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.

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

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

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

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

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.

Discussion

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

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

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

You heard it here first.

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

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

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

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

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:https://qrisk.org/three/

It has twenty variable factors. These are

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

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

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

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

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

At least three items on the list are caused by CVD

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

One of them sits completely alone

  • Atrial Fibrillation

As for the others:

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

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

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

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

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

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

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

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

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

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.’

 

1: https://www.diabetes.co.uk/in-depth/every-last-shred-evidence-low-fat-dietary-guidelines-never-introduced/

2: http://time.com/3705734/cholesterol-dietary-guidelines/

3: https://www.health.harvard.edu/blog/panel-suggests-stop-warning-about-cholesterol-in-food-201502127713

4: https://www.ncbi.nlm.nih.gov/pubmed/12133211

5: https://www.medscape.com/viewarticle/839360

6: https://www.pressreader.com/uk/daily-mail/20180109/282643212945759

7: http://bmjopen.bmj.com/content/8/3/e020167

8: http://www.zoeharcombe.com/2018/07/saturated-fat-consultation-sacn-my-response/

 

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.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

There were no identifiable risk factors for atherosclerosis.

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

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

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

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

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

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

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

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

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

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

Eggs are good for you – who knew!?

29th May 2018

I was sent this article a few days ago: ‘Associations of egg consumption with cardiovascular disease in a cohort study of 0.5 million Chinese adults.’ Now, there would be a time when such an article would excite me and fill me with an urge to tell everyone ‘Eggs are good for you.’ Nowadays I tend to sigh and think: “another study for everyone to ignore”. Move along, nothing to see here.

Then I thought again. No, here we have yet more evidence, from a truly enormous observational study, that eating a substance with a very high cholesterol content does not increase the risk of cardiovascular disease. Instead, it protects against cardiovascular disease – not by a massive amount, but not that shabby

So, I decided I should make the effort to spread the message far and wide and throw down a challenge to the ‘What The Health’ brigade.

Here was the main conclusion of the study:

‘Among Chinese adults, a moderate level of egg consumption (up to <1 egg/day) was significantly associated with lower risk of CVD, largely independent of other risk factors.’

Yes, I know, how can you eat <1 egg/day (less than one egg per day)? That is a dietary intake that includes zero. Such is the joy of scientific literature. What they meant was, eating almost one egg a day – I think it was 0.88 of an egg – on average.

Expanding it a bit: compared with non-consumers, those who ate (almost one) egg daily had a lower risk of CVD. An 11% reduction (relative risk).

Splitting that down further:

  • Death from Ischaemic heart disease was reduced by 12% (0.88 [0.84-0.93])
  • Death from haemorrhagic stroke reduced by 26% (0.74 [0.67-0.82])
  • Death from ischaemic stroke reduced by 10%. (0.90 [0.85-0.95]).

There was also a significant dose-response relationships of egg consumption with morbidity (non-fatal illness) of all CVD endpoints (P for linear trend <0.05). Which means that the more eggs you ate, the greater the benefit. Daily consumers also had an 18% lower risk of CVD death and a 28% lower risk of haemorrhagic stroke death compared to those who ate no eggs at all.1

Of course, the demonization of eggs has become somewhat of a thing of the past by many of those who used to be very firmly ‘anti-egg’. Here is what the British Heart Foundation has to say on the matter:

‘Now current research shows that for most healthy people, cholesterol in food, such as eggs, has a much smaller effect on blood levels of total cholesterol and harmful LDL cholesterol, especially when compared with the much greater and more harmful effects of saturated fatty acids found in foods such as butter and fatty meat. Eggs are, in fact, low in saturated fat. Recent research has also shown that moderate egg consumption – up to one a day – does not increase heart disease risk in healthy individuals and can be part of a healthy diet.

As such, since about 2000, major world and UK health organizations, including us and the Department of Health, changed their advice on eggs and there is now no recommended limit on how many eggs people should eat, as long as you eat a varied diet.’ 2

Given that the BHF are no longer that concerned about egg consumption, based on several other studies, what does this Chinese research add? Well, it demonstrates that eggs are not simply neutral, they are positively beneficial for health.

