Category Archives: Heart Disease

What causes heart disease part X


Yes, part X, and not at the end… yet. Before trying to sum up I thought I should discuss calcification of the arteries. This is an area I have tended to shy away from in the past, because I am not sure exactly where to place it. Association, end-result, cause… Ignore.

Firstly, what is calcification? It is generally accepted, and I think it is true, that calcification represents the final stage of atherosclerotic plaque development, or growth – or whatever word fits most accurately. The best way of looking at calcification, within the spectrum of CVD, would be to define it as the end stage of plaque development.

Having said that, this is not always the case. Not all plaques calcify. Some do, some don’t, and there are many other factors that have a key role in calcification. Various vitamins, such as Vitamin K(K2) and vitamin D are important. Warfarin, which blocks the effects of vitamin K, increases plaque calcification. The picture is complex.

You may have heard of a condition called fibrordysplasia ossificans progressiva, where muscle turns to bone. Not nice, but it does demonstrate that, in certain circumstances, various other tissues can also calcify – to one extent or another.

The main reason for mentioning calcification is that the Calcium artery score (CAC) has become the latest way of frightening people about CVD. You do a CT scan, count of the amount of calcium you can see, and score it. The more the calcium, the worse things are.

In truth, despite my slightly sceptical tone, measuring calcification seems to be one of the most accurate ways of assessing overall plaque burden, and your true risk of dying of CVD. Like everything else in this area, the CAC score is far from perfect. However, even with many provisos in place, if you have a high CAC then you are definitely at a higher risk of dying of CVD. Equally, if you have a zero calcium score, you can pretty much relax. So it is important.

I suppose you may be wondering, at this point, why would plaques calcify? What is the body doing here? Well, you might find these quotes interesting:

“Atherosclerotic calcification is an organized, regulated process similar to bone formation that occurs only when other aspects of atherosclerosis are present.” L Wexler, et al., American Heart Association Writing Group

In short – and, by the way, I fully agree with the above quote, calcification is not an accident, or an unwanted effect. It seems to be an organised, and regulated process. But organised, and regulated, for what purpose…

‘This chapter will show that vascular calcification is a physiologic defense against active, progressive atherosclerotic disease, that it is produced by physiologic mechanisms similar to those required for normal bone formation and that it is potentially reversible. 1

You might well then ask the following. If calcification is a physiologic defense mechanism… why would you want to reverse it? You might just be making things worse. It is certainly true that plaques pass through several different phases. The most dangerous of which seems to be the ‘unstable’ plaque. This is when the central core of the plaque is a kind of liquid goo which, if it ruptures, stimulates a massive – and potentially fatal – blood clot. Plaques in this state are sometimes called ‘vulnerable.’

On the other hand, once a plaque calcifies, it appears to become more stable, and less likely to rupture… and kill you. Which means that reversal of calcification may look good on a scan, and your doctor may smile with pleasure at your reduced CAC. But… it is all good? I have seen an argument used (by the pro-statin camp) that statins accelerate calcification – but this might be a good thing, because the plaque is less likely to rupture. Is this true? [It would by a nice irony].

Perhaps, here, you can see why I struggle a bit with the whole calcification thing. Is it a natural progression of the plaque? It is a way that the body closes down further damage, and stops further plaque progression. Does calcification help to strengthen the artery wall to prevent it rupturing? Should we be trying to reverse calcification… would we simple be turning a calcified plaque back into a vulnerable plaque?

Calcification is certainly not a new thing. CT scans of mummies – from a number of different cultures – have demonstrated that many/most mummified bodies have large areas of arterial calcification. Ergo, CVD is most certainly not a disease of modern humanity. The mummies from Egypt are well over two thousand years old.

As you can probably tell I am not sure exactly what to make of calcification. However, I think you can probably make the following statements:

  • If you do a CT scan and have no demonstrable calcification – after the age of about forty to fifty – you are at very low risk of dying of CVD
  • If you have a high CAC score this means that you have been developing plaques for quite a while, and therefore (unless you change something) you are at high risk of dying of CVD. [However, bear in mind that CAC represents your history, not necessarily your future].
  • Calcification can reverse. Vitamin K2s (Menaquinones) seem to be more protective/able to reverse calcification than Vitamin K1. Menaquinones are primarily found in meat and dairy-based foods and fermented soybeans (known as natto, commonly consumed in Japan)
  • Calcification is not a cause of CVD, it is (or seems to be) the final stage of plaque development. It may be a protective mechanism to stabilise plaques.
  • There is no evidence, that I am aware of, that if you reverse calcification you improve CVD risk. But it seems likely there would be benefit.

Sorry, I am not sure if that is very helpful, but I thought I had to discuss calcification in this series.


What causes heart disease part IX

Heart disease part IX? I think my little series is getting a bit like the Superbowl, with the ever increasing roman numerals. Oh well, it just started that way, now I’m stuck with it. Never mind.

I know people have been reading this series with different purposes in mind. Still, a number of people seem to be asking ‘OK, what’s the cause?’ In which case, I have failed rather miserably in my quest. My main theme is that there is no cause. I shall repeat. There is no cause. Or, perhaps to be more accurate – there is no single cause. There cannot be.

There is a process.

To reiterated what I have been trying to say up to now, you cannot identify real causes, unless you understand what is actually going on with CVD. Indeed, I firmly believe that the search for causes has been the main reason why we are in the current situation – a multifactorial mess. In 1981 the Journal Atherosclerosis searched for all the factors that had been identified as either causing CVD, or protecting against CVD. There were nearly three hundred. Some, such as copper in the diet, were simultaneously causal and protective.

If anyone were to try to scour all medical papers to carry out such a study today, there would be thousands more factors – this I can guarantee. Cholesterol alone itself has split and multiplied into good and bad, light and fluffy, small and dense LLD-C, LDL-P, eight subtractions of HDL (good cholesterol), dyslipidaemia, Lp(a)… Each one has somebody waving a flag furiously in support of it. New and expensive tests developed each and every day.

How could anyone possibly try to make sense of such a thing? Three thousand eight hundred and fifty causal factors, four thousand two hundred and eighty-six protective factors. Go figure. Get a super-computer and run it for the entire life-span of the rest of the Universe. You may be a trillionth of the way through working out how they all add and subtract, multiply, or divide risk.

I spent twenty-five years looking for a cause, or causes, and gave up. It was a fool’s errand. It was the transmutation of lead into the gold, the search for the missing chord, the creating of a perpetual motion machine, a discussion of how many angels can dance on the head of a pin – an attempt to fit planetary motion into a Geocentric model of the Universe (Everything rotates around the Earth). In short, impossible.

The first step to understanding CVD (and this happened for me, many years ago) was to strip cholesterol/LDL cholesterol out of the model. For so many people, then as now, Cholesterol was/is the Earth at the centre of the Geocentric model. It still represents the key jigsaw piece placed triumphantly in the middle of the puzzle. Hammered in, and decreed immovable by the likes of Ancel Keys, before anyone really knew what the picture looks like.

I have read paper after paper where people seem to be going in the right direction about heart disease, then they find they have to shoehorn cholesterol into the centre of their research. At which point everything distorts into a mess of twisted logic. A truth may be jumping up and down in front of them shouting ‘Me, me, me. Here. Look.’ But the truth is invisible. There are no so blind as those who will not see.

There is a process

The conclusion that I came to, eventually, is that we have to define the underlying process. As we should do with all diseases I suppose. However, the ‘disease’ model that medicine has become fixated with, as a way of thinking, was in major part started by a famous microbiologist Robert Koch in the late nineteenth century. His thinking was mainly directed microorganisms e.g. bacteria, viruses and suchlike. He decreed that for any microorganisms to be identified as a true cause of a disease, the following postulates must be fulfilled.

  • 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 reisolated from the inoculated, diseased experimental host and identified as being identical to the original specific causative agent.

Now, these are pretty tough criteria. If not just from an ethical perspective. You try putting a cultured microorganism into a healthily organism nowadays and see how far you get. ‘We are not sure that Ebola virus causes Ebola in humans. Let me isolate if from a patient and introduce into a healthy human.’ Good luck with that.

However, the main point I want to make here is the ‘single causal agent’ concept of medicine has become the meme. You start by looking for the cause of a disease. Once you believe you have it, all research, and all thinking starts to crystallize around that cause. It becomes the centre of all thinking, and dominates the landscape.

I see this in CVD researchers all the time. There are those who are still convinced that cholesterol causes heart disease. All facts are twisted and bent around to fit this central fact. Contradictions are ‘immunised’ against in various ways.

Me:                           ‘People with low cholesterol levels can still have plaques and an MI. So a raised cholesterol level is neither necessary, nor sufficient, to cause CVD.’ {See under Koch’s postulates}.

A.N. Expert:         ‘Actually the normal level of cholesterol in modern humans is far higher than the ‘healthy level.’ So, everyone actually has does have a high cholesterol level. Look at hunter gatherer’s, neonates and other animal species. Where cholesterol levels are much lower.’

The argument here is almost perfect. Everyone has a high cholesterol, so you cannot rule out a high cholesterol level as a cause of CVD- in anyone. [Total nonsense of course].

Me:                           ‘In the Framingham study, those whose cholesterol levels fell, in the first fourteen years of the study, had a greatly increased risk of CVD over the next eighteen years.’

A.N. Expert:         ‘The is reverse causality. A falling cholesterol is caused by an underlying disease, and it is the underlying disease causing the problem, not the low cholesterol.’

Me;                           ‘The French have higher cholesterol levels than the Russians and one tenth the rate of CVD

A.N. Expert:         ‘The French are protected by drinking red wine and eating lightly cooked vegetables and eating garlic.’

Me:                           ‘Asian Indians do not have high cholesterol levels, yet their rate of CVD is far higher than the surrounding population

A.N. Expert:         ‘The Asians are genetically susceptible to CVD.’

‘Ad-Hoc hypotheses – that is, at the time untestable auxiliary hypotheses – can save almost any theory from any particular refutation. But this does not mean that we can go on with an ad hoc hypothesis as long as we like. It may become testable; and a negative test may force us either to give it up or to introduce a new secondary ad hoc hypothesis, and on and on, ad infinitum.’ Karl Popper.

One of my favourite ad-hoc hypothesis, which covers the entire diet-heart/cholesterol hypothesis, rather than just the cholesterol hypothesis, was the use of teleoanlysis. Here, the authors looked at all the studies on using a low fat died and found they had no effect on CVD. However, they knew (and claimed as fact) that eating saturated fat raised cholesterol levels, and they knew (and claimed as fact) that raised cholesterol causes CVD. Ergo, eating saturated fat must cause CVD, so the trials must be wrong.

At which point, rather than relying on the published evidence, they decided that you simply make up studies in your head, and use them to prove that saturated fat does, actually, cause CVD. If you think I am making this up, here is the quote from the study, published in the BMJ

‘….teleoanalysis combines different categories of study to quantify the relation between a causative factor and the risk of disease. This is helpful in determining medical practice and public health policy. Put simply, meta-analysis is the analysis of many studies that have already been done; teleoanalysis provides the answer to questions that would be obtained from studies that have not been done and often, for ethical and financial reasons, could never be done.’

Yes, this was published in the BMJ, no less. I always enjoy this paper. It is so ludicrous that it goes well beyond despair and into surrealism. ‘Ceci n’est pas une Pipe.’ Ignore the evidence and, instead, rely on what you know to be true. This, of course, is the way high quality science should be done… not.

More recently we have equally mad studies on mendelian randomisation. Which may not immediately look like teleoanalysis, but at heart it is are exactly the same thing.

It has been found that older people with high cholesterol levels live longer than those with low cholesterol levels, and get less CVD. This does not fit well into a world where billions can be made lowering cholesterol levels – particularly in the elderly. The first attempt to refute this finding was to say that other diseases lead to low cholesterol levels (as mentioned earlier), and it is the other diseases causing the problem, not the low cholesterol. It was Iribarren who came up with this one.

This, so called ‘reverse causality hypothesis’, has been proven to be wrong in several major studies. So, a new attempt was made using ‘mendelian randomisation’ [Yes, genetics, after Gregor Mendel who proved the concept of genetic inheritance]. By using mendelian randomisation, you can identify people who would have had high cholesterol during most of their lifespan (they have genes associated with high cholesterol levels). So, their cholesterol may be low when you measured it, but it would have been high for most of their lifetime.

