollocks. And if it is complete bollocks, the Keys equation – which has driven all research in this area for seventy years – is also bollocks.

In truth, all possible combinations of LDL going up, down, and staying the same have been found in dietary studies. But I would like to focus on the most recent study. It formed the basis of an episode of a programme called ‘Trust me I’m a doctor’, on the BBC. Researchers studied the impact of different types of saturated fat on LDL and HDL levels.

‘For the experiment, the team recruited nearly one hundred volunteers, all aged over fifty. They were split into three groups and every day for four weeks each ate fifty grams of coconut oil (about two tablespoons), or fifty grams of olive oil – an unsaturated fat already known to lower bad LDL cholesterol – of fifty grams of butter.

This amount of coconut oil contains more than forty grams of saturated fat, twice the maximum recommended daily amount for women, according to Public Health England, but is the level previous research has revealed is necessary to show measurable changes in blood cholesterol over a four-week period.

Before the experiment, all the volunteers had their bad LDL and good HDL cholesterol measured, as well as their height, waist, blood pressure, weight and body fat percentage. Four weeks later, these tests were repeated.

The group who ate butter saw their bad LDL levels rise by about ten per cent, as expected. But the olive oil and coconut oil saw no rise in bad LDL – despite coconut oil having more saturated fat than butter.’

Even more surprisingly, while butter and olive oil both raised good HDL cholesterol by five per cent, coconut oil raised it by a staggering fifteen percent, meaning that it seemed to have a more positive effect on cholesterol related health than olive oil.’ 6

It is worth pointing out that this was the largest study of the kind ever to have been done. This may surprise you, but in many nutritional studies the number of subjects is often in single digits. In case you are thinking we can simply ignore a study done by the BBC, it was carried out to high standards, and has since been published in the BMJ. Equally I can see no reason why the BBC would have any desire to bias the conclusions in any direction.7

What they found was that coconut oil, containing the highest percentage of saturated fat, had absolutely no impact on LDL. But it did raise HDL (so-called ‘good’ cholesterol) by 15%. Which is no surprise. If VLDL goes down, HDL goes up. And in this experiment they kept everything else the same, but just added saturated fat. A single variable.

Anyway, the thing that interests me most, and the reason for writing this particular blog is that I have come to the realisation that the best way to find the answer to a scientific question is to immerse yourself in the science. I would like to believe the published research, because it would be lovely if you could look at a study and believe it to be correct/true/unbiased. But that is no longer possible, most especially in the connected fields of heart disease, and nutrition.

‘It is simply no longer possible to believe much of the clinical research that is published, or to rely on the judgement of trusted physicians or authoritative medical guidelines.” Marcia Angell – long-time editor of the NEJM.

‘The case against science is straightforward: much of the scientific literature, perhaps half, may simply be untrue…science has taken a turn towards darkness.’ Richard Horton – editor of The Lancet.

‘The poor quality of medical research is widely acknowledged, yet disturbingly the leaders of the medical profession seem only minimally concerned about the problems and make no apparent efforts to find a solution.’ Richard Smith – long time editor of the BMJ.

It is always, of course, risky to base your thinking and conclusions on what is known about the basic science. New facts can come along to upend your thinking at any time. However, with mainstream medical research in such a corrupt mess, I do not know how else to do it. The basic research tells us that there is no mechanism whereby saturated fat can raise LDL levels, and the research, such as it can be disentangled, appears to fully support this.

I looked at this blog again, and again, and I thought: Why did I write it…for sure? I wrote it because I wanted to make you aware of three things. First, how powerful a thought can be. Saturated fat raises the LDL level, and how difficult this is to shift. The power of a simple idea.

Secondly, so that you can see that the truth is out there. It is not to be found amongst the experts in the field. It cannot be found by reading the research, or the guidelines. But it is out there, if you look hard enough.

Third, the mainstream just will not change its mind. A recent conference in Switzerland, organised by the BMJ, and others, tried to discuss the dietary guidelines and the role of Saturated fat. I was invited, but did not go, as I was working. Zoe Harcombe went, and wrote a blog about it.8  As she wrote about the conclusion of the conference:

‘At the recent Swiss Re/The BMJ Food for Thought conference, the closing speakers tried to find some agreement on dietary fat guidelines…

Fiona (Fiona Godlee, editor of the BMJ) started with: “The point about saturated fat is: the evidence is now looking pretty good, but the guidance hasn’t shifted… there doesn’t seem to have been an enormous ‘mea culpa’ from the scientific community that we got it so wrong. That does surprise me.”

Salim replied: “We got brainwashed by a very questionable study, called The Seven Countries Study, many years ago and it was ingrained in our DNA and generations of us were brought up with that… Somebody said that you need to wait for guidelines committees to die before you can change the guidelines committees”!

Fiona then said: “Maybe one outcome of this meeting would be for this meeting to say ‘that’s gone now’, the science has changed. Am I right Salim? Am I right Dariush? It seems to be that should be an outcome of some sort from this meeting.”

Alas, the UK guidelines committee shows no signs of such change, let alone the ‘mea culpa’ that Fiona suggests might be in order.’











What causes heart disease? – part 49 (nearly there)

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 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.




Very high LDL and no cardiovascular disease – at all!

12th May 2018

[A classic black swan]

If your hypothesis is that all swans are white, the discovery of one black swan refutes your hypothesis. That is how science works. Or at least that is how science should work. In the real world, scientists are highly adept at explaining away contradictions to their favoured hypotheses. They will use phrases such as, it’s a paradox. Or, inform you that you didn’t measure the correct things, or there are many other confounding factors – and suchlike.

Anyway, accepting that the finding of someone with a very high LDL level, and no detectable atherosclerosis, will always be dismissed – in one way or another – I am still going to introduce you to a ‘case history’ of a seventy-two-year-old man with familial hypercholesterolaemia, who has been studied for many, many, years. Try as they might, the researchers have been unable to discover any evidence for cardiovascular disease (CVD) – of any sort.

In the past, I have spoken to many people with very high LDL and/or total cholesterol levels who are CVD free, even in very old age. The mother of a friend of mine has a total cholesterol of level of 12.5mmol/l (483mg/dl). She is eighty-five, continues to play golf and has not suffered from any cardiovascular problems.

However, none of these people had been studied in any detail. Which means that they can, and are, dismissed as irrelevant ‘anecdotes’. Yes, the widely used and highly exasperating phrase that I often encounter is that ‘the plural of anecdote is not data’. This, of course, is completely untrue, or at least it is untrue if you start dismissing detailed individual cases as anecdote.

Whilst an anecdote may simply be a story, often second hand, a case history represents a painstaking medical history, including biochemical and physiological data. In reality, the plural of case histories is data. That is how medicine began, and how most medical breakthroughs have been made. We look at what happens to real people, over time, we study them, and from this we can create our hypotheses as to how diseases may be caused and may then be cured.

So, a single case is NOT an anecdote, and cannot be lightly dismissed with a wave of the hand and a supercilious smirk.

In fact, the man who is the subject of this case history has written to me on a few occasions, to tell me his story. I have not written anything about him before, as I knew his case was going to be published, and I did not want to stand on anyone’s toes. With that in mind, here we go.

The paper was called ‘A 72-Year-Old Patient with Longstanding, Untreated Familial Hypercholesterolemia but no Coronary Artery Calcification: A Case Report.’ 1

The subject has a longstanding history of hypercholesterolemia. He was initially diagnosed while in his first or second year as a college student after presenting with corneal arcus and LDL-C levels above 300 mg/dL [7.7mmol/l]

He reports that pharmacologic therapy with statins was largely ineffective at reducing his LDL-C levels, with the majority of lab results reporting results above 300 mg/dL and a single lowest value of 260 mg/dL while on combination atorvastatin and niacin. In addition to FH-directed therapy, our subject reports occasionally using baby aspirin (81 mg) and over-the-counter Vitamin D supplements and multivitamins.

In the early 1990s, our patient underwent electron beam computed tomography (EBCT) imaging for CAC following a series of elevated lipid panels. Presence of CAC (coronary artery calcification) was assessed in the left main, left anterior descending, left circumflex, and right coronary arteries and scored using the Agatston score.

His initial score was 0.0, implying a greater than 95% chance of absence of coronary artery disease. Because of this surprising finding, he subsequently undertook four additional EBCT tests from 2006 to 2014 resulting in Agatston scores of 1.6, 2.1, 0.0, and 0.0, suggesting a nearly complete absence of any coronary artery calcification. In February of 2018, he underwent multi-slice CT which revealed a complete absence of coronary artery calcification.

So, here we have a man who has an LDL consistently three to four times above ‘average’. He had tried various LDL lowering agents over the years. None of which had done anything much to lower LDL. Therefore, his average LDL level over a twenty-year period has been 486mg/dl (12.6mmol/l.

Despite this he has absolutely no signs of atherosclerotic plaque, in any artery, no symptoms of CVD and is – to all intents and purposes – CVD free. What of his relatives? If he has FH, so will many others in his family.

‘He has one sister three years his senior who also has FH and a history of high lipid levels. She also has no history of myocardial infarction, angina, or other symptoms of coronary artery disease. His mother had FH, although she died of pancreatic cancer at age 77. She and her three siblings were never treated for, and had no history of, cardiovascular disease. The patient reports that his father had one high cholesterol score (290s), but was never diagnosed with FH, had no history of cardiovascular disease and died in his 80s during surgery for hernia repair.’

What to make of this? Well, I know that the ‘experts’ in cardiology will simply ignore this finding. They prefer to use the ‘one swallow does not a summer make’ approach to cases like this. For myself I prefer the black swan approach to science. If your hypothesis is that a raised LDL causes CVD, then finding someone with extremely high LDL, and no CVD, refutes your hypothesis.

Unfortunately, but predictably, the authors of the paper have not questioned the LDL approach. Instead, they fully accept that LDL does cause CVD. So, this this man must represent ‘a paradox’. They have phrased it thus:

‘Further efforts are underway to interrogate why our patient has escaped the damaging consequences of familial hypercholesterolemia and could inform future efforts in drug discovery and therapy development.’

To rephrase their statement. We know that high LDL causes CVD. This man has extremely high LDL, with no CVD, so something must be protecting him. I have an alternative, and much simpler explanation: LDL does not cause CVD. My explanation has the advantage that it fits the facts of this case perfectly, with no need to start looking for any alternative explanation.

And just in case you believe this is a single outlier, something never seen before or since. Let me introduce you to the Simon Broome registry, set up in the UK many years ago to study what happens to individuals diagnosed with familial hypercholesterolaemia (FH). It is the longest, if not the largest, study on FH in the world.

It has mainly been used as one of the pillars in support of the cholesterol hypothesis. However, when you start to look closely at it – fascinating things emerge. One of the most interesting is that people with FH have a lower than expected overall mortality rate – in comparison to the ‘normal’ population. Or, to put this another way. If you have FH, you live longer than the average person.

Even if we look at death from heart disease (those with FH have never been found to have an increased rate of stroke) we find that in the older population, the rate of death from Coronary Heart Disease (CHD) was actually lower than the surrounding population in some age groups.

For instance, in the male population aged 60 – 79 (who were CHD free on entry to the study) the rate of death from heart attacks was lower than the surrounding population. Not significantly, but it certainly was not higher.

In fact, in the total male population aged 20 – 79 with FH, the rate of death from CHD was virtually identical to the surrounding population. Over a period of 13,717 years of observation, the expected number of fatal heart attacks was calculated to be 46. The actual observed number was 50.

In women, the expected number of heart attacks in the population aged 20 – 79 was 40, the actual number of observed fatal heart attacks was 40. Which means that FH was not found to be a risk factor for CHD in those enrolled in the study – who had no diagnosed heart disease prior to enrolment2.

Which represents, I suggest, another fully grown black swan. There you go. Two in one day.




What causes heart disease part forty-eight (48)

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.





What causes heart disease part forty-seven

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.




What causes heart disease part 46

14th February 2018

The mind

The final big-ticket item on my list, of how to avoid CVD and live longer, is poor social interactions, and the strain caused by them, or whatever you want to call this rather difficult to define area. Here we have a whole range of different, interconnected, issues. Childhood abuse, family breakup, abusive partner, financial difficulties, abusive and bullying boss at work, social isolation, mental health issues, loneliness, no sense of being part of a supportive family or group – religious or otherwise.

The simple fact is that we humans are social animals. We require nurture and support by others. We need a sense of belonging, a sense of value and purpose. We need to be loved, not hit, or shouted at, or bullied, or treated with contempt.

When I first started looking at CVD, this was the area that I focussed on. It seemed obvious to me, that there was an enormously important mind/body connection that was simply being ignored by mainstream research into heart disease – and all other diseases. Despite the complete lack of interest by most researchers, whenever and wherever you look, if you chose to see, psychological/mental health issues were standing right there, waving their arms about and shouting me, me, me, me. Look at ME!

The full impact of negative stressors was highlighted in a study that was sent to me a few months back. Researchers found that people who suffer from significant money worries are thirteen times more likely to suffer a heart attack. Yes, thirteen times more likely, or 1,300%. Now that is the level of increased risk where I tend to prick up my ears and pay attention. Relative risk, or not1.

It is also clear that mental health, or mental illness, plays a massive role in overall health and life expectancy, as highlighted by researchers from Oxford University.

‘Serious mental illnesses reduce life expectancy by 10 to 20 years, an analysis by Oxford University psychiatrists has shown – a loss of years that’s equivalent to or worse than that for heavy smoking….

The average reduction in life expectancy in people with bipolar disorder is between nine and 20 years, while it is 10 to 20 years for schizophrenia, between nine and 24 years for drug and alcohol abuse, and around seven to 11 years for recurrent depression.’2

Yes, when your mind goes wrong, your body follows, with disastrous consequences for overall health. Of course, there is overlap between mental illness, drug use, smoking and suchlike. However, you can strip out all the other things, and you are left with the ferocious power of the mind/body connection. The power to nurture, and the power to destroy.

I usually tell anyone, still listening after I have bored them on various other issues, that health is a combination of physical, psychological and social wellbeing. Three overlapping sets. The holy trinity of wellbeing. You must get them all right, or nothing works. As Plato noted, a few years back “the part can never be well unless the whole is well.”

Who are the shortest-lived peoples in the world? Are they the poor? Not necessarily, although poverty can be a clear driver of ill-health. The shortest-lived people in the world are people who live in the places of greatest social dislocation and disruption. Or, to put it another way, people who have had their societies stripped apart. Australian aboriginals, NZ Maoris, North American aboriginals, the Inuit.

‘Indigenous Australians have the worst life expectancy rates of any indigenous population in the world, a United Nations report says. But it’s not news to Aboriginal health expert. They say it simply confirms what Australian health services have known for years.