The reason for highlighting this fact is, in part, to counter some of the ridiculous claims made by the massively influential documentary ‘What The Health.’ For those of you who have not heard of it, you can search it on the Internet.

It was created by a vegan network, and – amongst other ridiculous statements – made the claim that eating a daily egg was the equivalent of smoking five cigarettes a day. Now it turns out that eating an egg is the equivalent of going out for a five-mile run. Well, not quite, I exaggerate for effect.

I would like to know how the vegan network will decide to ignore and/or rubbish this study. Which they will undoubtedly try to do. Perhaps we should await some more pseudo-science from Dr Bernard, of the Physicians Committee for Responsible Medicine (PCRM). This sounds like a proper scientific organisation, but it is, at core, a highly vociferous, vegan pressure group.

Dr Bernard, up to now, has this to say about egg consumption:

‘Since one egg has the same amount of cholesterol as a Big Mac, it is unnecessary – even detrimental to your health – to consume eggs or egg products. One egg has more cholesterol than your body needs. In fact, any added dietary cholesterol is unnecessary because our bodies already produce more than the amount we require.

An excess of cholesterol leads to heart disease, so it’s no surprise that a 2010 study in the Canadian Journal of Cardiology found that those who consume the most eggs have a 19 percent increased risk for cardiovascular problems.3

One egg has more cholesterol than your body needs? What, per day, per week, per month…ever? In fact, a large egg contains around 185mg of cholesterol. An average adult will synthesize about 1gram of cholesterol per day. So, please try getting your facts somewhere close to correct.

I should add here that I have nothing against anyone deciding to be vegan. It is a lifestyle choice that I respect and can understand. I don’t agree with it, but everyone is free to make their own decisions. What I do not like is when science is sacrificed at the altar of a belief system, and people are then persuaded to take unhealthy decisions. Such as avoiding eggs.

Having got that off my chest, I will say that, to those who made the “What The Health” documentary, to those in the PCRM and the wider vegan community, I invite you to attack this study. Or maybe you are too ‘frit’ to enter the battleground.

References
1: http://heart.bmj.com/content/early/2018/04/17/heartjnl-2017-312651

2: https://www.bhf.org.uk/news-from-the-bhf/news-archive/2015/may/eggs-and-cholesterol

3: http://www.pcrm.org/nbBlog/index.php/the-incredibly-inedible-egg

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.

1: https://www.cureus.com/articles/11752-a-72-year-old-patient-with-longstanding-untreated-familial-hypercholesterolemia-but-no-coronary-artery-calcification-a-case-report

2: https://academic.oup.com/eurheartj/article/29/21/2625/530400

 

Will taxing sugar end up damaging the health of the nation?

28th April 2018

England recently introduced a sugar tax, making it more expensive to buy food and drink that contains sugar. We are mainly talking about soft drinks here, such as Coke and Irn Bru and concentrated orange juice and suchlike. Many people celebrated this as a great step forward in tackling obesity. Including many people that I like, and get on with, and agree with on most things.

Not, on this however. Firstly, on principle, I do not like the idea of using the state machinery of law making, banning, taxing and suchlike to enforce social controls. It is an attack on personal liberty and represents an unpleasant form of the nanny state. Where does it end?

Don’t climb mountains because you might fall and hurt yourself. Don’t swim in the sea, you may drown. Only state approved ‘healthy’ activities are to be allowed. Hmmmm. No thanks. I would rather make my own choices thanks very much.

Aside from this, you must be absolutely one hundred per cent certain that if you are going to use lumbering, soul destroying, personal freedom crushing, state machinery, that you are going to do a lot more good than harm. Indeed, you should do no harm at all.

Especially when it comes to dietary interventions, which will affect every single person in the country. As readers of this blog know, the dietary guidelines introduced in the US and UK in the late 1970s, early 1980s have almost certainly been the main driving force behind the modern epidemics of both obesity and diabetes. Eat less fat and more carbohydrates was the cry. Yes, and look what happened.

