Saturated fat and heart disease

The greatest scam in the history of medicine’ George Mann

I have been a bit quiet of late, mainly because I got a cough that ended up as a nasty chest infection, that also caused my brain to turn to mush for about three weeks. Maybe it was the antibiotics. Anyway proof, as far as I am concerned, that the mind and body are closely connected.

Yes, another little detour from my series, trying to explain what causes cardiovascular disease. But I thought I need to look, once again, at the hypothesis that saturated fat consumption is a cause – perhaps the cause of cardiovascular disease?

To be honest, I have studied saturated fat consumption many, many… many, many, times. The one thing that has always stood out, most starkly, is the complete lack of any real evidence to support the idea that it causes cardiovascular disease.

On the other hand, evidence contradicting it arrives on an almost daily basis. The following study was sent to me a few days ago, although it is now almost ten months since it was first published. The researchers looked at nearly thirty-six thousand people over twelve years. It was done in the Netherlands. The main conclusions were that that:

‘Total saturated fat intake was associated with a lower IHD (Ischaemic Heart Disease) risk (HR per 5% of energy 0.83). Substituting SFAs with animal protein, cis-monounsaturated fats, polyunsaturated fats or carbohydrates was significantly associated with higher IHD risks (HR 1.27 – 1.37).’1

One thing scientific researchers have learned over the years is that you can never say anything in a straightforward way. I think the game is that, if anyone can easily understand your findings, you lose. A game played to its illogical conclusion by French Philosophers. Something I remarked to my son, who was trying to quote Derrida at me. Here would be one snappy Derrida quote:

“Every sign, linguistic or nonlinguistic, spoken or written (in the usual sense of this opposition), as a small or large unity, can be cited, put between quotation marks; thereby it can break with every given context, and engender infinitely new contexts in an absolutely nonsaturable fashion. This does not suppose that the mark is valid outside its context, but on the contrary that there are only contexts without any center of absolute anchoring. This citationality, duplication, or duplicity, this iterability of the mark is not an accident or anomaly, but is that (normal/abnormal) without which a mark could no longer even have a so-called “normal” functioning. What would a mark be that one could not cite? And whose origin could not be lost on the way?”

Yes, indeed. Couldn’t agree more.

As with Derrida, so with scientific papers. What these researchers should have said is the following. ‘The more saturated fat you eat, the lower your risk of dying of cardiovascular disease, and vice-versa.’ A thirteen per cent reduction in death for every five per cent increase in energy obtained from saturated fat consumption. Why do they run away from making such easy to understand statements? I think Derrida could probably tell us. If we could ever understand anything he ever wrote, or said.

However, I am not going to bombard you with endless facts contradicting the saturated fat hypothesis, I am going to get a little more philosophical here. To ask, what is it about some scientific ideas/hypotheses that they become so quickly entrenched – without the need for the tedious requirement of any actual facts.

My thoughts were drawn to this issue by something seemingly unconnected. Which is a legal hearing the UK concerning shaken baby syndrome. Most experts in paediatrics are absolutely convinced that there is such a thing. It is quoted in textbooks as an undisputed fact. Many parents, and other adults, have been convicted, and sent to jail, for shaking their babies so hard that it caused the ‘triad’ of shaken baby syndrome: subdural hematoma, retinal bleeding, and brain swelling

On the other hand, we have Dr Waney Squier, a paediatrician who used to provide expert opinion on child abuse cases in the UK. She was struck off by the General Medical Council (GMC) for, well the exact judgement is, as per Derrida, impossible to understand.

The GMC judgement has certainly been criticized:

‘Michael Mansfield, Clive Stafford Smith and others argue that the General Medical Council is behaving like a “21st-century inquisition” in the case of Dr Waney Squier (Shaken baby syndrome doctor struck off, 22 March).’

The GMC responded thus:

‘Far from wishing to suppress different views, we recognise that scientific advance is achieved by challenging as well as developing existing theories, and importantly in this context we are absolutely clear that neither the GMC nor the courts are the place where such scientific disputes can be resolved. To be clear, it is possible that a doctor who ultimately was proved to have the correct theory could present their evidence in such a way as to mislead, just as it is possible for a doctor advocating a theory ultimately proved to be flawed to present their case in context and with integrity.’

Niall Dickson

Chief executive, General Medical Council

The only possible response to Niall Dickson’s remark is ‘bollocks.’ You can present the correct theory in a way to mislead, and you can present a flawed hypothesis with integrity? George Orwell would surely nod in approval of such perfect doublethink. You are right, but we don’t like the way you present being right. We would rather listen to someone talk absolute nonsense using the correct professional manner. Can I have my knighthood now, please?

Leaving the machinations of the GMC aside, the main issue is simple. Dr Waney Squier does not believe that shaken baby syndrome exists. Of course she knows that the triad of subdural haematoma, retinal bleeding and brain swelling exists. But she believes there could be other explanations. Including, perish the very thought, an accidental fall.

Because she does not believe in shaken baby syndrome, she has presented evidence in court which has tended to undermine the prosecution case against parents and carers, accused of shaking a baby and causing severe brain damage. Much to the annoyance of the police and they then, for it was indeed them, reported Dr Squier to the GMC.

Now, I know what most of you are thinking. Surely ‘shaken baby syndrome’ exists. This must have been proven. Well, it has not. If you think about it, how could it be proven? How do you think a study on shaken baby syndrome could ever be done? Get five hundred children, shake them forcefully and see what happens to their brains. I suspect you might find gaining ethical approval for a such a study might be tricky.

Despite this, and the fact that shaken baby syndrome represents an ‘unproven hypothesis’ almost all experts around the world are convinced that shaken baby syndrome exists. Dr Squier, who seems a well-rounded and sensible lady, has made the terrible mistake of questioning that this dogma. There could be, shock horror, other possible causes.

The police objected, judges objected, her peers objected, and she has been struck off. No longer able to practice medicine anywhere in the world. She has become a medical pariah.

The good news is that her case in going in front of an actual court of law in the UK. I strongly suspect (maybe I just hope) that her ‘conviction’ will be overturned. She does have the support of a number of other paediatricians around the world. However, in the meantime, other doctors, who do not believe in shaken baby syndrome, will not dare go to court to testify in support of those accused of shaking babies. Such is the power of the Spanish Inquisition.

Shaken baby syndrome: saturated fat consumption.

On the fact of it shaken baby syndrome and saturated fat consumption have very little in common. However, from another perspective the parallels are clear. Both are seductively simple ideas that appeal to common sense. That most deadly of all senses.

Most people can clearly see how a small, vulnerable, baby will suffer significant brain injury if it is shaken too hard. Close your eyes and you can virtually see it happening. If you can bear having that image in your head for any length of time.

Most parents, I think, can almost see themselves doing it, or having done it – when their child will ‘just not dammed well stop crying.’ In short, shaken baby syndrome can easily be visualised, and it triggers a kind of visceral horror. We can easily see how a feckless parent may lack the self-control required to stop themselves doing it. ‘Shut up, shut up, shut up….’

And that, dear reader, is as scientific as shaken baby syndrome gets. A hypothesis based on visceral fear, prejudice, and knee-jerk judgement. This makes it almost perfectly resistant to any contradictory evidence. Try to argue against it, and you will meet anger and bluster and the idee fixe.

I was once told a story which goes as follows. It concerns a psychiatrist trying to convince a patient that he is not dead. A battle that that had gone on for many years, eventually the psychiatrist comes up with a brilliant idea….

Psychiatrist:       ‘Do dead people bleed?’

Patient:                                   ‘No, I guess not.’

Psychiatrist:       (Takes pin from lapel and pricks the patient’s thumb, and a drop of blood appears). ‘Aha, do you see that?’

Patient:                 (Looks at thumb) ‘What do you know, I guess dead people do bleed then.’


The ‘saturated fat causing heart disease hypothesis’ comes from a very similar place called – well, it’s obvious isn’t it, just common sense. Heart disease is basically a build of fat in the arteries, isn’t it.? Where can that possibly come from? Fat in the diet. Especially the thick, sticky, gooey stuff that you get on a pork chop, or suchlike. That’s got to be it hasn’t it? The thick horrible squidgy gooey fat that you eat, ends up as thick horrible squidgy gooey fat in your arteries. Serves you right for eating fat, and MacDonald’s, and suchlike.

There rests the entire scientific argument against saturated fat. As such it is difficult to argue against. Facts simply bounce off. As demonstrated very clearly to me in a more recent publication. A very major review was published a few weeks ago on the Journal of Food and Nutrition Research called ‘Food consumption and the actual statistics of cardiovascular diseases: an epidemiological comparison of 42 European countries.’ 2

‘The aim of this ecological study was to identify the main nutritional factors related to the prevalence of cardiovascular diseases (CVDs) in Europe, based on a comparison of international statistics.

What did they find? Well, they found lots of things, but the key things they found were the following:

We found exceptionally strong relationships between some of the examined factors, the highest being a correlation between raised cholesterol in men and the combined consumption of animal fat and animal protein (r=0.92, p<0.001). The most significant dietary correlate of low CVD risk was high total fat and animal protein consumption.’

Now that paragraph really needs a however in it. Just after p<0.001 and the ‘The.’ Yes, they found that animal fat (mainly saturated fat) and animal protein did indeed raise cholesterol. However, animal fat and animal protein consumption showed the most powerful correlation with low risk of cardiovascular disease.

Which food items showed the highest correlation with increased CVD risk? Have a guess.

‘The major correlate of high CVD risk was the proportion of energy from carbohydrates and alcohol, or from potato and cereal carbohydrates.’

The conclusion of the authors:

‘Our results do not support the association between CVDs and saturated fat, which is still contained in official dietary guidelines. Instead, they agree with data accumulated from recent studies that link CVD risk with the high glycaemic index/load of carbohydrate-based diets. In the absence of any scientific evidence connecting saturated fat with CVDs, these findings show that current dietary recommendations regarding CVDs should be seriously reconsidered.’

When the British Heart Foundation was presented with the findings from this study they found a Dr Mike Knapton to make the following statement:

“Other studies, however, show diets high in saturated fat are linked to raised cholesterol levels, which is a risk factor for heart disease. So, for you and me, we should consider our diet as a whole to reduce our overall risk, such as a traditional Mediterranean style diet, which is a style of eating associated with a lower rate of coronary heart disease. The key is a balanced diet over all, rather than considering individual foods. There are many factors which cause heart disease and stroke and no single food or nutrient is solely responsible for this. We will continue to recommend switching saturated fat for unsaturated fat.”

As you can see, when presented with evidence, the BHF refuses to consider it, and turns to gibberish. Dr Mike Knapton argues that this study should be ignored, because other studies have shown that saturated fat raised cholesterol levels, and this is a risk factor for heart disease.

‘Hellooo Dr Knapton. This study also showed that saturated fat increased blood cholesterol levels. However, what it also showed is that this reduced the risk of heart disease. Did you even read that bit, or do you simply dismiss papers contradicting the diet-heart hypothesis on the basis they must be wrong – so what it the point of actually reading them?’

On many occasions I, and others, have tried to engage the BHF in debate. However, you can’t. They just provide ‘statements’. The statements never change, the evidence they use never revealed. However big a study, however contradictory it is, it will be met with statement such as Other studies, however, show diets high in saturated fat are linked to raised cholesterol levels, which is a risk factor for heart disease.

Made up scientific hypothesis are, I find, very difficult to dislodge with evidence.

1: ‘The association between dietary saturated fatty acids and ischemic heart disease depends on the type and source of fatty acid in the European Prospective Investigation into Cancer andNutrition–Netherlands cohort’ Jaike Praagman, Joline WJ Beulens, Marjan Alssema, Peter L Zock, Anne J Wanders, Ivonne Sluijs, and Yvonne T van der Schouw. Am J Clin Nutr doi: 10.3945/ajcn.115.122671


Buy this new book

Fat and Cholesterol Don’t Cause Heart Attacks

There is a group of doctors, scientists and researchers called the International Network of Cholesterol Skeptics (THINCS) I am a member, and recently a number of us have contributed chapters to a new book called Fat and Cholesterol Don’t Cause Heart Attacks And Statins are Not the Solution.

This was written in honour of the founder of THINCS, Uffe Ravnskov, a Swedish doctor and researcher who has been arguing against the current die-heart/cholesterol hypothesis for many years. He has written several books, many, many, research papers, and had the dubious honour of having one of his book burned, live, on television. [Finland 1992, the book was The Cholesterol Myths]. He has also been ruthlessly attacked, both professionally and personally. Yet he has never given up.

Ravnskov, like all of us in THINCS, started looking at heart disease, or cardiovascular disease (CVD) and recognised that the widely accepted views were simply wrong. Something recognised by many people over the years, including Professor George Mann (who helped to start up and run the Framingham study).

‘Saturated fat and cholesterol in the diet are not the cause of coronary heart disease. That myth is the greatest scientific deception of this century, perhaps of any century.’

George Mann, like many others was silenced. Kilmer McCully, who discovered the role of homocysteine in CVD, and suggested that it could be more important that cholesterol was also attacked. Funding for his research disappeared, leading to the loss of his laboratory. His hospital director told him to leave and ‘never come back’. His Harvard affiliation and tenure were terminated.

Another contributor to this book, Professor Michel De Logeril, set up and ran the seminal Lyon Heart Health Study. Possibly the seminal work on the ‘Mediterranean Diet.’ Yet he is a trenchant critic of the diet-heart hypothesis, and believes that statins do more harm than good. He is, again, attacked ruthlessly.

Yes, there is a pattern here. Dare to criticise the current dogma that saturated fat in the diet raises cholesterol, which then goes on to cause CVD, and your chances of progression in the research world are, precisely, zero. Your chances of getting anything published are, pretty close to zero. You will be attacked both personally and professionally. You will be accused of killing thousands of people by putting them of taking statins – and suchlike.

However, those in THINCS have never given up in their efforts to get the ‘truth out there’ and never will. This book is a further way to help inform the public about the true facts. There are chapters on competing hypotheses as to the cause(s) of CVD, there are chapters outlining the flaws in the current ideas. Some chapters are technical, others not.

Everything is held together by Paul Rosch, a brilliant researcher, writer and editor, clinical professor of Medicine and Psychiatry and New York Medical College, Chairman of the Board of the American Institute of Stress, and a great, deep thinker, on many subjects. Would that there were more like him.


You can get a copy direct from the Publishers here…

Or if you prefer to support Amazon, it’s on Amazon UK here and Amazon USA here

What causes heart disease part XXI

Now, when I say that CVD is complicated, I suppose I mean it. Here is a slide that I have been pondering for a couple of weeks. It comes from a paper called ‘DDAH Says NO to ADMA.’1 And that gets my official ‘acronym title of the year award’. Something that I do not hand out lightly. Here is the key diagram from the paper.


Actually, it is not that complicated, because it is explained thus. ‘The role of DDAH1 in the metabolism of the NOS antagonists ADMA and MMA. DMA indicates dimethylamine; PRMTs, protein arginine methyltransferases; SAM, S-adenosyl-L-methionine; SAH, S-adenosyl-L-homocysteine; SDMA, symmetrical dimethylarginine.’ That should have cleared everything up, I hope.

Joking aside. For those paying attention, and I must admit you will have to have a pretty good memory here, I did mention some time ago that PPIs increased the risk of CVD. PPIs are proton pump inhibitors such as omeprazole, lansoprazole, esomeprazole, pantoprazole and suchlike. If you take medicine to prevent stomach ulcers, or gastric reflux, and it ends in ‘zole’ it is a PPI. [Which, if you live in the UK, is not payment protection insurance, which banks mis-sold and are now paying billions in compensation].

The reason why I was pondering DDAH and AMDA is that, very recently, I was sent a paper which had the following results:

‘In multiple data sources, we found gastroesophageal reflux disease (GERD) patients exposed to PPIs to have a 1.16 fold increased association (95% CI 1.09–1.24) with myocardial infarction (MI). Survival analysis in a prospective cohort found a two-fold (HR = 2.00; 95% CI 1.07–3.78; P = 0.031) increase in association with cardiovascular mortality. We found that this association exists regardless of clopidogrel use. We also found that H2 blockers, an alternate treatment for GERD, were not associated with increased cardiovascular risk; had they been in place, such pharmacovigilance algorithms could have flagged this risk as early as the year 2000.2

Now, I already knew that PPIs increased the risk of CVD, but the risk seemed relatively small. However, the problem appears to be far worse that I thought. A two fold risk of dying of cardiovascular disease is worrying. Especially as these drugs are prescribed to millions of, mainly, elderly patients. Where the risk of CVD is already high.

For example. In England, in 2014, there were fifty three million prescriptions written for PPIs. This equates to around four million people taking PPIs every year. Almost all of them on long term treatment [The way the figures are presented makes it difficult to establish how many people actually take PPIs. Many prescriptions are written monthly, but not all. So I divided fifty three by twelve and rounded up a bit, then took a few again, because some prescriptions are two monthly – and not everyone takes them long term]

I figured that the number of people taking PPIs in the US is probably six times this, as the US has six times the population of England. [In fact, the number of PPI prescriptions per year in the US is 329 million/year – which is exactly six times that in England]. So we are talking around twenty million people in the US taking PPIs, usually long-term.

Run the figures a bit further, and the true scale of the problem emerges. Most people taking PPI are elderly, where the risk of death from CVD is pretty high, but I am going to use the average UK death rate of 150/100,000 per year from CVD [men and women combined]. So my figures are likely going to be a considerable underestimate.

Anyway, we now have a simple equation

PPIs appear to double the risk of death from cardiovascular disease. Thus increasing the CVD death rate from 150 to 300 per 100,000 per year (an increase of 150 per 100,00/year)

  • There are roughly four million people in the UK taking PPIs.
  • Four million divided by 100,000 = 40
  • Number of extra people in UK dying due to PPIs = 40 x 150 = 6,000 per year
  • Number of extra people in US dying to to PPIs = 240 x 150 = 36,000 per year
  • Number of extra people in US and UK dying due to PPIs = 42,000 per year

Which, for those of you who like such things, is the population of Grantham, the 244th largest town in the UK. Even if you don’t like such things, 42,000 excess deaths a year (rest of the world excluded) seems a big enough figure to do something about. My prediction – nothing at all will happen. When you have a problem as big and scary as this, nothing ever does.

Leaving this issue aside I was interested to find out, why do PPIs have this effect? Well, it is well known that they lower magnesium levels and sodium levels, which is not a good thing. They also seriously inhibit vitamin B12 absorption – leading to Vit B12 deficiency in many.

In my medical role, I have seen around twenty patients with such severe low sodium (hyponatraemia) due to PPIs, that they were diagnosed with delirium and required hospital admission. Which means that I have become increasingly wary of PPIs, and try to prescribe alternatives wherever possible.