Ergo, people with low cholesterol levels, and higher mortality rates, actually had higher cholesterol levels when they were younger, and the lifetime effect of these high cholesterol levels will have caused them to die of CVD. Not, I repeat not, the low cholesterol levels they now have. Yes, this stuff gets published too, and rolled out to confuse the hell out of everyone. [Luckily, I have contact with people within the pharma industry who set up and run genetic studies. They tell me this stuff is simply smoke and mirrors].

I shall paraphrase mendelian randomisation studies. ‘Your cholesterol level is not your cholesterol level…. So there. It is whatever we decide it is.’

Believe me, attempts to refute contradictions to the cholesterol hypothesis get more complex than this. As you can see, in the world of CVD you can play the game of ad-hoc hypothesis, ad-infinitum. In the end there are so many ad-hoc hypothesis created that A.N. Expert can slip from one the other and back again without ever having to accept that any single fact represents a contradiction to the hypothesis. The final trick, when you are getting close to nailing them they just say ‘Oh well, CVD is multifactorial.’ This is not an answer. It is just a polite way of saying ‘shut up and do as I say.’

I ended up with a further realisation. There is no point attacking the cholesterol hypothesis. Those who believe in it have created a majestic Byzantine world of mind-numbing complexity where you can wonder the corridors of ad-hoc hypotheses forever, and never escape.

So, I made a decision, which I have just gone back on. Do not bother attacking the diet-heart/cholesterol (whatever you want to call it) hypothesis. You just get dragged onto a playing field that is not your own, chasing round and round in circles, trying to refute the latest made up ad-hoc hypothesis. It is like discussing the existence, or non-existence, of God with a Professor in theology. They can call on two thousand years of well-rehearsed arguments to confuse you with. You don’t stand a chance.

Instead I have spent, what I hope to be more productive, years and years, working out a hypothesis that actually fits the facts. There is no need for ad-hoc hypothesis, no need for teleoanalysis, or mendalian randomisation. No need for planets doing little circles in the sky, to support the Geocentric model of the Universe.

I could only do this by moving away from looking at causes, and trying to establish the underlying processes at work in CVD. I am not the first to attempt this. Rokitansky was first, Duguid had a good go, Ross also attempted to demonstrate the ‘response to injury hypothesis.’ Up to now, those who believe that CVD is, essentially, a disease of dysfunctional blood clotting have simply bounced off the well-guarded walls of the cholesterol citadel.

In the end, though, someone is going to break through. It is just a matter of time. You can stomp on the truth for many years. You can concrete it over. But the truth has a major advantage over sophistry. It is immortal. No matter how deep you try to bury it, It lies there, waiting to be discovered, pushing little green shoots up into the sunlight waiting to be discovered.

What causes heart disease part VIII

The healing process

Most people, when they think about atherosclerotic plaques, think of them as starting very small – as fatty streaks and suchlike. Then they inevitably get bigger and bigger over many years. However, this is not correct:

‘Atherosclerosis was originally considered to be an ongoing process that was inevitably associated with age. However, plaques are highly dynamic, and are able to progress, stabilize or regress depending on their surrounding milieu. A great deal of research attention has been focused on understanding the involvement of high-density lipoprotein in atherosclerotic plaque regression. However, atherosclerotic plaque regression encompasses a variety of processes that can be grouped into three main areas: removal of lipids and necrotic material; restoration of endothelial function and repair of denuded areas; and cessation of vascular smooth muscle cell proliferation and phenotype reversal.’ 1

In short, progression is not inevitable. Plaques can shrink down in size, the smooth muscle proliferation (often considered and irreversible components of plaques) reversed, and endothelial function restored. In truth, you will most likely not end up with a perfectly healed plaque with no signs it was ever there. You will be left with a bit of a ‘scar’ or some sort. However, the important point is that we are not looking at a one-way street. The body can heal plaques. (Probably not once calcified, but that is another issue).

This leads me onto the third part of the process of CVD. As I have been discussing in this series, the process of CVD has four basic components:

  • Endothelial damage
  • Clot formation/dysfunctional clot formation
  • Clot repair/dysfunctional clot repair
  • The final, fatal, blood clot

Up to now I have mainly talked about endothelial damage, and clot formation, which are plaque ‘growth’ factors. However, repair is also very important. Anything that can interfere with the repair process is going to make plaques grow, rather than regress.

The key players in repair are: monocytes, macrophages and Endothelial Progenitor Cells (EPCs). As mentioned several times before, once the endothelium is damaged, and a clot formed, EPCs are attracted to the area to form a new layer of endothelium. So, clearly EPCS are critical players. Just to quote one paper:

‘BACKGROUND: Cardiovascular risk factors contribute to atherogenesis by inducing endothelial-cell injury and dysfunction. We hypothesized that endothelial progenitor cells derived from bone marrow have a role in ongoing endothelial repair and that impaired mobilization or depletion of these cells contributes to endothelial dysfunction and cardiovascular disease progression.

CONCLUSIONS: In healthy men, levels of endothelial progenitor cells may be a surrogate biologic marker for vascular function and cumulative cardiovascular risk. These findings suggest that endothelial injury in the absence of sufficient circulating progenitor cells may affect the progression of cardiovascular disease.’2 Which means that with fewer EPCS, plaques grow faster.

The critical part that EPCs have to play is also seen in patients who have angioplasty, or stents. Immediately following the procedure, the bone marrow starts making more EPCs.

‘In conclusion, endothelial injury from angioplasty can lead to time-dependent mobilization or homing of EPCs; mature EPC subpopulations are actively mobilized, and may contribute more to endothelial reparation; and the mobilization amplitude of the main EPC subpopulations is significantly influenced by the degree of endothelial injury and certain clinical factors.’3

It follows that, if you have fewer EPCs the risk of CVD will be much higher. This is clearly seen in Systemic Lupus Erythematosus (mentioned a few times before). The paper quoted from below looked at SLE, and the number of EPCs, and also haematopoietic stem Cells (HSCs) – which are the precursor to EPCs – found in the bone marrow:

‘SLE patients have lower levels of circulating HSC and EPC, even during clinical remission. Our data suggest that increased HSC apoptosis (cell death) is the underlying cause for this depletion. These observations indicate that progenitor cell mediated endogenous vascular repair is impaired in SLE, which may contribute to the accelerated development of atherosclerosis.’4

Other conditions, or factors, that reduce EPC numbers include:

  • Type II diabetes
  • Avastin
  • Rheumatoid arthritis
  • Smoking

To name but four.

Of course there tends to be a tight association between factors that damage the endothelial cells, and factors that reduce EPC number. This appears to be primarily modulated by nitric oxide levels. Anything that increases NO levels in endothelial cells and also helps to protect them from damage appears to increase EPC production in the bone marrow.

A non-exhaustive list of things can do this this are:

  • Exercise
  • L-arginine/L-citrulline
  • ACE-inhibitors (used for BP reduction)
  • Statins

Yes, the dreaded statins… Boooo! In truth, for many years I have accepted (albeit with great reluctance), that statins do have some benefits in CVD. Not enough, in my opinion, to overcome the damage that they can do. However, the benefit is there, it is real.

I knew it could be nothing to do with the impact of statins on lowering LDL, as LDL has nothing to do with CVD (well, almost nothing). So there had to be another effect. And that effect is, in my opinion, almost entirely to do with the ability of statins to increase nitric oxide (NO) production:

‘Endothelial nitric oxide (eNO) bioavailability is severely reduced after myocardial infarction (MI) and in heart failure. Statins enhance eNO availability by both increasing eNO production and reducing NO inactivation. We therefore studied the effect of statin treatment on eNO availability after MI and tested its role for endothelial progenitor cell mobilization, myocardial neovascularization, left ventricular (LV) dysfunction, remodeling, and survival after MI….. These findings suggest that increased eNO availability is required for statin-induced improvement of endothelial progenitor cell mobilization, myocardial neovascularization, LV dysfunction, interstitial fibrosis, and survival after MI. eNO bioavailability after MI likely represents an important therapeutic target in heart failure after MI and mediates beneficial effects of statin treatment after MI.5

Yes, when you decide to look through a different prism, you can find that things you thought were one thing, turn out to be another thing entirely. Professor Michael Oliver – a trenchant critic of the cholesterol hypothesis before statins came along – changed his mind, once he saw that statins lowered LDL and lowered CVD risk. Case proven – he said.

No, case not proven. Instead, if you look at EPCs and nitric oxide (NO) and take the view of CVD that it is all due to endothelial dysfunction, blood clotting and impaired repair, you can see exactly where statins may fit into the picture.

Next: The final event.







What causes heart disease part VII

For over thirty years I have been studying heart disease, or Cardiovascular Disease (CVD). I don’t think that I have Obsessive Compulsive Disorder…but maybe I have. I must admit that, at times there seemed to be no answers, at least no answers that did not have at least one Mount Everest sized contradiction.

At one point I simply decided that CVD was just a manifestation of ageing. It happened to everyone, at different rates. There was no cause – no causes. CVD was simply something humanity suffered from, get over it.

However, deep down, I knew that this could not actually be true. There were populations with almost zero rates of CVD, and others where the rates were extremely high. Just to give one example. Russia vs. Japan. In 2006 Russian men under the age of 65 suffered eighteen times the rate of CHD of men in Japan. I don’t think this ratio has changed this much.

I knew that Japanese men did not have any genetic protection. When they emigrated to other countries, their rate of CHD rose rapidly to match that of the surrounding population. Not always, but almost always. So it was obvious that something, or somethings, was causing massive differences in the rate. It wasn’t just fate, or genetics, it wasn’t just the ‘way it is.’ [By the way, the average cholesterol level in Russian men in 2006 was 5.1mmol/l, in Japanese men it was startlingly different at….. 5.1mmol/l]

Long, long ago I worked out that cholesterol, or LDL cholesterol has nothing much to do with CVD. Well, if two populations have exactly the same cholesterol levels and an eighteen-fold difference in the rate of CVD, cholesterol could only be causing 1/18th of the overall risk – absolute max. This figure assumes that the entire of the rate of CVD in Japan was caused by cholesterol, with no other factor playing any part. I don’t think I need bother telling what I think of that as a concept.

For a number of years, I pursued the alternative hypothesis that CVD was primarily caused by stress. There was a great deal of evidence to support this, and of course there still is. I still believe that stress (a concept which does need a bit of explanation) is the single most important cause of CVD. However, there were still many cases of death from heart disease and strokes where it was clear that stress had nothing (or nothing that I could see), to do with it.

For example, as mentioned before in this series of blogs. Systemic Lupus Erythematosus (SLE), where the increased (relative risk) rate of CVD in young women is up to 5,000% higher than the surrounding population. Now that is a proper increase in risk. In fact, it is the sort of increase that tells you that you are looking at a ‘true’ cause of CVD. Not some very wobbly and weak association.

I was also interested in Kawasaki’s disease. This is a vasculitis (inflammation of the blood vessels) that affects young children, who can then suffer heart attacks aged four, or five. Not exactly the same mechanism that causes heart attacks in adults, but very nearly. Again, this is highly significant. A condition that can kill children aged four from CVD is not just some anomaly that can be ignored. I knew I was looking at another true cause.

Later, my attention turned to Avastin. A cancer drug that was almost pulled from the market as it rapidly accelerated atherosclerotic plaque development, and death from CVD. No other risk factors needed to be present.

But how to link SLE, Kawasaki’s, and Avastin, through stress and other important risk factors such as smoking, or diabetes? When I discussed such things with ‘experts’ in cardiology, they would just end up saying that CVD was multifactorial. However, this has always seemed the ultimate cop out. ‘Yes of course, it is multifactorial.’ I would reply. ‘But how do this multiple factors actually fit together. Do they all create different diseases, or the same disease… through completely different process?’

In the end, if you are going to understand CVD you must be able to link all true causes of CVD into a single coherent process that fits all of the facts. If you cannot do this, you are really just stumbling about in the dark. Simply muttering ‘multifactorial’ whenever anyone asks you a question you cannot answer adds nothing to understanding.

Over the years, I found myself drawn back to the Scottish Heart Health study, for one very important reason. Which was that, in this study, fibrinogen emerged as the single most important risk factor for CVD. A fact that seemed to have popped out of nowhere. Never to be mentioned again. As a quick aside, in this same study it was found that the cholesterol was not a risk factor for heart disease. Another fact never to be mentioned again.

Was the Scottish ‘fibrinogen factor’ just an anomaly. A single observation, never to be replicated? I needed to find out. So I shifted my attention away from stress, to a focus on blood clotting factors. When I did so, I kept finding the same thing over and over again. Factors that increase blood clotting were always associated with a higher risk of CVD. Factors that reduced blood clotting always reduced the risk of CVD.