These guidelines were not turned into laws and taxes, in most countries, but Denmark did go as far as introducing a fat tax, in 2011. Luckily, they dropped it fairly rapidly. The Netherlands too have considered it, and it may happen:

‘Although the Netherlands has refrained from introducing a “fat tax”, support for such a tax is gaining momentum in several EU member states, thus raising the question whether the EU should consider stepping in so as to adopt an EU-wide “fat tax” scheme that is to be applied in all EU member states.’ 1

Things have gone a bit quiet on this front. Although it was interesting if we had both a fat tax and a sugar tax. Sugar is just the simplest form of carbohydrate, so you could argue we may shortly have both fat and carbohydrate taxes. What would that leave us to eat? Protein.

If I have seen one macronutrient that can cause major health issues, if eaten to excess, it is protein.

‘Protein poisoning (also referred to colloquially as rabbit starvation, mal de caribou, or fat starvation) is a rare form of acute malnutrition thought to be caused by a complete absence of fat in the diet.

Excess protein is sometimes cited as the cause of this issue; when meat and fat are consumed in the correct ratio, such as that found in pemmican (which is 50% fat by volume), the diet is considered nutritionally complete and can support humans for months or more.

Other stressors, such as severe cold or a dry environment, may intensify symptoms or decrease time to onset. Symptoms include diarrhoea, headache, fatigue, low blood pressure, slow heart rate, and a vague discomfort and hunger (very similar to a food craving) that can be satisfied only by the consumption of fat.

 Protein poisoning was first noted as a consequence of eating rabbit meat exclusively, hence the term, “rabbit starvation”. Rabbit meat is very lean; commercial rabbit meat has 50–100 g dissectable fat per 2 kg (live weight). Based on a carcass yield of 60%, rabbit meat is around 8.3% fat while beef and pork are 32% fat and lamb 28%.’2

In my practice I have seen two young super-enthusiastic body-builders who ate virtually nothing but protein and protein shakes and suchlike who became very ill indeed. Only when they cut out the protein did they recover. Now, this is not common, but there are only three macronutrients. Fat, carbohydrate and protein, and we are thinking of taxing two of them? Maybe we should just tax protein as well and be done with it.

All food found to be unhealthy, and to be taxed, by order of HM Govt.’

Anyway, to return to the sugar tax. What possible downside could there be to this, you may ask? Apart from infantilising the entire population. ‘You are too thick to make decisions about your life, so we will make them for you.’

Well, if you tax drinks containing sugar, more and more people are likely to shift to drinking zero carb alternatives. Coke zero and suchlike. These drinks contain artificial sweeteners, and so the consumption of artificial sweeteners is bound to rise pretty dramatically. Could this do more harm than good? Well, last year a paper came out in the journal Stroke. Called ‘Sugar and artificially sweetened beverages and the risks of incident stroke and dementia – A prospective Cohort Study.’

The main findings were, as follows:

‘Results—After adjustments for age, sex, education (for analysis of dementia), caloric intake, diet quality, physical activity, and smoking, higher recent and higher cumulative intake of artificially sweetened soft drinks were associated with an increased risk of ischemic stroke, all-cause dementia, and Alzheimer’s disease dementia.

When comparing daily cumulative intake to 0 per week (reference), the hazard ratios were 2.96 (95% confidence interval, 1.26–6.97) for ischemic stroke and 2.89 (95% confidence interval, 1.18–7.07) for Alzheimer’s disease. Sugar-sweetened beverages were not associated with stroke or dementia.3

In short, those who drank more artificially sweetened soft drinks were nearly three-fold more likely to have a stroke. In addition, they were very nearly three times as likely to suffer from Alzheimer’s disease. This, most certainly, does not come under my definition of ‘first do no harm.’

If I want a soft drink, I shall be paying the sugar tax. I do not want to end up with Alzheimer’s, thank you very much. I would be interested to know if the sugar tax will help pay for the millions of extra people who will now, very likely, develop dementia over the next few years.