That though, is an aside, as the adverse effects I mentioned do not increase CVD risk. So the question remains. How, exactly, do PPIs cause such a significant increase in CVD death? They do not raise blood pressure or blood cholesterol – or affect any of the traditional/mainstream risk factors for CVD

They do, however, have an effect on platelet aggregation. By which I mean thaty make platelets more likely to stick together – and thus start blood clotting. But this does not seem to the main mechanism at work here [although it does fit very nicely within the hypothesis that CVD is due to blood clotting abnormalities]. To quote the paper that found the increase in CVD risk with PPIs again:

‘Our observation that PPI usage is associated with harm in the general population—including the young and those taking no antiplatelet agent—suggests that PPIs may promote risk via an unknown mechanism that does not directly involve platelet aggregation.’2

If not platelet aggregation, then what? As it turns out, the mechanism by which they increase the risk of CVD is intriguing, and it all comes down to Nitric Oxide (NO). My favorite molecule. The explanation from the paper is, as follows. Again, there is much jargon here:

An alternative explanation is that the observed risk of PPIs is due to some unknown mechanistic pathway and that this pathway may not be restricted to vasculopathic patients (patients at high CVD risk – my words). In this regard, we recently reported that PPIs inhibit the enzymatic activity of dimethylarginine dimethylaminohydrolase (DDAH), which is responsible for 80% of the clearance of asymmetricdimethylarginine (ADMA)—an endogenous molecule known to inhibit the enzymaticactivity of nitric oxide synthase (NOS). An impairment in endothelial NOS (eNOS) is wellknown to increase vascular resistance, and promote inflammation and thrombosis. ADMA is a potent disease marker and independent predictor of MACE in prior observational studies. Our recent pre-clinical studies found that PPIs increase ADMA levels in human endothelial cells and in mice by about 20–30%.’

To rearrange this jargon as simply as I am able.

  • Asymmetricdimethylarginine (ADMA) inhibits nitric oxide synthase (NOS). NOS is the enzyme that converts L-arginine to l-citrulline + nitric oxide (NO). [Basically, it makes NO]
  • This means that the more AMDA you have, the less nitric oxide (NO) you can produce – especially in endothelial cells [A bad thing]
  • Dimethylarginine dimethylaminohydrolase (DDAH) is the enzyme which clears ADMA from endothelial cells (and everywhere else), by breaking it down to methylamines and citrulline
  • PPIs inhibit the enzymatic activty of DDAH, which means that you will end up with higher levels of AMDA floating about
  • With more ADMA in endothelial cells, you will have less NO
  • With less NO you are more likely to die from CVD

Now, I hope, the paper entitled ‘DDAH Says NO to ADMA’ makes perfect sense. Anagrams ‘R’ us.

In truth, I do love this stuff, when the underlying process is made clear. Perhaps that makes me Mr Supergeek 2016, but I don’t care. When I see a paper with the heading DDAH says NO to ADMA I know I am going to enjoy it. It brings together a number of strands that, when you know what you are looking for, all make sense. It reconfirms my belief that if you are going to understand a disease, you absolutely must – and I mean absolutely must – try to understand the underlying process. Or else you are just floundering about.

Once you have done this, if your underlying hypothesis is correct, then everything should fit together effortlessly. As readers of this blog know, I believe that CVD is primarily due to

  • Endothelial damage
  • Abnormal clot formation
  • Damaged clot repair systems

Which means that, when someone sends me a paper highlighting the fact that PPIs double the risk of cardiovascular death I immediately think. Does this fit into the processes above, or is it a contradiction? I hope that I can share some of the pleasure it gives me when a perfect confirmatory process emerges.

As it turns out, PPIs inhibit NO production, through a biochemical system that is well known, and has been clearly established. NO is probably the vital molecule in heart health. It protects the endothelium, it prevents blood clots, it stimulates the production of endothelial progenitor cells. Therefore, anything that damages NO synthesis will – inevitably – increase the risk of CVD.

I like to think, at moments such as this, that I get to feel a little of how Mozart must have felt whilst composing, or Einstein whilst thinking, or Michelangelo whilst sculpting. A moment of utter perfection. Order from chaos. Bliss.

Of course, I am also aware that many people will still be thinking ‘OK, this is all very well, and all very theoretical, but how do I avoid a heart attack. Give me the damned information.’

Ladies and gentlemen, I like to think that I am giving you the information. If not in exactly the form that everyone wants it. However, I promise that I shall try to lay it all out shortly – as well as I am able.

However, I can give you no absolutes. I can only help you change the odds in your favour. I do not have perfect knowledge, even if I did, the human body is still too complex (and maybe always will be) to state that ‘If you do this you cannot have a stroke, or heart attack.’

After all, whist it is an incontrovertible fact that smoking causes lung cancer, yet you can smoke all you like and never get lung cancer. On the other hand, you can never smoke, and still get lung cancer. I am equally certain that you can do everything possible to avoid CVD and still die of a stroke or heart attack. Equally, you can do everything wrong and stay CVD event free. The Gods do like to play dice with us feeble humans.


2: Shah NH, LePendu P, Bauer-Mehren A, Ghebremariam YT, Iyer SV, Marcus J, et al. (2015) ‘Proton Pump Inhibitor Usage and the Risk of Myocardial Infarction in the General Population.’ PLoSONE 10(6): e0124653. doi:10.1371/journal.pone.0124653

Medical censorship in the twenty first century

“If liberty means anything at all, it means the right to tell people what they do not want to hear.” George Orwell.

Many of you may be aware of an article published in the Lancet on the eighth of September. ‘Interpretation of the evidence for the efficacy and safety of statin therapy.’1 It caused a media stir, and I was asked to appear on a few BBC programmes to argue against it – tricky in two minutes. At one stage I was cut off when I attempted to bring up the issue of financial conflicts of interest amongst the authors. The lead author of this paper was Professor Sir Rory Collins.

In truth, I have been awaiting this article for some time. In fact, I am going to reproduce here a blog I wrote on February 16th 2015, predicting exactly what was going to happen, who was going to be involved, and (in broad terms) exactly what they were going to say:

A humiliating climb down – or a Machiavellian move?

Some of you may have seen a headline in the Sunday Express Newspaper ‘Statin, new safety checks.’ The subheading was ‘Oxford professor who championed controversial drug to reassess evidence of side effects.’

Those of you who read this blog probably know that the professor in question is Sir Rory Collins. He, more than anyone, has championed the ever wider prescription of these drugs. He has also ruthlessly attacked anyone who dares make any criticism of them.

You may remember that last year he tried to get the BMJ to retract two articles claiming that statins had side effects (correctly called adverse effects, but I will call them side-effects to avoid confusion) of around 18 – 20%.

He stated that these articles were irresponsible, worse than Andrew Wakefield’s work on the MMR vaccine, and that thousands would die if they were scared off taking their statins by such articles. Ah yes, the old ‘thousands will die’ game. A game I have long since tired of.

Is this story ringing any bells yet? The truth was that both articles quoted a paper which stated that 17.4% of people suffered adverse effects. So, yes, a pedant would say that the 18 – 20% figure was wrong – although not very wrong. Certainly not worth a demand of instant retraction, and apology, which is a very drastic step indeed.

Anyway, below is a short description of the findings of an independent panel set up by Fiona Godlee, editor of the BMJ, regarding the Rory Collins attacks:

“As previously reported, Rory Collins, a prominent researcher and head of the Cholesterol Treatment Trialists’ (CTT) Collaboration, had demanded that The BMJ retract two articles that were highly critical of statins. Although The BMJ issued a correction for both papers for inaccurately citing an earlier publication and therefore overstating the incidence of adverse effects of statins, this response did not satisfy Collins. He repeatedly demanded that the journal issue a full retraction of the articles, prompting The BMJ’s editor-in-chief, Fiona Godlee, to convene an outside panel of experts to review the problem.

The report of the independent statins review panel exonerates The BMJ from wrong doing and said the controversial articles should not be retracted:

“The panel were unanimous in their decision that the two papers do not meet any of the criteria for retraction. The error did not compromise the principal arguments being made in either of the papers. These arguments involve interpretations of available evidence and were deemed to be within the range of reasonable opinion among those who are debating the appropriate use of statins.”

In fact, the panel was critical of Collins for refusing to submit a published response to the articles:

“The panel noted with concern that despite the Editor’s repeated requests that Rory Collins should put his criticisms in writing as a rapid response, a letter to the editor or as a stand-alone article, all his submissions were clearly marked ‘Not for Publication’. The panel considered this unlikely to promote open scientific dialogue in the tradition of the BMJ.””1

To provide a bit more context at this point, you should know that for a number of years, people have been trying to get Rory Collins to release the data he and his unit (the CTT), holds on statins. [The CTT was set up purely to get hold of and review all the data on statins, it has no other function].

He has stubbornly refused to let anyone see anything. He claims he signed non-disclosure contracts with pharmaceutical companies who send him the data, so he cannot allow anyone else access. Please remember that some of the trials he holds data on were done over thirty years ago, and the drugs are long off patent. So how the hell could any data still be ‘confidential’ or ‘commercially sensitive’ now?

[The concept that vital data on drug adverse effects can be considered confidential, and no-one is allowed to see it, is completely ridiculous anyway. But that is an argument for another day.]

Now, amazingly, after running the CTT for nearly twenty years, Collins claims that ‘he has not seen the full data on side-effects.’ In an e-mail to the Sunday Express he stated that ‘his team had assessed the effects of statins on heart disease and cancer but not other side effects such as muscle pain.

Let that statement percolate for a moment or two. Then try to make sense of it. So, they have got the data, but not bothered to look at it? Or they have not got it – which surely must be the case if he hasn’t even seen it. Give us a clue. Either way, Collins states he has not assessed it.

Despite this, he still managed a vicious attack on the BMJ for publishing articles, claiming statins had side effects of around 20%. This was an interesting stance to stake, as he now claims he has no idea what the rate of side effects are? In which case he should make a grovelling apology to Fiona Godlee immediately.

What is certain, and must be reiterated, is that Rory Collins has consistently refused to allow anyone to see the side effect data, or any other data, that that the CTT may, or may not, hold. See e-mail below from Professor Colin Baigent to the ABC producer MaryAnne Demasi (she was trying to get the CTT to confirm that they would not release data, Colin Baigent is, or was, deputy to Rory Collins)

From: colin.baigent@xxxxxxxxxxx

To: maryannedemasi@xxxxxxxxxxxx


Date: Tue, 24 Sep 2013 17:02:23 +0000

Dear Maryanne

The CTT secretariat has agreement with the principal investigators of the trials and, in those instances where trial data were provided directly by the drug manufacturers, with the companies themselves, that individual trial data will not be released to third parties. Such an agreement was necessary in order that analyses of the totality of the available trial data could be conducted by the CTT Collaboration: without such an agreement the trial data could not have been brought together for systematic analysis. Such analysis has allowed the CTT Collaboration to conduct and report all of the analyses on efficacy and safety that have been sought directly or indirectly by others (eg by Dr Redberg in her papers on the efficacy and safety of statins in primary prevention, and in questions raised by the Cochrane Collaboration). Hence, the CTT Collaboration has made available findings that would not otherwise have emerged.

I would be very happy to ring you at whatever time is convenient for you in order to help you to understand our approach, and then address in writing any residual concerns. It would be a shame if we were not able to speak as this would be the most effective way of explaining things.

Please let me know where and some times when I can reach you, and I will endeavour to telephone.

Colin Baigent.

I put the word safety in bold in this copied e-mail. You will note that Professor Colin Baigent does not say that that the CTT do not have these data on safety. He just says that the CTT won’t let anyone else see any data.

If they do have it, why have they not done this critically important review before, as they have had much of the data for over twenty years. If they don’t have it, how exactly is Rory Collins going to review it – as he states he is going to? Sorry to keep repeating this point, but I think it is absolutely critical.

Picture the scene in a lovely oak panelled office in Oxford, the city of the dreaming spires….

Professor Collins:             ‘Hey guys, you’re just not going to believe this, but a researcher just found a big box in the airing cupboard, and guess what, it has all the safety data in it….phew.’

Professor Baigent:           ‘Ahem… Why that’s lucky Professor Collins, now we can do the safety review.’

Professor Collins:             ‘Ahem… Indeed, Professor Baigent, we can. So, let’s get cracking shall we?’

And lo it has come to pass that after all these years Professor Collins has deigned to look at the safety data. This review shall, in Collins own words ‘be challenging.’ But you know what. I really don’t think they should bother, because we all know exactly what they are going to find….

That they were right all along, statins have no side effects. Hoorah, pip, pip. Nothing to see here, now move along.

A.N.Other Researcher:                    ‘Please sir, can anyone else see these data that you hold, to ensure that you are being completely open and honest?’

Professor Collins:                               ‘Don’t be ridiculous, these data are completely confidential.’

At this point I feel that I should ask how much do you, gentle readers, believe you can trust a review by Collins, on the data that Collins holds, on behalf of the pharmaceutical industry. Data that no-one else can ever see. [And the data from clinical trials on side effects is totally inadequate anyway].

Were I to be given the task of finding someone to review the safety data on statins, Professor Sir Rory Collins would not be the first person I would ask. He might even be the last.


P.S. Actually, he would be the last.

I do not claim to be Nostradamus here. What was going to happen was obvious. The script had been written a long time ago. It was only a question of when, not if, it happened.

However, whilst the article itself is nothing new… and believe me, there is nothing new here. Just the same data stretched into three hundred references, and mind-blowing statistical obfuscation. It does, however, contain a few new Alice in Wonderland statements, such as the following:

‘If information on a particular outcome is not available from a randomised trial because it was not recorded, that would not bias assessment of the effects of the treatment based on trials that did record that outcome.’ How can this statement be made? For the first twenty years of trials on statins, no-one had noted that statins increase the risk of type II diabetes. It was not, as far as could be seen at the time, a problem.

Then, in a later study, JUPITER, all of a sudden it was found that there was a significant increase in type II diabetes. Now, it turns out that all statins increase the risk of type II diabetes. Had JUPITER not recorded the incidence of type II diabetes, this would never have been noticed. The cynics among you might say that they recorded this in the hope that the incidence would actually go down.

Here we have a perfect example of an outcome not recorded in the vast majority of statin studies. Had it been, it would have significantly biased the assessment of treatment. We also find that after two trials, 4S and HPS, found an increase in non melanoma skin cancer2, this outcome was not recorded, ever again, in statin trials. Outcomes certainly cannot make a difference if you do not record them. But if you did bother record them – who knows what might have happened.

This type of logic litters this Lancet paper, along with straw man argument after straw man argument. However, the purpose of this blog was not to discuss the evidence, such as it is, such as we are allowed to see, but to highlight why this paper was written and published. For this I shall turn to the editorial, accompanying the paper, written by Richard Horton. Who is the editor of The Lancet.

Read this, and be afraid, for it is the most frightening thing you will read this year. Possibly this decade and maybe the entire century as is a direct attack on human freedoms. Whilst couched in the usual life destroying scientific prose, what he is saying is that any who questions current accepted medical dogma should be very tightly controlled, and probably should not be allowed to publish anything at all.

The entire editorial is an exercise in trying to silence any dissent with what some might view as threats and bullying. This, I think, is the key paragraph (my emphasis in bold).

‘The debate about statins, as for MMR, has important implications for journals. Some research papers are more high risk to public health than others. Those papers deserve extra vigilance. They should be subjected to rigorous and extensive challenge during peer review. The risk of publication should be explicitly discussed and evaluated. If publication is agreed, it should be managed with exquisite care.’

Now that, when you strip it down, is basically censorship.

Despite the seriousness of what Richard Horton is proposing, it is amusing to know what his published views on peer review might be, consider his statement that ‘Those papers deserve extra vigilance. They should be subjected to rigorous and extensive challenge during peer review’:

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

Anyway, you can read the editorial in full here ( In addition to the paragraph highlighted above, I would like to draw your attention to a couple of other very worrying statements in the closing parapgraphs:

The Committee’s [Committee on Publication Ethics COPE] decision [not to investigate statin critics as demanded by ‘concerned’ scientists] points to a serious gap in UK science—the lack of a central institution where scientists who wish to question the actions or ethics of other scientists or scientific institutions can go. Allegations of research misconduct are best investigated by the institution where the original research took place. But that principle does not apply for some organisations, such as scientific or medical journals.

With no independent tribunal to consider allegations of research or publication malpractice, a damaging dispute has been allowed to continue unresolved for 2 years, causing measurable harm to public health.

The debate about statins, as for MMR, has important implications for journals. Some research papers are more high risk to public health than others. Those papers deserve extra vigilance. They should be subjected to rigorous and extensive challenge during peer review. The risk of publication should be explicitly discussed and evaluated. If publication is agreed, it should be managed with exquisite care.

Authors and editors should be aligned on the messages they wish to convey, and every eff ort must be made to avoid misinterpretations and misunderstandings in the media. Editors also have to separate their roles as gatekeepers and campaigners. It is tempting to publish science that confirms pre-existing beliefs, especially if those beliefs underpin a campaign. Two ongoing campaigns—against Too Much Medicine and for Statin Open Data—continue to imply that statins are overused and that hidden harms remain to be exposed. As the Review we publish makes clear, the best available evidence indicates that neither statement is true.

Would this be the same Richard Horton, editor of the Journal, the Lancet,  who wrote? ‘Journals have devolved into information laundering operations for the pharmaceutical industry.’3

Would this be the Richard Horton who said? “The case against science is straightforward: much of the scientific literature, perhaps half, may simply be untrue. Afflicted by studies with small sample sizes, tiny effects, invalid exploratory analyses, and flagrant conflicts of interest, together with an obsession for pursuing fashionable trends of dubious importance, science has taken a turn towards darkness.”4

And would this be the same man who followed it up with?

‘The apparent endemicity of bad research behaviour is alarming. In their quest for telling a compelling story, scientists too often sculpt data to fit their preferred theory of the world. Or they retrofit hypotheses to fit their data. Journal editors deserve their fair share of criticism too. We aid and abet the worst behaviours. Our acquiescence to the impact factor fuels an unhealthy competition to win a place in a select few journals. Our love of “significance” pollutes the literature with many a statistical fairy-tale. We reject important confirmations. Journals are not the only miscreants. Universities are in a perpetual struggle for money and talent, endpoints that foster reductive metrics, such as high-impact publication.’4

Couldn’t have put it better myself. Yet, despite the fact that Richard Horton knows that much of the research is flawed and distorted by ‘flagrant conflicts of interest’ he still seems to believe that the statin studies, uniquely in history, are perfect – and cannot be questioned in any way. “Doublethink means the power of holding two contradictory beliefs in one’s mind simultaneously, and accepting both of them.” (George Orwell).