Aboriginal Medical Services Alliance of the Northern Territory (AMSANT) chief executive officer John Paterson said the findings of the report, which examined the indigenous populations of 90 countries, were no surprise. The UN report – State of the World’s Indigenous Peoples – showed indigenous people in Australia and Nepal fared the worst, dying up to 20 years earlier than their non-indigenous counterparts. In Guatemala, the life expectancy gap is 13 years and in New Zealand it is 11.’ 3

Twenty years earlier. I think that figure is worth repeating. I cannot find anything else, from anywhere, that gets close to that sort of impact on health – on a population basis.

Or, to put it another way, do not be a stranger in your own land. It kills you. The differences in life expectancy in the US or the UK mirror these findings, albeit less dramatically. There are areas, within deprived inner-cities in the UK, where people do almost as badly as Australian aboriginals.

It does not take a genius to guess where they might be. Inner city Glasgow, Manchester, Liverpool. The same thing can be seen in ghetto areas in virtually all cities in the US. Where the marginalised poor live – but not for terribly long.

‘The differences between places [in the US] are sometimes stark. For example, the average person in San Jose (California District 19) lives to 84 years compared to just 73 years for someone from Kentucky District 5, in the rural south east of that state.’4

On a more positive note, living in supporting and positive environments, is exceedingly good for you. The Blue Zones are areas of the world where people live longer than anywhere else. For example: inland Sardinia, Loma Linda California, Nicoya (Costa Rica), Okinawa, Ikaria (Greece), and a couple of others. [I think I should point out here that they are also, sunny, something not mentioned in the book].

The most important factor was a sense of well-being, community, a connection with other people, a sense of purpose, and good relationships with friends and family. As a slight aside, the author of the book “The Blue Zones”, Dan Buettner, was very focused on the benefits of a high vegetable, low meat diet. He tried hard to promote the idea that diet was the primary driver of good health.

For example, in Sardinia, he wrote the following about the food that was eaten there:

‘It’s loaded with homegrown fruits and vegetables such as zucchini, eggplant, tomatoes, and fava beans that may reduce the risk of heart disease and colon cancer. Also on the table: dairy products such as milk from grass-fed sheep and pecorino cheese, which, like fish, contribute protein and omega-3 fatty acids.’

The Sardinians themselves, however, have a completely different view of what they eat, and they protested the misrepresentation of their diet:

‘In 2011, Sardinians called for formal recognition of their diet insisting that “the secret to a long life can be found in their traditional diet of lamb, roast piglet, milk and cheese.”’5

In fact, many years earlier, researchers studied another Italian community that defied all dietary expectations. This was in the town of Roseta in Pennsylvania. This community had moved, virtually lock stock and barrel, from Roseta in Italy, to a new Roseta in the US. It was noted that they had an extraordinarily low rate of CVD. Why? Here, once again, I quote an article from the Huffington Post:

‘What made Rosetans die less from heart disease than identical towns elsewhere? Family ties. Another observation: they had traditional and cohesive family and community relationships. It turns out that Roseto was peopled by strongly knit Italian American families who did everything right and lived right and consequently lived longer.

In short, Rosetans were nourished by people.

In all ways, this happy result was exactly the opposite expectation of well-proven health laws. The Rosetans broke the following long-life rules, and did so with a noticeable relish: and they lived to tell the tale. They smoked old-style Italian stogie cigars, malodorous and remarkably pungent little nips of a cigar guaranteed to give a nicotine fix of unbelievably strong potency. These were not filtered or adulterated in any way.

Both sexes drank wine with seeming abandon, a beverage which the 1963 era dietician would find almost prehistoric in health value. In fact, wine was consumed in preference to all-American soft drinks and even milk. Forget the cushy office job, Rosetan men worked in such toxic environs as the nearby slate quarries. Working there was notoriously dangerous, not merely hazardous, with “industrial accidents” and gruesome illnesses caused by inhaling gases, dusts and other niceties.

And forget the Mediterranean diets of olive oil, light salads and fat-free foods. No, Rosetans fried their sausages and meatballs in lard. They ate salami, hard and soft cheeses all brimming with cholesterol.6

The Okinawan’s, another of the Blue Zone populations are also known as the pig eaters. It is said that they eat every part of the pig, apart from the squeak. In short, you can focus on the diet of very long-lived people around the world, if you want, but you will find little or nothing here. Much in the same way, you can look at the French, with the highest consumption of animal fat in Europe, and the lowest rate of CVD.

Getting back to the main point in hand. What can we really learn about the Blue Zones is that social health is terribly, terribly, important. Perhaps the single most important factor of all. If your social health goes wrong, your psychological health will suffer, followed by your physical health. More recently it has been recognised, finally, that loneliness is a significant driver of ill health and early death.7

Be happy, be friendly, be healthy. Live long and prosper, my friend.








What causes heart disease part forty-five B – An addendum

29th January 2018


Someone very wise once said. ‘When the facts change, I change my mind. What do you do, Sir?’ Actually, it was John Maynard Keynes (yes, I looked it up).

In my last blog I wrote about Magnesium, thus:

‘As for magnesium. Magnesium deficiency is increasingly recognised as a major health issue and can greatly increase the risk of sudden cardiac death. I now routinely test patients for magnesium levels, as does the rest of the health service, which has belatedly woken up to the importance of this chemical. Magnesium deficiency can also trigger atrial fibrillation (AF) which, in turn, vastly increases the risk of stroke.

But I feel I am running away with myself a bit. I need to stop and take stock. The last thing I want people to do, is to worry too much about the levels of this and that in the blood. I do not want you rushing to the doctor, or private lab, to have everything repeatedly checked.

 Magnesium level deficiency for example. This is almost unknown if you do not take an acid lowering drug such as omeprazole, or lansoprazole (both proton pump inhibitors (PPIs)). Unless you are taking one of these, of any other ‘zoles,’ long term, you are extremely unlikely to be magnesium deficient.’

Well, as it turns out I was wrong. Who me? Someone sent me links to a paper published in the BMJ Open, published this very day, 29th Jan 2018. As it turns out magnesium deficiency is far more common that I thought. The paper is entitled: ‘Subclinical magnesium deficiency: a principal driver of cardiovascular disease and a public health crisis.

‘Subclinical magnesium deficiency is a common and under-recognised problem throughout the world. Importantly, subclinical magnesium deficiency does not manifest as clinically apparent symptoms and thus is not easily recognised by the clinician. Despite this fact, subclinical magnesium deficiency likely leads to hypertension, arrhythmias, arterial calcifications, atherosclerosis, heart failure and an increased risk for thrombosis. This suggests that subclinical magnesium deficiency is a principal, yet under-recognised, driver of cardiovascular disease. A greater public health effort is needed to inform both the patient and clinician about the prevalence, harms and diagnosis of subclinical magnesium deficiency.’

The paper can be read in full, here.

So, when I said I don’t want people to rush about getting the levels of this and that checked, with regard to magnesium I was wrong. I do want people to rush about getting the levels of magnesium checked. [Although I suspect you will not get very far with your local GP].

What is the normal magnesium level?

  • Normal’ serum magnesium levels 0.75–0.95mmol
  • A serum magnesium <0.82mmol/L with a 24-hour urinary magnesium excretion of 40–80mg/ day is highly suggestive of magnesium deficiency.
  • Serum magnesium levels above 0.95mmol/L may indicate hypermagnesaemia

There are more complex tests that can be done, that may need to be done? Because the vast majority of magnesium is not in the blood, it is stored in cells/tissues/organs, you can be down to virtually your last drop, without the blood level being affected.

To find out how your magnesium stores are looking, you can give a magnesium infusion, and see how much is then excreted.

Thoren’s intravenous magnesium load test for diagnosing magnesium deficiency

Provide ~360–480mg of magnesium intravenously over 1hour

If <70% (less than 70%) of the magnesium load comes out in the urine over 16 hours, this is highly suggestive of magnesium deficiency

I have never heard of anyone having this test, ever. Most doctors will never have heard of it either. I only know about it, because I just read this article. Maybe someone can tell me who does it, and how it costs.

Anyway, funny how things turn out. Here I am writing a blog of vitamins and supplements and two days later, out pops a major review article on magnesium. I must be psychic. Or maybe not. But I thought it was important to make you aware of this research. I leave it up to you to decide how to act upon it.

What causes heart disease part forty-five

27th January 2018

Vitamins and supplements and suchlike

I did say I was going to talk about strain and mental health next, but so many people have commented on vitamins and supplements, that I thought I should cover this area. I must say that I do like vitamins, I like the idea of them – and my mother did make me take vitamin C tablets every morning. So, perhaps she is to blame for my early age mental programming.

However, there is very little good evidence that any vitamin supplement is beneficial. In large part this is because there are not huge profits to be made from selling vitamins, as they cannot be patented.

If a company did a major clinical trial on vitamin K, and found that it saved lives, there would be nothing to stop anyone else selling vitamin K, whilst claiming the newly discovered health benefits for themselves. The company that took the financial risk, and funded the trials, would be unable to recoup any research costs.

Another factor in play here is that the pharmaceutical industry is doing its level best to attack vitamins as damaging and dangerous, and lobbying madly to have vitamin supplements banned.1

Once they achieve this state of Nirvana, they can then invent new synthetic vitamins, patent them, and sell them back to us at hugely inflated prices, making massive profits. I just made that bit up, but I wouldn’t put it past them. What they are more likely to do is to add vitamins to various other drugs, to extend patent life. As Merck attempted to do with statins and niacin – and failed.

Another of the problems in trying to get a handle on the potential benefits of vitamins, is that it can be very unclear what the optimal dose, or blood levels, might be. This, I believe is because of the way that vitamins were first discovered.

Over many hundreds of years, it was noticed that some diseases occurred when ‘something’ was missing from the diet. Scurvy was the first of these diseases to be well documented. In 1753 a Scottish surgeon first proposed that lemons and limes could prevent and/or cure the condition. Obviously, he had no idea what it was in the limes and lemons that did the trick.

Other diseases such as pellagra and rickets were then identified as being due to a lack of a substance, of some sort. The term for theses missing substances was coined as ‘vital – amines’. Shortened to vitamins.

It took some time before the vitamins themselves were isolated. The first was vitamin B1, in 1910, the last was vitamin B12 in 1948. There are generally accepted to be thirteen vitamins, many of them are B vitamins, of one sort or another. However, in my opinion there are only twelve. Vitamin D is really a hormone.

I think vitamin D was only classified as a vitamin because no-one knew that it could be synthesized in the skin, from sunlight. Whilst people lived mainly outside, there was no vitamin D deficiency, it was only when the industrial revolution started, and people began to live and work indoors that rickets, (bent malformed bones) became an epidemic. A lack of vitamin D in the diet was identified as the cause.

Thus, Vitamin D looked and acted like a dietary vitamin deficiency, but it was not actually a dietary vitamin deficiency. Or at least only in part. To prevent rickets, children were given milk. Unfortunately, we are now seeing rickets again, because darker skinned Muslim women now fully cover up their skin, and some of them are becoming severely vitamin D depleted.

The reason for this ramble, is to make the general point that vitamins were only identified when major, immediate, and potentially life-threatening illness were identified. Which meant that the first task was the find the dose, or blood level, that prevented things like scurvy and rickets and pellagra. At the time researchers were not looking for longer term effects e.g. prevention of CVD, or cancer, or suchlike. Which means that there is no recommended daily allowance that takes optimal health into account.

I sometimes think of the recommended daily intake of vitamins as being just enough to keep you alive, but no more. A bit like having houseplant that is small and shrivelled. But if you give it some form of plant feed, it bursts into vigorous growth, and is far healthier.

Unfortunately, because we have these hallowed recommended daily intakes, vitamins are viewed by the medical profession as very simple things. You give the vitamin, make sure it gets above a baseline level in the blood, and that’s that. Nothing to see here, move along.

But if we look at just vitamin B12, the reference range (normal range), is all over the place. In the UK is set at 110 – 900ng/l [Itis higher in some regions]. In the US is it between 200 – 900ng/l, and in Japan 500 – 1300ng/l.

In Japan and the US, with a level of 110 you would immediately be given additional B12, in the UK you would be ignored. ‘Your level is fine, go away.’ I have seen many patients who strongly believe that they need additional Vitamin B12 injections, as they feel tired, depressed and suchlike. The NHS simply ignores, unless they have level below 110. Perhaps I should advise them to emigrate to Japan.

An additional problem with vitamin B12 is that the synthetic Vitamin B12 normally used is called hydroxocobalamin. This is then converted into the active form, methylcobalamin, in the body. However, some people cannot metabolise into methylcobalamin and need methylcobalamin injections. Which they cannot get on the NHS. Jolly good. Yes, the more you look into the area, the more complicated, and frustrating, it gets.

Vitamin D is the vitamin most in the news at present. The debate and arguments about vitamin D are becoming quite vitriolic. Some doctors refuse to believe that anyone has a true vitamin D deficiency, others think that the entire population needs to be dosed with added vitamin D during the winter months. I am very much in the latter group.

For example, it has only recently been discovered that that vitamin D has potent anti-cancer effects, and may reduce the risk of CVD. What level of vitamin D is needed to provide these benefits. Almost certainly a much higher level than that required to prevent rickets. Has this level ever been established…no. What about the risk of developing thin bones in old age? No.

Even more recently, a low level of vitamin D has been associated with a much higher level of hospital admission with acute asthma 2. What level is needed to prevent this happening? No idea. As the potential benefits of vitamin D continue to pile up, the minimum blood level remains unchanged and, it seems, unchangeable.

Moving to folate which, despite its name, is another B vitamin. Folate is known to be essential to prevent neural tube defects in the unborn child, and to produce red blood cells and suchlike. Again, the doses to stop these things happening has been established.

However, a recent study in Cambridge has shown that B vitamins, including folate, have significant benefits in reducing homocysteine levels, and if you give them in high doses, way above those currently recommended, they may delay, or even prevent, Alzheimer’s disease and reduce, or prevent, brain shrinkage 3.So, what is the correct dose of folate? Enough to stop neural tube defects, or anaemia, or enough to stop Alzheimer’s?

Can vitamin K prevent atherosclerotic plaques from becoming calcified? Who knows, they have never tested the correct formulation. Can vitamin C reduce the risk of CVD? Who knows? It was tested once in humans, at the wrong dose – at least the wrong dose according to Linus Pauling.

We haven’t the faintest clue about the correct doses, and blood levels of vitamins, required to achieve optimal health. What I do know is that you can take far more than the recommended daily dosage with no problems whatsoever. Vitamins are almost entirely safe. In the US, in 2010, for example, not a single person died from taking a vitamin 4.