1: https://www.twobirds.com/en/news/articles/2013/uk/no-fat-tax-in-the-netherlands

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

3: Stroke. 2017;48:1139-1146. DOI: 10.1161/STROKEAHA.116.016027

A talk by Aseem Malhotra to the European Parliament

15th April 2018

Last week, Aseem Malhotra addressed the European Parliament to talk about the complete nonsense of the current dietary guidelines. Also, the power of the Nutritional and pharmaceutical industries to distort those guidelines and drive the use of more and more medications. I recommend that everyone has a look.

https://www.youtube.com/watch?v=H4uVNywg848

Thank you. I think this is important to view and share.

Statins and Amyotrophic Lateral Sclerosis

9th April 2018

Primum non Noncere’ – first do no harm.

Over a decade ago, in 2007, I was sent a link to a World Health Organisation study which reported the following:

‘The WHO Foundation Collaborating Centre for International Drug Monitoring (Uppsala Monitoring Centre [UMC]) has received many individual case safety reports (ICSRs) associating HMG-CoA reductase inhibitor drug (statin) use with the occurrence of muscle damage, including rhabdomyolysis, and also peripheral neuropathy. A new signal has now appeared of disproportionally high reporting of upper motor neurone lesions.’ 1

This reported has niggled at the back of my mind for a long time. There are few conditions that can match ‘upper motor neurone disease/amyotrophic later sclerosis’ for sheer bloody awfulness. Here I quote from Wikipedia:

‘Amyotrophic lateral sclerosis (ALS), also known as motor neurone disease (MND), and Lou Gehrig’s disease, is a specific disease which causes the death of neurons controlling voluntary muscles. Some also use the term motor neurone disease for a group of conditions of which ALS is the most common. ALS is characterized by stiff muscles, muscle twitching, and gradually worsening weakness due to muscles decreasing in size. This results in difficulty speaking, swallowing, and eventually breathing.

The cause is not known in 90% to 95% of cases. The remaining 5–10% of cases are inherited from a person’s parents. About half of these genetic cases are due to one of two specific genes. The underlying mechanism involves damage to both upper and lower motor neurons. The diagnosis is based on a person’s signs and symptoms, with testing done to rule out other potential causes.

No cure for ALS is known. A medication called riluzole may extend life by about two to three months. Non-invasive ventilation may result in both improved quality and length of life. The disease can affect people of any age, but usually starts around the age of 60 and in inherited cases around the age of 50. The average survival from onset to death is two to four years. About 10% survive longer than 10 years. Most die from respiratory failure. In much of the world, rates of ALS are unknown. In Europe and the United States the disease affects about two to three people per 100,000 per year.’

With ALS, your brain remains unaffected, whilst your body dies around you. People suffering ALS are often the ones you see in front of the High Court asking for a change in the law, so that they can be assisted to die, rather than suffocating to death. Thus far, in the UK, the courts have remained impervious to basic, caring, humanity. [You may infer what my views are on this matter].

Now, I have known for many years that statins are likely to cause damage to nerve cells. Probably through a direct effect on inhibiting cholesterol synthesis. Synapses are made, primarily, of cholesterol. Cholesterol is required to maintain the health of the myelin sheath, that surrounds and protects neurones. Glial cells in the brain, sustain the myelin sheath by synthesizing their own cholesterol and transferring it across to neurones, and suchlike.

Knowing how vital cholesterol is for the health of neurones, I have always been concerned that statins could well lead to ‘neurone damage’ of one sort of another. Which is why the WHO report from 2007 rang serious alarm bells. Bells which have never chimed again. Until very recently.