Just to give one specific example. High Density Lipoprotein (HDL cholesterol), so-called good cholesterol. Conventional thinking is that HDL sucks cholesterol out of atherosclerotic plaques and transports this back to the liver via the ‘reverse cholesterol transport’ system. A concept which has always seemed to me to look like a most desperate clutching at straws.


‘The antithrombotic properties of native HDL are also related to the suppression of the coagulation cascade and stimulation of clot fibrinolysis. Furthermore, HDL stimulates the endothelial production of nitric oxide and prostacyclin, which are potent inhibitors of platelet activation. Thus, HDL’s antithrombotic actions are multiple and therefore, raising HDL may be an important therapeutic strategy to reduce the risk of arterial and venous thrombosis.’1

Yes, HDL is actually a potent anticoagulant. In addition, it protects the endothelium and increases NO synthesis in endothelial cells. So, we don’t need a reverse cholesterol transport conjecture. HDL can be looked in a completely different way. I found it fascinating that the moment you decide to look at things from another direction a very different picture emerges.

Once I had my ‘clotting’ goggles on I began to ask myself: Is CVD simply the end result of dysfunctional (and I use the word dysfunctional in the broadest sense here) blood clotting?

Of course, for this to be true, atherosclerotic plaques have to be, at their core, blood clots. Well, are they? In 1856 Karl Von Rokitansky examined atherosclerotic plaques and declared them to be blood clots – in various stages of repair – or degeneration (depending on your point of view). They contained everything you find in blood clots, platelets, red blood cells, lipoproteins, fibrin and all the rest.

Karl Von Rokitansky’s problem? He could not explain how a blood clot could form within the arterial wall itself, underneath the endothelial cells. The reason why he could not explain this is that he did not know that Endothelial Progenitor Cells (EPCs), cover over clots that form in blood vessels. This, effectively, draws them into the artery wall.

Because he had never heard of EPCs, and could not counter the central criticism of his hypothesis, Rokitansky’s ideas never took off, and the cholesterol hypothesis filled the void. The rest, as they say, is history.

A few weeks ago I was presenting on CVD and I was asked, whilst waiting in the coffee line, ‘Come on then, what does cause CVD?’ The man who asked was a doctor, a pathologist, just retired, who had spent his life doing autopsies, and examining many, many, people who had died of heart attacks. I said to him. ‘Plaques are clots, and clots are plaques. It is all due to blood clotting.

He was not in the slightest surprised. He just nodded in affirmation. ‘I thought so.’ He said. ‘I have always thought that plaques were blood clots.’ Well, what else could they be? There is little else that they could be.

For example, if you start looking at platelets and plaques, a whole new world of information opens up. Platelets are, if you remember, small blood cells that are the key ingredient of all blood clots (thrombi). They are attracted to the site of arterial damage, they clump together and then stimulate the ‘clotting cascade’ which creates clots that are tightly bound together by fibrin.

If clots are plaques, and plaques are clots, you would expect to find that platelets are intimately involved in the entire process of plaque formation. Here, I quote a long section from a book called ‘Platelets in Thrombotic and Non-Thrombotic Disorders.’ For some, this may be a big technical, but I suggest a read, and re-read.

In this section it is pointed out that clots/thrombi form at areas of endothelial damage/stress. In addition, platelet rich thrombi are incorporated into the vessel wall at sites of injury…. Yes, the whole process is outlined here. Including the fact that platelets contain a substance that causes smooth muscles to grow and proliferate (a key finding in all plaques).

Where is cholesterol in all this…nowhere. Please read and inwardly digest:

‘von Rokitanksy and Virchow were early investigators who reported that in some instances, the development of atherosclerosis involved early vessel wall injury, thrombosis, and the incorporation of thrombi into the vessel wall. In 1887, Welch gave a clear description of arterial thrombi based on the experiments of a number of investigators, showing that they began as platelet-rich thrombi and are then transformed into masses rich in fibrin. Much later, these observations were reinforced by Duguid, Morgan, More and Haust and French.

In the 1960s, we observed that platelets were deposited on, and interacted with, the walls of arteries in regions of disturbed blood flow. These are the sites where atherosclerotic lesions develop and increased vessel permeability is demonstrable.

In 1973, Moore induced ‘thromobathererosclerosis’ in rabbits by continuous damage of the endothelium of the aorta with an indwelling catheter, and in 1976, he and his group showed that prior administration of anti-platelet serum to induce thrombocytopenia (very few platelets in the blood) prevented the development of these lesions. The finding by Ross and his colleagues in 1974 that stimulated platelets release a mitogen for smooth muscle cells (platelet derived growth factor PDGF) arose from a chance observation.

They noticed that serum prepared from platelet-free plasma did not support the proliferation of smooth muscle cells in culture, but when they prepared serum by blotting platelet rich plasma, the serum supported cell growth as effectively as serum prepared from whole blood. These results gave even more credence to the theory that platelets are involved in the development of atherosclerotic plaques because they promote the proliferation of smooth muscle cells.

The progression of atherosclerotic plaques also involved platelets since platelet rich thrombi have been shown to be incorporated into the vessel wall at sites of injury. Platelet rich thrombi that form on ruptured atherosclerotic plaque may occlude the lumen of the vessel, or may embolize (break off and travel down the artery).

When the thomboemboli impact in smaller downstream vessels, organ damage occurs. These concepts about platelets and atherosclerosis have stood the test of time. The picture developed by Ross of the development of an atherosclerotic plaque is not well known, and the signalling pathways, PGDF activated are being explored. The importance of platelet interaction with the components of ruptured atherosclerotic plaque in the thromboembolic complications of atherosclerosis is now generally accepted.2

When I read stuff like this I think. Come on guys, you know that plaques are clots and clots are plaques. It is staring you in the face. It has been staring humanity in the face for over a hundred and sixty years. Ever since Rokitansky and Virchow started to look closely.

Next: Impaired plaque repair


2: ‘Platelets in Thrombotic and Non-Thrombotic Disorders.’ Edited by Paolo Gresele. Page 5.

What causes heart disease part VI

A summary up to now

Heart disease is really a disease of the larger arteries in the body. Essentially it is a build-up of atherosclerotic plaques (thickenings and narrowings) in the arteries. This could more accurately defined as cardiovascular disease (CVD), in that it can affect all large arteries, not just the arteries in the heart, or neck.

The final stage of plaque formation is complete blockage of an artery due a large blood clot forming, usually, over an existing plaque. This is the underlying cause of most heart attacks. In the case of an ischaemic stroke, the clot breaks off the main artery in the neck (carotid artery) and gets stuck in a smaller artery in the brain.

Other forms of ‘heart attacks’ and strokes can occur due to different mechanisms e.g. atrial fibrillation causes a clot to form in the atria before breaking of and travelling into the brain. Or, sudden acute stress on the heart can lead to catastrophic ischaemia, causing a ‘heart attack’ – without any underlying plaque. These type of stroke and ‘heart attack’ are not covered in this series of blogs.

When it comes to CVD, the cholesterol hypothesis holds sway over the medical profession i.e. when the cholesterol level is high it is deposited on/in the artery creating the thickenings and narrowings.

I have long argued that this hypothesis makes no sense from any perspective, and that CVD is actually caused by another process that that has little, or nothing, to do with cholesterol (in whatever form cholesterol is described). Instead CVD is a four step process:

  • Endothelial damage
  • Clot formation/dysfunctional clot formation
  • Clot repair/dysfunctional clot repair
  • The final, fatal, blood clot

In short, plaques are simply blood clots – in various states of repair. The final event (heart attack or stroke) is simply one part of exactly the same process that caused the plaques to form in the first place. Just bigger and more deadly.

In this series, up to now, I have mainly focussed on the process of damaging the endothelium, and explained how this inevitably results in a blood clot forming over the area of damage. Repair of the clot consists of forming a new layer of endothelium over the blood clot, thereby drawing it into the arterial wall. At which point it is attacked and broken down by monocytes and macrophages – amongst other things.

However, if the endothelium is repeatedly and rapidly damaged – at the same spot – the repair systems become overwhelmed and the clot/plaque, rather than being broken down and removed, starts to grow and turn into a dangerous ‘vulnerable’ plaque. I am now going to look at the process of clot formation itself – ‘thrombogenesis’. (Thrombo = clot, genesis = starting)

Clot formation

Clot formation is complicated, very complicated. However, I am going to try and make it as simple as possible by looking at three main players. At least I will to start with.

  • Tissue factor
  • Platelets
  • Fibrinogen/Fibrin

As mentioned earlier, tissue factor (TF) sits within artery walls (and vein walls). It is the key trigger factor for most blood clots. Normally the blood is protected from contact with TF by the endothelium. However, if you damage the endothelium, TF is exposed to blood. This fires the starting gun for a massive and explosive cascade of blood clotting. This is known as the ‘extrinsic pathway.’ By extrinsic I mean basically factors that sit outside the bloodstream. And by this I basically mean TF (at least I do for the purposes of this discussion).

Having said this, it is possible to have blood clots form without TF involvement. This occurs primarily in veins, and is usually due to blood flow stasis i.e. the blood stops flowing in a blood vessel. This happens if you cross your legs, lie in bed, have a plaster cast on, or take a long haul flight, or suchlike. If the stasis lasts too long, the blood can slowly start to form a clot. A big one usually. This is usually referred to as a DVT (deep vein thrombosis).

The other place this can happen is, as described before, in the atria, when you have atrial fibrillation. Rather than the blood being rapidly ejected with each heart beat, when the atria fibrillate, the blood can become trapped in eddies, not moving. Then clotting, then escaping, then stroke.

Blood clots which are created mainly through the action of the intrinsic pathway are, usually, far less strongly bound together – because fibrin is not created to the same extent. Therefore, a DVT that forms in a large vein in your leg can easily break off, travel up the vein and into your heart. It can get stuck there – instant death. Or it can pass straight though the heart and into the lungs, where it gets stuck. Causing a pulmonary embolism. Can be fatal, but not always.

Intrinsic pathway clots are stimulated by all the clotting factors you may have heard of. Factor X, factor IX, factor VIII, prothrombin, and suchlike. If you want to stop these clots forming you can use various anticoagulants such as warfarin, or heparin, or the new oral anticoagulants (NOACs). These block various intrinsic factors making the blood ‘thinner’ and less likely to clot.

Warfarin, for example, interferes the action of vitamin K, which is needed by the liver to synthesize several clotting factors. Indeed, warfarin is often referred to as a vitamin K antagonist. Practically, this means that you can rapidly reverse the actions of warfarin by giving a massive dose of vitamin K.

Sorry, I said I was only going to talk about tissue factor, platelets and fibrinogen. But I think the fact that blood clotting has different pathways can help to explain why, for example, warfarin is very poor at preventing CVD, but very good at preventing stokes caused by atrial fibrillation, and can prevent dearth from DVT.

At times I am just staggered by the amazing ingenuity of human physiology. How the hell, I think to myself, did all of this evolve? Blood clotting is just one physiological system, one small part of how the body works, and just this one part is frighteningly complex.

Anyway, moving on. In the arteries, if you want to get a blood clot to form, you need expose the blood to TF and the clotting system then fires into action. The first part of the process is that platelets are attracted to the site of damage. Platelets are small blood cells which, when ‘activated’ become very sticky and start to clump together. They then release a massive family of different factors, including clotting factors, that stimulate the rest of the clotting cascade. [Platelets also contain quite a lot of TF, which is transferred to them by circulating monocytes – a tale for another day].

The final step of the clotting cascade is to join lots of small fibrinogen stands together. Fibrinogen consists of short thin strands of protein. If you stick hundreds of strands together, end to end, you get fibrin. This is a bit like fishing line. Long, tangly, sticky and extremely strong. It binds platelets together into a furiously strong clot.

At the same time, fibrin drags in almost everything else into the blood stream, and binds it into the clot. White blood cells, red blood cells, lipoproteins etc. Some of these may, or may not, be innocent bystanders in the clotting process. Although, the closer you look, the more you will find that almost all blood elements are actually players in the process.

Just to look at one example here, very low density lipoproteins (VLDLs), also known as ‘triglycerides’. These lipoproteins have significant effects on clotting. To understand how this happens I need to move sideways for a moment, and bring in something that most of you will never have heard of. Plasminogen activation inhibitor 1 (PAI-1).