What do other editors think of this latest paper? Well, we have the thoughts of Fiona Godlee (editor of the BMJ), and Rita Redberg (editor of the Journal of the American Medical Association). I will supply a few quotes from them in an article published in Medpage Today (

‘More generally, Godlee and Redberg lamented the absence of independent verification of the statin data. Redberg said that “none of the CTT data has been made available to other researchers, despite multiple requests.” “No one has seen these data except the trialists.” Godlee agreed. “Ideally all clinical trial data should be available for third-party scrutiny,” she said.

Godlee’s also noted that “this is not an independent review, this is a review by the trialists.” Redberg went further, saying that “the long declaration of interests is telling. The Oxford Clinical Trials Unit receives hundreds of millions of pounds of support from the pharmaceutical industry.”

Godlee said that the need for independent review is especially pressing in this case, given the public health implications of the call for widespread use of statins for primary prevention. Redberg went even further and observed that “all of this data is from industry-sponsored studies, with concern for bias.”

As they went on to say

‘Redberg also pointed out some unintended consequences of statin usage. “Data shows that people on statins are more likely to become obese and more sedentary over time than non-statin users, likely because people mistakenly think they don’t need to eat a healthy diet and exercise as they can just take a pill to give them the same benefit (Sugiyama et al. JAMA IM 2014). So it seems this review affirms that many healthy people who feel perfectly well can take a pill every day, not live any longer, suffer any number of adverse effects, all to treat the ‘disease’ of LDL. I maintain the best way to reduce cardiac risk is to eat a Mediterranean-style diet, get regular physical activity, don’t smoke, and enjoy yourself.”

Godlee also emphasized the limitations of primary prevention. “Evidence about poor adherence to statins has long been known,” said Godlee. “People don’t want to take a drug forever. The problem didn’t arise with the BMJ study.”

It also seems likely that the Lancet paper exaggerated the benefits of primary prevention. The long-term benefits of primary prevention in the paper were based on modeling. The calculated benefits might have been a best-case scenario.’

In short, they did not think much of this paper, and Fiona Godlee was particularly concerned about the censorship element:

‘Godlee rejected the comparison of the BMJ papers to the Lancet Wakefield paper and objected to the idea that it’s too dangerous to publish papers critical of statins. “Where do you stop and where does that begin?” she wondered. She also pointed out that public concern over statins in the U.K. became elevated, not after the publication of the BMJ papers, but after Collins brought attention to the papers in a public denunciation of the papers on the BBC.

“We have to allow debate, I don’t know where you would draw the line,” she said. “In terms of public debate, the statin debate is fascinating and deserves airing.”

So, thank goodness for them. I shall stop now, although there is much still to say, because this blog is already very long and people may fall asleep reading it. However, I think this is such an important issue – potential censorship in medical research – that I felt I absolutely had to write something. So, here it is.

I shall finish on two things. Firstly, to state the Uffe Ravnskov, who has been a long-term campaigner against the cholesterol hypothesis, and statins, had one of his books, burned, during a live television debate. I do not have any footage, but here is my attempt to replicate the scene using a photograph from the past.


Secondly, here is a list of some of the conflicts of interest of the authors of the paper.

Declaration of interests

JA, CB, LB, RC, JE, RP, DP, and CR work in the Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU) at the University of Oxford. The CTSU has received research grants from Abbott, AstraZeneca, Bayer, GlaxoSmithKline, Merck, Novartis, Pfizer, Roche, Schering, and Solvay that are governed by University of Oxford contracts that protect its independence, and it has a staff policy of not taking personal payments from industry (with reimbursement sought only for the costs of travel and accommodation to attend scientific meetings). RC is co-inventor of a genetic test for statin-related myopathy risk, but receives no income from it. DP has participated in advisory meetings for Sanofi related to PCSK9 inhibitor therapy in his previous employment. The CTT Collaboration, which is coordinated by CTSU with colleagues from the University of Sydney, does not receive industry funding. JD has received research grants from, and served as a consultant to, Merck and Pfizer. GDS hast twice received travel and accommodation funding and honoraria from Merck; DD receives compensation for serving on data monitoring committees for clinical trials (including of statins) funded by Abbvie, Actelion, Amgen, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Merck, Sanofi , and Teva. NW and ML are inventors of a combination formulation for the prevention of cardiovascular disease that includes a statin, covered by patents licensed to Polypill in which they both hold shares and which owns the website SMac has received research grants for research on statins and polypill development from Bristol-Myers Squibb and BUPA. SMar is co-inventor on a pending patent for a LDL cholesterol estimation method, and has served as an advisor to Sanofi, Regeneron, Quest Diagnostics, Pressed Juicery, and Abbott Nutrition. NP has received research grants and honoraria for participating in advisory meetings and giving lectures from Amgen, Lilly, Menorini, and Merck. PR has received investigator-initiated research grants from Amgen, AstraZeneca, Kowa, Novartis, and Pfizer. PSa has received research grants and honoraria for consultancies from Amgen and Pfizer. LS has undertaken advisory work unrelated to statins for AstraZeneca and GlaxoSmithKline. SY has received a research grant from AstraZeneca through Hamilton Health Sciences. AR declares that George Health Enterprises, the social enterprise arm of The George Institute, has received investment to develop combination products containing statin, aspirin, and blood-pressure-lowering drugs. JS has received grants from the National Health and Medical Research Council, Australia; Bayer Pharmaceuticals; Roche; and Merck Serono. RB, SE, BN, IR, and PSa declare no competing interests.

[This list is far from complete. Paul Ridker, for example was (and may still be) a board member of Merck Sharp and Dohme, the maker of simvastatin at the time. Something he failed to report in a paper entitled: ‘Association of LDL Cholesterol, Non-HDL Cholesterol and Apolipoprotein B level with risk of cardiovascular events among patients treated with statins: A meta-analysis.’6 And something he has not mentioned here either.]


1: Published online September 8, 2016

2: Hung SH, Lin SC, Chung SD. Statins use and thyroid cancer: a population based case-control study. Clin Enodocrinol (Oxf) 2014 published online 30 July 2014,doi:10.111/cen.12570

3: Richard Smith. “Medical journals are an extension of the marketing arm of pharmaceutical companies.” Public library of Science. (May 17, 2005).

4: Vol 385 April 11, 2015


6: Correction. “Unreported Financial Disclosures in: Association of LDL Cholesterol, Non-HDL Cholesterol, and Apoliprotein B levels with risk of cardiovascular events among patients treated with statins: a Meta-analysis.’ JAMA. (April 25, 2012].

Duane Graveline

I was pondering my next post, when I received some sad new today, the death of Duane Graveline.

‘Very sorry to report that Duane Graveline died in hospital this evening after a very short illness.
I run the site and I just got off the phone with his wife Suzanne.
I thought that you would be able to let everyone on the THINCS group know.
I know he had many friends there.



I never met Duane Graveline in person, but we communicated regularly. He was a doctor who trained as an astronaut with NASA. Sadly, he never made it into space. He was also a dedicated researcher and aerospace doctor

Superficially at least, a very conventional doctor, he was found to have a high cholesterol and his doctor put him on statins. He was initially grateful for this, firmly believing that raised cholesterol caused heart disease.

He then suffered an episode of transient global amnesia (TGA). A scary event, where you forget who you are or where you are, for a short period. Initially, he feared that he had suffered a stroke, but he had not. He stopped his statin, then re-started, and suffered another episode of TGA. His doctor assured him that the statin could not have been the cause.

However, he began to research transient global amnesia and a possible connection with statins. He found many other people who had suffered exactly the same symptoms – whilst on statins. An adverse effect still not listed, or accepted, by the medical profession. The normal response is that… statins don’t do that.

Following this, and with his faith in statins and the cholesterol hypothesis, seriously damaged, he concentrated his efforts into looking at all of the potential adverse effects that these drugs may cause. He had been repeatedly told that statins were absolutely safe and side effect free. He had been confidently informed that his own adverse effects were nothing to do with statins. A sadly familiar story to me. However, he no longer believed such reassurances, and set about trying to discover the truth.

One area where he focussed attention, probably due to his background in aerospace medicine, was a growing concern that any airline pilot taking a statin could suffer an episode of TGA – and simply forget how to fly the plane [an issue he raised that worries me still].

Shortly after (I am not entirely sure on the timeline here) he developed Amyotrophic Lateral Sclerosis. Called Lou Gehrig’s disease in the US – I believe. This condition is normally fatal within a couple of years. But his syndrome did not develop that rapidly. He believes, and so do I, that his ALS was caused by statins, and was therefore not true ALS. Difficult to prove, but there have been many other recorded cases, and the WHO issued a warning about a possible association between statins and ALS.

In time Duane became the most outspoken critic of statins – that I know of. He wrote books on the subject, including ‘Lipitor, thief of memory.’ And ‘The statin damage crisis.’ He set up the website where he collected an immense amount of data on statins and adverse effects data.

There was also ground-breaking research on co-enzyme Q10, trans-fatty acids and much else to do with CVD. In addition to this, he was gathering and compiling data from the FDA Medwatch database, and putting together an extensive and scary list of all the reported statin adverse effects [the tip of an iceberg]. For example, he calculated at least eight hundred recorded deaths from rhabdomyolysis.

He was not a zealot. He believed that statins do have benefits in CVD. He believed these benefits were due to anti-inflammatory actions – nothing to do with lowering cholesterol levels. Following from this, he thought that the beneficial, anti-inflammatory, effects of statins could be obtained at very low doses. Doses that would not cause severe adverse effects. We disagreed on the inflammatory aspect of CVD – but agreed on pretty much everything else. He sent me papers he had written, asking for my input and editing. I obliged when I could.

He was an energetic man, an honest man, and a man who was trying to do his best to help people, even into his ninth decade. He will be sorely missed.

What causes heart disease part XX


When I started looking at cardiovascular disease I wondered why French people suffered far less than the Scots. I concluded, somewhat prematurely, that it was because the French ate food in a completely different way. They ate slowly, with the family, and food was an important part of life. Whereas, in Scotland, food was to be endured, not enjoyed. As scientific proof I would present Bovril and mince pie, at half time, at a Scottish football match.

When the French ate it was slowly, in a relaxed fashion. This allowed all the stress hormones, and all the nervous system involved in ‘flight or fight’ to settle down. So the French could digest and absorb food properly. Sugar levels would not spike; insulin would not spike. We would not have a battleground of cortisol and glucagon vs. insulin, and suchlike. Many animals after they have eaten simply find somewhere to go to sleep, to digest. Many humans just keep rushing about. Fast food indeed.

This brought me to led me to look at the overall concept of ‘stress’ in far more detail. Years and years later I have emerged – at times more confused than when I started. In the process I have fully embraced Einstein’s view that ‘Not everything that counts can be counted, and not everything that can be counted counts.’ I prefer it in the version. ‘Most things that can be measured don’t matter, and most things that matter cannot be measured.’ At one point this was my screensaver.

Stress fits well into this view of measurment. Stress certainly exists. Or perhaps to be more accurate ‘strain’ exists. In fact, both things exist, but measuring them… well, that it a trickier task. Which is one reason why medicine, obsessed as it is with ‘that which can be easily measured’, has tended to dismiss stress as a cause of anything. Focussing instead on blood pressure and cholesterol levels and blood sugar levels, and suchlike.

One thing I think I need to add at this point is to say that people do not actually suffer from stress, they suffer from strain. A subtle, but important difference. In that, two people can suffer exactly the same stress/stressor, yet react completely differently. One may feel strain, the other may not.

If, for example, two people are asked to stand up in front on an audience and give a talk. One person may dread this, the other may love the opportunity. They are both exposed to precisely same stressor, but the strains on the individual are diametrically opposed.

Extending this thinking somewhat, it became clear that stress, if indeed we should use this word at all, needs to be differentiated into, at least, four parts.

  • Positive stressor
  • Negative stressor
  • Positive strain
  • Negative strain

Of course, it gets even more complicated than this. We have short term and long term stressors. We have individual resilience, and suchlike. A person feeling strong fit and well may deal with a stressor well one day, yet when feeling physically ill, may be unable to cope with exactly the same stressor.

What mattered, I came to recognise, was not to get hung up on individual stressors, but to look at how the body adapts to different forms of external stress. It is impossible to look at someone’s lifestyle and say ‘they must under huge stress.’ Well, maybe they are, but maybe they treat it all in a positive way and it has beneficial effects on them.

I remember a cardiologist reviewing a lady who lived in the countryside, surrounded by a flower filled garden, with no money worries etc. He remarked ‘Well, stress obviously cannot have contributed to her heart attack.’ I merely nodded and thought to myself. ‘How can you possibly know? Perhaps her husband is horrible to her every day, and bullies her. Perhaps she yearns for another life.’

Of course, if you cannot measure strain, then the discussion does become rather pointless. ‘Anyone who has heart disease must suffer from strain, because strain is the cause of cardiovascular disease.’ This would be one of Popper’s circular arguments. A statement that relies on itself to prove itself. Similar to the argument used when a young person, with no traditional risk factors for heart disease has a heart attack. ‘Oh, it must be genetic.’

‘How do you know it is genetic?’

‘Well, they have no risk factors, and had a heart attack, so it must be genetic.’

Yes, indeed, it must be genetic… not. Try again, you idiot.

So, my attention inevitably became drawn to two researchers. Sapolsky and Bjorntorp. Sapolsky has studied baboons for many, many, years. He found that Baboons were pretty similar to humans in social structures, also in being perfectly horrible to each other, battling to gain higher status, bullying weaker members, and suchlike.

However, life in a Baboon troop normally muddles along quite well, but when the social hierarchy is disrupted by a new alpha male trying to take control of the group, there is a massive rise in cortisol levels, and a subsequent fall in white blood cells in all the baboons. Both of these are very significant signs of strain. You can look up Sapolsky on Google, he is a very entertaining lecturer and writer. His best known book is ‘Why Zebras don’t get ulcers.’

But, of course, Baboons are baboons. Humans are humans. Which is where Bjorntorp comes in. He wanted to know If strain, in humans, could be measured objectively [He called strain stress – as does everyone except me]. He found that it could indeed be measured by looking for a dysfunction of the Hypothalamic Pituitary Adrenal axis (the HPA-axis).

The HPA-axis is an extraordinarily complex physiological system that co-ordinates our responses to external stimuli – both negative and positive. If a lion were to walk into your room, right now, the HPA-axis would do its thing, and trigger the flight or fight response. [I would recommend flight]

The main hormones involved in flight and fight are: cortisol, glucagon, adrenaline (epinephrine) and growth hormone. The sympathetic nervous system response acts alongside the hormones. In a situation that triggers fear, the sympathetic nervous system lights up. This raise heart rate, pushes blood to muscles, and suchlike. Of course, at the same time, the stress hormones make the blood hyper-coagulable (far more likely to clot). You don’t want to bleed in a fight.

Anyway, Bjorntorp decided to measure twenty-four-hour cortisol secretion, in different populations. By this I mean he looked at what happened to cortisol levels every hour (or half hour) during the day. A normal cortisol secretion rises in the morning, goes down, rises at lunch, goes down and up quite a lot for the rest of the day. It is, basically, flexible.

An unhealthy cortisol secretion is more of a flat line. It does not peak in the morning, then it does not fall so much. He described this pattern as a ‘burnt-out’ HPA-axis. The hypothesis being that if someone is exposed to repeated activation of the HPA-axis it eventually becomes unable to cope. The system becomes damaged/inflexible.

This is similar to many other conditions whereby a ‘flattening out’ of normal responsiveness is a sign of significant physiological damage. [See under fetal heart monitoring, or the final development of type 2 diabetes].

As a quick aside, I should add that [inevitably and depressingly], a number or researchers have decided to measure cortisol levels in the morning to look for signs of stress/strain. They found a low level, in those with cardiovascular disease, and concluded that stress has nothing to do with cardiovascular disease, because the people they looked at had low morning cortisol levels. Ho hum.

Back to Bjorntorp. Here is the abstract from his paper ‘The metabolic syndrome–a neuroendocrine disorder?’

‘Central obesity is a powerful predictor for disease. By utilizing salivary cortisol measurements throughout the day, it has now been possible to show on a population basis that perceived stress-related cortisol secretion frequently is elevated in this condition. This is followed by insulin resistance, central accumulation of body fat, dyslipidaemia and hypertension (the metabolic syndrome).

Socio-economic and psychosocial handicaps are probably central inducers of hyperactivity of the hypothalamic-pituitary adrenal (HPA) axis. Alcohol, smoking and traits of psychiatric disease are also involved. In a minor part of the population a dysregulated, depressed function of the HPA axis is present, associated with low secretion of sex steroid and growth hormones, and increased activity of the sympathetic nervous system.

This condition is followed by consistent abnormalities indicating the metabolic syndrome. Such ‘burned-out’ function of the HPA axis has previously been seen in subjects exposed to environmental stress of long duration. The feedback control of the HPA axis by central glucocorticoid receptors (GR) seems inefficient, associated with a polymorphism in the 5′ end of the GR gene locus. Homozygotes constitute about 14% of Swedish men (women to be examined). Such men have a poorly controlled cortisol secretion, abdominal obesity, insulin resistance and hypertension.

Furthermore, polymorphisms have been identified in the regulatory domain of the GR gene that are associated with elevated cortisol secretion; polymorphisms in dopamine and leptin receptor genes are associated with sympathetic nervous system activity, with elevated and low blood pressure, respectively. These results suggest a complex neuroendocrine background to the metabolic syndrome, where the kinetics of the regulation of the HPA axis play a central role.’ 1

In short. If you are exposed to constant negative stressors, you are likely to burn out your HPA-axis, you will end up with abnormal cortisol secretion, and suchlike. You will then develop central obesity, high blood pressure, high VLDL levels, low HDL levels, high levels of fibrinogen, and many other clotting factors.

For those of you who have been paying attention to this series up to now. All of these things will increase endothelial damage, stimulate blood clotting and impair the repair systems.

For many years I knew that ‘stress’ was a very important factor in increasing CVD risk. All the evidence supported this, no evidence (other than people who failed to understand how strain affects cortisol secretion in the morning) contradicted it.

Which is where I return to my earlier graph on the rate of CHD in Lithuania in men under 65. As you can see, it was falling from 1981 to 1989, at which point it spiked, returning to its point of decline about eight years later.


Exactly the same pattern can be seen in Latvia


Here, I think we see Sapolsky’s work on Baboons, mirrored in humans, and mirrored in two countries that lie side by side, next to Russia. In 1989 the Berlin wall fell, the Soviet Union collapsed, the established social hierarchies disintegrated. Strain rose dramatically, and so did the rate of CHD.