A couple of weeks ago I was sent the following paper that was published in the Journal Drug Safety. ‘Amyotrophic Lateral Sclerosis Associated with Statin Use A Disproportionality Analysis of the FDA’s Adverse Event Reporting System.’2

Here are the main results. I have copied them unchanged, as there are those who read this blog who will understand what they mean without any explanation

‘RORs [Relative Odds Ratios] for ALS were elevated for all statins, with elevations possibly stronger for lipophilic statins. RORs ranged from 9.09 (6.57–12.6) and 16.2 (9.56–27.5) for rosuvastatin and pravastatin (hydrophilic) to 17.0 (14.1–20.4), 23.0 (18.3–29.1), and 107 (68.5–167) for atorvastatin, simvastatin, and lovastatin (lipophilic), respectively. For simvastatin, an ROR of 57.1 (39.5–82.7) was separately present for motor neuron disease.’

An odds ratio, basically means increased (or decreased) risk of something happening relative to the standard risk of one. An odds ratio of two (2) means something is twice as likely to happen. An odds ratio of nine (9) means something is nine times as likely to happen. This can also be represented as 900% increase in risk.

Stripping these figures out, we find the following increased risk of ALS associated with the use of different statins. Some statins are more likely to enter the brain than others (atorvastatin, simvastatin and lovastatin) because they are lipophilic (attracted to lipids), these ones had higher RORs.

INCREASED RISK OF AMYOTROPHIC LATERAL SCLEROSIS

WITH DIFFERENT STATINS

STATIN ROR CONFIDENCE INTERVAL
Rosuvastatin 9.09 (809%) 6.57 – 12.6
Pravastatin 16.2 (1,502%) 9.56 – 27.5
Atorvastatin 17.0 (1,600%) 14.1 – 20.4
Simvastatin 23.0 (2,200%) 18.3 – 29.1
Lovastatin 107 (10.600%) 68.5 – 167

 

The two most widely prescribed statins are simvastatin and atorvastatin. Atorvastatin increases risk seventeen told, and simvastatin twenty three fold.

It is often said that association does not mean causation. However, this is only true up to a point. Most statisticians agree that an odds ratio > 6 represents proof of causation. When you find that people taking atorvastatin have a seventeen-fold increase in risk of ALS, this is proof of causation. The effect is too massive to be due to anything else.

So, what does all this mean in the real world. Well around two to three people per 100,000 develop ALS every year (call this 2.5/100,000). If you increase this seventeen-fold, then around forty more people will develop ALS every year, per 100,000.

Taking this up a scale. In the UK it is estimated that around seven million people are now taking statins. This figure would be around six times higher in the US, or around forty million, giving us forty-seven million statins users. Let us round this up to fifty million for the UK and US combined.

So, how many more people are likely to be developing ALS each year, as a result of taking statins? I have used a combined average OR of 20 (i.e., (17 + 23)/2 ), by combining simvastatin and atorvastatin in the calculation, as these are the most widely prescribed statins.

Let us first look at how many people out of 50,000,000 would develop ALS in the ‘non-statin treated’ population.

Number of people                                                        = 50,000,000

Number of people expected to develop ALS              = 2.5/100,000

Number of people developing ALS/ 50,000,000         = 50,000,000/100,000 x 2.5 = 1,250

In short, in a population of fifty million people, not taking statins, we can calculate that around 1,250 would develop ALS every year.

On the other hand, in a population of fifty million people taking statins (atorvastatin and simvastatin) we can expect that figure to be multiplied by around twenty. Now instead of 1,250 people developing ALS, we can expect to see 20 x 1,250 = 25,000.

Or, to put this another way. Each year, in the US and the UK, we can expect to see an extra 23,750 people developing Amyotrophic Lateral Sclerosis due to taking statins.

Now, you may think this is one hell of a lot of people, surely someone would notice. In truth, an increase like this is unlikely to be spotted by anyone. Looking at the UK, each year you might expect to see an extra 3425 cases of ALS each year.

There are around fifty thousand General Practitioners in the UK. So, each GP might expect to see an extra statin related ALS case every sixteen years or so. Or a maximum of two in their working life. You would have to be exceptionally alert to associate one extra case of ALS every sixteen years to statin use. The reality is that this would never, ever, happen.

How else can you spot a rise? Well, you might find this difficult to believe, but the number of people with ALS is not that accurately reported. Even when someone dies, and has ALS, this may not be recorded as the primary cause of death. They may be recorded as dying of a respiratory infection, with ALS as the secondary cause.