On the other hand, you may be interested to read about the total burden of damage and deaths due to correctly prescribed pharmaceuticals. Here, from Harvard University:

‘Few know that systematic reviews of hospital charts found that even properly prescribed drugs (aside from misprescribing, overdosing, or self-prescribing) cause about 1.9 million hospitalizations a year. Another 840,000 hospitalized patients are given drugs that cause serious adverse reactions for a total of 2.74 million serious adverse drug reactions. About 128,000 people die from drugs prescribed to them. This makes prescription drugs a major health risk, ranking 4th with stroke as a leading cause of death. The European Commission estimates that adverse reactions from prescription drugs cause 200,000 deaths; so together, about 328,000 patients in the U.S. and Europe die from prescription drugs each year. The FDA does not acknowledge these facts and instead gathers a small fraction of the cases.5

Zero deaths, versus 328,000 per year. If I were truly looking for something dangerous to ban, it sure as hell would not be vitamins.

So, which vitamins would I recommend taking? My own view is, take vitamin D in the winter, vitamin C always, along with thiamine and Vitamin K2. About five to ten times recommended daily intake should be fine.

What of other supplements, such as: magnesium, co-enzyme Q10, potassium, L-arginine, L-carnitine, Omega-3 fatty acids, and suchlike. Well I am keen on potassium, very keen. I first noted that higher potassium consumption was associated with significantly reduced mortality in the Scottish heart health study.

This was not some minor difference either. We are talking more than a fifty per cent reduction in overall morality, in men 6. Lesser effect in women. This was far from an isolated finding. In study after study, potassium reduces blood pressure and, in turn, reduces the risk of CVD and overall mortality. Interestingly, the Mediterranean diet, such as it exists, tends to be high in potassium 7.

As for magnesium. Magnesium deficiency is increasingly recognised as a major health issue, and can greatly increase the risk of sudden cardiac death. I now routinely test patients for magnesium levels, as does the rest of the health service, which has belatedly woken up to the importance of this chemical. Magnesium deficiency can also trigger atrial fibrillation (AF) which, in turn, vastly increases the risk of stroke.8 But I feel I am running away with myself a bit. I need to stop, and take stock. The last thing I want people to do, is to worry too much about the levels of this and that in the blood. I do not want you rushing to the doctor, or private lab, to have everything repeatedly checked.

Magnesium level deficiency for example. This is almost unknown if you do not take an acid lowering drug such as omeprazole, or lansoprazole (both proton pump inhibitors (PPIs)). Unless you are taking one of these, of any other ‘zoles,’ long term, you are extremely unlikely to be magnesium deficient. As for potassium, get some lo-salt (a mixture of potassium and sodium chloride), or eat lots broccoli and bananas, and you will be fine. Other vegetables are available.

What of Omega-3 fatty acids, the fabled fish oil. There is some good quality evidence that they can be good for you. They seem to have beneficial effects on the conduction of electrical impulses in the heart. They are mildly anti-coagulant, a bit like aspirin with fewer downsides, such as causing blood loss from the stomach. They also have some benefits on brain function.

So, should you take an Omega-3 supplement? Easier, I think, to eat fish once a week. Sardines on toast is my favourite. But if you feel the need to buy Omega-3 supplements, go ahead. The only downside is cost.

A few years ago, I was contacted by a small company that wanted to create a combination pill to reduce the risk of CVD. They asked me to give them some medical input and support, which I did, but they ran out of money. Before going bust, they did produce a few thousand tubs of Prokardia. A tablet that contained:

  • Vitamin K2 5µg
  • Thiamine 7mg
  • Folic acid 7µg
  • Potassium 50mg
  • Magnesium 50mg
  • L-arginine 600mg
  • L-carnitine  50mg
  • L-citrulline 7mg
  • Co-enzyme Q10 3mg

The L-arginine and L-citrulline on that list are ‘co-factors’ for the production of nitric oxide (NO) in endothelial cells. Co-enzyme Q10 is something I have talked about at some length, and L-carnitine is an amino acid that has been found to have many benefits in CV health. I would have added vitamin D and vitamin C to this list, but you can only get so much stuff in one tablet before it becomes a meal in itself.

I would have been more than happy to promote Prokardia as a supplement. It could do no harm, and everything on that list was potentially beneficial for heart health. Unfortunately, Prokardia does not now exist. However, if you took these supplements, in these doses x4 (you were supposed to take four tablets a day) you would not go far wrong.

Having said all this, I do not want everyone to get too carried away with supplements. I have read articles supporting supplement after supplement, and every single vitamin that exists, in high doses. However, it can all get a bit ridiculous. Eat good, natural foodstuffs, and it should be possible to get everything you need in the diet. After all, that was what we were designed to do. Our ancestors did not go around searching for potassium supplements, or L-citrulline. It was all right there, in the nearest woolly mammoth. All you needed to do was catch it.

4: Bronstein, et al, (2011) Clinical Toxicol, 49 (10), 910-941

What causes heart disease part 44

12th January 2018

I’m going to try and draw some of the strands together at this point, in an attempt to provide some advice as to how to reduce the risk of CVD. Of course, there is massive overlap with other health issues. Smoking, for example, does not just cause CVD; it also causes lung cancer, chronic obstructive pulmonary disease (COPD) and many other unpleasant things.

So, you could call this instalment of the blog: “How to remain healthier and live longer”. Here I am only going to focus on the big-ticket items, the things that have been shown to make a real difference to life expectancy. For example, even if you believe that statins are effective in reducing CVD risk, when you look at the clinical trial data – assuming you believe it, one hundred per-cent – the average increase in life expectancy is around four days, if you take a statin for five years1.

Which means that, if you start taking a statin aged fifty, and keep taking it religiously for thirty years, you could expect to live for an extra: 6 x 4 days = 24 days. Or a bit less than a month. You may think this is worthwhile, you may not. This, by the way is the best-case scenario.

On the other hand, it has been estimated that if you take regular exercise, you could live for an extra four and a half years. Which makes exercise at least fifty-four times more effective than statins. Or, to put it another way 5,400% more effective.

As I hope that you can see, I am trying to give you a sense of the scale of benefits, or harms, that I am discussing here. Most of what is hyped by the pharmaceutical industry, and others, sits on the cusp of completely and utterly irrelevant. Is coffee good or bad for you? Who cares, the effect on life expectancy is in the order of a couple of days – either way.

Looking at preventative cardiovascular medications, the only ones that make a really major difference are anti-coagulants (blood thinners) such as warfarin, rivaroxaban, apixaban and suchlike. These are primarily used to prevent stroke in atrial fibrillation. Here, you can reduce the absolute risk of a stroke by around 50% over ten years. I am not sure how this can be re-calculated into increased life expectancy. I am sure it could be done, but it is complicated. However, this is still a massive benefit, and would mean years, not days, of extra life.

In short, if you have atrial fibrillation, you most definitely should take an anticoagulant. You might want to explore magnesium supplementation, particularly if you are taking an anti-acid PPI such as omeprazole, lansoprazole – or any of the other ’…prazoles.’ These lower magnesium levels. They also lower NO and, vitamin B12 levels and double the risk of CVD death. So, I would recommend never, ever, taking these long-term.

You might also want to try reducing weight, alcohol intake, stress/strain, and carbohydrate intake at the same time to see if you can flip out of atrial fibrillation naturally. It may work, it may not.

Moving away from that slight detour, what are the other real, big-ticket items? Perhaps the most obvious is smoking, or not-smoking. Smoking twenty cigarettes a day will reduce your life expectancy by around six years. Not only that, it will reduce ‘healthy life expectancy’ by far more. By which I mean you may well have ten or twenty years of such nasty things as: difficulty breathing, repeated chest infections, leg ulcers, angina, and suchlike, before you then die – early.

At this point you may be thinking, this is all incredibly conventional. Well, yes, it is. However, there is absolutely no doubt that exercise, and not smoking, have a massive and positive effect on health. Which means that they can hardly be ignored.

Of course, some people smoke and live to ninety, and some people take no exercise and live to ninety. So, what does that prove? Nothing at all. You can play Russian roulette for several rounds without blowing your brains out, but it is going to get you in the end.

My next big-ticket item, however, is not conventional at all. It is sunshine. If there is one piece of mainstream medical advice that I would vote as the single most damaging, it would be the current, ever more hysterical, advice to avoid the sun. If we dare expose ourselves to a stray photon, we are told, then we will vastly increase the risk of dying of skin cancer.

It is true that fair skinned people, living closer to the equator than their skin was designed for, can suffer superficial skin damage with excess solar exposure. There is also a significant increase in the risk of several types of skin cancer: basal cell carcinoma, squamous cell carcinoma and rodent ulcers (non-melanoma cancers). Whilst not pleasant, they can be easily spotted and fully removed. Which means that they are not a major health risk, and will have virtually no impact on life expectancy.

The type of skin cancer of greatest concern is malignant melanoma. Whilst melanomas can also be spotted early, and successfully removed, they can grow deeper into the skin. At which point cancerous cells will break off from the main melanoma ‘body’, and travel about in the blood stream, before getting stuck in various other places and growing (metastases). Five-year survival for metastatic melanoma is around 15 – 20%.

So, this truly is a cancer to be avoided, even if it is not common. But does sun exposure cause, or increase, the risk of, malignant melanoma? Here, from the Lancet:

‘Outdoor workers have a decreased risk of melanoma compared with indoor workers, suggesting that chronic sunlight exposure can have a protective effect. Further, some melanomas form on sun-exposed regions; others do not…

It has long been realised that indoor workers have an increased risk for melanoma compared with those who work outdoors, suggesting that ultraviolet radiation is in some way protective against this (melanoma) cancer. Further, melanoma develops most often on the back of men and on the legs of women, areas that are not chronically exposed to the sun.’3

Essentially states that the more sunlight areas of your skin are exposed to, the less likely you are to develop a malignant melanoma. How does this fit with the fact that there has been a steady rise in the incidence of malignant melanoma (incidence means number of newly diagnosed cases per year).

The first to question to ask is simple. Is this a real rise, or has it been driven by increased recognition and diagnosis? A study in the UK concluded that there has been no true increase in incidence. It is publicity, fear, and misdiagnosis that has created the apparent epidemic of melanoma. As noted in this article in the British Journal of Dermatology:

Melanoma epidemic: a midsummer night’s dream?’

‘We therefore conclude that the large increase in reported incidence is likely to be due to diagnostic drift which classifies benign lesions as stage one melanoma…The distribution of the lesions (melanomas) reported did not correspond to the sites of lesions caused by solar exposure. These findings should lead to a reconsideration of the treatment of ‘early’ lesions, a search for better diagnostic methods to distinguish them from truly malignant melanomas, re- evaluation of the role of ultraviolet radiation and recommendations for protection from it, as well as the need for a new direction in the search for the cause of melanoma.’4

In short, the rise in malignant melanoma is most likely an artefact, driven by diagnostic drift, and an increased recognition of early, benign lesions (‘lesion’ is just a word for an abnormal ‘thing’ found on the body). In fact, if you look at the evidence more closely, it seems that sunlight may, in fact, protect against melanoma. A study in the US looked at people who had already been treated for melanomas, to review recurrence and long-term survival:

‘Sunburn, high intermittent sun exposure, skin awareness histories, and solar elastosis were statistically significantly inversely associated with death from melanoma.’

The conclusion of the paper:

‘Sun exposure is associated with increased survival from melanoma.’5

Maybe not quite what you expected. But then again, vitamin D is synthesized by the action on sunlight on the skin. It converts cholesterol to vitamin D, and vitamin D has potent anti-cancer actions. Remove this from the skin at your peril.

Enough of the fear of the sun and malignant melanoma. I don’t wish to get dragged any further onto the playing field of the anti-sun brigade. Instead, here is a list of benefits that have been found from increased sun exposure. I am giving you the most positive figures here (these are relative risk reductions).:

  • 75% reduction in colorectal cancer
  • 50% reduction in breast cancer
  • Non-Hodgkin’s lymphoma 20 – 40% reduction
  • Prostate cancer 50% reduction
  • Bladder cancer 30% reduction
  • Metabolic syndrome/type II diabetes 40% reduction
  • Alzheimer’s 50% reduction
  • Multiple sclerosis 50% reduction
  • Psoriasis 60% reduction
  • Macular degeneration 7-fold reduction in risk
  • Improvement in mood/well-being.6,7

Well, what do you know. If you raise your gaze from malignant melanoma there is a world of benefits associated with greater exposure to the sun. With all these benefits, you would expect to see a real improvement in life expectancy. Does this happen?

Indeed, it does. There have been a series of studies in Denmark and Sweden looking at the benefit of sunshine. One of them, which looked at overall life expectancy, concluded that avoiding the sun was as bad for you as smoking.

‘Non-smokers who avoided sun exposure had a life expectancy similar to smokers in the highest sun exposure group, indicating that avoidance of sun exposure is a risk factor for death of a similar magnitude as smoking. Compared to the highest sun exposure group, life expectancy of avoiders of sun exposure was reduced by 0.6-2.1 years.’’8

This was a twenty-year study. If average life expectancy is around eighty years, we can safely multiply those figures by four, to work out that a decent amount of sun exposure can add somewhere between three, to eight years, to your life expectancy. Let’s call it five.

But it is not just cancer, diabetes and Alzheimer’s that are reduced by sunbathing. Sun exposure is also particularly good for the cardiovascular system, mainly because it increases nitric oxide levels. This, in turn, reduces blood pressure, and the risk of developing blood clots. It also protects the endothelium, and has significant benefits on lowering blood pressure and suchlike9.

Not only that, but lying in the sun is free and enjoyable. So, who could possibly ask for anything more?

At this point, you now know my first three big ticket items for living longer. More importantly, living longer with more ‘healthy’ and enjoyable years.

  1. Do not smoke
  2. Take exercise
  3. Go out in the sun – and enjoy it.

These three things alone can add around sixteen years to your healthy lifespan. Next, the impact of mental health. The biggest hitter of them all.










What causes heart disease part 43

29th December 2017

What is stress?

I have talked about stress quite a lot, but as many people have pointed out, the word itself is meaningless. Or perhaps it would be more accurate to say that is has too many meanings, or that it means different things to different people.

Paul Rosch, a very brilliant man1, told me that when he was first looking at stress soon after the Second World War, he was working with Hans Sayle, a Hungarian. Sayle often commented that, had he understood English better, he would have used the word strain, not stress. He fully understood that ‘stress’ is the thing that creates ‘strain’ on the body. It is strain that matters, not the stress.

This, I think, is absolutely critical. You can look at some people’s lives and they may seem highly ‘stressful’, whereas others appear to be relaxed, and avoiding stresses wherever possible. However, you have no idea at all who is under the greater strain.

I remember a cardiologist, many years ago, pointing to an elderly woman who had just had a heart attack. ‘She lives in an idyllic cottage in the middle of the country, married, with loving children. No stress at all. So, don’t tell me stress causes heart disease.’ I merely shrugged. How could the cardiologist possibly know what was going on under the surface?

Perhaps her husband came home and beat the living daylights out of her every Saturday night. I remember seeing another lady, a few years earlier, who was deeply upset because she had been in hospital for an operation, and whilst there her husband had her two, very large, dogs put down.