This affected various Soviet Union states in slightly different ways. Poland, which had gone through the strikes and the battles of Solidarity years earlier, was very little affected in 1989, but the same basic pattern can be seen. In Belarus CHD skyrocketed, and has stayed very high [Belarus is the only dictatorship left in Europe]. In 1981 the rate of CHD in Belarus was 137/100,000 per year. In 2009, the last year with published data, it was 213. The Ukraine, and Russia also remain very high, both at 186.

During the same period, in Western Europe, absolutely nothing happened to CHD rates other than a slow and steady decline in all countries, year on year. The UK has gone from 143 to 33. Austria 83 to 29. Italy 62 to 19. France 39 to 15 etc.

I do not wish to hark back to a subject that I have previously covered. However, I can think of no other possible explanation for the rise in CHD in all ex-soviet countries after 1989 than the fact that there was a tremendous social upheaval, creating enormous strain. This signal is extremely strong and the data are remarkably consistent.

Data that links the work of Sapolsky and Bjorntorp who, in my opinion, ought to be recognised as the man who established, beyond doubt, how negative stressors can create measurable dysfunction of the HPA-axis which leads, in turn, to the metabolic problems that cause CHD. Or, to put it more simply. How stress causes heart disease. [No, it is not the only cause, but it is probably the most important single cause].


What causes heart disease part XVIIII


As I have written this series of blogs I have noted with interest the comments that people have come up with, and the discussions that have followed. It is interesting, though not unexpected, that almost everyone has focussed, almost entirely, on diet, and little else.

There are those who are utterly convinced that the cause of cardiovascular disease is a high carbohydrate diet. There are others who argue that this is not the case. There are also many who promote various dietary supplements, and vitamins and suchlike.

Within the mainstream, the discussions also seem to focus almost entirely on diet [and the effect diet has on cholesterol levels in the blood]. Over the years the ‘experts’ have moved on from cholesterol in the diet to saturated fat, to saturated/polyunsaturated ratios, to Omega-6 to Omega-3, to even or odd chained saturated and polyunsaturated fats… and on and on and on.

Sixty years ago Ancel Keys proposed the diet-heart hypothesis of cardiovascular disease. He started by stating that cholesterol in the diet raised cholesterol levels, which then cause cardiovascular disease. He ended up stating that saturated fat raised cholesterol levels and, well, you know that last bit. At least he only changed direction once.

Juhn Yudkin was Keys’ main rival in the diet-heart stakes. He stated that is was sugar in the diet that was the culprit. Unfortunately, Ancel Keys was a far better political operator and self-publicist. So he crushed Yudkin and won the argument. At least he won it for a while. Now, more and more people are saying that Yudkin was right all along.

Whatever you may think of Ancel Keys, and my thoughts should never be put down on paper without significant filtering out of swear words, he certainly managed to set the agenda for all discussions that followed. The agenda being that cardiovascular disease is caused by ‘something’ in the diet. Thus, diet has become playing field, and almost everyone fights here. It is this in the diet, not that. It is that, not this.

The problem I have here is that I do not believe that diet has much of a role to play in cardiovascular disease. There is evidence that vegetarians can live long, long and healthy lives. There is evidence that meat eater live long, long and healthy lives. In the West, we are eating more and more sugar and carbohydrate and the rate of cardiovascular disease falling. France maintains a very high saturated fat diet, and their rate of cardiovascular disease also falling.

I read the Blue Zones, which looked at people who live the longest, and I can see nothing whatsoever in the diet that links them together. Although the authors made various attempt to suggest that a vegetarian diet was healthy, the evidence does not stack up to support their assertions.

Of course I will be told that is not a simple as this. We need to look at sub-fractions of monounsaturated fats, or the glycaemic index, or grass fed this, or grain fed that or the specific impact of fructose on lipogenesis and insulin production…. On and on it goes. I sometimes feel that a complexity bomb has been thrown at CVD the purpose of which is to fractalise the debate.

Big fleas have little fleas,

Upon their backs to bite ’em,

And little fleas have lesser fleas,

and so, ad infinitum.

If there is anything, powerfully linking diet to cardiovascular disease, then I cannot see it. The only link that I can see is that people who eat a higher carbohydrate diet are more likely to become obese and develop diabetes. Or, perhaps I should say, develop diabetes and become obese. [A comment I may have to explain at some point].

As people who have diabetes are more likely to die of CVD then it seems highly sensible for those with diabetes to reduce carbohydrate consumption. This is also true of those who seem to be relatively intolerant to carbohydrates. Perhaps I should rephrase this as ‘people who tend to produce more insulin in response to diabetes.’

Blast, again here I am finding myself dragged into the diet debate. It seems impossible to release the discussion from this intellectual black hole. The meme is firmly entrenched. CVD is primarily to do with diet. Ancel Keys may be, posthumously, about to lose the argument on saturated fat However, he certainly succeeded in anchoring almost all discussions within the wider hypothesis that CVD is primarily due to diet.

It is not.

What causes heart disease past XVIII

[Yes, this one took a long time to write]

When I started looking at heart disease, or cardiovascular disease (CVD) it was initially because I was interested to know why the Scots and the French had such different death rates. I had also just finished a book by James le Fanu called ‘Eat your heart out’ in which he made it very clear, or at least he did to me, that fat/saturated fat in the diet had nothing to do with CVD in any way shape of form.

However, at the time le Fanu was very much a voice crying in the wilderness. The experts had a very different song, or dirge. Namely that the Scots diet was terribly unhealthy, and this fully explained why they kept keeling over from heart attacks. Their bad diet raised cholesterol levels and…. thud (sound of Scots person falling over dead).

This is still very much the case. All of our medical authorities still announce the absolute truth of the ‘terrible Scottish diet’ with adamantine confidence. They usually bring out the almost mythical ‘deep fried mars bar’ as the perfect example as to why the Scots die of heart attacks, and strokes, and suchlike. ‘Well, what can you expect of a nation that eats deep fried mars bars… ho, ho.’

The truth is that hardly any Scotsman, or women, has ever eaten such a thing. And if they did it once, they will most certainly never do it again (I was certainly put off for life after one drunken foray on a Saturday night). Of course, there is also a perfect irony here. A mars bar is almost entirely made up sugar (not fat). When you fry it, it will be in vegetable/polyunsaturated fat – as saturated fats have been virtually banned in deep fat fryers. So, in theory, a deep fried mars bar should be somewhat more heart healthy than a ‘virgin’ mars bar. As it now contains a mass of hot sugar plus some heart ‘healthy’ polyunsaturated fat.

I suppose this example, at least to me, highlights the complete lack of any consistent logic or thought in the diet heart world. A fact that I became very painfully aware of, over many years. Indeed, I came to realise that there is no area of human existence where more nonsense is spouted than the ever-changing beliefs about what constitutes a healthy, or unhealthy diet. Frankly, it is almost entirely wall to wall rubbish.

At one point I made an effort to look at the classical ‘risk factors’ for heart disease between France and Scotland. This was done some years ago as part of a paper I wrote called ‘Does Insulin Resistance cause atherosclerosis in the post-prandial period?’ Something which I still think is at least part of the picture of CVD.

Here is the table I put together from a number of different sources – there was no single source for the data I was looking for. [I could not find separate UK and Scottish figures for a number of the factors, so I had to look at the UK as a whole. In addition, at there were no clear cut data on saturated fat, so I used animal fat as a proxy – which is almost the same thing]

Risk factors and death rates from CHD in the UK and France per 100,000/year (men 55 – 64)
France UK
Animal fat % total energy intake 25.7% 27%
Fruit/veg % total energy intake 5.0% 4.3%
Percentage smoking 32% 29%
Total cholesterol level 6.1mmol/l 6.2mmol/l
HDL level 1.3mmol/l 1.3mmol/l
Systolic BP 150 148
Prevalence type II diabetes ~2% 2%
Percentage who never exercise 32% 24%
Mean BMI 26.6 26.6
Death rate from IHD (IHD 410-4) 128 487

As you can see, there was virtually no difference in the classical risk factors for UK men and French men. Despite this, the French had one quarter the risk of death from ischaemic heart disease [what you or I would tend to call heart disease]. Since that time the French rate of heart disease has continued to fall, as it has also done in the UK, whilst the French consumption of saturated fat has risen. Interestingly total cholesterol levels have fallen in both countries.

So, whatever was going on had very little to do with diet. And if it had very little to do with diet, then it also had little to do with cholesterol either. If your hypothesis is that eating saturated fat increases cholesterol, or LDL cholesterol levels, which then causes CVD then how can two countries with exactly the same saturated fat consumption and cholesterol level (and all other risk factors equal) have such a different rate of CVD? And how could France, whilst continuing to eat more saturate fat, have a falling cholesterol levels? And how does the Ukraine, which currently has the lowest saturated fat intake in Europe, end up with the highest rate of CVD etc. etc. etc.

When you start looking at facts like this you must start to question the diet-heart cholesterol hypothesis. Or at least I thought you must. How wrong I was. Virtually the entire medical profession was wedded to the diet-heart cholesterol hypothesis – still is. Facts appear to have no impact whatsoever on this belief system.

Anyway, once I started to look at CVD in more detail, I was confronted with a choice. Accept that I must be wrong. After all, how can all the researchers and experts and Nobel prize winners be wrong. They must surely be seeing things that I cannot. Or, accept that the diet-heart cholesterol hypothesis was wrong. The blue pill, or the red pill.

Dear reader, I chose the red pill, in the sure and certain knowledge that rejecting the conventional thinking was certainly not going to be an easy path to follow. I also knew that if I was going to reject the diet-heart/cholesterol hypothesis, then I had to try and find out what does actually cause CVD. When I looked around at first there, were few alternative voices, or hypotheses out there. If truth be told, there seemed to be none (at least initially). But if not cholesterol, then what?

Over time, as I looked around, some ghosts in the machine began to emerge. I was aware of a doctor (whose name I cannot even remember) who firmly believe that fibrinogen was the main cause of CVD, and I went to a talk that he gave on the subject – not paying it much heed in truth. Then the Scottish Heart Health Study was published, and the single most powerful risk factor that emerged for CVD risk was… fibrinogen. A blood clotting factor. Aha. Could CVD actually be due to blood clotting abnormalities?

This was a time before the internet, before search engines, before finding information was so easy. This was an era when you had to traipse down to the medical library and pull actual books from actual shelves if you wanted to find out stuff. After pulling a lot of books off a lot of shelves I learned of Duguid, a Scottish doctor, who argued that blood clotting was the cause of CVD (I paraphrase).

His work was published shortly after the second world war, and has remained mostly unread. Then I went all the way back to Karl von Rokitansky who, in 1852, felt that atherosclerotic plaques were, in fact, just blood clots – in various stages of repair. An observation which, from time to time, other researchers have noted. Most particularly a doctor called Smith, from Aberdeen. He is no longer active in this area of research.

Here is the abstract from his paper ‘Fibrinogen, fibrin and fibrin degradation products in relation to atherosclerosis’. I have quote the abstract in full, for those who like to see a bit more detail. Others may glaze over, or skip to the last sentence:

‘Many human atherosclerotic lesions, showing no evidence of fissure or ulceration, contain a large amount of fibrin which may be in the form of mural thrombus on the intact surface of the plaque, in layers within the fibrous cap, in the lipid-rich centre, or diffusely distributed throughout the plaque. Small mural thrombi are invaded by SMCs (smooth muscle cells) and collagen is deposited in patterns closely resembling the early proliferative gelatinous lesions. In experimental animals, thrombi are converted into lesions with all the characteristics of fibrous plaques, and in saphenous-vein bypass grafts, fibrin deposition is the main cause of wall thickening and occlusion. There seems little doubt that fibrin deposition can both initiate atherogenesis and contribute to the growth of plaques.

Epidemiological studies indicate that increased levels of fibrinogen and clotting activity are associated with accelerated atherosclerosis, and although blood fibrinolytic activity has given inconsistent results, in arterial intima both fibrinolytic activity and plasminogen concentration are decreased in cardiovascular disease. Fibrin may stimulate cell proliferation by providing a scaffold along which cells migrate, and by binding fibronectin, which stimulates cell migration and adhesion. Fibrin degradation products, which are present in the intima, may stimulate mitogenesis and collagen synthesis, attract leukocytes, and alter endothelial permeability and vascular tone.

In the advanced plaque fibrin may be involved in the tight binding of LDL and accumulation of lipid. Thus there is extensive evidence that enhanced blood coagulation is a risk factor not only for thrombotic occlusion, but also for atherogenesis. Enhanced blood coagulation frequently coexists with hyperlipidaemia and, together, these may have a synergistic effect on atherogenesis.’ 1

For those whose eyes did glaze over, concentrate only on the last sentence. ‘Enhanced blood coagulation frequently coexists with hyperlipidaemia and, together, these may have a synergistic effect on atherogenesis.’

Here, ladies and gentlemen, lies my little secret. My evil twin brother who I have kept in the attic for the last twenty years, gnawing at the floorboards. The terrible truth that there is an association between LDL levels/familial hypercholesterolemia and CVD. Something which I appear to have argued against for many, many, years.

Does this mean that the experts have been right, all along? High LDL cholesterol levels do cause CVD? Well maybe, maybe not. At this point I need to take you back to the statement again. ‘Enhanced blood coagulation frequently coexists with hyperlipidaemia.

Does this mean that hyperlipidaemia actually causes enhanced blood coagulation? Or does it mean that something else causes both. Here is the old ‘yellow fingers and lung cancer’ discussion.

‘People with yellow fingers are more likely to die of lung cancer.’

Why… because people with yellow fingers smoke, and smoking causes lung cancer. Ergo yellow fingers are simply a sign of smoking, they do not actually cause lung cancer.

‘People with raised LDL are more likely to die from CVD’

Why… because people with raised LDL are also more likely to have enhanced blood coagulation. Ergo, raised LDL levels are only associated with enhanced blood coagulation, they do not actually cause CVD. It is the blood coagulation factors.

Alternatively, raised LDL may actually enhance blood coagulation, all by itself.

Where does the answer lie? In truth the answer has been very difficult to tease out. Even now, after many years, I do not feel that I can fully disentangle the data. Here for example, is a paper called ‘Maternal familial hypercholesterolaemia (FH) confers altered haemostatic profile in offspring with and without FH.’

Children with (n=9) and without (n=7) FH born of mothers with FH, as well as control children (n=16) born of non-FH mothers were included in the study. The concentrations of tissue plasminogen activator, plasminogen activator inhibitor (PAI-1), tissue factor (TF), TF pathway inhibitor (TFPI), thrombomodulin, fibrinogen, prothrombin fragment 1+2 and von Willebrand Factor were measured. Our findings show i) higher levels of PAI-1 and TFPI in children with and without FH born of mothers with FH compared with control children, ii) lower levels of thrombomodulin in children with FH compared with control children, and iii) significant correlations between maternal PAI-1 levels during pregnancy and PAI-1 levels in the offspring.’2

What this tells us is that, if a mother has Familial Hypercholesterolaemia, she passes on abnormalities of blood coagulation to her children. Both those that have, and those that do not have FH. [Not all children of mothers with FH will end up with the FH gene]. Some of this may be epigenetically modulated. In short, it is not the LDL that is important, it is simply the mother’s genes….

Or is it? Here is a paper suggesting that the LDL itself, independently of anything else, makes platelets more likely to stick together (a key step in blood clotting).

The interaction of platelets with lipoproteins has been under intense investigation. Particularly the initiation of platelet signaling pathways by low density lipoprotein (LDL) has been studied thoroughly, since platelets of hypercholesterolemic patients, whose plasma contains elevated LDL levels due to absent or defective LDL receptors, show hyperaggregability in vitro and enhanced activity in vivo. These observations suggest that LDL enhances platelet responsiveness….’ 3

However, maybe these researches misinterpreted what they were seeing. For example, another paper found that the level of LDL in those with FH was not related to their risk CVD. It was purely the level of clotting factors that was related to CVD. This paper entitled: ‘Coronary artery disease and haemostatic variables in heterozygous familial hypercholesterolaemia.’

‘Haemostatic variables were measured in 61 patients with heterozygous familial hypercholesterolaemia, 32 of whom had evidence of coronary heart disease. Age adjusted mean concentrations of plasma fibrinogen and factor VIII were significantly higher in these patients than in the 29 patients without coronary heart disease, but there were no significant differences in serum lipid concentrations between the two groups. Comparisons in 30 patients taking and not taking lipid lowering drugs showed lower values for low density lipoprotein cholesterol, high density lipoprotein cholesterol and antithrombin III, and a higher high density lipoprotein ratio while receiving treatment. The results suggest that hypercoagulability may play a role in the pathogenesis of coronary heart disease in patients with familial hypercholesterolaemia.’4

So it is not the high LDL? It is the raised blood clotting factors that are found in some, but not all of those with FH. As you can see, it is not straightforward at all.

Just to complicate the picture further, here is a paper strongly suggesting that HDL is directly anti-coagulant.

‘Native HDL prevents platelet hyperreactivity by limiting intraplatelet cholesterol overload, as well as by modulating platelet signalling pathways after binding platelet HDL receptors such as scavenger receptor class B type I (SR-BI) and apoER2′. 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.’ 5

And what about VLDL?

There is a considerable body of evidence supporting an association between hypertriglyceridaemia (high level of VLDL), a hypercoagulable state and atherothrombosis. A disorder of triglyceride metabolism is a key feature of the metabolic syndrome that increases risk of both ischaemic heart disease and type 2 diabetes approximately 3-fold. An increasing prevalence of obesity and metabolic syndrome is likely to contribute markedly to the prevalent ischaemic heart in the foreseeable future, and therefore it is crucial to understand mechanisms linking hypertriglyceridaemia and a hypercoagulable state. Activation of platelets and the coagulation cascade are intertwined. VLDL and remnant lipoprotein concentrations are often increased with the metabolic syndrome. These lipoproteins have the capacity to activate platelets and the coagulation pathway, and to support the assembly of the prothrombinase complex. VLDL also upregulates expression of the plasminogen activator inhibitor-1 gene and plasminogen activator inhibitor-1 antigen…6 etc.

You can go back and forward in this area, finding research that contradicts itself upside down and inside out again. What I think I know for certain is the following:

  • High LDL levels/familial hypercholesterolemia is closely associated with increased blood coagulation (in a high percentage of those with FH, though not all) – through many different interrelated mechanisms. Some genetic, some possibly directly due to LDL itself.
  • VLDL (triglyceride) seems to increase blood coagulation – and this seems a very consistent finding
  • HDL has anticoagulant effects

I don’t know how powerful these different pro and anti-coagulant effects are, but they certainly exist. To an extent I could just say what does it matter if LDL does, or does not increase blood coagulation directly – but is simply associated with blood clotting abnormalities. It all fits within the processes that I have outlined in this series of blogs. Namely, anything that increases the risk of blood clotting increases the risk of CVD. And LDL (directly, or through genetic association) does increase the risk.