To explain. Blood clots, when they form, incorporate within them an enzyme called plasminogen. This enzyme, when activated, can slice strands of fibrin apart and, thus, break down blood clots into tiny bits. After a heart attack, or stroke, you can be given tissue plasminogen activator (tPa) – or something very similar. This activates plasminogen within the blood clot, and causes the clot to disintegrate. Thus, a blocked artery will be reopened.

Now, as with everything else to do with blood clots, we have yin and yang. On one side we have plasminogen; on the other side we have plasminogen activator inhibitor – 1 (PAI-1). This does exactly what you would expect. It inhibits the action of plasminogen. This is not surprising. In all parts of the clotting system, for every factor that reduces blood clotting tendency, there is an equal and opposite factor increasing blood clotting. All is in balance.

Plasminogen slices clots apart, PAI-1 prevent this from happening. Clearly, therefore, the more PAI-1 you have, the more difficult it is for a clot to be broken apart. So any factor that increases PAI-1, will make any blood clot that forms bigger and more difficult to shift. Which brings us back to VLDL – a.k.a. triglycerides.

‘In vitro data have shown that triglyceride-rich very low density lipoprotein (VLDL) particles enhance PAI-1 secretion from endothelial cells and liver cells Furthermore, it has been shown that VLDL stimulation of PAI-1 expression in endothelial cells is mediated through transcriptional activation of the PAI-1 gene, and a VLDL response element has been identified in the promoter region.’ 1

Or, to put this more simply. If you have lots of VLDL in your blood, you will stimulate the production of PAI-1. So, you will have impaired breakdown of blood clots (impaired fibrinolytic activity). Which means that (from the same paper):

Hypertriglyceridemia is associated with an increased risk of coronary heart disease (CHD). Impaired endogenous fibrinolytic function is a frequent finding in subjects with hypertriglyceridemia.’

The most common condition where you are most likely to find high VLDL levels is type II diabetes. In type II diabetes there is, always, a high PAI-1 level. I am not sure if this needs a reference, but you are getting one anyway, with regard to type II diabetes:

‘The combination of hypertriglyceridemia, glucose intolerance and inflammation is linked with increased production of the primary inhibitor of endogenous thrombolysis, plasminogen activator inhibitor-1 (PAI-1). Recent data suggest that PAI-1 contributes directly to the complications of obesity, including type 2 diabetes, coronary arterial thrombi, and may even influence the accumulation of visceral fat.2

The bigger picture – other factors

I think, as always, I have become in danger of heading off down a narrow channel here. Time to drag the discussion back to the main process. The point I want to make clear, in this part of the argument, is that after you have damaged the endothelium a clot will form. This is quite natural.

However, if you have factors in the blood that make any clot that forms bigger, or more difficult to break down, the chances are that any clot that forms will end up within the artery wall as a bigger plaque. Or the clot may simply block the artery altogether, first time.

Some of the other factors that make blood clots likely to be bigger, and/or more difficult to clear up, in addition to type II diabetes and high VLDL levels, are:

  • Raised fibrinogen levels
  • Raised Lp(a) levels
  • Antiphospholipid syndrome (Hughes syndrome)
  • Smoking
  • Raised homocysteine levels

Not an exhaustive list by any manner of means, and I am only going to look at two of these in this blog. Fibrinogen and Lp(a) levels.


It would seem common sense that raised fibrinogen levels would make blood clots bigger when they form, and thus more difficult to clear up, as they are a key component of any blood clot.

The importance of a high fibrinogen level was something I first saw in the Scottish Heart Health Study. This was a major study that lasted ten years and included thousands of people. The researchers looked at many different factors which were thought to be involved with causing heart disease (and death from all causes). Raised cholesterol was found to have no effect. Instead they found that:

‘Fibrinogen is a strong predictor of coronary heart disease, fatal or non-fatal, new or recurrent, and of death from an unspecified cause, for both men and women. Its effect is only partially attributable to other coronary risk factors, the most important of which is smoking.’  

The increase in (relative risk) between the highest and lowest fibrinogen levels was:

  • 301% for men and 342% for women (CVD death)
  • 259% for men and 220% for women (Death from any cause)

In fact, a high fibrinogen level was the single most important risk factor they found – just beneath already suffering a previous heart attack. A raised fibrinogen was an even more powerful risk factor than smoking (although smoking can raise fibrinogen levels, which complicates this picture somewhat).

This finding was reinforced by the Prospective Cardiovascular Münster (PROCAM) study.

The incidence of coronary events in the upper tertile (top third) of the plasma fibrinogen distribution was 2.4-fold higher than in the lower tertile (bottom third)… plasma fibrinogen was found to be an independent risk indicator for CHD (P < .05). Individuals in the high serum low-density lipoprotein (LDL) cholesterol tertile who also showed high plasma fibrinogen concentrations had a 6.1-fold increase in coronary risk. Unexpectedly, individuals with low plasma fibrinogen had a low incidence of coronary events even when serum LDL cholesterol was high.’ 3

[Ah yes, the old ‘high cholesterol low rate of heart disease conundrum.’ It must be, let me see, a paradox. I do love the word unexpectedly. Mainly, because, here is where scientific truths hide]

I feel the need to add that a 2.4-fold increase in coronary events = relative risk increase of 240%, which is in the same ball park as the Scottish Heart Health study. Some of the things that can raise your fibrinogen levels are:

  • Smoking
  • Stress (physical or psychological)
  • Type II diabetes
  • Depression
  • Cushing’s disease
  • Post-traumatic stress disorder (PTSD)
  • Obstructive sleep apnoea

Of course, all of these things are also associated with a greatly increased risk of CVD. You can have hours of fun by typing CVD raised fibrinogen and… (insert favourite risk factor for CVD of your choice here).

Lipoprotein (a) (Lp(a))

There has been much discussion of Lp(a) of late. What it is, what does it do, why does it matter? The first thing to point out about Lp(a) is that it is, essentially, LDL a.k.a. LDL-cholesterol a.k.a. ‘bad cholesterol.’ However, it differs in one way. It has a special strand of protein attached to it, known as apolipoprotein A.

This protein is very interesting, from a blood clotting perspective, in that it is chemically identical to plasminogen. Yes, the one and only clot busting enzyme, switched on by tissue plasminogen activator.

But, big but. Apolipoprotein A is folded into a slightly different structure than plasminogen. Let us say it has a right handed thread, instead of left handed thread. (This is not fully accurate, but it is close enough).

This is important because almost of the receptors in the body have a symmetry to them, as do most of the molecules that nature provides, and most of them are left handed (levo-rotated). If you aim a right handed molecule at a left handed receptor very little happens – or strange and unpleasant things can happen. Thalidomide for example The L handed version causes no problems, but the R handed version causes serious birth defects – or was it the other way round. Remove one, or the other, version and you could give thalidomide perfectly safely in pregnancy. I would dare you to try.

As it is, thalidomide has been relegated to a cancer treatment, under the brand name Immunoporin. How does it work? It works by stopping angiogenesis (formation of new blood vessels) which cancer cells need to grow into a larger tumour mass.

The way that Thalidomide does this is that it damages endothelial cells, and endothelial progenitor cells (EPCs), as discovered in this study: ‘Thalidomide attenuates nitric oxide mediated angiogenesis by blocking migration of endothelial cells.’

‘….thalidomide interferes with nitric oxide-induced migration of endothelial cells at the initial phase of angiogenesis before cells co-ordinate themselves to form organized tubes in endothelial cells and thereby inhibits angiogenesis.4

Okay, maybe that means nothing to you. What it means is that thalidomide stops new blood vessels forming, by blocking the action of NO on both endothelial cells and endothelial progenitor cells (EPCs). Whilst this is a good thing in cancer treatment, it is not so great in the developing fetus.

A pregnant women taking thalidomide will find that new blood vessels do not form properly in her baby. This means that arms and legs cannot get blood supply, so they don’t develop, so you are left with a severely deformed baby, often with missing limbs.

It would be interesting to know what impact thalidomide has on CVD risk? We already know what impact Avastin has on CVD risk. It increases it massively. Avastin, like thalidomide, works primarily by inhibiting endothelial cell growth and EPC production. Whilst this stops tumours growing, it also greatly accelerates CVD. Oooh, I do love the way everything is connected.

Anyway. To return to apolipoprotein A again. If you incorporate Lp(a), and thus apolipoprotein A, into a blood clot, it cannot be broken down. This is because tissue plasminogen activator cannot activate it, because it is right handed. Effectively, therefore, apoliporotein A blocks the enzymatic destruction of fibrin, thus protecting the clot from destruction. Why, you may ask, would the body create such a stupid thing?

Well, as with everything the body does, it is not stupid. It is very, very, clever. Lp(a) is only made in animals that cannot synthesize vitamin C. Guinea pigs, fruit bats, great apes and…humans. The reason for this is that, if you are vitamin C deficient, the body cannot manufacture certain important support materials/connective tissue, the most important of which is collagen.

Without collagen, your blood vessels start to crack apart. When this happens, blood escapes, so you start bleeding from the gums, and suchlike. This condition is known as scurvy. In scurvy you start bleeding all over the place and, in the end, you die from blood loss. It is what killed many sailors of in the olden days.

Along to the rescue comes Lp(a).. well, it can rescue you for a bit. Lp(a) sticks to cracks in blood vessel walls and forms, impossible to break up blood clots that ‘plug’ the gaps created by collagen deficiency. So you can see that Lp(a) is actually evolution’s way of protecting animals, that cannot synthesize vitamin C, from the early stages of scurvy.

All of which means that if you don’t eat enough vitamin C, and you have a high level of Lp(a), you will end up with a multitude of very difficult to break up blood clots scattered all over your arterial walls, and inside your arterial walls too. Thus, you are going to develop CVD at a rapid rate.

This, the ‘vitamin C deficiency’ theory of CVD was proposed by Linus Pauling (double Nobel prize winner) and Matthias Rath (and you can look him up too – but be prepared for some interesting information). Here is a short section from their modestly entitled paper ‘A Unified Theory of Human Cardiovascular Disease Leading the Way to the Abolition of This Disease as a Cause for Human Mortality.’

We have recently presented ascorbate (Vitamin C) deficiency as the primary cause of human CVD. We proposed that the most frequent patho-mechanism (think of this term as the ‘process) leading to the development of atherosclerotic plaques is the deposition of Lp(a) and fibrinogen/fibrin in the ascorbate-deficient vascular wall. In the course of this work we discovered that virtually every patho-mechanism for human CVD known today can be induced by ascorbate deficiency.’

So there you go, vitamin C deficiency is the answer to CVD? No, it is not THE answer, but it is an answer, or a part of an answer. There is no doubt that a low level vitamin C is a bad thing. There is equally no doubt that a low vitamin C level, associated with a high Lp(a) is a double bad thing. Furthermore, there is absolutely and completely no doubt that taking extra vitamin C would be a good thing for everyone – just in case.

However, Pauling and Rath, brilliant though their thinking was, made the number one error in medicine. They looked for the single cause, and the single cure of a disease. They became so certain they were right, that they stopped looking elsewhere.

Having said this, their ideas about the process of CVD were, in my opinion, absolutely right. They realised that the essential underlying process was: arterial wall damage, followed by blood clots, followed by the development of atherosclerotic plaques. But they thought it could all be explained by a single factor, Vitamin C deficiency. In this they were wrong. It is a great shame they did not look at the wider picture.

However, I hope you can now see what Lp(a) is, what it does, and why it is important in the whole CVD argument. It is not a clotting factor per se, but it has a huge impact on the clots that do form. Unfortunately, it seems that Lp(a) levels are genetically determined and there seems little you can do to alter them. I would suggest that, if you decided to get your Lp(a) level tested, and it is high, you should make sure you get plenty of vitamin C in your diet.


I realise that you may think I have taken you off on a couple of wide detours in this blog. More than a couple actually. However, my cunning plan was to give a sense of how everything in the physiology of endothelial health and blood clotting can be fitted together. Also, how it can be seen that any factor which has an impact on the development of blood clots (following endothelial damage), will have an impact on CVD through mechanisms that can be easily understood.

Looking at an even wider picture I hope that you can now see, why drugs such as thalidomide – which may seem a million miles away from CVD – are actuallly closely related. How Lp(a), which at first glance may appear to have nothing to do with the four step process of CVD, can be brought into the picture. In addition, where, and how, such things as VLDL and PAI-1 fit in…. to name only a few. Over the years I have followed the story down a million different pathways. Each fascinating, but there are far too many to discuss them all here.