Yes, she loved the dogs, but her main anxiety was that she had bought them for protection. When her husband went out for an evening and drank, he would come home and beat her mercilessly. She had bought the dogs for to keep her safe, now they were gone.

This couple were upstanding members of the community. They were regarded as having a perfect marriage and a perfect life. He was a magistrate and a local businessman, she ran a couple of charities. Having heard her story, I later watched them together, smiling and a laughing at local events. This was after I knew what actually went on in the home. Superficially, I could not tell anything was amiss between them.

On the other hand, some people can appear to lead lives that are full of stressors, yet can cope very well. Probably because have good physical and psychological resources, and are highly resilient. They usually have many other supportive factors in their lives. A loving partner, friends, family, and suchlike.

I think we are all also guilty of deciding that what causes us strain, will also cause someone else strain, and vice-versa. In fact, identical stressors can create very different effects. I give a few lectures every year. I quite enjoy it, I feel in control, and confident that I am good at giving talks and I find the process positive and enjoyable. However, I know of people who find the idea of standing up in front of other people absolutely terrifying. To them, giving a lecture would create massive negative strain.

In short, we cannot know the strain that someone else is under by looking at what they do, or how they act. Even massive events, such as having a partner die, will not have the same impact. For most of us this would be shocking and terrible. However, if your partner has been an abusive bully for thirty years, their death may come as a relief. Yes, it is all complex stuff indeed.

The reality is that, if you want to know if someone has suffered a level of negative stress, sufficient to have damaged them, you have to measure it. Yes, the dreaded objective medical science. Of course, before measuring things you have to have a hypothesis to test.

The hypothesis here is reasonably straightforward. It is as follows. Long term negative stressors (or one overwhelming acute event) can create damage to the neuro-hormonal system that coordinates the physiological reaction to strain. This, in turn, has negative physiological effects that can lead to serious disease e.g. CVD, or diabetes, or both.

If a tiger walked in the room, we would all react in pretty much the same way. Sudden terror. This would activate a vast array of different responses, and this reaction starts in the hypothalamus – deep within the brain. When stimulated, the hypothalamus releases hormones that, in turn, activate the pituitary gland to release further hormones. These hormones travel to the adrenal glands where the stress hormones are synthesized. Cortisol, adrenaline (epinephrine) and suchlike. This is called the Hypothalamic-Pituitary-Adrenal axis (HPA-axis).

The stress hormones that are released, speed up the heart rate, release glucose into the bloodstream, dilate the pupils, shunt blood supply from the guts to the muscles, and suchlike. At the same time the unconscious nervous system, which is tightly interwoven with the HPA-axis, lights up, and this puts every other system in the body onto ‘fight or flight’ mode. The blood pressure goes up, sweat glands are activated, blood clotting factors are released, and so on and so forth.

This is all normal, and natural and, assuming you survive, after about twenty minutes, or so, all systems start to wind back down to ‘normal.’ If the fight or flight system switches on ‘accidentally’ due to a perceived threat, that is not a real threat, this is usually called a panic attack. Which is why some people go nuts on aeroplanes and try to open the doors at 35,000 feet. In the midst of a panic attack the conscious mind is over-ridden, as the persons ‘inner chimp’ desperately tries to flee the situation. [The ‘Inner chimp’ is the part of the brain fuelled on impulsive emotion and gut instinct].

Some people who suffer from post-traumatic stress disorder (PTSD) are far more likely to see threatening situations all around them, and trigger panic attack mode far more often than others. Their fight or flight system has been set to super-sensitive mode. A child shouting may trigger the memory of a battlefield attack. Ditto a plane passing overhead, or a car changing direction rapidly. Not easy to live in a state of hair-trigger fight or flight.

Children who have been physically, or sexually abused have much the same hair-trigger systems in place. They live life on high alert, and are ready for fight or flight at any time. Billy Connolly, a Scottish comedian, who was abused when he was a young boy, always said he did not like being touched. It brought back memories that setoff deep, negative reactions.

All this is well known, and widely accepted. What is less widely accepted is that repeated activation of fight or flight can, in time, lead to a breakdown/burn-out/dysfunction of the HPA-axis and the unconscious nervous system – usually called the autonomic nervous system. In part, this is because people have steadfastly measured the wrong things, at the wrong times.

Perhaps the single greatest ‘measurement’ problem is to look at cortisol levels only n the morning. Cortisol is a key ‘stress’ hormone that is released in response to stressful situations. It also naturally fluctuates during the day. It rises to its highest level in the morning, just before you wake up, then it drops. Then rises and falls during the day.

Researchers, looking to link ‘strain’ to heart disease, and diabetes, and suchlike, have made the mistake of only measuring early morning cortisol in those with CVD, and found it to be lower than normal. They have then stated that HPA-axis dysfunction cannot be an underlying cause of CVD and/or diabetes – or any other serious medical condition.

This, of course, is exactly the wrong interpretation. If the HPA-axis is damaged, the normal rise and fall of cortisol, will break down. Or, to put it another way. A burnt-out HPA-axis leads to ‘flat-line’ cortisol production. It gets pumped out at the same rate – no matter what is going on Therefore, if you measure the cortisol level in the morning, in those with HPA-dysfunction, it can appear to be low, not high.

The correct way to diagnose HPA-axis damage, is to take regular cortisol measurements over a twenty four hour period. This was known by a Swedish researcher called Per Bjorntorp, who used hourly measurements of cortisol, to see what the flexibility of the HPA-axis was in people suffering from ‘cardio-metabolic disease.’ That is, people who have the ‘metabolic syndrome.’

The metabolic syndrome is a group of abnormalities that are often found clustered together. Abdominal obesity, high blood pressure, raised blood sugar levels (sometimes high enough to be called type II diabetes), raised clotting factors, high triglycerides/low HDL, higher LDL levels, high insulin levels.

This syndrome is also (has also been) called: insulin resistance syndrome, pre-diabetes, syndrome X and Reaven’s syndrome. Whatever you call it, it is the same thing. It is associated with a greatly raised risk of CVD. Around six-fold in some studies a.k.a. 600%.

Per Bjorntorp did a series of studies looking at HPA-axis dysfunction, and the metabolic syndrome, and he concluded that the underlying cause of the metabolic syndrome was indeed HPA-axis dysfunction. Here, I quote from his paper. ‘The metabolic syndrome – a neuroendocrine disorder?’

‘Central obesity is a powerful predictor for disease. By utilizing salivary cortisol measurements throughout the day, it has now been possible to show on a population basis that perceived stress related cortisol secretion frequently is elevated in this condition. This is followed by insulin resistance, central accumulation of body fat, dyslipidaemia and hypertension (the metabolic syndrome). Socio-economic and psychosocial handicaps are probably central inducers of hyperactivity of the hypothalamic–pituitary adrenal (HPA) axis. Alcohol, smoking and traits of psychiatric disease are also involved. In a minor part of the population a dysregulated, depressed function of the HPA axis is present, associated with low secretion of sex steroid and growth hormones, and increased activity of the sympathetic nervous system. This condition is followed by consistent abnormalities indicating the metabolic syndrome. Such ‘burned-out’ function of the HPA axis has previously been seen in subjects exposed to environmental stress of long duration.’ 2

It shouldn’t really be a great surprise that if you damage the HPA-axis/autonomic nervous system that you will end up with the metabolic syndrome. The short-term effects of activating the flight or fight system are to: raise blood pressure, raise blood clotting factors, raise blood sugar levels, raise LDL, and direct energy stores out of subcutaneous fat.

If this becomes a chronic state, you will end up with chronically: raised blood pressure, raised blood clotting factors, insulin resistance/type II diabetes and increased abdominal fat/central obesity, as fat stores are moved from the subcutaneous to the central fat stores.

We have a perfect model confirming this sequence with Cushing’s disease. This is a condition where excess cortisol is produced in the adrenal glands (usually due to a small cortisol secreting tumour). The long-term effects of Cushing’s disease are:

  • Raised blood pressure
  • Raised blood clotting factors
  • Insulin resistance/type II diabetes
  • Raised VLDL, low HDL (dyslipidaemia)
  • Central obesity
  • Greatly increased risk of CVD, around 600%

In short, long term increased cortisol production, creates a severe form of the metabolic syndrome, and a very high rate of CVD.

I suppose the final link in the chain is to look at what happens if we prescribe people cortisol. In truth, we do not do this, not exactly. Instead, we prescribe them corticosteroids. These are often just called ‘steroids’. They are used to treat inflammatory conditions, such as asthma, Crohn’s disease, Rheumatoid arthritis and suchlike.

All the prescribed corticosteroids are synthesized from the basic cortisol template. Cortisol is also called a corticosteroid, because it is a steroid hormone manufactured in the ‘cortex’ of the adrenal gland. One commonly prescribed corticosteroid is prednisolone, and the chemical structure of cortisol and prednisolone can be seen in the two diagrams.


If you prescribe steroids long-term, they too cause insulin resistance, then the metabolic syndrome, then type II diabetes, and much higher risk of CVD. The risk of CVD is increased by, up to, 600%. 3

Personally, I see this whole issue as a bit of a ‘slam dunk,’ where all the evidence fits together in an almost perfect causal chain:

Bjorntorp, in a series of well controlled studies, demonstrated that environmental ‘stressors’ can lead to HPA-axis dysfunction/physiological strain. This, in turn, leads to the metabolic syndrome. The metabolic syndrome, in turn, leads to a vastly increased risk of CVD.

PTSD is also a condition where the HPA-axis is dysfunctional4, and the rate of CVD is vastly increased5. Equally those who are victims of childhood abuse demonstrate HPA-axis dysfunction6 and a greatly increased risk of CVD7. Severe depression is also associated with HPA-axis dysfunction8 and a greatly increased risk of CVD9.

The key hormone in this process appears to be cortisol, because a high level of cortisol, independently of HPA-axis dysfunction, also leads to the metabolic syndrome, and a very high rate of CVD. In addition, if you prescribe corticosteroids they, too, lead to the metabolic syndrome and a very high rate of CVD.

Which of the elements of the resultant metabolic syndrome are most important? This is not entirely clear. Is it the raised blood pressure, the clotting factors, the high insulin or sugar? To an extent it does not matter that much. If you can get rid of the underlying cause, they will all disappear.

Next blog. How to get rid of the underlying cause?











What causes heart disease part XLII (forty two)

9th December 2017

Stress/strain – again

It has been a long time since my last blog, but life can get in the way of other things. Three lectures to give, a deadline for my book and revalidations. The latter a complete pain that UK doctors have to go through every five years, which means gathering together evidence of all the things I have done, the learning I have learned, the hoops I have jumped through – and suchlike.

Then, my cousin dropped dead of a cerebral haemorrhage. At least he died doing something he enjoyed. He had just holed a putt on a golf course near Edinburgh, when his number came up in the great lottery of life. It reminds me that whatever we know, however much we learn, fate rules us all, and makes a mockery of our belief that we can control everything. ‘As flies to wanton boys are we to the gods.’

In this blog, I am going to return to stress, which I prefer to call strain.

Just after writing my last blog someone was kind enough to send me information about a study that had been done, showing that people who are under financial stress are thirteen times more likely to die of cardiovascular disease, and people in stressful jobs are six times as likely to have a heart attack. Not yet published research, but presented at a conference in South Africa. You may have read it1.

As those who have read my blog over the years will know, I have long argued that chronic negative stress is, from a population perspective, the single most important driver of cardiovascular disease. The mind/body connection is key to health, and thus, illness. This, I think I further emphasised by the point that mental illness is associated with the greatest impact on life expectancy.

‘Serious mental illnesses reduce life expectancy by 10 to 20 years, an analysis by Oxford University psychiatrists has shown – a loss of years that’s equivalent to or worse than that for heavy smoking….

The average reduction in life expectancy in people with bipolar disorder is between nine and 20 years, while it is 10 to 20 years for schizophrenia, between nine and 24 years for drug and alcohol abuse, and around seven to 11 years for recurrent depression.’2

Up to twenty years reduction in life expectancy.

Yes, when your mind goes wrong, your body follows, with disastrous consequences for physical health. Of course, there is overlap between mental illness, drug use, smoking and suchlike. However, you can strip all the other things out, and you are left with the ferocious power of the mind/body connection. The power to nurture, and the power to destroy.

I usually tell anyone, still listening after I have bored them on various other issues, that health is a combination of physical, psychological and social wellbeing. Three overlapping sets. The holy Trinity of wellbeing. You must get them all right, or nothing works. As Plato noted, a few years back, “the part can never be well unless the whole is well.”

Who are the shortest-lived peoples in the world? Are they the poor? Not necessarily, although poverty can be a clear driver of ill-health. The shortest-lived people in the world are people who live in the places of greatest social dislocation. Or, people who have had their societies stripped apart, with massive resultant stress. Australian aboriginals, NZ Maoris, North American aboriginals, the Inuit.

‘Indigenous Australians have the worst life expectancy rates of any indigenous population in the world, a United Nations report says. But it’s not news to Aboriginal health experts. They say it simply confirms what Australian health services have known for years.

Aboriginal Medical Services Alliance of the Northern Territory (AMSANT) chief executive officer John Paterson said the findings of the report, which examined the indigenous populations of 90 countries, were no surprise. The UN report – State of the World’s Indigenous Peoples – showed indigenous people in Australia and Nepal fared the worst, dying up to 20 years earlier than their non-indigenous counterparts. In Guatemala, the life expectancy gap is 13 years and in New Zealand it is 11.’3

I continue to find it absolutely amazing that mainstream medical thinking casually dismisses mental ‘stress’ as a cause of anything, other than mental health. The connection is always dismissed in the following way.

People who are depressed, anxious, suffering from PTSD and suchlike are more likely to drink and smoke and participate in other unhealthy lifestyles, and it is this that causes their higher rate of CVD and reduced life expectancy, and suchlike. There is a degree of truth to this, but some researchers have looked at this issue and found that the ‘unhealthy lifestyle’ issue explains very little.4

Underlying such an explanation, it has been noted that financial worries can increase your risk of heart disease by thirteen-fold (relative risk). Many of the arguments about CVD currently rage around diet, with people battling about HFLC vs LFHC, [high fat low carb vs low fat high carb].

In all the dietary studies I have seen, we are talking about increased, or reduced, risks in the order of 1.12, or 0.89. Which means a twelve per cent increased risk, or an eleven per cent reduced risk. These figures may just reach statistical significance, but they are so small as to be, to all intents and purposes, completely irrelevant.

On the other hand, a thirteen-fold increase in risk can be written another way. This is a 1,300% increase in risk. Compare this to anything to do with diet, or raised cholesterol, or blood pressure, or blood sugar or – any of the other mainstream risk factors. It is like comparing Mount Everest to a mole hill.