However, I thought it would be dishonest of me not to highlight the fact that there could well be a causal association between LDL (and VLDL) and CVD. Also there does seem to be a causal protective mechanism provided by HDL.

Or, to put this another way, perhaps all the experts were (a bit) right all along. Even if they have consistently promoted a process that does not make any sense at all i.e. LDL leaks into artery walls causing inflammation and plaque growth etc.

A further proviso is that I cannot see that the LDL/VLDL/HDL effects are very strong. After all I just co-authored a paper showing that higher LDL levels in the elderly are associated with increased life expectancy and a slight reduction in CVD risk. [There are many other factors clouding the issue here – too many to discuss in one go]. Confused yet… welcome to my world.

So where did I get to. I think I got to the point where I accept that:

  • LDL is pro-coagulant and – at very high levels e.g. in FH – increases the risk of CVD [though it is difficult to disentangle this from intertwined genetic pro-coagulant factors]
  • VLDL is pro-coagulant, and increases the risk of CVD
  • HDL is anticoagulant and protects against CVD

Which then brings onto statins, and how they work. First to re-iterate that statins do reduce the risk of CVD [Something, I have never disputed]. However, they do it not by lowering LDL, but because they have anticoagulant effects. Not that potent, about the same as aspirin, but the effect does exist.

Here from a paper entitled ‘statins and blood coagulation’:

The 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase inhibitors (statins) have been shown to exhibit several vascular protective effects, including antithrombotic properties, that are not related to changes in lipid profile. There is growing evidence that treatment with statins can lead to a significant downregulation of the blood coagulation cascade, most probably as a result of decreased tissue factor expression, which leads to reduced thrombin generation…. Treatment with statins can lead to a significant downregulation of the blood coagulation cascade….’ 7 An effect confirmed by their protection against DVT.

‘Venous thromboembolism (VTE) includes both deep vein thrombosis (DVT) and pulmonary embolism. The 2009 JUPITER trial showed a significant decrease in DVT in non-hyperlipidemic patients, with elevated C-reactive protein (CRP) levels, treated with rosuvastatin.’ 8 Yet, the experts continue to tell us that statins work, purely, by lowering LDL levels. Ho hum.

Whilst I could have written this series and simply pushed LDL, VLDL and HDL to one side. I thought I needed to bring them into the discussion. Not to dismiss them but, I hope, to explain what their role within CVD may actually be – pro and anti-coagulant agents. Here is where they fit, and make sense. Looking at lipoproteins in the light also helps to explain how statins actually work.

4: Br Heart j 1985; 53: 265-8

What causes heart disease part XVII


If you are going to try and explain what causes cardiovascular disease (CVD) you need to study epidemiology. By which I mean, how many people die of heart disease and strokes in different countries, and communities. Also, what has been happening to CVD death rates over time.

You might think this would be relatively straightforward. If so, please think again. Then keep thinking again until your brain bursts. After that, start again. The reality is that there is almost no fact about CVD epidemiology that I have not seen challenged. Quite rightly challenged in many cases.

You might believe that when someone dies, it is pretty clear what they died of. Again, if you think that, please think again, and keep thinking until your brain bursts. You might further believe that that what is written on death certificates is an accurate record of cause of death… Ho ho.

When I started in medicine, if a patient was old, and developed a cough, then died, they would most likely be recorded as dying of chronic bronchitis. Thus it came to be that, chronic bronchitis was one of the most common causes of death. At least in the UK. Then, one fine day, it was decreed that you could not use Chronic bronchitis as a primary cause of death on a death certificate. And lo, no-one died of chronic bronchitis ever again. A fantastic medical achievement in curing the UK of chronic bronchitis?

Change your definitions, and codes, and you can cure the world of a disease – at the stroke of a pen.

Until 1948, not a single person died of Ischaemic Heart Disease (IHD), (IHD is what most people would call heart disease), anywhere in the world. Then, suddenly, millions were dying of IHD. IHD is a relatively broad diagnostic code, which incorporates myocardial infarction (MI).

What was the cause of this epidemic? Well, in 1948 the WHO decided that disease diagnoses ought to be standardised around the world, so that researchers would have some idea what they were actually looking at. So they created the International Classification of Disease (ICD). Which included IHD. And lo, an epidemic of IHD swept the world. Not, of course, in France, where they use their own diagnostic system – until 1968. A heart attack (MI) was called Cardiac Insufficience (I believe – I may be wrong on this exact terminology).

However, even after 1948, were people really diagnosing CVD/MI in the same way around the world. Were pathologists being accurate, or not. Were doctors simply writing the most likely cause of death on a death certificate, without having the slightest clue what the person actually died of? Who knows – for sure.

One thing I do know for sure is that, before 1948, you can forget looking at epidemiology for any answers, about anything to do with CVD. Now, you can argue this if you want, but I think the data are just too messy to rely on. In truth, you can probably forget anything before about 1960. Do you really think the entire worldwide medical community was suddenly diagnosing everything, in the same way, accurately, all of sudden, from 1948 onwards? If so, you need to go and lie down for a bit.

It was perhaps not until much later that a real effort was made to start ensuring that CVD diagnosis and deaths was actually standardised.:

‘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.’

Accurate at last? Certainly more accurate.

So, what sort of things do these newly accurate figures tell us? Well, looking at the UK, and looking at men under the age of 65, and looking at the death rate from heart disease (IHD), it has been falling and falling, year upon year.

In 1981 the death rate, per 100,000/year was 143. By 2009 (latest figures from MONICA) it was 33.


In case you were wondering, the other graphs: for women under sixty-five, and older men and women, have almost exactly the same shape. I must say, I love graphs like this. I can spend hours trying to work out what these figures mean. I also try to avoid jumping to conclusions (subtle hint to everyone reading this blog).

I also enjoy it when people claim that statins are responsible for the fall in CVD in the UK over the last twenty years. When were statins first introduced? About 1990 (ish). Although, of course, hardly anyone was taking them at first. Not until about the year 2000 did statin prescribing really take off. Look hard at that graph and see if you can see anything dramatic happening. A slight levelling off perhaps?

However, you are not going to learn a great deal just looking at one country. It is far more interesting, and useful, to compare and contrast. If we move from Western to Eastern Europe, the pattern over time is dramatically different. For example, in Lithuania, there is a very differently shaped graph indeed.


As you can see, in Lithuania, the figures are generally much higher, although it is still possible to discern a general downward trend over time. Obviously, however, there was a pretty dramatic blip that started in 1989. What could this be? Let me think? You know what, I think the Berlin wall fell in 1989, as did the entire Soviet Republic.

What then happened in Russia, you may ask. Of course the wall came down in 1989, but Gorbachov managed to remain in power until 1991, keeping things relatively stable within Russia itself. At which point he was overthrown by the rather more mercurial Boris Yeltsin.

As you can see from the graph, in 1992 the rate of death from CHD accelerated rapidly, then it fell, then it went up again in 1999. In 1999 Yeltsin resigned, or was pushed, and appointed Putin as his successor. [At which point, of course, Russia became a peaceful and stable democracy]


In my opinion, the different patterns of social upheaval in Lithuania and Russia, perfectly match the different pattern of deaths from heart disease. I think it would be true to say that Lithuania suffered a sudden, gigantic, social upheaval in 1989. Since then it has become a very different place indeed. Joining the EU, becoming fully democratic etc. In short, things settled down fairly rapidly.

On the other hand, Russia was not immediately affected by the fall of the Berlin wall, at least not to the same extent as Lithuania. It was not until Gorbachev was overthrown by Yeltsin two years later, that all hell broke loose as the social structures totally fragmented. Russia has also gone through many more difficult changes since 1991 with continuing social upheaval, including wars with Chechnya, Georgia and the Ukraine.

Now you can, of course, explain these graphs in different ways. I am sure that people will choose their own favourite interpretation. Mine was, and is, that psychosocial stress/social upheaval is the single most important cause of death from CVD.

In the next instalement I will demonstrate how psychosocial stress links to the processes of endothelial damage and abnormal clot formation.

What causes heart disease part XVI

When you start thinking about things in a new way it is funny where it takes you. You end up seeing connections, where you may previously only have seen confusion. You see links where they could not, or should not, seemingly exist before. In this blog, I am going to take you from migraine to sickle cell disease, and explain how they both cause CVD – and how they both do it through exactly the same underlying mechanisms.

Before reading on, perhaps you might like to think about how this can possibly work … It is always much more satisfying to work things out for yourself. Or maybe that’s just me.

To begin. As you will have picked up from this blog, I believe that cardiovascular disease (CVD) is, essentially, a disease created by endothelial damage and/or dysfunctional blood clotting. With a bit of impaired clot repair thrown in. I spend too much of my life tracking down anything, and everything, that may cause CVD to see if this hypothesis fits – or does not.

Which is why I was interested to see a headline that appeared very recently on Doctors Net (A website for doctors in the UK). It was entitled Migraine cardiovascular link examined’. Up to this point, I had not realised that migraine and CVD were related. So it was something new to me:

As the article, in the BMJ, went on to say:

Young women who suffer from regular migraine attacks appear to have an increased risk of cardiovascular disease, researchers warn today.

Women are three to four times more likely to experience regular migraines. The condition has previously been linked to an increased risk of stroke, but although the physiology of migraine has close links to the vascular system, the way in which migraine increases risk of stroke is unclear.

A team led by Professor Tobias Kurth of the Institute of Public Health in Berlin, Germany, looked at this association, and the link with cardiovascular disease in general.

They used details on 115,541 women aged 25 to 42 years at baseline, taking part in the US Nurses’ Health Study II, which began in 1989. Over the 20 years of follow-up, 15% of the women were diagnosed with migraine.

Cardiovascular disease was 50% more likely among the women with migraine. Heart attack was 39% more likely, stroke 62% more likely, and these women were 73% more likely to have a revascularization procedure.

In addition, women with migraine were 37% more likely to die from cardiovascular disease than women without migraine, and the risk was not significantly altered by age, smoking, high blood pressure, or use of hormone medications.1

So here is, yet another possible cause of CVD. There was no explanation put forward in this study, it was simply an observation. However, I find that unexplained observations are where the answers lie. These are the ghosts in the machine. Truths that occasionally emerge from the dark depths of the ocean, like oarfish, or giant squid, before slipping back into the abyss.

When I see a study like this, the first thing that I do is to look for an association with blood clotting, or endothelial damage, or both. If there is no association, then my hypothesis has suffered a serious blow. On the other hand…

So, taking a deep breath, I looked around the research done in this area. There has not been a great deal, but to my relief. [Yes, I know, a true scientist should never get too attached their own ideas. But, you know what, it’s hard not to….] To my relief I found that migraine is associated with, or causes, blood clotting abnormalities – and also damage to the endothelium.

Just to quote one short section from the Stroke Association:

Migraine-Related Stroke – There is evidence that patients with migraine, particularly migraine with aura, have an increased risk of stroke. The mechanism for this is unclear, although migraine is associated with abnormalities of platelet, coagulation and blood vessel inner lining function, and that may contribute to an increased risk of stroke.’ 2

Just to add further to the connections that potentially open up, I was interested to stumble across a case study where a patient’s migraines were ‘cured’ by using warfarin.

An unusual case report on the possible role of warfarin in migraine prophylaxis


Background: Migraine is a complex disease whose physiopathological mechanisms are still not completely revealed.

Findings: We describe an unusual case, not yet described in literature, of a patient who reported migraine remission, but still presented aura attacks, since starting a therapy with Warfarin.

Conclusions: This case report brings out new questions on the role of the coagulation, especially the blood coagulation pathway, in migraine with aura pathogenesis, and on the possibility to use vitamin K inhibitors, Warfarin or new generation drugs, as possible therapy to use in migraine prophylaxis.3

I must admit I never saw that one coming. Migraines can be treated with warfarin? Though, I suppose, had I thought things through, I might have worked it out. Or maybe not.

Anyway, pulling this information together, we now know that migraines increase the risk of CVD, – more often strokes than heart disease. When you look deeper, you find that migraines are also associated with endothelial dysfunction, and blood clotting abnormalities.

As should be pretty obvious, this all fits perfectly with the ‘CVD is all caused by blood clotting’ hypothesis. On the other hand, if you would like to try to explain how migraines cause CVD through any another process, please let me know. Of course, it could be that another deeper process causes both blood clotting abnormalities, and migraines, but that is for another day.

Of greater interest to me is that, whilst I was studying migraine and CVD, another condition kept popping up on the search criteria. Something that was, again, completely new to me. Which is that there is a very strong association between sickle cell disease (SCD), and CVD. I had never previously thought to link these conditions. However, a number of the migraine articles pointed me towards sickle cell disease (SCD).

Sickle cell disease is a genetic condition whereby red blood cells are malformed and have a sickle shape. This accounts for the name. It is a genetic mutation that, in milder forms, is thought to to protect against malaria, because mildly sickle shaped red blood cells are more difficult for the malaria parasite to enter. However, in its more severe forms, sickle cell disease is quite damaging. Sickle cells can burst, get stuck in smaller blood vessels, form clots in blood vessels in the eyes – leading to blindness, lung and kidney problems etc.

To cut a long story short, in sickle cell disease there are all sorts of ‘clotting’ problems. There is also the potential for significant endothelial damage due to the abnormal shape and function of the red blood cells. Given this, you might expect increased risk of CVD. Which there is, as covered in the paper ‘Atherosclerosis in sickle cell disease – a review:’

Ischemic (lack of oxygen) complications are the major causes of morbidity and mortality in patients with sickle cell disease (SCD). The pathogenesis (what causes these problems) of these complications is poorly understood. Ischemic events in these patients have been attributed to the effects of hemoglobin polymerization, resulting in rigid, dense and sickled cells trapped in the microcirculation. Therefore, vascular occlusion is often considered to be synonymous with occlusion of microvasculature by sickled red blood cells. Several observations suggest that other factors may also play a pathogenic role. Atherosclerosis is one of these factors and may affect many arteries all over the body.

It is fascinating what you find, when you decide to look at things from a different perspective. You start looking at the connection between migraine, CVD, and blood clotting, and end up studying sickle cell disease. I must admit that I get a great sense of satisfaction when I come across facts like this. Somewhat like completing a jigsaw puzzle. ‘Yes, hoorah, it all fits. In fact, it all fits perfectly.’

Indeed, the article on Atherosclerosis in sickle cell disease goes on to bring in Nitric Oxide and L-arginine. I have covered both of these factors in some in detail earlier on in this series. [Sorry this section a bit jargon filled]:

‘The sickling process leads to vascular occlusion, tissue hypoxia and subsequent reperfusion injury, thus inducing inflammation and endothelial injury. This causes a blunted response to nitric oxide (NO) synthase inhibition. In recent years, investigators’ attention has been attracted by the effects of chronic hemolysis on vascular bed integrity and function in patients with congenital hemolytic anemias. Hemolysis results in the release of free hemoglobin.

On one hand, it scavenges NO by oxidizing it to nitrate and releasing red blood cell arginase. On the other hand, it hydrolyzes L-arginine, the substrate of NO synthase. Because of these effects, NO bioavailability and its action is limited. All the previous mechanisms cause impairment of NO production. NO is an important vascular relaxing factor and its deficiency would lead to large artery stiffness. In addition, NO promotes general vascular homeostasis by decreasing endothelial expression of adhesion molecules, decreasing platelet activation, and inhibiting fibroblast, smooth muscle cell and endothelial cell mitogenesis and proliferation.

In one short section on SCD we have virtually everything I have been writing about in this series so far. There is:

  • Reduced NO synthesis
  • Damage to the endothelium
  • Increased risk of blood clotting in general
  • Increased platelet activation and adhesion
  • Inhibition of endothelial cell repair and proliferation
  • Increased risk of CVD and accelerated atherosclerotic plaque development

Another highly important point here is, as follows. You may recall that I said atherosclerosis almost never forms in the blood vessels in the lungs (pulmonary blood vessels). The only time it does is if you have pulmonary hypertension (high blood pressure in the blood vessels in the lungs).

Well, I just found out that if you have sickle cells disease, you are at high risk of developing atherosclerosis in the lungs:

The pulmonary artery is one of the common sites of atherosclerosis in sickle cell disease (SCD). Autopsy of the pulmonary artery in patients with SCD showed that approximately one-third of the patients had histological evidence of medial hypertrophy, intimal proliferation, and subintimal proliferation and fibrosis.’

Now you may not think this is particularly important, but to me it is a killer fact. Atherosclerosis in the pulmonary arteries is something so unusual that when you find it, you are looking at the mother lode. If you can cause atherosclerosis here, then you are gazing at a true underlying cause, with all other risk factors stripped out.

Here is the process (or processes) revealed. Deep joy. It is not often that I come across a fact that I had no idea existed before. Certainly not one that confirms so perfectly everything that I have been saying.

I realise that I have repeatedly stated that the primary purpose of science should be to contradict hypotheses. Here, all I have ended up doing, is providing more facts that support my own hypothesis. I would ask you to believe that I started out looking for a contradiction. I ended up with greater confirmation. Confirmation from places where I had never previously even thought to look.


1: BMJ 1 June 2016; doi: 10.1136/bmj.i2610




What causes heart disease part XV

Scientific hypotheses are easy. You can make up thirty a day if you want. In the arena of cardiovascular disease, I have watched many a hypothesis spring to life in the middle of a conversation. For example, I was at a meeting where an ‘expert’ was attempting to describe what foods cause CVD. Pizza was held up as a very unhealthy food.

I pointed out that there had only been one study done on pizza consumption and CVD. It showed, very clearly, that the more pizza you ate, the lower your risk of CVD. Quite a strong protective effect as a matter of fact. The study was done in Italy.

The moment the geographical location was mentioned, the expert simply replied. ‘Oh yes, but Italian Pizzas are far healthier than pizzas in the UK.’ Thus, ‘the healthy Italian Pizza hypothesis’, was simply plucked from thin air. It was based on no evidence whatsoever, but it seemed reasonable to the expert at the time I suppose. Who knows, it may even be true. Although I suspect not.

Now, I have nothing against the creation of any scientific hypothesis that anyone cares to put forward. Science progresses, primarily, through the development of new ideas. But if you are going to propose a new hypothesis it is beholden upon you to do something that few people then seem willing to do. You need to try and disprove it. There is no point looking for supporting data, you can find supportive data for almost any idea you decide to come up with.