To quote from the US ALS association: ‘First, ALS is not a notifiable disease, and ensuring that all newly diagnosed and prevalent ALS cases in the United States are collected in the Registry is challenging.’ In short, we do not really know how many people have ALS, how many are coded as having something else, and suchlike.

I have looked around for evidence of a rise, and it does seem to exist. In Finland, after the introduction of statins the rate of ALS tripled 3. It also went up sharply in the UK but has levelled off since the mid-nineties. In Norway, it doubled in the nineteen nineties4. It is increasing in the US, but the authorities have written this off as due to better detection and notification.

In Australia ALS has risen. ‘In 2015, 758 people with MND died compared with 592 people with MND who died in 2001. The cause of this increase is mostly unknown.’ 5

So, there are strong signals that ALS has sharply increased in several countries. Cause and effect? Well, if the study in Drug Safety is correct, there must have been a rise in ALS caused by statins.

Frankly, I don’t expect my fifty million number is that accurate. It is clear that many people simply stop their statin after a year, or so. So, although fifty million may be the estimate of how many people are taking statins in the US and UK, it is probably more like ten to twenty million, who regularly take their statins. So, my figure of 23,750 is probably more like 10,000.

However, you must ask yourself this question. If statins are causing ALS in 10,000 people each year in the UK and the US, alone, should we not be demanding an immediate review? Because the number one requirement of medicine is Priumum non Noncere. First, do no harm.

1: https://www.ncbi.nlm.nih.gov/pubmed/17536877

2: https://doi.org/10.1007/s40264-017-0620-4

3: https://www.ncbi.nlm.nih.gov/pubmed/11589652

4: https://www.ncbi.nlm.nih.gov/pubmed/11087765

5: https://www.mndaust.asn.au/Get-informed/What-is-MND/Facts-and-figures.aspx

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.

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

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

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

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

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.

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

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

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

Meeting in London

4th March 2018

A bit on the late side, but I want to make readers of the blog aware of a meeting to be held in in London 17th/18th March.

It is part of the Health Icons Lecture Series. The main guest will be Gary Taubes. It will be in London at 1 America Square. Details are here: https://re-findhealth.com/event/health-icons-lecture-series-gary-taubes/

Other guests/speakers will be

  • Ivor Cummins
  • Campbell Murdoch
  • David Unwin
  • Aseem Malhotra
  • Andreas Eenfeldt
  • Me

Here is some of the blurb

For the past half a century, the concept of a healthy diet has been synonymous with a diet low in fat, and particularly low in what is all-too-often referred to as “artery-clogging” saturated fat, the fat found in quantity in eggs, butter, meat and dairy products. The result has been a national dietary prescription to eat ever more plant-based diets: copious fruits, green vegetables and whole grains, while we minimize our consumption of animal products.

For those of us who are overweight or obese, this advice has been accompanied by the insistence that we got that way merely by eating “too much” and that the only way to solve our problems is to eat less and exercise more. And yet this now ubiquitous dietary advice has coincided with unprecedented increases in the prevalence of obesity and diabetes, raising the obvious question of whether this advice and the belief system associated with it may somehow be to blame.

Are they based on sound science? And if they’re not, which the evidence strongly suggests, then how did we come to believe them and why? And, perhaps most important, what’s the alternative? Why do we get fat and diabetic, and what can we do about it?

By asking these questions for the past 20 years, Gary Taubes has become perhaps the single most influential journalist covering nutrition and health today. He’s certainly the most controversial. His investigative reporting on the science of nutrition and the dietary triggers of obesity and diabetes are fundamentally changing the way we eat and live. Michael Pollan has described him as the closest thing we have to a “scientific Alexksandr Solzhenitsyn,” exposing the intellectual bankruptcy of current nutrition science. The Atlantic recently described his investigative journalism as so tenacious and obsessive that he had “fallen through a wormhole from reporting into expertise.”