Yet, and yet, attempting to divert attention, and discussion, away from diet, or cholesterol, or sub-fractions of cholesterol, or suchlike seems an impossible task. People may say that they cannot see how stress can cause CVD. To which I say, every single step has been worked out, many times, by many different people.

Chronic stress → dysfunction of the hypothalamic pituitary adrenal axis (HPA-axis) → sympathetic overdrive + raised stress hormones → metabolic syndrome (raised BP, raised blood sugar, raised clotting factors, raised cortisol, raised all sorts of things) → endothelial damage + increased blood clotting → plaque formation and death from acute clot formation.

And if you want to close this loop further, stress also increases LDL levels, in some studies by over 60%5. So, when you see raised LDL, in association with increased CVD, it is not the LDL causing the CVD. It is stress, causing both.







What causes CVD part XL1 (Part forty-one)

12th November 2017

Another slight detour I am afraid. This is due to the recent publication of the ORBITA study. Reported in the British Medical Journal (BMJ), thus:

‘Percutaneous coronary intervention (PCI) is not significantly better than a placebo procedure in improving exercise capacity or symptoms even in patients with severe coronary stenosis, research has found.1

The ORBITA study, published in the Lancet, is the first double blind randomised controlled trial to directly compare stenting with placebo in patients with stable angina who are receiving high quality drug treatment.’ Compared to the sham-controlled group:

  • PCI did not significantly improve exercise time. The numerical incremental increase in average exercise time was 16 seconds (P=0.20).
  • PCI did not significantly improve measures on well-validated patient-centered angina questionnaires.
  • PCI did not significantly improve the Duke treadmill score or peak oxygen uptake.
  • PCI did significantly improve the dobutamine stress echo wall-motion index, indicating that stenting reduced ischemic burden.

In short, PCI did nothing at all. I can hear cardiologists across the US putting plans for new swimming pools on hold. 2

As many people know, the purpose of a stent is to open up obstructed coronary arteries, and then keep them open, using a metal framework ‘stent’, that sits within the artery. This procedure has been done on thousands, millions, of people. In an acute myocardial infarction (MI or heart attack to you) it provides benefits. However, in non-acute blockage it does nothing, apart from enrich interventional cardiologists.

Frankly, I was surprised that these researchers got ethical approval for this study. Carrying out a sham operation is a pretty major thing to do to a patient. I am further surprised they managed to get any volunteers, but they did. I very much take my hat off to these researchers. Bold, very bold, indeed. They must have been pretty damned certain they were going to see no benefit from stents.

Anyway, this study only proves what many people had suspected for some time. Stents, in the non-acute situation, do not work. Of course, this study has already been attacked and dismissed. Here is one review from SouthWestern medical centre, entitled ‘Stents do work: A closer look at the ORBITA study data.’:

ORBITA was small – too small, in fact, considered definitive evidence that cardiologists should change the role of stents in clinical practice.

I participate in a number of cardiology care guidelines committees and even wrote a piece about the ORBITA trial for the American College of Cardiology. In order for regulating bodies to change clinical practices, research studies must present data from a much larger pool, such as the 2007 COURAGE PCI study, which enlisted more than 2,000 participants. In general, larger trials present data that are more statistically significant and more appropriate to apply to specific patient segments.3

Too small? Wrong patient type, no doubt the wrong atmospheric pressure as well. Unlike the studies that were used when cardiologists first started doing stents, where the study size was precisely zero. In fact, if you read the entire article from the Southwestern medical centre, it is gibberish. But it will have the desired effect. The ORBITA study will have no impact stenting revenue. Like many other ideas in medicine, it is too seductive, and far too lucrative. The artery is blocked, it must be opened. End of.

Many years ago, Bernard Lown had precisely the same issue with Coronary Artery Bypass Grafting (CABG). Another massively lucrative intervention which rapidly became the operation – based on no evidence whatsoever. It was such an obviously brilliant idea that to question it was to defy ‘common sense.’ You have a blockage in an artery, bypass it with a graft.’

One thing that you find about good science is that it is usually very far removed from ‘pure common sense.’ It is counterintuitive. It is counterintuitive because it challenges established thinking a.k.a. prejudices. As Einstein had to say. ‘Common sense is nothing more than a deposit of prejudices laid down in the mind before age eighteen.’ He also said that ‘It is harder to crack prejudice than an atom.’

If you want a really good read, I recommend Bernard Lown [he is my hero]. He was the first to challenge the orthodoxy that CABG was an unquestioned good. For which he was of course, roundly attacked. His essay on this can be read here4. I include a particularly poignant section by Bernard Lown discussing CABG:

‘One might wonder why patients acquiesced to undergoing a painful and life-threatening procedure without the certainty of improving their life expectancy. I have long puzzled at such acquiescence. Surprisingly, patients not only agreed to the recommended intervention but commonly urged expediting it. Such conduct is compelled by ignorance as well as fear. Patients are readily overwhelmed by the mumbo-jumbo of medical jargon. Hearing something to the effect of “Your left anterior descending coronary artery is 75 percent occluded and the ejection fraction is 50 percent” is paralyzing. To the ordinary patient such findings threaten a heart attack or, worse, augur sudden cardiac death.

Cardiologists and cardiac surgeons frequently resort to frightening verbiage in summarizing angiographic findings. This no doubt compels unquestioning acceptance of the recommended procedure. Over the years I have heard several hundred expressions, such as: “You have a time bomb in your chest” and its variant “You are a walking time bomb.” Or, “This narrowed coronary is a widow maker.” And if patients wish to delay an intervention, a series of fear-mongering expressions hasten their resolve to proceed: “We must not lose any time by playing Hamlet.” Or, “You are living on borrowed time.” Or, “You are in luck — a slot is available on the operating schedule.” Maiming words can infantilize patients, so they regard doctors as parental figures to guide them to some safe harbour.’

The man is a genius and he can write far better than wot I can. I should hate him.

Some forty years later, or so, we find that CABG has been replaced by PCI/stenting. Exactly the same knuckle headed stupidity has driven stenting. The noise of sheep bleating ‘Narrow artery bad, open artery good,’ fills the air. My goodness, I think they’ve got it. Who could possibly argue with that? Kerching!

Those who have read my endless blog on the causes of on CVD will know I have long been highly sceptical of stenting as the answer to anything very much. Other than the removal of large sums of money from person A, to hospital B, and interventional cardiologist C.

Why does it not work? How can it possibly not work?

Because the heart is not simply a pump, arteries are not simply pipes, and humans are not inanimate objects whereby our function, or lack thereof, is purely dependant on some form of medical or surgical intervention. Thus endeth the lesson on stenting.





What causes heart disease part XL (part forty)

27th October 2017

As readers of this blog will know, for many years I have pursued the idea that ‘stress’ was the primary cause of cardiovascular disease. Actually, it is strain. Stress is the force applied, strain is the effect that stress produces. For the sake of simplicity, I will just use the word stress.

This journey started when I began to take an interest in the rate of heart disease death in Scotland and France. Being Scottish born and bred, (OK, my father was English, but I forgive him) I felt I knew a bit about the lifestyle of the average Scot, aye Jimmy.

I had also travelled to France many times, so I felt I knew a bit about the French as well. The other reason for looking at France and Scotland was that, in my formative years, Scotland had one of the highest rates of heart disease in the world, perhaps the highest. I am talking primarily about death from myocardial infarction here. On the other hand, the French rate was very low, perhaps the lowest in the world, and has since then got lower.

Why such a massive difference? The conventional explanation was that the Scots had such a terrible diet. The famed deep-fried Mars bar is oft quoted. ‘How can a country that deep fries a Mars bar expect anything less.’ As if everyone in Scotland does nothing but stuff their faces with deep-fried Mars bars, all day, every day.

I do not have the statistics to hand, but I would be very surprised to find that even fifty per cent of Scots have eaten even one. Indeed, if you have made the mistake of eating a deep-fried Mars bar, you will never (unless very drunk) eat another. However, the Scottish ‘unhealthy diet’ meme is so firmly embedded in most people’s brain that it cannot be removed.

Ironically, a Mars bar contains almost no fat at all, it is made almost entirely from sugar a.k.a. carbohydrate. If you wrap it in batter, and stick it in a deep fat fryer full of vegetable fats, you have, according to current thinking, just made it significantly healthier. More carbs wrapped round the outside, and now dripping with vegetable/polyunsaturated fat. Mmmmm … you can just feel your arteries unclogging.

In reality, as with most other well-known facts about heart disease, when I started to look closely, the only significant difference that I could find about the diets in France and Scotland, was that the Scots ate slightly less saturated fat. They also ate fewer vegetables.

On the other hand, the French smoked more, took a bit less exercise and, at the time, had an identical BMI and blood pressure to the Scots. Rates of diabetes were also identical, as were average total cholesterol levels.

In short, I could find no significant difference in ‘classic’ risk factors. If anything, they slightly favoured the Scots over the French. Yet, and yet, age-matched, the French suffered one fifth the rate of deaths from heart disease. If you open up a risk calculator designed for a UK population, and use it to calculate risk for the French, you still have to divide the answer you get, by four. [Which might suggest that risk calculators are not capturing the major causes of CVD].

This gave me to think that there may be something else going on. Other than diet.

What? There have been many papers written about the ‘French Paradox’. The paradox being that they eat masses of saturated fat (highest consumption in Europe, probably the world), they have average to high cholesterol levels and a vanishingly low rate of heart disease.

Scientifically the French paradox should really be called the ‘French refutation of the diet-heart hypothesis and the LDL hypothesis, and all other hypotheses about cardiovascular disease you can think of’. Instead, a range of protective factors have been proposed. Eating garlic, drinking red wine, lightly cooked vegetables, and suchlike. But if you chase them down, and I have, they explain nothing – at all. Primarily, because they are just not true a.k.a. unsupported by evidence.

So, what was going on? What was the key thing that caused the Scots to die of heart disease in great numbers? One obvious and outstanding difference between the Scots and French was not what they ate, but the way that they ate. Scots saw, and in many cases still see, eating very much as a refuelling exercise. On the other hand, mealtimes, and eating, is a massive part of French life. Time is taken, food is appreciated, families tend to eat together – and suchlike.

Could it be, I thought, that the way food is eaten is more important that what is eaten?

If you eat whilst you are relaxed and socialising with friends and family, will your body deal with food in a different way? The answer is, of course, yes. Just to put it in the most basic terms. If you are highly stressed, either physically or psychologically, your fight or flight system will be activated. The sympathetic nervous system will be directing blood from the digestive system, to muscles, acid production in the stomach will be down, the heart rate will be up – and suchlike.

At the same time the stress hormone: adrenaline (epinephrine), growth hormone, glucagon, and cortisol levels will be high and surging round your bloodstream. This will be activating catabolism – the breakdown of energy stores – sugar levels will be up, free fatty acids circulating, blood clotting systems activated, insulin levels down, and on and on. This is not, it should be added, the perfect metabolic situation in which to eat food.

If you look at most animals, after they have eaten they like to lie down, relax and fall asleep. This allows the food that has been eaten to be digested. Humans seem happy to leap to their feet and rush about after eating. I started thinking about the fast food culture of the US. They began the trend for fast eating, fast living, eating and driving. Rush, rush, busy, busy, work, work, bang, bang. They were first to suffer a high rate of heart disease.

I began to study the effect of stress on metabolism. I looked at a condition known as post-aggression metabolism. The state the body finds itself in after trauma such as a car crash or major operation. In such cases the stress hormones are sky high, blood sugar moves into the diabetic level, insulin cannot achieve anything as it is battling against a catabolic system on full throttle. Not a good time to be eating food.

Then I looked at less dramatic situations. My attention drifted onto Cushing’s disease. A condition where the stress hormone cortisol is over-produced by the adrenal glands. Usually because of a cortisol secreting tumour. Cushing’s disease represents a form of chronic ‘fight or flight’, constant stress.

I discovered that, in Cushing’s there is a spectrum of metabolic, and other physiological, abnormalities such as:

  • High blood sugar level
  • High insulin level
  • High clotting factors
  • High VLDL (triglycerides)
  • Low HDL
  • High blood pressure
  • Abdominal obesity.

I also noted that, Cushing’s increases the risk of CVD by, at least, 600%.

I then realised that Cushing’s syndrome and the metabolic syndrome shared exactly the same set of metabolic and physiological abnormalities. So I began to think. ‘This is beginning to look interesting.’ Actually, I was thinking this before the term metabolic syndrome existed. At the time is was called either Reaven’s syndrome, or syndrome X. The term “insulin resistance syndrome” is now popular.

Then I was pointed to the work of Per Bjorntorp, who had been looking at the Hypothalamic Pituitary Adrenal axis (HPA-axis). This is the central control system for the stress/flight of fight response. It links together the sympathetic and parasympathetic nervous system, with the actions of the stress hormones, the adrenal glands, thyroxine, glucagon, insulin etc. etc. A complex beast of a thing.

Bjorntorp established that chronic psychological stress (chronic strain) creates a dysfunction of the HPA-axis that can be monitored, most easily, by looking at twenty-four-hour cortisol secretion. A dysfunctional HPA-axis leads to a flattened and unresponsive (burnt-out) cortisol release during the day. This does not mean cortisol levels are high, or low, they just flat-line.

He studied various populations e.g. Sweden and Lithuania, and found that the Lithuanians (at the time) were far more likely to have a dysfunctional HPA-axis than the Swedes, and their rate of CVD was four times as high as that in Sweden. A study done only on men at the time. I then started to look at other conditions where the HPA-axis is damaged. Depression, schizophrenia – in fact almost all psychiatric illness – PTSD, survivors of childhood abuse. In all cases the same pattern emerged. HPA-axis dysfunction, greatly increased risk of metabolic syndrome/insulin resistance syndrome and greatly increased risk of CVD death.

I detoured round spinal cord injury. Most people are probably unaware that spinal cord injury is associated with a very much higher rate of CVD. People who suffer spinal cord injury also have a damaged HPA-axis. Some more than others. It depends on the level of the damage, and whether or not the autonomic nervous system is damaged. [The autonomic nervous system is the name given to the network of nerve fibres that make up the sympathetic and parasympathetic nervous system. It travels down the spine, but not in the spinal canal].

I then had a look at corticosteroids. These are the drugs used in many diseases as anti-inflammatory agents. They are used in diseases such as asthma and rheumatoid arthritis and Crohn’s disease and systemic lupus erythematosus (SLE), all ‘auto-immune’ diseases where the body attacks itself. Corticosteroids dampen down the ‘inflammatory’ response.

Corticosteroids are synthesized from cortisol, which is one of the body’s own steroid hormones. Which is why they are called corticosteroids (steroids manufactured in the cortex of the adrenal gland). They are fantastic drugs, and widely used. However, if you take corticosteroids for a long time you will end up with the metabolic syndrome, and a greatly increased risk of CVD, around a 400% increase.