There is a fairly well-known and humorous explanation for CVD (humorous the first fifty times you are told it anyway) that goes like this:

  • Japanese eat very little fat and suffer fewer heart attacks than us
  • Mexicans eat a lot of fat and suffer fewer heart attacks than us
  • Chinese drink very little red wine and suffer fewer heart attacks than us
  • Italians drink excessive amounts of red wine and suffer fewer heart attacks than us
  • Germans drink beer and eat lots of sausages and fats and sufferfewer heart attacks than us
  • The French eat foie-gras, full fat cheese and drink red wine and suffer fewer heart attacks than us

CONCLUSION: Eat and drink what you like. Speaking English is apparently what kills you

How would I disprove the ‘speaking English’ hypothesis? Assuming, that is, I could be bothered. I would point out that, currently, speaking Ukrainian kills you. Ukrainians have ten times the rate of CVD of the UK, and the US. Ergo, it is not speaking English that kills you. Next.

Moving to slightly more serious things. Disproving is where I started with in my long term search for a hypothesis about CVD. I did not start out with my own hypothesis. I started out trying to disprove other hypotheses.

Which inevitably meant that I started with the diet-heart/cholesterol hypothesis, as this was, and remains, the number one hypothesis in the area. I am not going to go through all the refutations again. Suffice to say that it failed in so many ways that it was clearly bunk.

Of course, this left me thinking, if CVD has nothing to do with saturated fat in diet, or cholesterol levels, it must be something else. What could that something else be? I began by looking at stress (I realise that the term stress is not remotely precise). I started with the thought that stress, whilst eating, could be a cause/the cause. If you are stressed you will be releasing stress hormones, these antagonise insulin, so when you eat blood sugar levels spike and VLDL levels spike etc.

I became interested in the idea that we measure almost all metabolic parameters e.g. blood sugar, VLDL, cortisol, glucagon in the fasting period. Yet, perhaps all the damage was being done within two hours of eating. So it seemed that we may, to use an analogy, be trying to understand football by visiting a football stadium only before and after the match is being played. ‘Blimey, nothing different ever happens here at all.’

I felt I was onto something, but thinking then moved on to a more general stress hypothesis. I felt that I got most of the way to creating a perfect scientific hypothesis. I had causes and pathways and a mass of supportive data. However, I could still find plenty people with an increased risk of CVD who were not in any way stressed. They had such things as antiphospholipid syndrome (Hughes syndrome). Or they were children with Kawasaki’s disease. Or they had type II diabetes, or they were taking drugs, such as non-steroidal anti-inflammatories, or Avastin. Or… the list went on.

Equally, I could find factors that reduced the risk of CVD, that had nothing to do with reducing stress. For example, aspirin (not a massive effect, but it does exist). Von Willibrand disease, omega-3 fatty acids, potassium, vitamin C. As with causal factors, the ‘nothing to do with stress’ list went on.

So, what did this mean? That stress did not cause CVD, or that it caused only one type of CVD. Or it caused CVD through a completely different process than other causes of CVD? It was at this point that I began to realise I was looking at things the wrong way round. There was no point in saying what things may, or may not, cause CVD – and compiling an ever-lengthening list of ‘risk’ factors.

I had to work out the process through which any factor may operate, both causal and protected. As some of you will know, in this series, I have pointed this out before… many times. But I think that it cannot be said often enough.

So I turned the entire thinking process inside out, and started again. I began by asking the question, what are atherosclerotic plaques? What do they consist of? What do they contain? It became very clear that they are primarily blood clots – in various stages of development and repair.

Having recognised this, I went further back, or forward, to look at the final event in CVD. This is, basically, the formation of a blood clot. Heart attacks occur when a blood clot blocks an artery supplying blood to the heart (there are caveats here, but I am not going into them at this point). Stokes occur when a blood clot blocks an artery in the brain (further caveats).

There is little disagreement that the blood clot is the final event in CVD. Most acute treatments for heart attacks and strokes are, essentially, ways of removing any clot that has formed. You can use aspirin, or more potent clot busters, or you can stick in a catheter to remove the clot/open it up/stick in a stent. You can do a bypass, diverting the blood round the clot… etc. Interventional cardiology could, pretty, accurately be described as ‘blood clot management.’

Many of the drugs used to prevent heart attacks and/or strokes are also anti-coagulants e.g. aspirin, Clopidogrel, warfarin, apixiban etc. [Statins are also potent anticoagulants]. Yet, and yet, no-one seemed willing even to countenance the possibility that blood clots also cause atherosclerotic plaque development. ‘Yes, blood clots kill you, but they have nothing to do with plaque formation.’

‘What, even when plaque contain such things as red blood cells, cholesterol crystals, fibrin, fibrinogen and Lp(a) and….’ the list of things found in both blood clots and plaques is very long.

But of course no expert can agree to this ‘blood clot’ hypothesis. To do so means that you have to discard the cholesterol hypothesis. Which ain’t going to happen anytime soon. So we currently have the dual hypothesis. Cholesterol causes plaques to form, then blood clots kill you. The ‘atherothrombosis’ hypothesis. Which can look as though the mainstream is agreeing about the importance of thrombosis, but is actually a way of keeping the cholesterol hypothesis alive.

For a while I half agreed with this atherothrombosis hypothesis, but the more I thought about it, the more it started to fall apart. I began to focus down on one thought. Can you explain CVD though the ‘abnormal’ development of blood clots alone? Can you link any and all factors, known to cause CVD by their impact on one of two things:

  • Endothelial damage (which triggers blood clot formation)
  • Increasing blood coagulability (making clots more like to form, become bigger and/or less easy to break down)

Then I started writing out a list of things that I knew did one, or both, of these things. There was no particular order to this:

  • Smoking
  • Cocaine use
  • Cortisol
  • Kawasaki’s disease
  • Diabetes
  • Rheumatoid Arthritis
  • Kidney failure
  • Non-steroidal anti-inflammatories e.g. brufen, naproxen
  • Biomechanical stress (within arteries)
  • Dehydration
  • Systemic Lupus Erythematosus
  • Antiphospholipid syndrome (Hughes syndrome)
  • Vitamin C deficiency
  • Raised fibrinogen levels (key clotting factor)
  • Homocysteine
  • Bacterial infections inc. gingivitis
  • Increased plasminogen activator inhibitor – (1 PAI-1) levels (critical factor in blood clot repair/breakdown)

I could have kept going, but that is enough for now. What do all of these things have in common. They increase the risk of atherosclerotic plaque formation, death from CVD. Most importantly, of course, they cause endothelial damage and/or increased blood coagulability. And I could not, and cannot, think of anything else that links them all together.

Then I started to think about factors that reduce the risk of CVD.

  • Exercise (overall, not whilst doing it)
  • Moderate alcohol consumption
  • Aspirin
  • Clopidogrel (expensive aspirin)
  • ACE- inhibitors (a blood pressure lowering agent)
  • Yoga
  • Haemophilia
  • Statins
  • Von Willibrand disease (lack of a specific clotting factor in platelets)
  • B vitamins (enough to reduce homocysteine)
  • Adequate Vit C (no idea what the correct intake should be)
  • Potassium (higher consumption reduces platelets sticking together)
  • Vitamin D
  • Nitric Oxide (through sunlight – and other nutrients e.g. l-arginine)
  • Magnesium (and other micronutrients)

Again, I could keep going. What do all of these things have in common. Well, once again, they either protect the endothelium, or they reduce blood clotting. And they all reduce the risk of CVD.

To my mind there was, and is, an almost perfect correlation. But, as I said earlier. Looking for supportive data is all very well. Can you find the black swan? Or black swans. Are there facts that completely contradict the ‘it’s all to do with blood clots’ hypothesis of CVD?

Warfarin could be one such black swan. Warfarin reduces the risk of stroke (in atrial fibrillation), but it does not really reduce the risk of heart attacks. It is a very powerful anti-coagulant, so surely it should do both. Yet it does not. Why not? Is this a black swan, or can it be explained?

My conjecture is, as follows.

Warfarin is a vitamin K antagonist. It is active in the liver, and interferes with the production of a number of clotting factors (mainly prothrombin and factor VII). This tends to inhibit clots forming, spontaneously, within the blood itself. Which is why warfarin is very effective in Atrial Fibrillation.

In Atrial Fibrillation, the upper chambers of the heart fibrillate (twitch rapidly) so some of the blood tends to get stuck in the upper chambers (the atria). Blood in stasis tends to start clotting. A clot forms, it is then ejected into the lower chamber (the ventricles) where it is then immediately pumped out into the rest of the body. These clots can get stuck anywhere the blood vessel narrows sufficiently – often in the brain, causing a stroke.

Warfarin also works well when you have blood stasis in the veins. For instance, if you break your leg, you will be put in a cast. At which point, due to physical immobility, the blood tends to stop flowing freely, if at all. At which point clots can form, a deep venous thrombosis – DVT. This can then break off and travel through your heart into your lungs causing a pulmonary embolus (PE), which can kill you. Warfarin tends to stop this ‘stasis’ blood clot formation. [Long distance flight and sitting anywhere for a long time can have the same effect]

So why does warfarin have little effect on the clots that cause myocardial infarction. This is probably because damage to the endothelium – the trigger for all the other downstream problems – exposes tissue factor (TF) to the blood. Tissue factor sits within the artery wall itself, and it is the big daddy of clotting.

As you can imagine, the body views damage to an arterial wall as a potential emergency situation that requires immediate and powerful clotting. A damaged artery wall exposes TF Once TF is in play, it will ride straight over such things as a lack of factor VII and prothrombin. TF will directly drive platelets to stick together, and form a plug over the area of damage. It can also directly activate thrombin etc.

Thus, whilst warfarin will prevent the slower ‘stasis’ clots from forming, it will have little effect on the emergency ‘damage to the artery wall’ clotting caused by exposure to TF. I am not going into any more detail on this, but it could be said that warfarin is a good ‘intrinsic’ anticoagulant. But has far less impact on the ‘extrinsic’ clotting system.

On the other hand aspirin, which prevents platelets sticking together, will have a more significant effect on reducing clot formation after activation of TF, as will Clopidogrel, as will a lack of von Willibrand factor (as found in Von Willibrand disease). This, to my mind at least, fits with the fact that ‘less potent’ anticoagulant factors can reduce risk of heart attacks (albeit by differing amounts), whereas warfarin does not.

So, the lack of effect of warfarin on heart attacks can be understood, in relation to where it actually acts in the coagulation system. In addition, because warfarin is a vitamin K antagonist, and vitamin K appears to protect against the build of calcium in various tissues, warfarin accelerates calcification in artery wall. Which could be a further problem in itself – leading to a higher rate of CVD.

Now, you could think this is all rather convoluted. An attempt to explain why an apparent contradiction is not a contradiction all. You could, of course, be right to think this. But firmly believe that the lack of effect on warfarin, on heart attacks, can be explained. Through a deeper understanding of the clotting system. In fact, the different effects of different anticoagulants on CVD risk supports rather than undermines the hypothesis.

Perhaps, now, you may gain an inkling as to why it has taken me so many, many, years to try and establish the true underlying cause of CVD. It did not take too long, at least once I got my thinking the right way round, to work out that blood clotting may be the underlying process that underpins CVD. What has really taken the time is looking for contradictions.

And, in the spirit of true scientific endeavour, I welcome as many attacks/contradictions as people can think of. What does not kill a scientific hypothesis can only make it stronger.

What causes heart disease part XIV

I have been much cheered by all the discussion on my series about what caused heart disease a.k.a. cardiovascular disease. Because of various comments, my series has gone off in a few different directions. I realise that not everyone agrees with everything (or anything?) I have to say, and that several issues I thought were clear, clearly are not. This is fine. Science should progress by discussion and debate and contradictions.

In this blog, in order to answer some of what people have written (albeit indirectly), I am going to look at two of the conventional risk factors for CVD in a bit more detail, and try to explain why they represent a major problem for conventional thinking.

As many of you may have discovered, if you go to see your GP – almost anywhere in the world – they will use a list of ‘standard’ risk factors to calculate your risk of a cardiovascular ‘event’ over the next five or ten years.

There are a few of these calculators, but two of most commonly used are probably QRISK2 and the ASCVD, created by the American College of Cardiology and American Heart Association. [ASCVD = atherosclerotic cardiovascular disease]. I cannot find out where the term QRISK comes from – perhaps someone can help me.

The ASCVD is a bit shorter than QRISK. It looks at:

  • Age
  • Gender
  • Race
  • Total Cholesterol
  • HDL
  • Systolic blood pressure
  • Diastolic blood pressure
  • Treatment for blood pressure
  • Diabetes
  • Smoker

The QRISK is a UK developed risk calculator. It is a bit bigger and more complicated than ASCVD. It looks at:

  • Age
  • Sex
  • Systolic blood pressure
  • Diastolic blood pressure
  • Total Cholesterol
  • Total Cholesterol/HDL ratio
  • Serum triglyceride
  • Smoking
  • Glucose Impaired glucose tolerance/diabetes
  • Left Ventricular hypertrophy
  • Central obesity
  • South Asian (South Asians, in the UK, have a far higher risk of CVD)
  • Family history of CVD

Now, there is no doubt that all of the factors on both lists are associated with CVD – to a greater or lesser degree. At least they are for the US and UK population currently living. It has to be pointed out thought, that if you use QRISK in France, you have to divide the risk by 4… ahem, slight problem.

A further problem is that it has been discovered that they both vastly over-estimate risk in US and UK population.

‘A widely recommended risk calculator for predicting a person’s chance of experiencing a cardiovascular disease event — such as heart attack, ischemic stroke or dying from coronary artery disease — has been found to substantially overestimate the actual five-year risk in adults overall and across all sociodemographic subgroups. The study by Kaiser Permanente was published today in the Journal of the American College of Cardiology.

The actual incidence of atherosclerotic cardiovascular disease events over five years was substantially lower than the predicted risk in each category of the ACC/AHA Pooled Cohort equation:

  • For predicted risk less than 2.5 percent, actual incidence was 0.2 percent
  • For predicted risk between 2.5 and 3.74 percent, actual incidence was 0.65 percent
  • For predicted risk between 3.75 and 4.99 percent, actual incidence was 0.9 percent
  • For predicted risk equal to or greater than 5 percent, actual incidence was 1.85 percent

“From a relative standpoint, the overestimation is approximately five- to six-fold,” explained Dr. Go. “Translating this, it would mean that we would be over-treating a good many people based on the risk calculator.”’1

So, you feed your risk factors in a risk calculator that took many years to create, using data carefully gathered by experts from the world of cardiology, and your true risk is overestimated five to six fold. Excellent. That mean millions upon millions of people have been told to take a statin based on a calculation that is so inaccurate as to be virtually meaningless. [This was always going to happen, because risk was established using clinical data from decades ago, since when, CVD rates have fallen dramatically]

Anyway, leaving the horrible inaccuracy of these risk factor calculators aside for the moment. What of the risk factors themselves? I am not going to look at all of them here, just two. Firstly, age. There is no doubt that age is the single most important risk for CVD. Your risk at 65 is around ten times as high as at age 35 – no matter what the overall risk may be in your particular country.

In fact, if you have no other factors at all, in the US, your future CVD risk at the age of 67 is so high (according to the calculator) it means that you are advised to go on a statin immediately, for the rest of your life. Ho hum. For women it is a few years later. ‘Here’s your first pension payment – with built in statin prescription.’

I find it fascinating that almost everyone seems to accept age as a risk factor for CVD, without really questioning why this should be so. Age does not necessarily increase the risk of diseases. There are many which are more common when you are younger, and the risk diminishes as you age.

The argument seems to be that CVD slowly progresses. Thus, as you get older, the risk increases. Yes, perhaps. However, if you have no conventional risk factors for CVD, why should it progress at all? At the risk of repeating myself, I shall repeat myself. You have no risk factors for CVD. Yet, as you grow older, your risk of CVD reaches the point where you are statinated. Because your future risk is so high.

But what is causing the atherosclerosis in your arteries to develop. Age? Through what process can age created atherosclerotic plaques, assuming no other risk factors? Raised cholesterol… well you don’t have raised cholesterol. Raised BP? Well, you don’t have raised BP. Smoking, well, you don’t smoke… etc.

The other major risk factor where we have an acceptance of a fact – without even an attempt at explanation is gender. In most populations younger men have a far higher risk of CVD than women. The different in risk varies greatly, but averages at about three to one. By which I mean, a women aged 55 women will have around one third the risk of a man aged 55 (living in the same country). Even if they have exactly the same risk factors.

For years it was stated, with great confidence, that this difference was due to female sex hormones. These hormones in some – never fully stated fashion – protected women against CVD. It has now been proven, beyond a molecule of doubt, that this is not true. Female sex hormones do not protect against CVD. Indeed, they probably accelerate it.

So, what does protect women against CVD. There is no explanation. It just is. Feed gender into the calculator and a different risk pops out for men and women. Why, because men and women, have a different risk of CVD. Why? Because they do. [BTW, the South Asian issue is much the same. Multiply the risk by 1.4. Why, because you do].

The reality is that age, and gender, are two of the most powerful risk factors for CVD. In that, if you use the ASCVD or QRISK calculator and change only age, and gender, the risk will go from close to zero, in a young woman to dark red – danger, danger, in an older man. Even if you set all other risk factors to zero.

It has always baffled me that experts in cardiology seem utterly unconcerned about this. They do not even consider that this is an issue. However, if the two most powerful risk factors you have for CVD, cannot be explained, are not explained, then you really have a major problem. Even if you cannot even comprehend that you do.

If you cannot explain why age, and gender, cause CVD… you cannot explain CVD.


What causes heart disease – part XIII

Heart disease and inflammation.

A few people have sent me links to a recent paper called ‘Inflammation and Atherosclerosis.’ This was published in Circulation, and the authors were: Peter Libby, MD; Paul M. Ridker, MD; Attilio Maseri, MD. Remember two of the names.

Here is a relatively long section of the abstract:

‘Atherosclerosis, formerly considered a bland lipid storage disease, actually involves an ongoing inflammatory response. Recent advances in basic science have established a fundamental role for inflammation in mediating all stages of this disease from initiation through progression and, ultimately, the thrombotic complications of atherosclerosis. These new findings provide important links between risk factors and the mechanisms of atherogenesis.

Clinical studies have shown that this emerging biology of inflammation in atherosclerosis applies directly to human patients. Elevation in markers of inflammation predicts outcomes of patients with acute coronary syndromes, independently of myocardial damage. In addition, low-grade chronic inflammation, as indicated by levels of the inflammatory marker C-reactive protein, prospectively defines risk of atherosclerotic complications, thus adding to prognostic information provided by traditional risk factors.

Moreover, certain treatments that reduce coronary risk also limit inflammation. In the case of lipid lowering with statins, this anti-inflammatory effect does not appear to correlate with reduction in low-density lipoprotein levels. These new insights into inflammation in atherosclerosis not only increase our understanding of this disease, but also have practical clinical applications in risk stratification and targeting of therapy for this scourge of growing worldwide importance.