Taubes’s skeptical, rigorously scientific approach to nutrition science is unparalleled and now he wants to share both the approach and the implications to our health and how to eat to remain healthy.

I hope some people can get along.

Vendetta – The Tim Noakes affair

20th February 2018

[The high fat low carb conspiracy]

Some of you may remember I wrote a blog about Professor Tim Noakes being dragged in front of the Health Professionals Council of South Africa (HPCSA) last year to face charges of “Doing something quite bad, but we are not quite sure what – and we will keep changing the charges until we find something that sticks”.

The case centred around a tweet that Tim Noakes wrote several years ago, on a discussion forum. He was accused of providing a medical consultation – online. [The HPCSA had no guidelines on what constituted an online consultation]. Earlier in the hearing, which started way back in 2015, witnesses for the HPCSA said a consultation was required before any advice could be given or diagnosis made.

The tweets were:

The mother’s tweet read: “@ProfTimNoakes @SalCreed is LCHF eating ok for breastfeeding mums? Worried about all the dairy + cauliflower = wind for babies?? [sic]”

The mum obviously knew what LCHF was (real, nutritious food) & tweeted Noakes and his co-author of Real Meal Revolution. Noakes replied: “Baby doesn’t eat the dairy and cauliflower. Just very healthy high-fat breast milk. Key is to ween [sic] baby onto LCHF.

The primary accusation was that Professor Tim Noakes was guilty of serious professional misconduct. Really, to be struck off on the basis of one tweet, that tweet, and that’s it. The accusation was based on two questions:

Question One: does this constitute a medical consultation?

Question Two: if this is advice, is it dangerous or damaging?

Both accusations, plus a few others, were thrown out at the first hearing last April. Even though the HPCSA was acting as judge, jury, and executioner, as part of its own enquiry, set up by itself. So, they must have had a bloody weak case if the HPCSA itself couldn’t even convince itself that it was right!

You would think that would have been the end of it. But no. The HPCSA obviously feels that the HPCSA is completely incompetent, so it appealed its own decision. You can read in more detail the utter ridiculousness of what it going on here: http://foodmed.net/2018/02/noakes-hpcsa-appeal-evidence-dietitians-setup/

If this were not so Kafkaesque and strange, it would be funny. It is not funny because it is crystal clear that certain members of the HPCSA, who some would allege have significant financial conflicts of interest, are pursuing a vendetta against Professor Tim Noakes. Just as happened to the Australian Orthopaedic surgeon, Gary Fettke.

In Australia, Gary Fettke, was silenced by the Australian Health Practitioners Regulatory Authority (AHPRA) for daring to advise patients to eat fewer carbs and more fat – a High Fat Low Carb (HFLC) diet.

He had been struggling to operate on obese patients and wondered if anything could be done to help them lose weight. He found that the high fat low carb worked. His tale is both hilarious and deeply upsetting. His wife is now blogging on his behalf: http://www.nofructose.com/gary-fettke/

Following various hearings, Gary Fettke was warned not to give any more advice on diet. And, even if his views on HFLC become accepted medical practice, he will not be allowed to talk about them to any patient – ever. Which is perhaps the most stupid judgement in the history of any medical authority – and that takes some doing. A doctor unable to tell his patients about best medical practice.

Patient:            “Tell me Dr Fettke, what do you think I should eat to help me lose weight and control my diabetes?”

Dr Fettke:         “I am sorry I am not allowed to talk to you about such matters, for I am a mere orthopaedic surgeon who cannot understand such complex things. For that you must talk to a dietician.’’

Yes, really. Yes…really.

I watched MaryAnne Demasi ripped to shreds in Australia, losing her job at the Australian Broadcasting Corporation (ABC) for daring to produce and present two programmes, one supporting a high fat, low carb diet – the other criticising statins. There, are of course many others who have been attacked. Even me, although the attacks have been more ‘character assassination’ than any attempt to strike me off the medical register – so far.

You do not need to be a conspiracy theorist to be very deeply worried about the tactics used to silence anyone who dares to promote a high fat low carbohydrate diet. You don’t need to be a conspiracy theorist, because it is quite clear that there is conspiracy to silence anyone who dares stick their head over the parapet on this issue.