The more I looked, the more it seemed very clear that the unconscious neuro-hormonal system was the key player in CVD, both heart attacks and strokes. It also seemed that cortisol was probably the lynch pin. It still does. Which is why my favourite graph on CVD comes from Lithuania. I have used it before, and I make no bones about using it again.

The rate of heart disease in Lithuania was gradually falling during the 1980s, until the year 1989. At which point the Berlin wall came down, the Soviet Union broke apart and the structure of society was torn apart. It was a very, very, stressful time.

What happened to the rate of heart disease in men, under 65.

Latvia and Estonia showed the same pattern, as did Russia three years later when Gorbachov was deposed by Yeltsin. In non-Soviet European countries, nothing happened. Heart disease rates continued their gentle fall.

I had been looking for evidence that abrupt social disruption leads to stress which leads to CVD. The problem is that, normally, gigantic social disruption = war. During war medical statistics tend to get overlooked, or other causes of sudden death distort the picture.

For the first time in history, a gigantic social upheaval occurred right in front of our eyes. It was not war, and the WHO was there, recording away, as part of the MONICA project. [Myocardial infarction and coronary deaths in the World Health Organization]. Cause, and effect? I believe so.

Which takes me back to Scotland. Glasgow was a very big city, then it shrank. It shrank because social engineers decided to move people from the tenements, which were considered crowded and unhealthy, to wonderful new towns, and high-rise flats. Such as these shown below.

As you can imagine people very much enjoyed living in these inhuman monoliths. A great sense of community and fun developed. So much so that they have now all been demolished.

Whilst this great forced location of people was taking place, the rate of CVD in and around Glasgow exploded. Yes, Scotland as a whole had a high(ish) rate, but greater Glasgow, whilst all this was going on, had by far the highest rate of all. Cause, and effect?

So, my thought experiment that started in Scotland, ended up back in Scotland. I then looked around the world for populations with extraordinarily high rates of CVD. I hypothesized that populations that had suffered enormous social stress would have high rates. So I looked at Australian aboriginals, Maoris, migrant populations, native Americans, and suchlike.

What did I see. Well, pretty much the same things everywhere. Social upheaval followed by high rate of CVD. At present Australian aboriginals have, I believe, the highest rate of CVD in the world. A population where lifestyle and culture has been shredded. If you use a CVD risk calculator on a young aboriginal woman, you have to multiply the predicted ten-year risk by thirty.

Exceptions, of course, exceptions. The Rosetta community of Pennsylvania US. An immigrant population that had moved from Rosetta Italy to Rosetta US – en masse. They became famous for a very, very, low rate of heart disease. What made them different? Here is a section from a Huffington Post article:

‘What made Rosetans die less from heart disease than identical towns elsewhere? Family ties. Another observation: they had traditional and cohesive family and community relationships. It turns out that Roseto was peopled by strongly knit Italian-American families who did everything right and lived right and consequently lived longer.

In short, Rosetans were nourished by people.

In all ways, this happy result was exactly the opposite expectation of well-proven health laws. The Rosetans broke the following long-life rules, and did so with a noticeable relish: and they lived to tell the tale. They smoked old-style Italian stogie cigars, malodorous and remarkably pungent little nips of a cigar guaranteed to give a nicotine fix of unbelievably strong potency. These were not filtered or adulterated in any way.

Both sexes drank wine with seeming abandon, a beverage which the 1963 era dietician would find almost prehistoric in health value. In fact, wine was consumed in preference to all-American soft drinks and even milk. Forget the cushy office job, Rosetan men worked in such toxic environs as the nearby slate quarries. Working there was notoriously dangerous, not merely hazardous, with “industrial accidents” and gruesome illnesses caused by inhaling gases, dusts and other niceties.

And forget the Mediterranean diets of olive oil, light salads and fat-free foods. No, Rosetans fried their sausages and meatballs in…..lard. They ate salami, hard and soft cheeses all brimming with cholesterol.2

The tenements of Glasgow were filthy and rat infested and crowded and had poor sanitation. But if you speak to those who lived in them, their memories were of close family ties, strong community support, fun, playing football in the street. Then they were shifted to the Brave New World of sterile social engineering. Isolation, loneliness, breakdown of community. Death.

You want to know one of the most important ways to avoid dying of CVD?


1: 1


What causes heart disease part XXXVIII (part thirty-eight)

24th September 2017

‘The flow of rivers and streams in their boundaries . . . the circulation of the blood in our arteries and veins . . . the flight of the insect, the bird and the airplane; the movement of a ship in the water or of a fish in the depths . . . these are all, in major degree, varied expressions of the laws of fluid mechanics … Everywhere we find fluids and solids in reactive contact, usually in relative motion; and everywhere in this domain, the laws of fluid mechanics must control.

Application of the laws of fluid mechanics to the natural conditions in the circulatory system reveals a rational and demonstrable basis for the localization, inception, and progressive development of atherosclerosis.

Atherosclerosis does not occur at random locations. It does occur uniformly at specific sites of predilection that can be precisely defined, predicted, and produced by applying the principles of fluid mechanics. The areas of predilection for atherosclerosis are consistently found to be the segmental zones of diminished lateral pressure produced by the forces generated by the flowing blood.

Such segmental zones of diminished lateral pressure are characterized by tapering, curvature, bifurcation, branching, and external attachment. Serpentine flow in a relatively straight vessel also produces segmental zones of diminished lateral pressure.

Although these anatomic configurations occur in many variations of geometry, their common feature is a pattern of blood flow conducive to the production of localized areas of diminished lateral pressure. This is the initial stimulus.

Atherosclerosis may therefore be considered to be the biologic response of blood vessels to the effect of the laws of fluid mechanics, that is, the diminished lateral pressure generated by the flowing blood at sites of predilection determined by local hydraulic specifications in the circulatory system.’1

Not my words, and quite poetic I suppose. What does it mean. It means, if you accept what is written, is that atherosclerosis forms exactly where you would expect it to form – if the initial stimulus is ‘diminished lateral pressure’.

My last blog was primarily a looking at the primary stimulus for the initial formation of atherosclerotic plaques. I like to use the term biomechanical stress. I am not entirely certain if this means anything. But the general idea is that atherosclerotic plaques start at the points in blood vessels where there is the greatest ‘biomechanical stress.’

Several people who know far more about fluid dynamics questioned this. I think that they are all probably right in what they say, and the mathematics are well beyond my understanding. However, what I do know, and what are facts, are the following:

  • Atherosclerotic plaques inevitably occur where is there is tapering, curvature, bifurcation, branching and areas of external attachment.
  • Plaques never develop in veins, regardless of tapering, curvature and branding and suchlike.
  • Plaques never develop in the arteries and veins in your lungs – unless you develop pulmonary hypertension (raised blood pressure in the lungs) – though a caveat applies.
  • Plaques often appear on one side of an artery, and not the other (i.e., they do not encircle the artery).
  • If you take a vein from the leg, and use it as a coronary artery bypass graft, it will rapidly develop atherosclerotic plaques.

Therefore, whatever term you want to use, however, you wish to understand it, it is clear that in order to get a plaque to start, you need to apply some form of ‘stress’ to the blood vessel, and the blood pressure needs to be at a certain level – or else nothing will happen. This is true, no matter what the LDL level, or the blood sugar level, or whether you smoke, or [insert any one of eight thousand risk factors here].

Ergo, there must be some form of damage occurring at the point of high biomechanical stress, that triggers plaque development. Under biomechanical stress, the first part of the artery to suffer will be the endothelium – the layer of cells that lines the arteries. If endothelial cells are stressed, damaged, or dysfunctional, this is the trigger for plaques to start:

In view of the ever-increasing prevalence of ischaemic heart disease in the developed and developing world, it has become imperative to identify and investigate mechanisms of early, potentially reversible pre-atherosclerotic changes in the endothelium. To date, the most clearly defined and well-understood early precursor of atherosclerosis is Endothelial Dysfunction. In fact, Endothelial Dysfunction can be regarded as the primum movens of atherosclerotic disease.’2

I guess that primum movens is Latin for ‘the single most really important thing.’

In short, you damage the endothelium, and that releases the atherosclerotic dogs of war. What sort of things are known to increase endothelial stress/damage. Here is a list, off the top of my head, of a few factors that have been identified.

  • Smoking
  • Air pollution
  • Diabetes
  • Cocaine use
  • Dehydration
  • Infections/sepsis
  • Systemic Lupus Erythematosus (SLE)
  • Lead
  • Stress hormones
  • Avastin
  • Omeprazole
  • Cushing’s disease
  • Kawasaki’s disease.

I could go on, and on, but I think that is enough to be going on with. All of these factors have been demonstrated to cause significant damage to the endothelium – in different ways – and there is another thing that they all do. They all increase the risk of dying of CVD. Some of them enormously increase the risk. A young woman with SLE has an increased risk of dying of CHD of 5000% (relative risk increase).

When you are looking at a 5000% increase in risk you are, without the slightest shadow of a doubt, looking at a cause.

The only other increased risk I have ever seen to match this, or in fact beat this, is in young people with sickle cell anaemia where the increased risk of stroke is 33,000% (relative increase in risk). Yes, not many young people get strokes, but an increase of 33,000% is difficult to argue with.

Why do they get so many strokes? It is, in part, because the ‘sickle’ shaped red blood cells clump together more easily than normal shaped red blood cells. Once they clump together, they form clots, and these clots block arteries. Often in the brain – but also elsewhere. It is not as simple as this, but that will do for now.

There is another thing about sickle cells anaemia that I find of great interest. It is the only condition (at least the only condition I have come across), where atherosclerotic plaques can form in the lungs – at normal blood pressure.3

Why does this happen? Well sickle cells are not round and smooth. They are crescent shaped, and spiky at the ends, and stiffer than normal red blood cells, and they are more likely to cause mechanical damage to the endothelium.

‘A further mechanism of endothelial dysfunction is attributed to the rigidity of sickled erythrocytes (red blood cells) causing mechanical injury to the endothelial cells.’3

In addition:

‘The sickling process leads to vascular occlusion, tissue hypoxia and subsequent reperfusion injury, thus inducing inflammation and endothelial injury. This causes a blunted response to nitric oxide (NO) synthase inhibition.’3

Yes, our old friend Nitric Oxide again. Put simply, sickle cells crash into, and damage endothelial cells, which then stop producing as much NO. This endothelial dysfunction then leads on to atherosclerosis. All of this happens with no other risk factors present, and in arteries where atherosclerosis is normally never seen. Which means that we are looking very directly at cause, and effect. Physical damage to endothelial cells, no other factors required.

Now, I am aware that many people wonder why my series on what causes heart disease/cardiovascular has been so long and meandering. One major reason is that there is so much to try and find out, and explain. Also, and perhaps more critically, if you are going to try and understand cardiovascular disease fully, you must attempt to fit everything together, and that does take time.

For example, you must explain how: SLE, sickle cell anaemia, Kawasaki’s disease, omeprazole, diabetes, smoking and infections (to name but seven) can all cause CVD when, superficially, there is nothing to link them. Certainly none of the established, mainstream, risk factors.

There is no point in saying that, yes, they all cause heart disease, and that’s that, just add them to the list. There is a requirement to fit them within a single process, and it must make sense. It also has to be supported by the facts – as far as that is possible.

Equally, there is no point in saying CVD is ‘multifactorial’, which is the normal defence of the mainstream when pressed on why many people, with no risk factors for CVD, still get CVD. The word “multifactorial” explains nothing, it is just an escape route for those pressed to explain the many ‘paradoxes’ or refutations that keep on appearing.

If, for example, you cannot explain how sickle cell anaemia causes atherosclerotic plaque formation, in pulmonary arteries, this means you do not understand, or do not wish to understand, the underlying process. It fits nowhere within the accepted major risk factors, yet it increases the risk of stroke by 33,000%, and causes plaques to develop in the lungs. So, you cannot just ignore it, relatively rare though it may be.

So, where have we got to? Where we have got to, I believe is to demonstrate that the trigger factor for CVD is damage to the endothelium. If you don’t damage the endothelium nothing else happens. The damage happens at well recognised places where the biomechanical stress is at its greatest. Which means that, with no biomechanical stress, there can be no atherosclerotic plaques.

However, it takes more than just biomechanical stress. You also have to have, at least one, extra factor present to trigger endothelial dysfunction. Then … next episode.


1: From Chapter 8 Coronary Heart Disease: The Dietary Sense and Nonsense: George V. Mann: 9781857560725: Books



What causes heart disease part XXXVII (Part thirty-seven)

16th September 2017

Beginning at the end.

Whilst there is significant controversy about how atherosclerotic plaques may start, and grow, the final event in cardiovascular disease is, in most cases, pretty much accepted – even by me. The formation of a blood clot. Yes, there are many caveats here, and also a number of different processes that can occur, but I am not covering them in this blog. I am using the simple ending. The obstructive blood clot.

If a blood clot forms in the coronary arteries – blood vessels supplying blood to the heart – it can fully block the artery, jam up blood flow, vastly reduce oxygen supply, and cause a myocardial infarction (MI). The clot usually forms on the surface of a pre-existing atherosclerotic plaque.

If a blood clot forms in the carotid arteries – main blood vessels supplying blood to the brain – it can then break off, travel up into the brain where it gets stuck, jams up blood flow, reduces oxygen supply, and cause a cerebral infarction (ischaemic stroke). Again, blood clots in the carotid arteries almost always form on the surface of atherosclerotic plaques formed earlier.

What this means is that reducing the formation of blood clots will, or definitely should, reduce the risk of heart attacks and strokes. And, of course, it does. Aspirin, for example, has anticoagulant action, and it lowers the risk of CVD, although not by a huge amount.

However, recently, a study was published in the New England Journal of Medicine which demonstrated that if you add rivaroxaban – an anticoagulant, primarily used to prevent strokes in patients with Atrial Fibrillation – to aspirin, this further reduces the risk of CVD1.

The trial was reported thus, in the Daily Mail on the 11th of September:

‘Phenomenal’ pill slashes the risk of death from heart disease by 22% and could save millions of lives, ‘ground-breaking’ trial finds.’

Oh yes, we do like a phenomenal pill, do we not. Mockery of such ridiculous hype aside, this was an impressive result. Far more impressive than any statin trial, it must be added – with no impact on LDL levels at all. Only one slight problem, it would be rather expensive to add rivaroxaban to everyone taking aspirin. Minimum cost, about £6Bn/years ($8Bn/year) in the UK alone.

Of course, there are other things that can reduce the risk of blood clotting. Omega 3 fatty acids, for example which reduce ability of platelets to stick together2 – an action almost identical to aspirin. Then there is Von Willibrand disease – a condition where people lack a key blood clotting element called the Von Willebrand factor. Patients with this condition have a 60% reduction in the risk CVD.

Those with haemophilia had – prior to the development of clotting factors to replace those that were missing –around 20% the risk of CVD of the surrounding population.