Yes, it is a complex story. Did you really think it would be easy? Did you really think there would be ONE factor that caused everything, and ONE factor that cured everything? CVD is not binary, it is about propensity, chaos theory. It is about changing the odds here and there. It is about the weighting of the dice. You can improve the odds in your favour, but you will never make them zero.

Next….the repair process.





What causes heart disease part V

The first stage of cardiovascular disease is damage to the endothelium. The single layer of cells lining the arteries. After this, we need to look at what then happens? Before looking at this more closely, I would like to take you back in time around one hundred and sixty years. This was when the first scientific debates about plaque development were taking place.

Rudolf Virchow and Karl von Rokitansky were the proponents of different hypotheses at this time. I am grateful to Professor Paul Rosch for providing the information on Virchow’s ideas. He provided this description in one of his newsletter.

Rudolph Virchow was the first to demonstrate the presence of cholesterol in atheroma in 1856. He described atherosclerosis as “endarteritis deformans” The suffix “itis” emphasized that it resulted from an inflammatory process that injured the inner lining of the arteries, and that the cholesterol deposits started to appear subsequently

Virchow was very specific about this when he wrote. ‘We cannot help regarding the process as one which has arisen out of irritation of the parts, stimulating them to new, formative actions; so far therefore it comes under our ideas of inflammation, or at least of those processes which are extremely nearly allied to inflammation.

We can distinguish a stage of irritation preceding the fatty metamorphosis, comparable to the stage of swelling, cloudiness, and enlargement which we see in other inflamed parts. I have therefore felt no hesitation in siding with the old view in this matter, and in admitting an inflammation of the inner arterial coat to be the starting point of the so-called atheromatous degeneration and the cholesterol deposits came later.’

So, even one hundred and sixty years ago, eminent professors recognised that atherosclerotic plaques started with ‘inflammation of the inner arterial coat’ a.k.a…the endothelium. The cholesterol deposits came later. Quite so. Or to put this another way, the cholesterol was not the cause of the plaque, the appearance of cholesterol in a plaque was part of the second stage of plaque development.

However, whilst agreeing on this observation, Karl Von Rokitansky had a further hypothesis.

‘Rokitansky proposed that the deposits observed in the inner layer of the arterial wall were derived primarily from fibrin and other blood elements rather than being the result of a purulent process. Subsequently, the atheroma resulted from the degeneration of the fibrin and other blood proteins and finally these deposits were modified toward a pulpy mass containing cholesterol crystals and fatty globules.’

Or, to put it another way. He believed that plaques were, in fact, blood clots, in various stages of repair. He believed this because plaques looked exactly like blood clots, and contained everything that you can see in a blood clot. Perhaps most critically, a great deal of fibrin, which is the key component of all blood clots.

However, Virchow objected to this idea on the simple basis. ‘How can a blood clot form within the arterial wall?’ Or, how can a blood clot form under the endothelium. A good point, and Rokitansky had no effective response. So he lost.

However, there is a very simple explanation as to exactly how a blood clot can be found beneath the endothelium. And this is, because the endothelium wasn’t there when the clot formed. It grew over the top of the clot afterwards. Which takes us to Endothelial Progenitor Cells (EPCs).

After my last blog, a poster made the following comment.

‘And then… the clot, now trapped under the new endothelium, becomes plaque? If true, seems a stupidly “designed” 🙂 healing process.’

Well, superficially, this is a good point. Simply incorporating clot into arterial wall, where is forms a plaque and then kills you, does not seem a great idea. However, I would ask you to consider what would happen to a blood clot, lying on an artery wall, that simply broke off and travelled down the artery. What would happen?

The answer is simple; it would jam up as the artery narrowed. This could cause a stroke, or a heart attack, or suchlike. Exactly as happens with atrial fibrillation. Where small clots that break off from the atria travel into the brain and get jammed. The body does not like blood clots floating about in the arterial system.

So this does not happen/is not allowed to happen. When the endothelium is damaged, a clot forms on top of it. It is true that a certain amount/a great deal of this clot will be shaved away into very small (not stroke creating sized) pieces, but a ‘core’ will be left. This has to be got rid of in some way.

How are you going to do this? There is only one possible way. Firstly, you cover it over with another layer of endothelium, then you attack it, break it down, and destroy it. And this is exactly and precisely what the body does.

Once a blood clot has stabilized, Endothelial Progenitor Cells (EPCs), that are manufactured in the bone marrow, and float around in the bloodstream, are attracted to the clot. They stick to it, then they grow into fully mature endothelial cells, forming a new layer of endothelium, effectively drawing the clot inside the arterial wall. Then the clot is attacked and got rid of. How?

Well, a critical fact to add in here is that. EPCs do not always become endothelial cells, they can go down another developmental pathway as well. They can become monocytes, which in turn become macrophages. Macrophages are the ‘clear up’ cells of the immune system. They attack alien material and then engulf/ingest it. After this they either exit back into the blood stream or travel directly into the lymphatic system. Whereupon they are transported to lymph glands where they are broken down and all the ‘alien material’ is disposed of.

The body is amazingly clever is it not? After endothelium is damaged, and a clot forms, EPCs not only cover over the area of damage, they can also turn into the very cells that can clear up the clot/plaque and get rid of it. So, not a stupidly designed healing process at all. One of absolute brilliance. In fact, this is probably happening inside your artery walls right now.

The problems start to occur when the process of endothelial damage is occurring too rapidly for the healing system to clear up the mess. Repeated endothelial damage and clot formation over the same spot, time and time again. At which point, instead of having clot/plaque healing we end up with clot/plaque growth and development. Or as Rokitansky put it so eloquently

‘Subsequently, the atheroma resulted from the degeneration of the fibrin and other blood proteins and finally these deposits were modified toward a pulpy mass containing cholesterol crystals and fatty globules.’

Next, clot formation and associated problems.

What causes heart disease – part III

In most diseases it is best to start at the beginning and work forwards. This should be the case with cardiovascular disease (CVD) too. However, for complex reasons I found myself starting at the end, and working backwards. The main reason for this is that I had to start with certainty. Yet, almost everywhere I looked there was mush. For example, the epidemiology of CVD.

Now you would think that there would be agreement about how many people actually die from CVD in different countries and at different times. Not a bit of it.

A researcher:                                    ‘The French have a low rate of CVD.’

A N Other researcher:            ‘Oh well the French, they don’t agree with the normal definitions, they don’t classify CVD properly. Who knows what the true rate may be?’

True? False? A bit true? Taking another example. I have looked at the figures from the US and, you know what. Not a single person died of Ischaemic Heart Disease before 1948. Amazing. What was protecting them? [Dying from IHD is what you would also call a heart attack, or MI]. What was protecting them was the fact that IHD did not exist in the US as a disease classification, before 1948.

This then changed. In 1948 the World Health Organisation was created, and one of the first things they did was to create an International Disease Classification system (ICD). Heart disease is 1. Cancer is 2. (example for illustrative purposes only). Of course it is a bit more complex than that. Just to look in more detail at Ischaemic Heart Disease: [See box]:


Not every country took up the ICD system. Until 1968 the French did not use the ICD codes (so I am told, which no doubt means this is not true). Therefore, in France, statistics on deaths from IHD in France, before this date, are completely unreliable.

It goes without saying that, before 1948, no-one else used the ICD system either, because it did not exist. So, what can we tell about the epidemiology of CVD before 1948? Nothing. Or at least nothing you could hang your hat on. IHD would have been mixed within a much broader ‘Heart Disease’ in the death certificate statistics. And heart disease could mean almost anything, from cardiomyopathy to pericarditis, to atrial fibrillation.

Even after the ICD system was introduced, and even after France came on board, many countries clearly did not use it in the same way. Which is why the WHO set up the MONICA study.

‘The MONICA (Multinational MONItoring of trends and determinants in CArdiovascular disease) Project was established in the early 1980s in many Centres around the world to monitor trends in cardiovascular diseases, and to relate these to risk factor changes in the population over a ten year period. It was set up to explain the diverse trends in cardiovascular disease mortality which were observed from the 1970s onwards. There were total of 32 MONICA Collaborating Centres in 21 countries. The total population age 25-64 years monitored was ten million men and women. The ten year data collection was completed in the late 1990s, and the main results were published in the following years. The data are still being used for analysis.’

It was also an attempt to see if different countries were actually looking at the same diseases, and classifying them in the same way. Even after that, the data was still not absolutely clear cut, as further studies were then set up to see if the US system ARIC, and MONICA, actually matched each other. This was 1984.

‘To foster collaboration between the World Health Organization MONICA Project and the NHLBI Study of Atherosclerosis Risk in Communities (ARIC). To ensure that valid comparisons could made between findings in MONICA and ARIC by supporting activities to standardize coding, classification, and analysis of coronary and stroke events, risk factors, and medical care according to MONICA protocol.’

In simple terms, the US has its system, ARIC, and Europe had its system MONICA. Do they actually match? In short we can see that, even as late as 1984, there was clear uncertainty about how diagnoses were being made and how data were being gathered around the world. Did it all match, or not.

Given such uncertainly on both definition and diagnosis, can we say that the US epidemic of CVD in the 1960s actually happened. Or were doctors just putting IHD on death certificates when they didn’t really know what killed the patient. Personally, I think the epidemic did occur. Actually I think it happened a bit earlier. It is my belief that it took a while for US doctors to start using the new-fangled WHO ICD system.

Anyway, the point I am trying to make is that it is incredibly difficult to find the ‘bedrock.’ By which I mean facts that are inarguable. Things you can base your thinking on that are absolutely true, or that are as close to absolutely true, as possible.

Which is why I ended up at the end, the formation of the final, often fatal, blood clot. A blood clot which, generally, forms over an existing atherosclerotic plaque. There is widespread agreement that this is the case. So we can, I think safely, start here.

[There are, undoubtedly other things going on, such as sympathetic stress, mitochondrial damage and acidosis with heart muscle. that play a hugely important role. But the clot is, usually the final event

It is also widely agreed that factors which increase blood clot formation (thrombophilc factors) increase the risk of dying from CVD, and that things that reduce blood clotting reduce the rate of death from CVD. Here are a few things that increase the risk of blood clots forming, in no particular order:

  • Dehydration
  • Waking up in the morning/getting up in the morning
  • Acute physical stress
  • Acute psychological stress
  • Having a high fibrinogen level
  • Diabetes
  • Cocaine use
  • Smoking
  • Cushing’s disease

Here are some of the things that reduce the risk of blood clots

  • Haemophilia
  • Von Willibrand Disease
  • Aspirin
  • Moderate alcohol consumption
  • Clopidogrel
  • Yoga
  • Regular exercise

I suppose I should add that all of the things that increase the risk of blood clotting also increase the risk of death from CVD, and vice versa.

This is hardly a complete surprise. If blood clots kill you, things that reduce blood clots will prevent you from dying, and vice-versa. Let us not fall to the ground in stunned amazement over this statement of the bleeding obvious.

At this point, and slightly out of sequence, I would like to introduce statins to the list of factors that reduce the risk of blood clots

Readers of this blog know that I am not keen on statins, to say the least. However, if the studies are to be believed, they do reduce the risk of CVD. Not to any great extent, but the effect certainly does exist. Many people use this fact to attack my view that raised cholesterol does not cause CVD. ‘Well, what about statins,’ they bellow in delight. ‘They lower cholesterol and reduce the risk of CVD. Case proven…next’

Well, as with all drugs, statins do many other things than lower cholesterol levels. For example:

‘Recent studies have shown that statins reduce thrombosis via multiple pathways, including inhibiting platelet activation and reducing the pathologic expression of the procoagulant protein tissue factor.’1

So, as they say, there. In fact, one could quite sensibly propose that statins work pretty much the same as aspirin. They are anti-coagulants, and lowering blood cholesterol is simply a nasty and unfortunate side-effect of statins.

In reality, statins have a far more important effect on CVD (through other actions also related to clot formation) that I will get to later. I just thought I would pop that statin fact in. I even provided a reference. I have not really done much referencing in this series up to now. I believe that it is very simple to type, for example, ‘regular exercise and reduced thrombus formation’ into Google and see what you get. Or ‘Yoga and reduced blood coagulation.’

Where was I? Oh yes. Things that increase blood clot formation are more likely to kill you from CVD, and vice versa. Nothing controversial here. But the potentially controversial bit starts right here.

Are there two processes or one?