So, yes, I want to teach the world to sing… Sorry, got that wrong. I want to teach the world to sign a petition supporting Professor Tim Noakes and his battle in South Africa.

https://www.change.org/p/health-professions-council-of-south-africa-stop-the-harassment-of-prof-tim-noakes

I also want to do what I can to keep this issue up there, in front of as many people as possible. Otherwise Professor Tim Noakes will be shredded, on made up charges, held in virtual secrecy. After which, the industry sponsored PR machine will get to work. ‘Tim Noakes guilty of professional misconduct for promoting high fat low carb diet in children.’ ‘Panel members warn of serious harm to children from Tim Noakes advice.’

A lie, as Winston Churchill once opined, is halfway round the world, before the truth has a chance to get its boots on. Let us shine a bit of light on the lie, before the starting gun fires.

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.

1: https://www.medicalnewstoday.com/articles/320037.php

2: http://www.ox.ac.uk/news/2014-05-23-many-mental-illnesses-reduce-life-expectancy-more-heavy-smoking

3: http://www.sbs.com.au/nitv/article/2010/01/15/indigenous-life-expectancy-worst-world

4: https://www.fastcompany.com/3045495/the-wellbeing-of-all-436-us-congressional-districts-mapped-and-indexed

5: http://www.statinnation.net/blog/2014/8/12/did-dan-buettner-make-a-mistake-with-his-blue-zones

6: https://www.huffingtonpost.com/dr-rock-positano/the-mystery-of-the-roseta_b_73260.html

7: http://journals.sagepub.com/doi/full/10.1177/1745691614568352

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

29th January 2018

Magnesium

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. http://openheart.bmj.com/content/openhrt/5/1/e000668.full.pdf

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.

1: http://www.anh-usa.org/fda-massive-attack-on-supplements/
2: http://www.telegraph.co.uk/science/2017/10/03/vitamin-d-supplements-protect-against-severe-asthma-attacks/and
3: http://www.pnas.org/content/110/23/9523.short
4: Bronstein, et al, (2011) Clinical Toxicol, 49 (10), 910-941
5: https://ethics.harvard.edu/blog/new-prescription-drugs-major-health-risk-few-offsetting-advantages
6: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2127508/pdf/9314758.pdf
7: https://www.health.harvard.edu/heart-health/potassium-lowers-blood-pressure
8: http://circ.ahajournals.org/content/127/1/33

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.

1: http://bmjopen.bmj.com/content/5/9/e007118

2 http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1001335

3: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2804%2915649-3/fulltext

4: https://www.ncbi.nlm.nih.gov/pubmed/19519827

5: https://www.ncbi.nlm.nih.gov/pubmed/15687362

6: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5129901/

7: https://academic.oup.com/jnci/article/97/3/161/2544132

8: https://www.ncbi.nlm.nih.gov/pubmed/26992108

9: https://www.karger.com/Article/Fulltext/441266

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?

 

1: https://www.stress.org/about/chairmans-blog/

2: https://www.cambridge.org/core/services/aop-cambridge-core/content/view/S0007114500000957

3: http://www.bmj.com/content/345/bmj.e4928

4: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3182008/

5: https://www.ncbi.nlm.nih.gov/pubmed/27566327

6: https://www.ncbi.nlm.nih.gov/pubmed/15471614

7: https://www.ncbi.nlm.nih.gov/pubmed/24923258

8: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC181180/

9: https://academic.oup.com/eurheartj/article/35/21/1365/582931

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.

 

1: https://www.medicalnewstoday.com/articles/320037.php

2: http://www.ox.ac.uk/news/2014-05-23-many-mental-illnesses-reduce-life-expectancy-more-heavy-smoking

3: http://www.sbs.com.au/nitv/article/2010/01/15/indigenous-life-expectancy-worst-world

4: http://www.euro.who.int/__data/assets/pdf_file/0005/98438/e81384.pdf

5: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4370130/