On the other hand, there are situations where the risk of blood clotting increases. Use of non-steroidal drugs e.g. brufen, naproxen, diclofenac etc. These increase the risk of clotting, and CVD. There are conditions, such as Hughes syndrome and Factor V Leiden where the risk of blood clotting goes up, and so does the risk of CVD and so on, and so forth.

In fact, I think it can be stated with complete confidence that any drug, condition, or anything else that reduces the risk of blood clotting, also reduces the risk of CVD, and vice-versa. Of course, if you reduce the risk of blood clotting, you can also increase the risk of serious bleeding. So, it is not all positive. All is balance. Yin and Yang, and suchlike. Even the relatively benign aspirin, in low doses, can lead to chronic blood loss, anaemia, and, in extreme cases, death.

What does this prove. Well it certainly proves that blood clotting and CVD are intimately related. So much so that the word ‘atherothrombosis’ is often used to describe the processes of CVD. ‘Athero-‘ = the atherosclerotic plaque growing then ‘-thrombosis’, the clot that forms top of the plaque that then kills you. That, at least, is the official Soviet party line.

However, I never liked the idea that we have two almost completely different processes going, that are linked together, but only at the final event. I wanted to explore the idea that a single process – blood clotting – could be responsible for plaque starting, growing and then ‘rupturing’ causing the whole spectrum of atherothrombosis. Blood clots, from start to finish.

This took me on a pretty amazing journey, a long and winding route indeed. I have come to believe that the system of blood coagulation must be, just about, the most complex physiological system in the body. It is beyond mind-boggling. Just when you think you have read about every factor involved, another one pops up. Indeed, I think I am forgetting facts about blood clotting faster than I can learn them. My brain is full.

However, the other day, I came across an expression that captured something about blood clotting that I have always struggled to put into words. It described the coagulation system as ‘idling’, as in sitting with the engine running. The blood coagulation system is never ‘off’ it is always turning over in the background, constantly producing small combination of substances that make up a full blood clot.

I suppose this is because, if you suffer a significant wound, or damage to a large blood vessel, the coagulation system cannot hang about. It must accelerate from zero to one hundred in the blink of an eye. Bang, go, stamp on the accelerator. At the same time, if it accelerates out of control, the clot will be too big, it will spread too rapidly, blocking blood vessels all over the place.

So, almost the moment you stamp on the accelerator, you are hammering on the brake. Accelerate, brake, accelerate, brake. Build up the clot, break down the clot. A fantastically dynamic system with feedback loop upon feedback loop. Too little clotting, you die. Too much clotting, you die. This is going on, all the time, in your body. A system constantly hunting, and hunting, to find equilibrium.

What is the greatest, the most powerful trigger, for a clot to form? It is a substance called Tissue Factor (TF). It is found almost everywhere in the body, but it is found in the highest concentrations within the walls of the larger arteries and veins. This, of course, makes perfect sense. If an artery, or vein, is damaged, the place you want a blood clot to form is exactly at that point. Bang, go.

Tissue factor is sometimes called extrinsic factor. It is called this because it does not float about (freely) in the bloodstream, it sits ‘externally/extrinsically’ to the blood. [In fact, platelets and white blood cells also contain TF, but it is inactive/not expressed unless other things are triggered first].

Other parts of the clotting system are often referred to as intrinsic factors that trigger the ‘intrinsic clotting system’. Factors you may have heard of, such as factor VIII, or factors IX and X and Xa etc. The intrinsic system tends to operate more slowly, and less powerfully, than the extrinsic (massive over-simplification warning).

Normally, the ‘intrinsic’ clotting factors, and the extrinsic system operate together to drive and amplify the clotting response once it is triggered. All of which means that, normally, you want to keep the blood well away from contact with TF, because the moment there is contact, all hell breaks loose and a blood clot will form, instantly, at that point.

The single most important barrier that keeps the blood separated from TF is the endothelium. Which means that an intact and healthy endothelium is the best protection against accidental blood clots forming. Yes, blood clots can form with no TF contact. A deep vein thrombosis (DVT) can develop in veins with intact endothelium. The process is different, the blood clot formed is also very different. It is mainly an intrinsic process.

Forgetting other types of blood clot that can form elsewhere in the body, the only way a clot will form in the larger arteries is due to endothelial damage. No endothelial damage, no clot. Once a blood clot has formed, then stabilised, what happens?

Well, normally the clot will not have been allowed to get too big, because all the feedback loops will kick into action to slow things down. So, most clots will not fully block an artery, nor even half block an artery. They also get shaved down in size quickly. Primarily through the action of Tissue Plasminogen Activator (TP(a)).

TP(a) is an enzyme floating about in the bloodstream that converts plasminogen into plasmin. Plasminogen is an inactive enzyme that is incorporated into all blood clots as they form. When TP(a) converts plasminogen to plasmin, it slices fibrin apart, chopping blood clots into small pieces. A process known as fibrinolysis. Two of the major components of a blood clot are platelets – small sticky cells that coordinate the clotting response – and fibrin – long sticky strands of protein that binds the clot together.

However, there will be always be a part of the clot that remains clamped to the artery wall. Because if all the clot was fully broken down/fibrinolysed, the bloodstream would be exposed to TF again, and the entire blood clotting process would simply kick off…. again.

Which means that once a clot has been formed, a part of it will always be left stuck to the artery wall. This then needs to be got rid of. How does this happen? Well, it is not like scratching your skin, whereby a clot (scab) forms, the endothelium re-grows underneath it, then the scab falls to the ground. If this were the process that happened in an artery, where do you think that clot would go? Down the artery, to get stuck where it narrows, to cause an infarction. Not a very good design feature, I would argue.

So, what happens is something far cleverer. A replacement endothelial layer is created from Endothelial Progenitor Cells (EPCs). These are synthesized in the bone marrow, and float about in the bloodstream. Chemicals released, when endothelium is damaged, attract EPCs to the area of damage/blood clot.

Once they arrive they stick to the surface of any remaining clot, then they grow into fully mature endothelial cells, forming a new endothelial layer. What this means is that any remaining blood clot now sits beneath the new endothelial layer, and within the artery wall itself. It cannot now break off and get stuck somewhere else in the body.

Even more clever is the fact that EPCs have the capability, to become something other than mature endothelial cells. They can travel down another road in the developmental pathway, to become monocytes. Monocytes, in turn, mature into macrophages.

Macrophages are white blood cells whose job it is to clear up all alien materials in the body. Dead cells, invading bacteria, any damaged tissue. They squirt nitric oxide out, oxidise dead and damaged material, such as anything found in a blood clot, then engulf it, before travelling off to the lymph glands. Here, the dead, damaged and alien materials are further broken down, before excretion from the body.

Thus, with EPCs, you have the entire repair and clearance system all in one package. Some of the EPCs that arrive on the scene, form the new endothelial layer. The rest turn into monocytes, then macrophages, which clear away the remnant blood clot.

This process of repair and clearance is what I call ‘healing’. Others choose to call it inflammation, and claim it is the underlying cause of CVD. Good for them. I suspect it may not be a fertile route to travel down.

The other thing to note here is that the substance which is most intimately bonded to the exposed endothelium, at least in humans, is lipoprotein (a) (LP(a). Lipoprotein (a) is Low Density Lipoprotein (LDL) with an extra protein attached to it. A protein called apolipoprotein A. This protein is fascinating, because it has an almost identical structure to plasminogen. Identical apart from a single amino acid.

However, this difference, though very slight, is critical, because it means that TP(a) cannot have any effect on apolipoprotein A. There can be no conversion to plasmin. Thus, any blood clot, or part of the blood clot, containing Lp(a) is extremely resistant to fibrinolysis. It cannot be broken apart, and so remains attached to the artery wall, and will be a major component of the remnant blood clot that is then drawn into the artery wall – and then broken down by macrophages.

This is where Linus Pauling, Mattias Rath, vitamin C, and guinea pigs come into play. I have discussed this area before, but I am going to discuss it again…. Soon.

Before fully signing off on this blog I shall leave you with another thought, which is this. Lp(a) is identical to LDL ‘bad cholesterol’ – apart from a single attached protein – apolipoprotein A. So, if you were closely studying the contents of an atherosclerotic plaque, it would be quite easy to think you were looking at LDL, when you were actually looking at Lp(a)?

Of course, what I have done here is to describe a process of clot formation, and repair, that is probably happening all the time. The next question is obvious. When, and how, can this process become ‘abnormal?’ When, and how, does it lead to CVD?



P.S. those interested in a great deal more complexity, this paper is a belter.

Here is one section that explains a great deal in a few words. ‘Recent evidence suggests that ECs [endothelial cells] in regions of disturbed flow in arteries are primed for activation (they have increased levels of NF-κB in their cytoplasm) and that systemic imbalances (e.g. associated with sepsis or cardiac risk factors) may result in the translocation of NF-κB to the nucleus and increased expression of procoagulants such as tissue factor (TF) and adhesion molecules. TM, thrombomodulin; t-PA, tissue-type plasminogen activator; EPCR, endothelial protein C receptor; TFPI, tissue factor pathway inhibitor; VWF, von Willebrand factor.’ And there, I think you have it, in a nutshell. Although I realise that most people have never heard of any of those things.

What causes heart disease part XXXVI (part thirty-six)

5th September 2017

Wipe your mind clear of all previous ideas about CVD. About as easy as standing in the corner and not thinking about a tiger. In reality, once you have read about, and talked about, and researched, and thought about anything, patterns are created in your mind. Familiar landscapes develop, and well-worn pathways become the comfortable and easy routes to travel down.

Say what you like about Ancel Keys (and I had better not, for I would end up swearing a lot), he created the tightly patrolled mental box for everyone. Diet and cholesterol and cardiovascular disease. These are the great beacons that mark out, the map of the mind, where all thinking and discussion must take place. They illuminate all, and beyond them is darkness.

Now, blow out the beacons. Move out into darkness. We shall create a new landscape of thought. We have control of the vertical, and the horizontal, you are entering the Outer Limits. [I suspect some people may not get that reference]. We are breaking free of the box. In fact, there is no box, it no longer exists.

In the distance, there is a glimmer of light… it is our first fact. At least we hope it is a fact. We approach the glittering light and scrape way the grime that has been obscuring it for many years, to reveal…

Atherosclerotic plaques only develop in larger arteries.

Quite close to it, almost hidden away, lies another fact.

Atherosclerotic plaques never develop in veins.

There are two exceptions to the second fact – well, there are more, but these are the most obvious. First, if you take a vein, and use it to create a coronary artery bypass graft, it will develop atherosclerosis very rapidly. Secondly, if you create an arteriovenous fistula AV-fistula (fusing an artery and vein together) for dialysis patients, the venous section will develop atherosclerotic plaques.

Setting aside these exceptions, these two facts were as close to inarguable as I have been able to find. Inevitably, they lead to my first question. Why do plaques develop in arteries, and not in veins? Right now, I can see you doing what everyone does, searching for a simple answer, with thoughts such as:

  • There is less oxygen in veins, and oxygenation is damaging to arterial walls
  • The pressure is less in veins
  • The LDL level is lower in veins (it’s not, but I have heard a lot of people say this)
  • Arteries and veins have a different structure (they do not).

And so on, and so forth. Isn’t the search for a quick and simple answer fun…?

After exploring almost every avenue that I believed could possibly be involved in CVD, I found myself returning more and more often to the difference in blood pressure in veins and arteries as the place where the answers were most likely to be found.

However, I knew pressure, by itself, is not going to cause anything, unless you succeed in ‘bursting’ an artery, or ‘bursting’ the lining of the artery. I mean, this can be done. You can develop an aneurysm (thinned and ballooned area) in an artery, which can then rupture – usually with catastrophic consequences.

But before that, what can pressure do? Force things carried within the artery into the artery wall behind? No, that does not make sense. For that would mean everything carried in the bloodstream would simply be blasted into all artery walls, everywhere. The smallest molecules would go first, molecules such H20 to start with. Does this happen…. No, of course not. Our arteries, and the endothelial cells that line our arteries (and veins), are not leaky.

In short, differences in pressure cannot provide any sort of an explanation.

However, there is a law of fluid dynamics which says – words to the effect – if the pressure in a tube is higher, the velocity of the fluid flowing through a tube will also be higher. Which means that blood is travelling far faster in an artery than a vein. A veritable white-water maelstrom, compared to a meandering river as it approaches the sea.

Thus, it is easy to imagine that anything lining an artery is going to be exposed to far greater ‘forces’ than anything lining a vein. These forces, which I shall call biomechanical stresses, will be particularly intense in certain places. For example, where arteries branch (bifurcate) e.g. where the carotid arteries, that supply blood to the brain, branch off (bifurcate) from the aorta.

Another place of extreme biomechanical stress is within the coronary arteries. These arteries are exposed to a unique stress, in that they are compressed with great force when the heart contracts. Some have likened this to stomping on a hose every second. Indeed, blood cannot flow in coronary arteries during systole (ventricular contraction) because they are squeezed shut.

In general, if you look at where atherosclerotic plaques develop, you find that they most often occur at maximum biomechanical stress. Where carotid arteries (main arteries supplying blood to the brain) branch from the aorta, and also where other arteries branch from the aorta, and within the coronary arteries. It seems, therefore, that biomechanical stress is required for plaques to develop. This is not the same as high blood pressure, but it is closely associated with high blood pressure.

In truth, this idea is not in any way contentious. This is a highly jargon filled section from a paper called ‘Biomechanics of Atherosclerotic Coronary Plaque: Site, Stability and In Vivo Elasticity Modelling.’

Although the coronary and peripheral systems in their entirety are exposed to the same atherogenic cells and molecules in the plasma, atherosclerotic lesions form at specific regions of the arterial tree. Such lesions appear in the vicinity of branch points, the outer wall of bifurcations and the inner wall of curves. Pathologic studies, have shown that healed plaque ruptures are predominantly in the proximal portions of the left anterior descending (LAD), right coronary (RCA), left circumflex (LCx) and left main (LM) arteries. Investigations over the last decade have elucidated both fluid mechanical and most recently structural biomechanical factors that mediated the site of plaque formation.’1

Which is all fine and sensible. However, this very same paper states the following:

‘Plaque formation is now recognized as an inflammatory process triggered by high levels of serum LDL that enter the coronary wall, encounter oxygen reactive species, and become oxidized. The oxidization, in turn, stimulates the recruitment of monocytes that convert to macrophages to phagocytize oxidized LDLs. This forms a necrotic core with recruitment of smooth muscle cells from the media to seal over the fatty core.’

That is the official party line as to how CVD starts, and develops. But if you believe that, you immediately face a conundrum. How can you reconcile the hypothesis that raised LDL entering the artery wall initiates plaque development, with the observation that atherosclerotic lesions form at specific regions of the arterial tree? It is surely one, or the other, but it cannot be both. Sorry, but at this point I need to take you back into the landscape of raised LDL and CVD.