Currently, whilst conventional thinking on CVD accepts that blood clot formation is almost always the final event in CVD. This represents a completely separate process to the development of the atherosclerotic plaque itself. In short, we have two unrelated physiological processes:

  • Plaque formation
  • Clot formation on top of plaque

I apologize for saying, essentially, the same thing in different ways. But I think it is important.

Strange then, is it not, that plaque formation and clot formation share so many risk factors? Smoking, for example. Diabetes, for example. In fact, you could say (with certain provisos) that the risk factors for plaque formation and blood clot formation, are exactly the same.

Which gives one to think. Well it certainly gave me to think. Could it be that plaque formation, and blood clot formation, are simply two different manifestations of exactly the same underlying disease process. From a pure scientific perspective, I liked the idea. I liked it because it seems clumsy to have a disease, CVD, that is made up of two, essentially unelated processes

In medicine, as in all of science, one single disease process always looks much better, much cleaner, and much more likely to be right. This is the principle of Occam’s razor:

‘The principle in philosophy and science that assumptions introduced to explain a thing must not be multiplied beyond necessity, and hence the simplest of several hypotheses is always the best in accounting for unexplained facts.

Next: The four step process of CVD


What causes heart disease – part II

[By heart disease I mean, the development of atherosclerotic plaques in large arteries. Mainly the coronary arteries (supplying blood to the heart) and carotid arteries (supplying blood to the brain). This, I will refer to as Cardiovascular Disease CVD. Not entirely accurate, but language never is.]

At this point, I am going to start at the end. What kills people? (Or what causes myocardial and cerebral infarctions). You might think that this was clear cut, but of course it is not, far from it. For example, there is a major cause of death from ischaemic strokes that has nothing whatsoever to do with CVD. This is Atrial Fibrillation.

Atrial fibrillation (AF), is a condition where the upper chambers in the heart (atria) do not contract in a regular and co-ordinated fashion. Instead, they fibrillate – AF definition : ‘(of a muscle, especially in the heart) make a quivering movement due to uncoordinated contraction of the individual fibrils.’ AF is pretty common.

People who have AF tend to develop blood clots in the atria. These can break loose, and are then ejected from the heart into other parts of the body. Quite commonly these clots travel into the brain. As the artery the clot is traveling down narrows, the clot gets stuck, and blood supply is cut off, leading to an area of ‘ischaemia’ (no oxygen) and a stroke. A cerebral infarction.

Which means that it is perfectly possible to have strokes (cerebral infarctions) that are unrelated to CVD. If, that is, you define CVD as the development of atherosclerotic plaques. You can also have strokes where an artery in the brain bursts, causing bleeding into brain tissue, which is called a haemorrhagic stroke. This is clinically indistinguishable from an ischaemic stroke. You need a brain scan to see what type of stroke has happened.

Ergo, whist death from a stroke is clearly a form of cardiovascular disease, many strokes have nothing whatsoever to do with atherosclerotic plaques – which is what I am calling CVD.

Equally you can die from something commonly defined as a ‘heart attack’ which has nothing to do with atherosclerotic plaque development either. You can, for example, develop a fatal arrhythmia. This is where the conduction system in the heart goes wonky, the heart stops contracting regularly, and you die. [Of course, quite often this happens as part of a myocardial infarction].

If we put aside these forms of dying of strokes and heart attacks, we can then focus more clearly on the event that kills you with CVD? Which is, in general, a clot forming on a vulnerable plaque, and blocking an artery, leading to a myocardial infarction (heart attack).

Looking at strokes. If a clot forms in a carotid artery, it does not tend to block the artery completely. Instead, a part of the clot breaks off, and travels up into the brain where is gets stuck – causing a stroke (as per AF).

But… there are those who disagree with this simple model. Mainly with regard to heart attacks. I am fully aware of a growing movement which states that the myocardial infarction (heart attack) happens first, then the clot forms afterwards. (Incidentally, this concept is not new; it was first proposed over eighty years ago. You may think that is seems completely mad. However, there is strong evidence that would appear to support this ‘reverse’ hypothesis’ (infarction first, then the blood clot forming in the artery).

For example, in many cases after a confirmed and accurately diagnosed myocardial infarction, you cannot find any blood clot in the artery leading to the infarcted area. In other cases, you can find a blood clot that is several days, or weeks old. This age of the clot can be established because of the ‘evolved’ state of the thrombus. In short, there is no ‘temporal’ connection between the blood clot forming and the heart attack occurring.

On the other hand, you can find an acute blockage of a coronary artery that has not caused any symptoms, let alone a myocardial infarction.

Anyway, if you try to bring these facts together you find that:

  • Myocardial infarctions can occur without any clot being found in an artery
  • A clot can form in coronary artery days, or weeks, before any symptoms of an MI
  • A clot can fully obstruct the coronary artery, without causing a myocardial infarction

Given these facts (facts which, incidentally, are not in dispute), you can make a pretty strong case that there is no causal association between a blood clot blocking a coronary artery, and an MI taking place. Instead people can, and indeed do, argue that the process is the other way around. Infarction first, then clot.

Perhaps, now, you can begin to understand why it has taken me thirty years to try and work out the underlying process of CVD. At times I have thought that there isn’t any… but that is another story, for another place

The reverse hypothesis – why it is not correct

I have studied the ‘reverse hypothesis’ – if that is a reasonable term for it – for many years, and I believe that it is wrong. The primary cause of a heart attack is simply a blood clot blocking a coronary artery. However, there are two major complications that lead to the apparent contradictions listed above. In no particular order they are the following:

  • An infarction does not mean that heart muscle dies
  • Collateral circulation develops

What is an infarction?

Cardiology is, unfortunately, dominated by highly simplistic thinking. Namely, plaque develops, clot forms, infarction occurs. The infarction occurring within minutes of the clot formation.

But this is nothing like the reality of what actually happens. Heart muscle, like all tissues in the body, is enormously complicated. If you suddenly reduce the blood supply, it can do several different things. It can infarct, it can hibernate, or it can do nothing much.

Just to look at infarction. The dictionary definition is… ‘obstruction of the blood supply to an organ or region of tissue, typically by a thrombus or embolus, causing local death of the tissue.’ Well, I’ve got news for you, heart muscle does not die (not unless the organism surrounding it dies).

Infarction, in the case of myocardial infarction, does not mean death of the tissue. Instead, the heart muscle undergoes a complex transformation into a different cell type. One that needs far less oxygen to survive and one that cannot do the contracting thing. But it is not dead. Because dead cells become necrotic and necrotic cells disintegrate. After a heart attack do you see disintegrated areas of the heart? No, you most certainly do not. You see a form of scar tissue developing.

There is also a halfway house that lies between infarction, and nothing happening. This is ‘hibernation’, a state whereby heart muscle simply decides to stop contracting/beating (to save oxygen use). If you do MRI scans on the heart, in those with known heart disease, such ‘silent’ regions are a relatively common finding. Sometimes these regions wake up and start beating again, sometimes they do not. Sometimes they go on to infarct.

Adding further to the complication, if a coronary artery starts to narrow, the heart will create small ‘collateral’ blood vessels to get round the narrowing, and keep the blood supply up. When, and if, the artery fully blocks, the collateral circulation will maintain the blood flow, and so nothing very much will happen, even if the coronary artery is fully blocked. Many people survive on collateral circulation alone.

All of which means that, after an artery blocks, one of three things can happen:

  • There is a sudden infarction (could be large enough to be fatal)
  • The heart muscle decides to hibernate, if there is sufficient collateral circulation to keep things ticking along
  • Nothing much happens. If there is high level of collateral circulation, the heart just carries on much as before.

Only in the first case will the obstructive blood clot closely precede the heart attack. In case two the hibernating heart muscle may later decide to infarct, if the circulation does not improve. This can happen under periods of high physical or psychological stress. Thus the formation of the blood clot can precede the infarction by days, weeks or months. Indeed, the clot may have been fully cleared away by the time infarction occurs.

In short, the apparent contradictions to the: clot → blockage → infarct hypothesis can be explained, reasonably easily. So long as you realise that what happens inside the heart is not a case of simple pipe-work, where there a fixed number of tubes (arteries) supply oxygen to a pump (the heart). If you block one tube, the pump is immediately damaged.

Heart attacks and strokes

However, my main reason for disbelieving the ‘reverse hypothesis’ is that the standard model works for both heart attacks and (most) ischaemic strokes.

In ischaemic strokes, as mentioned before, a blood clot forms over a plaque in a carotid artery. This rarely blocks the artery; as carotid arteries are much wider bore than coronary arteries. However, what happens next – after a variable time period – is that the clot breaks off and travels into the brain.

This is, essentially, exactly the same process as a heart attack – except the clot lodges further down the vascular tree. Not only are the processes of stroke and heart attack virtually identical, the risk factors for both are virtually identical. Perhaps most telling is the fact that people with plaques in their coronary arteries almost always have plaque in their carotid arteries, and vice-versa. For example, here is the title of a paper on this topc: ‘Tight relations between coronary calcification and atherosclerotic lesions in the carotid artery in chronic dialysis patients.’1

This is further supported by a study that has just come out, and published in BMJ open. Key points were:

  • We studied the risk of heart disease following a stroke in those patients with no cardiac history. This study is the largest of its kind and, by bringing together multiple data sets, robustly quantifies the risk of heart disease following stroke. As with all meta-analyses, the main limitation of this work relates to publication bias.
  • Most patients with stroke die of heart disease.
  • One in three patients with ischaemic stroke with no cardiac history have more than 50% coronary stenosis.
  • 3% are at risk of developing myocardial infarction within a year of their stroke.
  • Patients with stroke need to be screened for silent heart disease and appropriate and aggressive management of total cardiovascular risk factors is required2.

In short, the two conditions are the same. It is beyond any reasonable doubt that with ischaemic stroke, and myocardial infarctions, we are looking at the same underlying disease. To be frank I don’t think may people would disagree with this. But it does lead to a critical point. Namely has anyone, ever, argued that cerebral infarctions (strokes) happen before the blood clot blocks an artery in the brain?

No they have not. Because to do so would, quite frankly, be bonkers. We can be absolutely certain that blood clots cause infarctions in the brain. Yet many people quite strongly argue that with myocardial infarction it is the other way around. For the reasons outlined above I do not, and cannot, believe this. There is only one process, and no need to start searching for another.

You may wonder why I have gone off in such a wide detour here? There are two reasons. First to make it clear that this area is gigantically complex. Secondly, to reinforce the point that wherever and however you look at CVD, alternative hypotheses have been proposed. Until you have tracked them down, and examined them fully, you cannot really move on.

Next: Some answers.



What causes heart disease?

I have been somewhat silent on this blog for a while. Mainly because I have been putting together ten thousand words on the true cause of heart disease. Of course, by heart disease I mean the thickenings and narrowings in the larger arteries in the body (atherosclerotic plaques). I am also focussing almost entirely on the arteries supplying blood to the heart (coronary arteries), and the main arteries that supply blood to the brain (carotid arteries).

Whilst atherosclerotic plaques can develop in other arteries that supply, for example, the kidneys, or the bowels, problems here are generally less common, and less severe – although not always. In general, however, the main killers in ‘heart disease’ are heart attacks and strokes (not all strokes, only the most common form of stroke, an ischaemic stroke). So, at the risk of becoming over-pedantic, and simultaneously sloppily inaccurate, I am calling heart disease Cardiovascular Disease (CVD), and looking at heart attacks and strokes.

With that out of the way, what causes cardiovascular disease (CVD)? Whilst it took me only a few days of research, many years ago, to realise that the diet-heart/cholesterol hypothesis was clearly nonsense. It has taken over thirty years to work out what is actually going on. In truth I could not truly progress until it suddenly dawned on me that I should not be looking for causes. For that is a mugs game.

Once you start looking for causes, you find that there is almost nothing that a human can ingest, or do, that has not been claimed to be a cause of CVD, or a cure for CVD. In many cases both… simultaneously. In 1981 a paper was published in the journal Atherosclerosis which outlined several hundred possible ‘factors’ involved in causing or preventing CVD. Today, if you hit Google, or Pubmed, I can guarantee that you could find several thousand different factors. If, that is, you could be bothered.

If you could be bothered, what could you possibly make of ten thousand different things involved in CVD in one way or another? Can they all be true risk factors? Some of them are certainly only associations, not causes. A few are simply statistical aberrations, found in one study and contradicted in another. Even removing them, there are so many, so very very many. Pick your favourite and trumpet it to the world. Vitamin K, Vitamin D, coffee, leafy green vegetables, omega 3 fatty acids, intermediate chain monounsaturated fats, HDL raising agents, selenium, lowering homocysteine…. on and on it goes.