This paper interested me for a number of reasons. I focused down for a few moments on the phrase ‘Atherosclerosis, formerly consider a bland lipid storage disease…’ Does this mean that the world is moving on… Atherosclerosis has nothing to do with lipids e.g. LDL a.k.a. ‘bad cholesterol’? Now that would be something. Especially as it was published in the mainstream CV journal ‘Circulation.’

It seems that these authors are trying to shift the thinking away from cholesterol to inflammation. However, before discussing anything else I wanted to point out something that most people may have missed – by looking at a bit of background on the authors. First, Paul Ridker, who ran the JUPITER study, and who is a hugely influential cardiologist.

It should be noted that Paul Ridker has a major interest in moving thinking about atherosclerosis from a lipid storage disorder to an inflammatory condition. Because he has patent on the high sensitivity CRP test (C-reactive protein).

‘Dr Ridker is named as a coinventor on patents filed by the Brigham and Women’s Hospital that relate to the use of inflammatory markers in cardiovascular disease.’

What this means is that every time someone uses a high sensitivity CRP test, Paul Ridker becomes a little bit richer. However, in this paper, this massive financial conflict of interest is not mentioned. Instead, we get Acknowledgements:

This work was supported in part by grants from the National Heart, Lung, and Blood Institute to Drs Libby (HL-34636, HL-48743, and HL-56985) and Ridker (HL-58755 and HL-63293), and by the Leducq Foundation (to Drs Libby and Ridker). Dr Ridker is also supported by a Distinguished Scientist Award from the Doris Duke Foundation. Dr Maseri is supported by a grant from Fondazione Internazionale di Ricerca Per il Cuore onlus

No conflicts Dr Ridker? Mind you, Paul Ridker does have considerable form in not disclosing his financial conflicts. Some years ago, the Journal of the American Medical Association JAMA, was forced to publish a statement on ‘Unreported Financial Disclosures’ that were spotted in paper ‘Associations of LDL, Cholesterol, Non-HDL Cholesterol, and Apolipoprotein B levels With Risk of Cardiovascular Events Among Patients Treated with Statins: A meta-analysis.’

This statement mentioned many, many conflicts that the authors had failed to mention at the time. The section on Dr Ridker reads thus:

‘…Dr Ridker reports board membership of Merck Sharp and Dohme and receipt of a grant or pending grant to his institution from Amgen.’ [Amgen, as you may know are pushing PCSK-9 inhibitors]. This is covered in my book Doctoring Data.

Just to spell this out in a little more detail, Paul Ridker was an author on a meta-analysis of statins, yet failed to report that he was a board member of a pharmaceutical company (Merck) that marketed statins.

In truth, the moment I saw a paper promoting the ‘new idea’ that atherosclerosis is all due to inflammation, my antennae started to twitch. Especially when I knew that Paul Ridker was involved. A man who holds patents on a test for the inflammatory marker that we should be using.

I then immediately wondered, Is Paul Ridker now running a clinical trial on behalf of a pharmaceutical company, looking at the use of an anti-inflammatory agent to treat CVD. So, I had a little look round the internet. And guess what. Paul Ridker is, indeed, running a trial on an ant inflammatory for the treatment of CVD. The CANTOS study If you look down the list those on the committee running this study, you will find that Peter Libby is also on the steering committee. A conflict that remained unmentioned in the Circulation paper either.

What is the drug, it is Canakinumab. Here, from Wiki:

Canakinumab (INN, trade name Ilaris, previously ACZ885) is a human monoclonal antibody targeted at interleukin-1 beta. It has no cross-reactivity with other members of the interleukin-1 family, including interleukin-1 alpha.

Canakinumab was approved for the treatment of cryopyrin-associated periodic syndromes (CAPS) by the U.S. Food and Drug Administration (FDA) on June 2009[4] and by the European Medicines Agency in October 2009.CAPS is a spectrum of autoinflammatory syndromes including familial cold autoinflammatory syndrome, Muckle–Wells syndrome, and neonatal-onset multisystem inflammatory disease.

Canakinumab was being developed by Novartis for the treatment of rheumatoid arthritis but this trial was completed in October 2009. Canakinumab is also in phase I clinical trials as a possible treatment for chronic obstructive pulmonary disease, gout and coronary artery disease. It is also in trials for Schizophrenia. In gout it may result in better outcomes than a low dose of a steroid but costs five thousand times more.

I thought I would highlight the final sentence, just to give you some idea of the potential cost of this drug, should it ever be marketed for the treatment of CVD.

I know that this may seem a diversion. However, I have been around the world of cardiovascular research for long enough to take nothing at face value. Here is a paper suggesting that atherosclerosis has little or nothing to do with lipids. It is primarily due to inflammation. Which is a reasonable hypothesis. But guess what, one of the authors has a patent for an inflammatory marker. He and another author are running a clinical study, funded by Novartis, on the use of an anti-inflammatory agent in CVD.

However, just because there is money in the background, it does not necessarily mean that everything written is wrong. Perhaps inflammation truly is the underlying cause of atherosclerosis. Many other people have been saying this for years. Some of them, I know, certainly believe it from a purely objective scientific perspective. For example, Duane Graveline – who writes a great deal about CVD on his blog, and is also a friend. He fully believes that atherosclerosis is an inflammatory condition, and he has no horse in the race.

My own take on this matter is slightly different. Yes, if you have a high C-reactive protein (CRP) level, this means that there is inflammation going on within the artery, and this is a sign of increased CVD risk. This is true, but what does it mean? Is the inflammation causing the CVD?

Whenever I see anyone stating that inflammation is a cause of anything I simply change the word inflammation to the word ‘healing,’ to see how sensible it then sounds. Inflammation is, in most cases, the way the body heals itself after injury. If you twist your ankle, it will become swollen and inflamed. The injury comes first, then you get the inflammation/healing. You would be hard pressed to state that inflammation causes twisted ankles.

Of course, there are some conditions where the inflammation itself can become greater than the original problem. Just to name three: Asthma, Crohn’s disease and Rheumatoid arthritis. In these diseases the body’s inflammatory/healing system becomes revved up, and starts attacking itself. This out of control inflammation can then lead to further problems downstream e.g. joint destruction. Such conditions are often ‘treated’ or controlled by anti-inflammatory agents e.g. steroids.

Equally, if you have Systemic Lupus Erythematosus (SLE), this is an ‘inflammatory’ disease, and you also have a severe vasculitis (inflammation of vasculature). As mentioned before SLE can raise the risk of CVD, in young women, by up to five thousand per cent. Case proven? Inflammation causes atherosclerosis?

No, I don’t think so. The sequence in SLE is that the vasculature is damaged (the endothelium is damaged). This stimulates the body to try and heal the damage. The healing is what we call inflammation and the C-reactive protein level goes up.

Get rid of the inflammation, and you will not be treating anything. You will simply be interfering with the healing process, and the CVD will, most likely, accelerate. Even if C-reactive protein levels go down, along with any observable inflammatory action.

If I may return for a moment or two to twisted ankles. To quote Dr Mirkin:

‘When I wrote my best-selling Sports medicine Book in 1978, I coined the term RICE (Rest, Ice, Compression, Elevation) for the treatment of athletic injuries. Ice has been a standard treatment for injuries and sore muscles because it helps to relieve pain caused by injured tissue. Coaches have used my “RICE” guideline for decades, but now it appears that both Ice and complete Rest may delay healing, instead of helping.’

As he goes on to say:

‘Anything That Reduces Inflammation Also Delays Healing [I cannot resist stating that, this is because inflammation is healing]

Anything that reduces your immune response will also delay muscle healing. Thus, healing is delayed by:

  • cortisone-type drugs,
  • almost all pain-relieving medicines, such as non-steroidal anti-inflammatory drugs like ibuprofen
  • immune suppressants that are often used to treat arthritis, cancer or psoriasis,
  • applying cold packs or ice, and
  • anything else that blocks the immune response to injury.’

At least Dr Mirkin has had the grace to admit that he was wrong. RICE reduces inflammation, but interferes with healing.

I am pretty certain that exactly the same thing will happen with ‘inflammation’ in CVD. I can state this with relative confidence, because the most powerful anti-inflammatory agent known to man are steroids/corticosteroids. Corticosteroids e.g. prednisolone, or hydrocortisone are potent anti-inflammatory agents, they are all based on the natural stress hormone cortisol – produced in the adrenal glands. Steroids = corticosteroids = cortisol (just about).

Cushing’s disease is a disease whereby too much cortisol is produce in the adrenal glands, usually due to a small tumour that overproduces the hormone. So, if you have Cushing’s disease, you have a powerful anti-inflammatory agent coursing through your blood vessels – at all times. And what is the effect of this on CVD?

‘In patients with Cushing’s syndrome (CS) cardiovascular complications determine a mortality rate four times higher than in an age- and gender-matched population.’

The same thing happens when you prescribe steroids, for various conditions:

‘Individuals who use glucocorticoids and exhibit iatrogenic (caused by the medicine) Cushing’s syndrome should be “aggressively” targeted for early screening of cardiovascular (CV) risk factors, say researchers.

Laurence Fardet (University College London, UK) and colleagues found that individuals with iatrogenic Cushing’s syndrome who were prescribed glucocorticoids had a significantly higher incidence of CV events (including coronary heart disease, heart failure, or ischemic cerebrovascular events) than individuals prescribed glucocorticoids without iatrogenic Cushing’s syndrome, or those not prescribed glucocorticoids.

Indeed, Cushing’s syndrome patients prescribed glucocorticoids had a CV incidence rate per 100 person-years at risk of 15.1 compared with 6.4 and 4.1 in those without Cushing’s but who were prescribed glucocorticoids and those not prescribed glucocorticoids, respectively.

Multivariate analysis revealed that iatrogenic Cushing’s patients had a 2.27-fold increased risk for coronary heart disease, a 3.77-fold increased risk for heart failure, and a 2.23-fold increased risk for ischemic cerebrovascular events.’

Proving a medical hypothesis is never that simple. However, if you believe that CVD is due to inflammation, then the world’s most potent anti-inflammatory agents ought to decrease CVD risk. Instead, it increases it by at least 400%. [Far more in some studies]

Other anti-inflammatory agents, known as Non-steroidal anti-inflammatories (NSAIDs) also greatly increase the risk of CVD. Vioxx (a potent NSAID), launched then pulled off the market, was estimated to have killed over one hundred thousand people in the US alone, from increasing CV risk.

In short, if CVD is primarily a disease of inflammation, then potent anti-inflammatory agents ought to reduce the risk. Instead they increase it massively. There is no doubt that inflammation is associated with CVD. Equally, if you measure C-reactive protein (a marker of inflammation), a high level is associated with a higher risk of CVD. However, it is not a cause, and if you try to reduce inflammation you will almost certainly increase the risk of CVD, not decrease it.

Ergo. Inflammation is sign of active CVD. That is all.

What causes heart disease part XII

Twelve parts and not finished yet. Oh well.

At this point I have an admission to make – having recently been thinking about things in a different way. Up to now I have been using a model which I have called the ‘four step’ process of cardiovascular disease.

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

I still think that all the parts of the model are correct. However, it is probably best to look at this more as overlapping sets, rather than steps. Whilst it is true that, until the endothelium is damaged, nothing else can happen in the process of atherosclerotic plaque development. Once endothelial damage has occurred we are not looking at step 2, step 3, step 4 – as a linear process. After the first episode of endothelial damage, all the processes can be going on, virtually simultaneously (apart from the final, fatal clot obviously).

So, the thought I wish to make at this point, is that we are looking at a dynamic process, where all processes overlap and interconnect. Endothelial damage can be going on, whilst dysfunctional clot repair is also happening, in addition to further clot formation.

I was trying to think of a good analogy. The best I could come up with was rust on paintwork on a car. Before you can get rust, you need some damage to the paintwork. After that other factors can come into play. Water, salt…. Um, water and a bit more salt…um. Well, I am sure that other things can make cars rust more quickly, but hope you get the general idea.

Thus, I have decided not to call this the four step process anymore. I shall call it the four process process. No, that is rather clumsy. I shall call it the…not sure. The quadrilateral process. The ‘four process clotting’ hypothesis of heart disease. Anyway. I hope you know what I am going on about (those that have read the previous eleven blogs may do).

The role of lipoproteins

Now I am going to take this discussion in a direction those who have followed my writing thus far, may not quite expect. I want to look at the role of lipoproteins in blood clotting. Mea Culpa. I have spent a great deal of time telling people that lipoproteins have nothing to do with CVD. This is not entirely true. They can, and do, play a role.

The reality is that virtually every substance that can be found in the blood has some influence on blood clotting – and there are an enormous number of substances in the blood. So, it should come as no real surprise to find that high density lipoprotein (HDL), low density lipoproteins (LDL) and very low density lipoproteins (VLDL) are also involved.

Just to recap on one lipoprotein, namely lipoprotein (a) (Lp(a). As I have discussed earlier Lp(a), is produced by the body to plug areas of damage to artery wall. It is found in animals that cannot synthesize vitamin C – and are therefore at high risk of scurvy. Scurvy is, primarily, a disease of connective tissue e.g. collagen (which needs vitamin C for its synthesis).

Breakdown of collagen leads to cracks in blood vessels, and Lp(a) plugs the gaps. Thus, here is one lipoprotein, the entire function of which, is to help form very strongly bound blood clots. What I wish to highlight here is that Lp(a) could also be called LDL(a). Because Lp(a) is LDL which has one different protein attached to it.

With LDL and Lp(a) being virtually identical, it should come as no surprise that LDL itself also has an impact on blood clotting, through a number of different mechanisms. Indeed, the interaction between LDL and blood clotting is mind-boggling in its complexity. I am not going into things here in too much detail, and I will just highlight one study. It has the catchy title: ‘LDL receptor cooperates with LDL receptor–related protein in regulating plasma levels of coagulation factor VIII in vivo.’ Here we go:

‘High levels of FVIII in plasma (greater than 1.5 U/mL) constitute a major risk factor for arterial and venous thrombosis in humans. Our observation that the up-regulation of hepatic LDLR protein expression in mice by gene transfer accelerated FVIII clearance from the circulation may be of therapeutic interest for patients who have elevated plasma FVIII levels. In humans, the up-regulation of LDLR protein is achieved by treatment with 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase inhibitors, also called statins. Statins are widely recognized in the treatment of hypercholesterolemia in humans.1

What is all this about? Basically if you have fewer LDL receptors (LDLR) there will be slower clearance of factor VIII (a key blood clotting factor) and the level in the blood rises. If you increase LDL receptors, by using statins, more factor VIII will be removed, and the risk of blood clotting will fall. So, here we have statins reducing the risk of cardiovascular disease by increasing the number of LDL receptors on the liver, which causes factor VIII (a blood clotting factor) to be removed from the blood.

In addition to this LDL interacts with platelets (the key blood cells involved in blood clotting) and the more LDL you have, the greater the tendency of platelets to clump together:

Platelets and lipoproteins are intimately involved in the pathogenesis of a wide variety of disease including atherosclerosis, thrombosis, and coronary heart disease. Evidence accumulated over the years suggests the possibility of a direct relationship between plasma lipoproteins and the hemostatic function of platelets. A number of studies demonstrated that native LDL enhanced the platelet sensitivity to stimulation and induced platelet activation.’2

In short, LDL activates platelets, and activate platelets are the starting point for blood clot formation.

The enormous complexity of the clotting system is further revealed when we look at High Density Lipoproteins (HDL) a.k.a. ‘good’ cholesterol. It is widely accepted that HDL is protective against death from CVD. It is generally believed that this protection comes through the process of reverse cholesterol transport i.e. HDL sucks cholesterol out of plaques. [Which I do not believe]

However, this is almost certainly not how HDL works. It has other important and potent effects on blood coagulation:

‘….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.’3

VLDL (triglyceride)

Finally, for now, what to triglycerides do – with regard to blood clotting? More jargon here, but a very powerful statement linking VLDL/triglyceride levels to blood clotting.

‘Activation of platelets and the coagulation cascade are intertwined. VLDL and remnant lipoprotein concentrations are often increased with the metabolic syndrome. These lipoproteins have the capacity to activate platelets and the coagulation pathway, and to support the assembly of the prothrombinase complex. VLDL also upregulates expression of the plasminogen activator inhibitor-1 gene and plasminogen activator inhibitor-1 antigen and activity, a process accompanied by platelet aggregation and clot formation. The surface membrane of activated platelets also supports the assembly and activity of the prothrombinase complex, resulting in further thrombin generation and amplification of the coagulation cascade.’4

If you don’t like the jargon, I will simplify:

  • High levels of LDL increase the risk of blood clots forming
  • High levels of HDL reduce the risk of blood clots forming
  • VLDL/triglycerides increase the risk of blood clots forming

To this, I will just add that ‘oxidised’ LDL is particularly pro-coagulant. It reduces Nitric Oxide synthesis in the endothelium, triggers platelet activation and damages the endothelium. Thus the condition known as ‘dyslipidaemia’ is particularly dangerous. Dyslipidaemia consists of low HDL, high VLDL and more ‘oxidised’ LDL. It is usually caused by insulin resistance a.k.a. the metabolic syndrome a.k.a. pre-diabetes.

So, ahem yes, blood borne lipoproteins do have a role to play in CVD. The role is not key, but it is there. I thought I should get that off my chest.



2: Yashika Gupta, V. Mallika* and D.K. Srivastava: ‘INTERACTION OF LDL AND PLATELETS IN ISCHAEMIC AND ISCHAEMIC RISK SUBJECTS’ Indian Journal of Clinical Biochemistry, 2005, 20 (1) 97 – 92



Greater Cholesterol lowering increases the risk of death

Sorry to get distracted from my series on what causes heart disease, yet again. However, I felt the need to blog about this article published in the BMJ on the 12th April 2016.

A group of researchers went back through the data from the Minnesota Coronary Experiment run between 1966 and 1973 in the US – on many thousands of participants. They were, in part stimulated to do this because they had previously looked at the Sydney Diet Heart Study 1966 – 73. In their own words:

‘Our recovery and 2013 publication of previously unpublished data from the Sydney Diet Heart Study (SDHS, 1966-73) belatedly showed that replacement of saturated fat with vegetable oil rich in linoleic acid (a polyunsaturated fat) significantly increased the risks of death from coronary heart disease and all causes, despite lowering serum cholesterol. Our recovery of unpublished documents and raw data from another diet-heart trial, the Minnesota Coronary Experiment, provided us with an opportunity to further evaluate this issue.’1

To make this clear. The Sydney Diet Heart Study (SDHS) was set up to show that replacing saturated fat with unsaturated fat would reduce the risk of heart disease The original researchers who set up and ran the SDHS did not fully publish their data at the time (one can only speculate as to why this may be so).

When this current group of researchers finally managed to get hold of the full data from the SHDS, it was found that replacing saturated fat with polyunsaturated fat did lower cholesterol, however:


I am not normally a great fan of capitalisation, and using bold, but I think this statement needed that treatment.