You may think, in fact you probably are already thinking: “Well, biomechanical stress damages the endothelial cells, allowing LDL to enter.” Now, that could be true. However, if that is true, then you have (if you believe in the cholesterol hypothesis), just made a move that will result in checkmate against you.

The argument goes like this:

If LDL can only leak into the artery wall at an area where the endothelial layer is damaged, and this is where plaques develop, this means it cannot leak through in areas where the endothelium is not damaged. Ergo, the first step in the development of plaques cannot be LDL ‘leaking’ into the artery wall past the endothelium, it is damage to the endothelium. Ergo, a raised LDL level is not the primary cause of CVD. Checkmate.

You don’t like that logic? If you prefer a few more facts, using a different approach.

If you think LDL is capable of, simply, transporting itself past the endothelium, then you need to define a mechanism. Is it simply osmotic pressure, with LDL travelling down a concentration gradient from the bloodstream into the artery wall? Is it actively transported through endothelial cells? Does it leak between the endothelial cells? These are the mechanisms that I have seen most commonly proposed – although they are often presented with so much surrounding jargon that it is almost impossible to work out what is being said.

In truth, I have spent years and years trying to establish if LDL can, or cannot, move into the arterial wall, past the healthy, undamaged, endothelium. If I had been organised enough, I could have gathered together ten thousand papers saying that it can, and another ten thousand saying that it cannot.

Having torn up twenty thousand papers, on the basis of complete uselessness, I began with, what may seem a simple question, a thought experiment if you like. Why would endothelial cells allow LDL to pass through them, to then allow LDL to be oxidised in the arterial wall behind? This process serves no physiological purpose, other than to kill you from cardiovascular disease!

The idea that endothelial cells simply cannot prevent this from happening is, frankly bonkers. Cells can quite easily control the passage of single atoms/ions through their cell membranes Indeed, this is one way that all cells function. To give one example, they can pump individual sodium ions out, and individual potassium ions in, to maintain an electrical action potential. They only lose the ability to control their own internal environment, within very tight parameters, when they die.

Therefore, the idea that an endothelial cell cannot prevent a relatively massive LDL molecule from entering the side facing the bloodstream, then passing straight though, then ejecting itself out the other side, is complete nonsense. Complete… nonsense.

Indeed, it has been well established that the only way LDL can enter a cell, is for that that cell to manufacture an LDL receptor, wave it about it the bloodstream to lock onto an LDL molecule, before dragging the receptor and the LDL back inside. Ergo, LDL does not get into an endothelial cell, unless the cell wants LDL to enter. It activates complex processes to allow this to happen.

The reason why some people have very high LDL levels is because they cannot manufacture enough LDL receptors, or the LDL receptors they manufacture are faulty. A lack of LDL receptors, or faulty receptors is, of course, the underlying problem in Familial Hypercholesterolaemia(FH). Proof, if proof were truly needed, that LDL cannot force its way into cells – no matter what the concentration in the bloodstream.

In short, even a superficial understanding of how cells control the passage of atoms and molecules, leads to the inescapable conclusion that LDL cannot possibly travel straight through an endothelial cell, without the activation of complex and highly controlled cellular process.

This problem has been duly noted by those who support the LDL/cholesterol hypothesis. So, the current thinking, although I have never seen it expressed clearly, is that there must be gaps between endothelial cells, wide enough for LDL to leak past.

Again, no. The fact is that, in a healthy artery wall, with healthy endothelium, there simply are no gaps between endothelial cells. Here, from a paper entitled. ‘Endothelial Cell Junctional Adhesion Molecules.’ [jargon alert].

‘Endothelial cells line the lumen of all blood vessels and play a critical role in maintaining the barrier function of the vasculature. Sealing of the vessel wall between adjacent endothelial cells is facilitated by interactions involving junctionally expressed transmembrane proteins, including tight junctional molecules, such as members of the junctional adhesion molecule family, components of adherence junctions, such as VE-Cadherin, and other molecules, such as platelet endothelial cell adhesion molecule.’2

At the risk of simply repeating what this paper says, there are no gaps between endothelial cells. Instead, there is a highly complex structure of proteins and other molecules between each endothelial cell ensuring that nothing gets past – unless the endothelial cells are instructed to let them past. This happens with white blood cells, they can open the junctions between endothelial cells, and move into the artery wall – then out again. Clever stuff.

Of course, if most things travelling in the bloodstream had to overcome complex barriers to get past the endothelium you would die, as your blood would simply circulate round and round, struggling to exchanging nutrients back and forth with the underlying tissue. Which kind of negates the point of having a circulatory system in the first place.

Nature, in the way that nature does, noted this potential problem, and came up with a solution. As blood vessels get smaller, and smaller, the endothelium develops holes – called fenestrations. These fenestrations allow almost everything present in the blood to flow freely in and out of the surrounding tissues/organs. Red blood cells would be one exception.

Why, you could ask, would endothelial cells have fenestrations in them to allow the free passage of molecules in and out, if things can freely pass in and out of non-fenestrated, tightly bound, endothelium?

At this point, I am overwhelmed with the need to make a quick summary:

1: It is impossible for LDL to pass straight through a living endothelial cell

2: Endothelial cells are tightly bound together, and will not allow anything to pass between them.

In addition, here are a couple of other facts to consider.

The first of which is that, in the brain, the endothelium never becomes fenestrated. There are no holes, even in capillaries (the smallest blood vessels in the body). Which means nothing can move into, or be removed from the brain, that the endothelial cells do not grant passage. This barrier function is usually referred to as the blood brain barrier (BBB):

‘Cholesterol is a major constituent of the human brain, and the brain is the most cholesterol-rich organ. Numerous lipoprotein receptors and apolipoproteins are expressed in the brain. Cholesterol is tightly regulated between the major brain cells and is essential for normal brain development. The metabolism of brain cholesterol differs markedly from that of other tissues. Brain cholesterol is primarily derived by de novo synthesis and the blood brain barrier prevents the uptake of lipoprotein cholesterol from the circulation.’ 3

To put this another way, if LDL could pass the BBB, then the brain would not need to synthesize its own cholesterol, and the brain does synthesize cholesterol within specialised glial cells. Which is further confirmation that an intact, non-fenestrated endothelium, blocks the passage of LDL.

Now here is a final fact (a final fact in this blog at least) that I would like you to ponder. Which is that large blood vessels have their own blood vessels, known as vasa vasorum. Literally, ‘blood vessels of the blood vessels’. Vasa vasorum surround and penetrate large arteries, and veins, supplying them with the required nutrients.

They are, of course, fully fenestrated (full of holes). Thus LDL, or anything else, can simply leak out of the vasa vasorum and into the artery wall if it so wishes – yes, even down a concentration gradient, if you like to think of it in this way.

Which means that there is absolutely no need for LDL, or anything else, to be absorbed through the endothelium lining the arteries, as it can get in from ‘behind’, so to speak. Which takes me back to my first question here. Why would endothelial cells transport LDL past themselves, and into the artery wall behind – if LDL can perfectly easily get into the artery wall from the vasa vasorum? This truly would be an exercise in pointlessness.

I could go on, as I have only touched upon a small part of the complexity involved here. But I hope to have given you enough food for thought. Yes, you easily can make statements such as ‘Plaque formation is now recognized as an inflammatory process triggered by high levels of serum LDL that enter the coronary wall’. Certainly, if you say it fast enough, and do not think about it, such a statement can seem reasonable.

However, if you start looking at the actual process required for LDL to travel into the arterial wall, you begin to realise that it is (with a healthy and intact endothelium) simply not possible. Or, if it is possible, it should be happening everywhere, in all arteries and veins. Not at discrete points.

At which point, you begin to realise that the cholesterol hypothesis, whilst is sounds superficially reasonable, requires mechanisms of action that just do not exist.

LDL cannot enter the arterial wall, at least not from the lumen of the artery, unless the endothelium has been damaged in some way. If you damage the endothelium, all hell breaks loose – and then we have a completely different story on our hands. One where LDL may have a role in plaque formation, or it may not, but it most certainly cannot be the primary role.

This is a conclusion that I arrived at a long time ago. Not, initially, because I set out to debunk the hypothesis. I simply wanted to understand how a raised LDL could cause atherosclerosis. ‘Because it does’, has never ever been a reply that I am happy to accept. In fact, nowadays I would translate this particular ‘because it does’ into ‘because it must.’ It must, because if LDL cannot pass through, or past, a healthy endothelium, the cholesterol hypothesis is wrong. And it can’t, so it is.

Now I have got that out of the system, I shall move on to look at what happens when you damage the endothelium. For that, logically, must be the first step in plaque formation.




What causes heart disease part XXXV (thirty five)

19 August 2017

Having spent many years smashing everything into pieces in an attempt to work out what is going on with cardiovascular disease, I am now going to attempt the amazing feat of bringing everything together in some sort of coherent structure. I have no idea how long this may take, so please bear with me while I first set the scene by making a couple of point that need to be made.

Point One:

Explanations exist; they have existed for all time; there is always a well-known solution to every human problem — neat, plausible, and wrong.’ H.L. Mencken.

Cardiovascular disease is best seen as a process. Attempts to find the key, single, cause has created the massive multifactorial monster we see before us today. Unfortunately, the trap of searching for a/the cause seems to be hard wired into our thinking. This approach has worked well for things such as infectious diseases and suchlike, but it does not work here. I have lost track of the number of times someone has come up with the new cause of CVD, then tried to crowbar all observations to fit. Or simply dismiss contradictory evidence.

  • It’s caused by infections
  • It’s all due to vitamin C deficiency
  • It’s all due to blood sugar
  • Its’ all due to inflammation etc. etc. etc. etc. etc.


In truth, I was as guilty of this as everyone else. I believed that ‘stress’ was the cause, and everything could be incorporated within this factor. This is not true. Stress/strain represents one factor that is capable of causing CVD – quite an important one – but it cannot explain everything.

Whilst there obviously are ‘causes’ of cardiovascular disease, they cannot be understood in isolation from process(es). What is going on, and why, and how can things that seem to cause cardiovascular disease be fitted into these processes.

It may seem intellectually unsatisfactory to move away from a simple, single, cause model. We all want the E=MC2 moment, or the untangling of the structure of DNA moment. Eureka! That was never going to happen here, or it would already have happened. If there truly were a single cause it would have been found by now – and it hasn’t.

Point Two:

The evidence base is flawed. In part because studying complex biological systems is, in itself, very difficult to do. The number of variables involved is mind-boggling, and the number possible interactions between those variables is mind boggling to the power one trillion. If you are looking for absolute certainty…. look elsewhere.

Just to give one example of how many potential factors there are. Here is part of a paper by researchers, who looked at geomagnetic disturbance and its impact on heart attacks and strokes (Russian paper):

‘It was shown statistically that during geomagnetic disturbances the frequency of myocardial infarction and brain stroke cases increased on the average by a factor of two in comparison with quiet geomagnetic conditions. These results are close to results obtained by (Stoupel, 1999), for patients suffering with acute cardiological pathology. Our recent study (with L.Parfeonova) revealed the relation between heart ventricular ectopic activity (VEA) and geomagnetic conditions in patients with CHD. On the average 1995 episodes of VEA having on one patient within 24 hours have been revealed in patients, whose records coincided with the periods of geomagnetic storms and 1440 VEA episodes for active conditions. Minimal quantity of VEA episodes was found for unsettled condition: 394. In a quiet geomagnetic condition VEA episodes appeared more often than in periods of unsettled conditions.’1

How many researchers have taken geomagnetic disturbances into account as a potential confounding factor in their research? I would suggest, none. Yet here is a factor that can (possibly) increase the risk of CVD events by 100%.

I chose this example, almost at random, to highlight the point that this stuff is complicated, and there any many, many, uncertainties involved. Can you control any study for all factors ever found to be associated (causally or otherwise) with CVD? No, you cannot.

Alternatively, you can do what many people do. Dismiss research that seems contradictory, or just daft. I can see many people automatically seeking to dismiss a Russian study about the effect of geomagnetic disturbance on CVD on the dual grounds that is a: Russian and b: bonkers. That would be unwise.

Of course, there is the other problem that much of medical research (especially in the highly lucrative area of CVD) has been funded by the pharmaceutical industry, resulting in the problem that most research findings are false:

‘There is increasing concern that most current published research findings are false. The probability that a research claim is true may depend on study power and bias, the number of other studies on the same question, and, importantly, the ratio of true to no relationships among the relationships probed in each scientific field. In this framework, a research finding is less likely to be true when the studies conducted in a field are smaller; when effect sizes are smaller; when there is a greater number and lesser preselection of tested relationships; where there is greater flexibility in designs, definitions, outcomes, and analytical modes; when there is greater financial and other interest and prejudice; and when more teams are involved in a scientific field in chase of statistical significance. Simulations show that for most study designs and settings, it is more likely for a research claim to be false than true. Moreover, for many current scientific fields, claimed research findings may often be simply accurate measures of the prevailing bias.2

This is a famous paper, one of the most cited and read in medical research history. It was written in 2005 and things have got worse, not better, since then.

Oh, but of course, peer review keeps everything on the straight and narrow:

‘The mistake, of course, it to have thought that peer review was more than a crude means of discovering the acceptability – not the validity – of a new finding. Editors and scientists alike insist on the pivotal importance of peer review. We portray peer review to the public as a quasi-sacred process that helps to make science our most objective truth teller. But we know that the system of peer review is biased, unjust, unaccountable, incomplete, easily fixed, often insulting, usually ignorant, occasionally foolish, and frequently wrong.’ Richard Horton, editor of the Lancet.

In this morass, where does one turn?

This is a question that has no definitive answer. Shall I just choose evidence that suits my argument, and dismiss all else? To an extent, the difficulty in disentangling evidence was my spur to write the book Doctoring Data. In it, I attempted to determine what is valid and what is not. How to spot the biases and errors. How to know what it true, from the other stuff?

Answer… it cannot be done. Not for certain. Whatever evidence I choose, it can be criticised – in one way or another. Did the study I am quoting control for geomagnetic disturbance or not? As a general rule, any study – and I mean any study – can be pulled apart and dismissed, if you so wish. Which could leave most of what I do as a smoking ruin.

However, most of the research I look at has one major advantage. There is not much, if any, financial interest, behind it. Other than suppressing it, I suppose.

Yes, of course, I bring certain biases to the discussion. I am almost entirely anti-statin. I am not a great believer in blood pressure lowering – at least not at current levels. I do not believe in the cholesterol hypothesis and I think that the anti-saturated fat dogma is completely bonkers and has no evidence to support it – at all. I believe that salt is good for and, in most people, protects against CVD.

I believe that a high carbohydrate low fat diet is utterly bonkers – especially in those with diabetes. And suchlike. In short, I believe that almost everything we are told is good for you, is bad for you, and vice-versa. With the exception of smoking (bad) and exercise (good).

Having got that out of my system. Let us begin….. in the next blog.