Is there any other hypothesis where you have to fit in ten thousand different factors? No, there is not. Yet no one has been put off identifying more and more things. This is why, I believe, we have such a terrible mess. I amuse myself sometimes looking at the knots the cholesterol hypothesis ties itself into to.

Just to give one example. We have had ‘good’ cholesterol and ‘bad’ cholesterol for some time now. More recently we have ‘bad good’ cholesterol (raised HDL increasing CVD risk during the menopause), and ‘good bad’ cholesterol (light and fluffy LDL that protects against CVD). Now, that’s what I call a non-disprovable hypothesis. A risk factor that can be good, or bad. Or ‘Good bad’ and ‘bad good’.

Whilst contemplating such nonsense it came to me, in a moment of the blindingly obvious, that in order to understand CVD I had to move away from trying to fit ten thousand factors into the biggest intellectual jigsaw known to man, and move on. I had to know what the actual process is. What is actually happening in the arteries.

Once you start to look at CVD through this window, you suddenly realise that very little is ever written on this topic. The world famous cardiology bible ‘Braunwald’s Heart Disease’ is virtually silent on the matter. Or at least it was when I looked through it a few years ago.

In a massive book on heart disease, the process of CVD development is covered in less than half a page. The cholesterol hypothesis itself is usually left completely unexplained. Or there are gaping holes, and bits that you just have to take on faith. Raised LDL leaks/travels/gets into the artery wall where it creates inflammation and plaques develop. The end.

Then you start to ask, so why do plaques never develop in veins? Same structure as arteries, same level of LDL. Why do plaques never develop in the blood vessels in the lungs (pulmonary arteries and veins?). What has oxidised LDL got to do with it? Where does oxidation occur? How does LDL leak into coronary arteries, and carotid arteries, but cannot leak into arteries within the brain itself?

Questions, questions, questions and almost no decent answers. There is a kind of collective brouhaha noise with a lot of ‘well it just does’ thrown in when you start to ask. ‘Explain again, how does LDL get into the arterial wall. Each step please?’. You are usually met with perfect anti-Popparin logic. We know that raised cholesterol causes heart disease, so it must get into the arterial wall using some mechanism or other. And look, there is cholesterol in atherosclerotic plaques. So it must get through.

Of course, it is true you can find cholesterol in atherosclerotic plaques. No-one is going to deny that. But you can also find, for example, red blood cells (RBCs). Now, you might be able to explain how LDL can pass through endothelial cells (the cells that line the arteries) in some fashion. Although I would argue that, if so, why does LDL not pass through endothelial cells in veins. And why cannot it pass through, or between, endothelial cells in the arteries with the brain?

LDL molecules, after all, are minute in comparison to an endothelial cell. However, RBCs and endothelial cells are pretty much the same size. So, please try to explain to me how a RBC finds itself within the artery wall, underneath the endothelium? Try getting one cell, virtually the same size as another, to pass through it. A very clever trick indeed.

Then, if you start exploring further, you find that the cholesterol you find in atherosclerotic plaques almost certainly comes from the cholesterol rich membranes of RBCs.

The view that apoptotic macrophages (dead macrophages) are the predominant source of cholesterol in progressive (atherosclerotic) lesions is being challenged as new lines of evidence suggest erythrocyte membranes contribute to a significant amount of free cholesterol in plaques.’1

Oh look, it seems that the cholesterol does not come from LDL. Anyway, I am jumping ahead of myself here, and getting dragged back into explaining why the cholesterol hypothesis is nonsense. Which is playing the game on the opponents’ pitch, under their rules.

The simple fact is that, to replace the Cholesterol hypothesis, there is a need to come up with something better, which actually fits all the facts. That, of course, is rather trickier as – boy – there are a lot of facts. Also, some of them may seem utterly disconnected.

My simple credo is that, if your hypothesis cannot explain everything about CVD you cannot explain anything. Attempting to do otherwise means that you are left suggesting that there are many different causes, and many different processes, all of which end up causing CVD through non-connected mechanisms. Well if that is true, then we just have to give up. Smoking causes CVD like this, LDL causes it like that, diabetes in a completely different way.

This is why I get so frustrated when people simply shrug their shoulders in a debate on CVD, and retreat to the position of inarguable logic when they tell me that CVD is ‘mutifactorial.’ To which I agree that of course it is bleeding mutlfactorial (as are all diseases). But that the statement itself is meaningless, unless you can then tell me how all the ‘multi’ factors fit together within a single, unified process.

In short, with CVD, if you are going to explain it, you need to be able to explain how, for example, the following factors increase risk, and through what single mechanism, or process. [This is not an exhaustive list by any means, but these are all definite, and potent, causes]:

  • Rheumatoid arthritis
  • Steroid use
  • Systemic Lupus Erythematosus
  • Smoking
  • Kawasaki’s disease
  • Use of Non-steroidal anti-inflammatory drugs e.g. ibuprofen, naproxen and suchlike.
  • Being a deep coal miner – especially in Russia
  • Using cocaine
  • Getting older
  • Getting up in the morning – especially on Mondays
  • Type II diabetes
  • Raised fibrinogen level
  • Cushing’s disease
  • Air pollution
  • Acute physical or psychological stress
  • Chronic kidney disease
  • Avastin – a cancer drug

Looking at one of these risk factors, System Lupus Erythematosus. Young women with this condition have, in some studies, an increased risk of CVD of 5,500%. Compare that with, for example, raised LDL. Even if you believe that it raises the risk of CVD, which is debatable, the increase in risk (as defined by mainstream research) is 66% for a 3mmol/l increase in the LDL level2. Changing the LDL level by this much takes you from low risk, to Familial Hypercholesterolaemia (FH).

If we accept that the 66% figure is, indeed, correct, we can see that SLE increases the risk 83 times more than having a very high LDL level. Or, to frame this differently. SLE increases the risk of CVD 8,300% more. Clearly, therefore, SLE has far more to tell us about what really causes CVD than raised LDL ever could. Deep coal miners in Russia have their final, fatal, heart attack aged 42, on average. Children with Kawasaki’s disease can die of a heart attack aged 3.

Here, therefore, are the real causes of CVD. Super accelerated CVD with death at a young age. No need for statistical games. This is the where the answers truly lie. Now comes the difficult bit. How can you fit them all together within a single disease process, without finding anything contradictory?

Ladies and gentlemen, it took me thirty years.



Cholesterol goes up heart disease goes down

As readers of this blog will know well, I do not believe that cholesterol levels have anything to do with heart disease, which would more accurately called coronary artery disease (CAD) or coronary heart disease (CHD). This is not a view that is widely accepted in the medical community, nor in society as a whole. In fact, this view places me very firmly in the ‘nut job’ category. I have been told that my views mean that I feature on several quack watch sites. Hoorah, fame – of a kind – at last.

So when I come across information that supports my position, I am always keen to make as much noise about it as possible. Today, or at least today as I write this, someone sent me an article entitled ‘Continuous decline in mortality from coronary heart disease in Japan despite a continuous and marked rise in total cholesterol: Japanese experience after the Seven Countries Study.

Now, that’s the kind of thing that I like to see. Cholesterol levels go up; heart disease rates go down. Here is the abstract of the paper, published in the International Journal of Epidemiology:

The Seven Countries Study in the 1960s showed very low mortality from coronary heart disease (CHD) in Japan, which was attributed to very low levels of total cholesterol. Studies of migrant Japanese to the USA in the 1970s documented increase in CHD rates, thus CHD mortality in Japan was expected to increase as their lifestyle became Westernized, yet CHD mortality has continued to decline since 1970. This study describes trends in CHD mortality and its risk factors since 1980 in Japan, contrasting those in other selected developed countries.

We selected Australia, Canada, France, Japan, Spain, Sweden, the UK and the USA. CHD mortality between 1980 and 2007 was obtained from WHO Statistical Information System. National data on traditional risk factors during the same period were obtained from literature and national surveys.

Age-adjusted CHD mortality continuously declined between 1980 and 2007 in all these countries. The decline was accompanied by a constant fall in total cholesterol except Japan where total cholesterol continuously rose. In the birth cohort of individuals currently aged 50–69 years, levels of total cholesterol have been higher in Japan than in the USA, yet CHD mortality in Japan remained the lowest: >67% lower in men and >75% lower in women compared with the USA. The direction and magnitude of changes in other risk factors were generally similar between Japan and the other countries.

Conclusions: Decline in CHD mortality despite a continuous rise in total cholesterol is unique. The observation may suggest some protective factors unique to Japanese.’1

This paper was actually published in July, but I missed it until now. I have to say that I like everything about the abstract (and the entire paper) apart from the last ten words. ‘The observation may suggest some protective factors unique to Japanese.’ You may be thinking, what’s wrong with that suggestion. It seems completely reasonable.

I put it to you, members of the jury, that we have a situation whereby we see continuously rising cholesterol levels in a population, whilst the rate of heart disease in that population (already very low), falls even lower. This, despite the fact that their other risk factors are just as high, if not higher than in all the other countries studied. Just to compare and contrast Japan with the USA and the UK. These figures are from the latest year 2008 where all figures are available (figures for men).

% WHO SMOKE 35.4% 23% 17.2%
AVERAGE BP (SYSTOLIC) 130.5mmHg 131.2mmHg 123.3mmHg
CHOLESTEROL LEVEL 5.2mmol/l 5.4mmol/l 5.1mmol/l
RATE OF CHD/100,000/year 45.8 143.7 150.7

Perhaps most important thing in this study is that the rate of CHD in men in Japan was 62.4 (per 100,000/year) in the years 1980 – 83, when their average total cholesterol level was 4.8. Since then cholesterol has risen 9% to 5.2mmol/l; meanwhile the CHD rate has fallen by 27%. In fact, this trend of rising cholesterol and falling CHD has been going on since the 1960 – which is also mentioned in this paper2.

More dramatically, the rate of stroke in Japan, which was once the highest in the industrialized world, has dropped by more than 80% over the last fifty years, or so. Most people bring together deaths from coronary heart disease, and stroke, under the overall banner of cardiovascular disease (CVD). Raised cholesterol is considered a major risk factor for both, and statins are prescribed for both. Yet, as cholesterol levels have steadily risen in Japan, deaths from both major forms of CVD have fallen massively.

Where was I. Oh yes, I was putting it to the jury that the evidence from Japan utterly and completely contradicts the cholesterol hypothesis. Utterly and completely. Facts like these should leave the hypothesis as a smoking ruin. But of course, this has not happened, as it never does.

Karl Popper, the famous scientific philosopher, would say that such a finding represents a black swan. If your hypothesis is that all swans are white, finding more and more white swans slightly strengthens the likelihood that your hypothesis is correct. However, if you find one single black swan, your hypothesis is wrong and must be discarded.

Unfortunately, a recurring theme in medical research is that, when someone does discover a black swan, the medical experts immediately come out and tell you that this black swan is not, in fact a black swan at all. It is a swan that may look black but it will, in time, turn out to be have been white all along. A more bullish tactic is to state that, as all swans are white, a black swan cannot be a swan at all. It is a member of a different class. ‘The black bird that looks exactly like a white swan.’

Both approaches come under the banner of ‘Our hypothesis is right, we absolutely know that it is right, so any evidence that contradicts our hypothesis must be wrong.’ Or can be explained away. Otherwise known as painting the black swan white.

Explaining away also comprises a few other, well established, techniques. Firstly, to denigrate the researchers, or their research. They didn’t measure this correctly, the ignored that, they can’t be trusted, this is rubbish work – please ignore. I call this technique ‘kill the unbeliever.’

The next form of explaining is to call your finding a paradox. i.e. we know that this looks just like a black swan, but an explanation will be found at some time for its apparent blackness. Let us simply ignore this finding until the correct explanation comes along to explain it. I call this technique ‘Hide the black swan away in a cupboard and hope everyone forgets it was ever there.’

Fortunately, or unfortunately, depending on your position on the cholesterol hypothesis, these techniques won’t really work here. This study was funded by the National Institutes for Health, which makes it difficult to rubbish the results, or the researchers. Also, the data have been gathered by the WHO under the MONICA study. A massive and high quality data set which I have never seen anyone argue with. It was also published in the International Journal of Epidemiology. Generally considered a high quality medical journal.

Equally, it is rather difficult to call the Japanese data a paradox. We are not looking at a sudden, one-off finding. What we have in Japan is over sixty years of data, all pointing exactly the same way, year after year. The Japanese cholesterol levels have gone up, year on year, and there has been a steady (yet massive overall) reduction in the rate of heart disease and stroke. This data comes from a population of over one hundred million. Sorry guys, this Paradox hasn’t gone away.

It is also exceedingly difficult for mainstream researchers to attack this current data, as the Japanese were once held up as poster boys for the cholesterol hypothesis. ‘Look at the Japanese’ the researchers shouted loudly in the 1960s. ‘Very low cholesterol levels and very low rates of heart disease… case proven.’ In fact, the Japanese data were one of the strongest drivers of the cholesterol hypothesis. It is entirely possible that, without the Japanese data, the cholesterol hypothesis would never have been accepted in the first place.

Well, look at the Japanese today. Not shouting about them from the rooftops now, are we chaps? Sorry, what was that…couldn’t quite hear you. You may be thinking, at this point. Ah, so the Japanese must be genetically protected against heart disease. Well, this is not correct. To quote from the paper again:

‘Studies of migrant Japanese to the USA in the 1970s reported a dramatic increase in CHD rates within one generation of migration. It was thus expected that exposures to more a Westernized lifestyle among native Japanese after World War II (WWII), for example increase in dietary intake of saturated fat, would cause sizeable rise in blood total cholesterol, leading to a considerable increase in CHD rates in Japan. Between 1960 and 1990, dietary intake of fat and cholesterol in Japan more than doubled. The current levels of blood total cholesterol in Japan, especially among individuals born after WWII, are comparable to those in other developed countries, very different from the 2-mmol/l difference in total cholesterol at the time of the Seven Countries Study.

Moreover, age adjusted mortality from other diseases related to Westernized lifestyle, such as colon, breast and prostate cancers, more than doubled during this period. Very surprisingly, age-adjusted CHD mortality in Japan started to decline in 1970 as in Western countries, and has remained one of the lowest in developed countries: >67% lower in men and >75% lower in women compared with the USA, accounting partly for the greatest longevity in the world among Japanese.’

I liked the words ‘very surprisingly’ in that section. There is only one reason why you should be very surprised in science. That is, when everything you thought you knew about something proves to be wrong.

Just to summarize here. The data from Japan are robust, the researchers free from commercial bias. We are not looking at poor quality research, nor are we looking at a paradox, it is a pure black swan. Yes, of course, the researchers tried to find something, anything, that could explain away this finding. They looked at salt intake. Ooops, the Japanese have way higher salt intake than every other country they looked at. Sorry, ignore.

They did find that the Japanese ate more fish than in most other countries and that, my friends, was that. In fact, even they didn’t believe that this provided any explanation. For we are left with this statement at the end of the discussion section:

The lower CHD mortality in Japan compared with the USA is very unlikely to be due to the difference in trends in other CHD risk factors, cohort effects, misclassification of causes of death, competing risk with other diseases or genetics. The observation may suggest some protective factors unique to Japanese which merit further research.’

I shall give you a different conclusion from this study. One that actually fits the facts that these researchers round.

‘A raised cholesterol level is not a cause of CHD/CVD. ‘

There you are, nice and simple. There is no need for the creation of unknown and undiscovered ‘unique’ protective factors. It just fits. And when a hypothesis fits all the facts, without the need for any fancy adaptations, you know that it is right. That, my friends, is called science.


1:  Continuous decline in mortality from coronary heart disease in Japan despite a continuous and marked rise in total cholesterol: Japanese experience after the Seven Countries Study’ International Journal of Epidemiology, 2015, 1614–1624 due: 10.1093/ije/dyv143

2:   Ueshima H, Sekikawa A, Miura K et al. Cardiovascular disease and risk factors in Asia: a selected review. Circulation 2008;118:2702–09.

A Swiss Investment Bank gets it completely one hundred per cent right

[Yes, that’s right, a Swiss Investment Bank!]

A kind reader of my blog pointed me at a report by Credit Suisse entitled ‘Fat, the New Health Paradigm.’ I suppose I half expected the usual. Saturated fat causes heart disease, cholesterol causes heart disease. ‘We are a respected bank, what the hell did you expect – that we would rock the boat in some way. Don’t be daft.

What seems to have happened is that they actually looked at the evidence in this area and came to the conclusion that the current dietary advice is utter bollocks and is not based on anything at all. I shall start with a few key points from the Introduction:

‘Saturated fat has not been a driver of obesity: fat does not make you fat. At current levels of consumption the most likely culprit behind growing obesity level of the world population is carbohydrates. A second potential factor is solvent-extracted vegetable oils (canola, corn oil, soybean oil, sunflower oil, cottonseed oil). Globally consumption per capita of these oils increased by 214% between 1961 and 2011 and 169% in the U.S. Increased calories intake—if we use the U.S. as an example—played a role, but please note that carbohydrates and vegetable oils accounted for over 90% of the increase in calorie intake in this period.

A proper review of the so called “fat paradoxes” (France, Israel and Japan) suggests that saturated fats are actually healthy and omega-6 fats, at current levels of consumption in the developed world, are not.

The big concern regarding eating cholesterol-rich foods (e.g. eggs) is completely without foundation. There is basically no link between the cholesterol we eat and the level of cholesterol in our blood. This was already known thirty years ago and has been confirmed time and time again. Eating cholesterol rich foods has no negative effect on health in general or on risk of cardiovascular diseases (CVDs), in particular.

Doctors and patients’ focus on “bad” and “good” cholesterol is superficial at best and most likely misleading. The most mentioned factors that doctors use to assess the risk of CVDs—total blood cholesterol (TC) and LDL cholesterol (the “bad” cholesterol)—are poor indicators of CVD risk. In women in particular, TC has zero predictive value if we look at all causes of death. Low blood cholesterol in men could be as bad as very high cholesterol1.’

At one point they go on to say…

Here is our final hypothesis on why health authorities have remained so certain of their position and unwilling to change their view on saturated fats, omega-6 or carbohydrates:

  1. Health authorities advance very slowly and are afraid to change the market’s status quo (not a wise medical posture).

We have known since the 1960-70s that dietary cholesterol has no influence on blood cholesterol. Yet it took more than fifty years for the USDA/USDHHS to lift recommended upper limits of fat consumption. It took close to 20 years in the U.S.—that was quick—to ban transfats. So we should not look at public health authorities as leading indicators of potential health hazards, but rather as lagging behind.

Bureaucracy tends to move slowly, but when the health risks tied to “incorrect” information are so high, one would hope for swift action and the courage to reverse past mistakes. There was no fundamental reason to move from butter to solvent extracted vegetable oils. If we assume that research was the main reason—as it was claimed at that time—the health authorities now have enough information to change their recommendations, or if still in doubt issue no recommendations.

All quite extraordinary. This report is about as scathing as an organisation like Credit Suisse could possibly be. They have stripped apart the evidence on eating fats and saturated fats. They have come to exactly the same conclusions as I, and many others, have done. When they say:

There was no fundamental reason to move from butter to solvent extracted vegetable oils

That means, there was not one single scrap of evidence. Nothing, zip, nada, zero. So when you see various flower-like margarine manufactures promoting their products as super-healthy…. You know it is just the most complete nonsense. Even a Swiss Investment Bank says so.

And what do they have to say on raised cholesterol levels? Well they have many things to say, mainly that it does not cause heart disease. The shortest summary of their conclusions would be the following:

We can draw the following conclusions:

  1. High cholesterol (above 240mg/dl) (this is 6.2mmol/l) is only a marker of higher cardiovascular death for men. Please note that high cholesterol does not cause heart attacks, it is just a marker.
  2. For all other illnesses, higher cholesterol levels pointed to lower death levels. Why? Because cholesterol helps support, or is a marker of, a better immune system.

I know that this report will be ruthlessly attacked and vilified. Mainly on the basis that it was written by a Bank! And what can bankers possibly know of medical research? How very dare they? My own view on this is that, you know, anyone can read medical research, and if you are in possession of a functioning brain you can also work out what that research is saying.

Indeed, in my opinion, the best placed people to review any form of research are those who do not have a dog in the fight. The authors of this report have no reputations to maintain in medical research. They have no reason to support one side or the other. These people represent an investment bank, and all they are interest in doing is advising their ‘customers’ on what is really true, and what is likely to happen. They are a bit like bookmakers. No emotions involved just ‘what are the odds.’

As they say that odds are, as follows

‘The bottom line of these assumptions is that fat consumption per capita is likely to soar by 23% from now until 2030, protein by 12%, and carbohydrates will likely decline by 2%. This implies annual compound growth of 1.3% for fat consumption, compared to 0.9% over the last fifty years. Total demand for fat will be much higher—43% up for fat or 1.9% a year— given the 16% growth in the global population expected over the next fifteen years.’

Pork bellies are a ‘buy.’ How strange to find myself on the same side of an argument as a Swiss Investment Bank. I would have given you bloody good odds on that yesterday.


Tranny fats ha ha ha

[An apology. Some people have objected to the work Tranny, as this is considered offensive to trans-gendered individuals. I was attempting a play on words from Roddy Doyle’s well known book Paddy Clarke ha ha ha. I had not the slightest intention of causing offense in this way, and I apologise if I have done so. I hope the title can be taken in the ‘innocent’ way that it was meant]

Many years ago a man, who they say, had an ego the size of a planet decided that he just knew what caused heart disease. It was cholesterol consumption in the diet that raised blood cholesterol and killed us all. Unfortunately, for him, he did some research that however much cholesterol you ate, it had no effect on the cholesterol level in the blood.

No matter.’ He laughed gaily. ‘What is the point of a good hypothesis if you cannot change it upon a whim?

So he then decided that it was dietary fat that raised cholesterol levels in the blood and caused us all to die of heart disease. Only it wasn’t that one either. So then he thought it was animal fat (wrong again!) and finally settled upon saturated fat.

Then, through a combination of his forceful personality, and a good bit of merciless bullying anyone who disagreed, Ancel Keys promoted his message far and wide, and those in power decided he was right.

This set in chain a whole series of seemingly disconnected phenomena. The first of these was to start telling everyone that they should not be eating saturated fats, assumed to be animal fats, or else they would die. Thus, recommendations about what was healthy to eat became moved away from those horrible, unhealthy fats, and focussed entirely on eating carbohydrates.

At which point the obesity epidemic began- as you would expect. This was closely followed by the epidemic of diabetes – as you would expect. If you know anything about human physiology.

Then it was realised that diabetics, who were more likely to develop heart disease than anyone else really, really, should not eat any sort of fat. Saturated or otherwise. They were all advised to switch to eating carbohydrates. This of course, makes perfect sense. We have a group of people who cannot control their blood sugar levels, so we tell them to eat almost nothing but sugar.

We now spend more on medication for diabetes than any other form of medicine in the world. Why, because no-one can get their blood sugar levels under control any more. Quelle surprise?

In parallel with this nonsense it was decided that we should replace saturated fats with ‘healthy’ polyunsaturated fats and suchlike. Which inevitably included trans-fatty acids. These were first discovered many years ago, when oils were turned into margarine. The margarine was, at first, coloured pink – as it was considered unfit for human consumption, and was only fed to animals.

Gradually trans-fats, which are also polyunsaturated fats, found their way into almost everything anyone ate – including of course margarine (no longer coloured pink, instead with pretty coloured flowers on the tub). MacDonald’s were virtually forced into cooking their fries in vegetable fat, so that no-one would be exposed to the deadly, evil saturated fats. Hey ho, what happens to vegetable fats at high temperatures? Well, they turn into trans-fatty acids, of course. Who knew? Apart from all chemists in the world.

More recently we find that trans-fatty acids are uniquely unhealthy substances that should be banned, and excluded from human consumption. What a surprise, a range of chemical compounds almost unknown to nature may not be healthy….well, who’d a thunk? This morning I was listening to a debate on the radio about whether the UK should ban all trans-fatty acids. [Well, you can’t ban them all, because some are found in natural foodstuffs.]

I just sat and listened, and thought that the entire world of nutrition was bonkers, and remains bonkers. An egocentric megalomaniac called Ancel Keys decided that ‘HE KNEW’ what caused heart disease, and would brook no dissent. His legacy is that we now force carbohydrates into diabetics, and almost everyone else. We also forced manufacturers to stop selling saturated fat and, instead, switch to super-healthy trans-fats. We made MacDonald’s French fries uniquely unhealthy. A perfect and delicious irony. Accuse MacDonald’s of selling unhealthy food, then make them do it.

God knows how many have died prematurely because of this complete and utter nonsense. Tranny fats, ha ha ha.