Now, a few years later, the researchers who re-analysed the Sydney Diet Heart Study decided to try and find all the unpublished data from the Minnesota Coronary Experiment (MCE). (One can again only speculate as to why the original researchers did not reveal all of their data). The main points from this re-analysis were the following

  • Though the MCE intervention lowered serum cholesterol, this did not translate to improved survival
  • Paradoxically, MCE participants who had greater reductions in serum cholesterol had a higher, rather than lower, risk of death
  • Results of a systematic review and meta-analysis of randomized controlled trials do not provide support for the traditional diet heart hypothesis

I shall paraphrase their findings:


The Minnesota Coronary Experiment (MCE), a randomized controlled trial conducted in 1968-73, was the largest (n=9570) and perhaps the most rigorously executed dietary trial of cholesterol lowering by replacement of saturated fat with vegetable oil rich in linoleic acid. The MCE is the only such randomized controlled trial to complete post-mortem assessment of coronary, aortic, and cerebrovascular atherosclerosis grade and infarct status and the only one to test the clinical effects of increasing linoleic acid in large prespecified subgroups of women and older adults.

Those who have read my ramblings over the years will not be in least surprised by this finding. Because, as you may know by now. I believe that raised cholesterol has nothing whatsoever to do with the heart disease. So, this finding is not a paradox to me. It is simply further confirmation of many, many, other studies which utterly contradict the cholesterol hypothesis.

I would not, however, hold my breath waiting for this study to make any difference to anything. My current favourite comment on this study comes from an opinion leader from the British Heart Foundation. It is, as follows:

‘Professor Jeremy Pearson of the British Heart Foundation commented: “This is an interesting study which shows that decreasing your intake of saturated fat can have a positive impact in helping lower cholesterol. More research and longer studies are needed to assess whether or not eating less saturated fat can reduce your risk of cardiovascular death.’

Read and weep gentle readers. Here is a man so completely and utterly convinced of the dangers of saturated fat consumption and raising blood cholesterol that he is incapable of grasping what this paper is saying. Max plank said that ‘Science advances one funeral at a time.’ There is at least one funeral, currently, that I can think would help to move science along.

Perhaps time from a quote from Professor John Ioannidis, who wrote a rather sad article recently, entitled Evidence-based medicine has been hijacked: a report to David Sackett.

‘This is a confession building on a conversation with David Sackett in 2004 when I shared with him some personal adventures in evidence-based medicine (EBM), the movement that he had spearheaded. The narrative is expanded with what ensued in the subsequent 12 years. EBM has become far more recognized and adopted in many places, but not everywhere, for example, it never acquired much influence in the USA. As EBM became more influential, it was also hijacked to serve agendas different from what it originally aimed for. Influential randomized trials are largely done by and for the benefit of the industry. Meta-analyses and guidelines have become a factory, mostly also serving vested interests. National and federal research funds are funnelled almost exclusively to research with little relevance to health outcomes. We have supported the growth of principal investigators who excel primarily as managers absorbing more money. Diagnosis and prognosis research and efforts to individualize treatment have fuelled recurrent spurious promises. Risk factor epidemiology has excelled in salami-sliced data-dredged articles with gift authorship and has become adept to dictating policy from spurious evidence. Under market pressure, clinical medicine has been transformed to finance-based medicine. In many places, medicine and health care are wasting societal resources and becoming a threat to human well-being. Science denialism and quacks are also flourishing and leading more people astray in their life choices, including health. EBM still remains an unmet goal, worthy to be attained….

He concludes

“David, I was a failure when we started this conversation and I am an even bigger failure now, almost 12 years later. Despite my zealot efforts, my friends and colleagues have not lost their jobs. The GDP devoted to health care is increasing, spurious trials, and even more spurious meta-analyses are published at a geometrically increasing pace, conflicted guidelines are more influential than ever, spurious risk factors are alive and well, quacks have become even more obnoxious, and approximately 85% of biomedical research is wasted . I still enjoy science tremendously, focusing on ideas, rigorous methods, strong mathematics and statistics, working on my weird (and probably biased) writings alternating with even more desperate poetry, and learning from young, talented people. But I am also still fantasizing of some place where the practice of medicine can still be undeniably helpful to human beings and society at large. Does it have to be a very remote place in northern Canada close to the Arctic? Or in some isolated beautiful Greek island where corpses of unfortunate refugees are found on the beach or floating in the water almost every day, as I am writing this commentary, although no naval battle has been fought? Is there still a place for rational thinking and for evidence to help humans? Sadly, you cannot answer me any longer, but I hope that we should not have to escape to the most distant recesses of geography or imagination. Twenty-five years after its launch, EBM should still be possible to practice anywhere, somewhere—this remains a worthwhile goal.”2

David Sackett, the founder of Evidence Based Medicine, is now dead. I presume he is spinning in his grave at what has happened to medicine and medical research. Which is, currently, not based on any evidence at all. If the evidence does not fit with the currently dogma it is simply not published.

Does anyone in the higher reaches of the medical establishment actually give a stuff about this? It seems that they do not. Meanwhile the shelves of our supermarkets groan under the weight of the super-healthy polyunsaturated fat products that we are encouraged to eat, by the likes of the British Heart Foundation.

Yet, here is what the uncovered evidence from the largest study done in this area is screaming at us:

Greater cholesterol lowering, using polyunsaturated fats, increases the risk of death

So, British Heart Foundation, the question must be asked… are you killing people with your advice on saturated fat consumption? Perhaps you ought to think about changing it, before more people die.

Here is what the BHF currently say about saturated fats:

‘Swap these for unsaturated fats. Eating too much saturated fat increases the amount of cholesterol in your blood.’3

Do you have any actual evidence to base this advice on… any at all? If so, let’s see it. If not, change it.




Lowering cholesterol has no effect on heart disease

Yes, if anyone is interested, I enjoyed my holiday. Mountains, snow, skiing, food, France. What more could you ask for?

Whilst away I kept an eyes on a whole series of stories on cholesterol and statins and adverse effects of statins, and suchlike, unfold across various newspapers. Many of you were kind enough to send me said various articles and stories. Some of which were easy to follow. One, in particular, was completely incomprehensible.

HOPE-3, was a study done by Astra Zeneca looking at the use of rosuvastatin vs. placebo. Actually, it was a study done using rosuvastatin alone vs. antihypertensive medication vs. rosuvastatin and antihypertensive medicine vs. double placebo (a term I have never come across before). Double placebo has twice the power of a single placebo? Yes, its ‘Double Placeboman’ playing at a cinema near you.

I have read the HOPE-3 article, and given up several times. I just cannot understand it. Professor Michel de Lorgeril (who ran the Lyon heart health study) also had a go at making it easier to understand. Below is part of his simplification which (I am afraid) is not terribly simple. But it may give you some gist. There is a prize for anyone who gets to his final point:

  1. No effect on all-cause mortality.
  1. No effect on cardiovascular mortality.
  1. As cardiovascular disease is a serial killer, we could conclude that rosuvastatin is shown useless in that trial (as in the previous trials). We could stop the analysis at this point.
  1. Since the authors do suggest that rosuvastatin was protective, it means that these patients are as “deaths cured”’ or “death prevented”, which is probably not what they expected when taking the pills.
  1. All this despite the LDL reduction that was close to 30%.
  1. HOPE 3 investigators curiously examine the effects of rosuvastatin on two “combined primary endpoints” (called “first and second co-primary outcome” as shown on Table 2, below) suggesting that there were two primary hypotheses. This is not “in line” with basic Methods in clinical trial sciences [one trial, one primary hypothesis]. That strange and novel strategy should have been presented long before starting the trial. In any case, the probability of a difference between rosuvastatin and placebo for the first co-primary outcome [the only one to be considered] should have been adapted, a kind of Bonferroni correction; p should have been much lower than 0.05 to be significant; which is not “clinical significance”.
  1. HOPE 3 investigators present the comparison of rosuvastatin with placebo (Table 2, below) as if there were only two randomized groups. In fact, there were 4 groups as there was a second randomization to test an antihypertensive treatment; and also the combination of cholesterol lowering and blood pressure lowering. In summary, these investigators tested many more than two primary hypotheses. They say that they can pool the data from all the patients taking rosuvastatin (plus antihypertensive) to make the comparison with all the patients taking a placebo, including those taking antihypertensive; thus comparing two groups of about 6300 patients rather than 4 groups of about 3100 patients each) because there was no interaction between treatments. This is not exactly true as we see a clear interaction between treatments for at least two components (myocardial infarction and stroke) of the two co-primary outcomes (see Table S20 in the supplementary materials, below). It would have been therefore imperative to present data and full statistics for the 4 groups together to examine the effects of rosuvastatin vs. placebo. It is a mistake not to do that. 6- HOPE 3 investigator also say that there were fewer heart attacks; but after almost 6 years and with about 13,000 patients randomized, there were only 114 heart attacks (45 vs 69 in a simplistic analysis of 2 groups only, Table 2 below).
  1. In fact, things are not so clear when looking at Table 2: they report for the first co-primary outcome (CV deaths + myocardial infarction + stroke) 304 events in the placebo group and 235 in the rosuvastatin group, thus numbers different from the sum of 171+69+99 (total 339, placebo group) Michel de Lorgeril 2016 and 154+45+70 (total 269, rosuvastatin) according to the numbers given in Table 2. This means that they do not use the same numbers in the Table and in the statistics. This is a way of misleading the readers.

Ahem. Perhaps not as simple as you may expect, but I hope you get the general drift. All I did, rather than Lorgeril, was attempt to pull out the figures of greatest interest, to me. Which should be the figures of greatest interest to everyone taking rosuvastatin. The absolute difference in number of deaths between those taking rosuvastatin and double placebo.

  • After five years of treatment, in 3,181 people taking rosuvastatin, there were 171 deaths (of all causes)
  • After five years of taking double strength placebo, in 3,168 people, there were 178 deaths (of all causes)

This represents a difference of 7 deaths over 15,905 years of treatment. Or, one death delayed for every 2,272 years of treatment. This is both statistically, and clinically, insignificant. It is well within the limits of a chance finding. It is a difference that can simply be ignored.

Of course, it was hailed as a triumph, and further proof of the cholesterol hypothesis.

Of more interest, in many ways, and coming out at almost exactly the same time as HOPE-3 was the ACCELERATE trial. Which looked at the use of evacetrapib on lowering LDL (‘bad’ cholesterol), and raising HDL (‘good cholesterol) on the risk of CVD. It was reported thus…

‘Cleveland Clinic researchers studying evacetrapib have shown that despite reducing levels of low-density lipoprotein (LDL, or “bad” cholesterol) by 37 percent and raising levels of high-density lipoprotein (HDL, or “good” cholesterol) by 130 percent, the drug failed to reduce rates of major cardiovascular events, including heart attack, stroke, angina or cardiovascular death.

The phase 3, multi-center clinical trial was discontinued in October 2015, on the recommendation of the independent Data Monitoring Committee after preliminary data suggested the study would not meet its primary endpoint of a reduction in major cardiovascular events. The research is being presented at the American College of Cardiology’s 65th Annual Scientific Session

“Here we have a paradox. The drug more than doubled HDL and lowered LDL levels by as much as many statins, but had no effect on cardiac events,” said Steve Nissen, M.D., chairman of Cardiovascular Medicine at Cleveland Clinic. “These findings illustrate the importance of performing large, high-quality outcome trials. Just looking at the effects a therapy has on cholesterol levels doesn’t always translate into clinical benefits.”

The ACCELERATE trial involved more than 12,000 patients at more than 540 sites who were at high risk for serious cardiovascular problems. They were randomized to receive either 130 milligrams of evacetrapib or a placebo daily, along with standard medical therapy throughout the trial. Study participants either had an acute coronary syndrome 30 days to one year before enrolling, had cerebrovascular atherosclerotic disease, had peripheral vascular disease, or had both diabetes and coronary artery disease.’

In HOPE3, LDL was lowered 30%, had some (very slight) impact on CVD, and was hailed as a triumph for cholesterol lowering. In ACCELERATE LDL was lowered 37%, HDL raised 130%, with no effect whatsoever on CVD. Aha, but, there is an answer…

The ACCELERATE trials was, you’ve guessed it. A paradox. [Question, how many paradoxes can a hypothesis sustain before it collapses in a smoking ruin?]

Karl Popper would call such a thing a black swan. Which is a refutation of your hypothesis. Karl Popper, as we all – ahem – know ‘proposed falsification as a solution to the problem of induction. Popper noticed that although a singular existential statement such as ‘there is a white swan’ cannot be used to affirm a universal statement, it can be used to show that one is false: the singular existential observation of a black swan serves to show that the universal statement ‘all swans are white’ is false—in logic this is called modus tollens. ‘There is a black swan’ implies ‘there is a non-white swan,’ which, in turn, implies ‘there is something that is a swan and that is not white’, hence ‘all swans are white’ is false, because that is the same as ‘there is nothing that is a swan and that is not white’.

One notices a white swan. From this one can conclude:

At least one swan is white.

From this, one may wish to conjecture:

All swans are white.

It is impractical to observe all the swans in the world to verify that they are all white.

Even so, the statement all swans are white is testable by being falsifiable. For, if in testing many swans, the researcher finds a single black swan, then the statement all swans are white would be falsified by the counterexample of the single black swan.’2

Here is another ‘white swan’ hypothesis

Researchers, looking at those living in Framingham, in the US, found that younger men with high cholesterol levels were more likely to die from CVD. From this they concluded. Raised cholesterol causes CVD. ACCELERATE clearly falsifies their simplistic hypothesis. It is a black swan. Thank you, and goodnight.

Next, part XII as to what causes heart disease.



What causes heart disease part XI

This blog was going to be all about bringing together all of the strands about what causes heart disease. However, as often seems to happen, I was sent an article about a study that will be presented at the American College of Cardiology conference in Chicago. It led me down a slight detour, which is actually highly relevant to what I have been discussing.

At present I have no more details of this study than can be found in this press release.

Depressed CAD Patients May be at Higher Risk For MI, Death

Patients with coronary artery disease (CAD) who are depressed may have a much higher risk of myocardial infarction (MI) or death compared to those who are not depressed, according to research published March 23 which will be presented at ACC.16 in Chicago.

The study, conducted by Natalie Szpakowski, MD, and colleagues, included 22,917 patients who had been diagnosed with stable CAD following a coronary angiogram for chest pain. Results showed that the incidence of depression following a diagnosis of stable CAD was 18.8 percent. Patients who were female or who had more severe angina were more likely to be diagnosed with depression.

Further, depressed CAD patients were 83 percent more likely to die from any cause compared to those who were not depressed. They were also 36 percent more likely to present at a hospital for MI. Those who were diagnosed with depression 90 to 180 days following the diagnosis of CAD were at greatest risk.

According to the authors, these findings suggest that these patients may need to be screened for mood disorders, either by their family physician or their cardiologist.

“Based on these findings, there may be an opportunity to improve outcomes in people with coronary heart disease by screening for and treating mood disorders, but this needs to be further studied,” says Szpakowski. “Stable chronic angina due to narrowing of the coronary arteries is common, and our findings show that many of these patients struggle with depression. Our follow-up was at most five years, so many more might be affected.”1

Here, I thought, was an opportunity look at the process(es) by which depression can lead to heart disease. Up to now, the ‘experts’ in cardiology have stated that have heart disease causes depression…yawn. In this way they have dismissed the need to explain how, or why, depression could cause heart disease. Primarily, because this association cannot be explained using the currently accepted risk factors.

I thought this study represented a perfect opportunity to demonstrate exactly how, and why, depression will increase the risk of CVD, using the four step model for CVD (cardiovascular disease) which I have outlined in this series:

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

Your first thought may well be. How does depression damage the endothelium, or increase clot formation… or anything else in the four step process?

Well, clearly depression cannot directly damage the endothelium, or increase dysfunctional clot formation. However, the pathways that lead from depression to the four step process are easily defined, pretty straightforward, and supported by a mass of evidence, and they go like this.

Depression, from whatever cause, creates a dysfunction of the hypothalamic-pituitary-adrenal axis (HPA-axis). Sorry to bring in the jargon straight away. However, in an attempt to keep this is simple as possible, think of the HPA-axis as the ‘unconscious’ system of hormones, and nerves, that control how we react to stress. We are talking about hormones such as adrenaline, cortisol, glucagon and suchlike.

We are also talking about the sympathetic and parasympathetic nervous systems which control heart rate, pupil dilation, blood flow to muscles, contraction of the bladder – so just about involved in everything we do. The HPA-axis can also be thought of as the central management system for the ‘flight or fight’ response.

When I use the term, ‘dysfunctional HPA-axis’, what I mean that the HPA-axis has been knocked out of whack. Usually this means it is overproducing stress hormones (particularly cortisol), and is overdriving the sympathetic nervous system. [Yes, I know it is actually all far more complex than this – for those who will undoubtedly write in to tell me so].

The type of things that damage the HPA-axis are: episodes of extreme stress, leading to PTSD, anxiety, depression, schizophrenia. In fact, most mental disorders will be reflected in a dysfunctional HPA-axis – to one degree or another.

If you want more information on this, I suggest going to Google and typing in depression and HPA-axis and/or stress. Or PTSD and HPA-axis dysfunction etc. You will find that much information springs to life before your very eyes. Essentially, you will begin to see how stress, mental illness, depression, anxiety etc. can all be linked through the HPA-axis, to one degree or another.

In short, if you suffer from stress/anxiety/depression… etc, your HPA-axis will go wrong. It will go wrong in many, many, different ways. The complexities and interactions of HPA-axis dysfunction stretch as far as the eye can see – and further. Believe me, I have disappeared over the horizon in many different directions over the years.

However, for the sake of brevity, and understanding, I will look at focus on one hormone, Cortisol. Cortisol is quite easy to measure, and it usually the hormone used to diagnose HPA-axis dysfunction. If the levels of cortisol are high, or low, or do not go up and down in a flexible fashion during the day, you have HPA-axis dysfunction.

Yes, unfortunately, measuring cortisol levels can result in much confusion. I can guarantee that if you look into this area you will end up mind-boggled and mired in apparent contradictions. Just to give one example. Finding a low cortisol level in the morning does not mean that do not have a ‘stress’ related problems, which would normally lead to high cortisol levels.

It simply means that your neuro-hormonal system has ‘burnt-out,’ leading to low cortisol levels in the morning (but overall higher levels over 24 hours). Somewhat similar as to what happens in diabetes where the pancreas eventually gives up the effort of producing insulin to overcome insulin resistance, and ‘burns-out.’ At which point you may well be diagnosed with type II diabetes.

Is that a good analogy… yes, I think so. Because I have seen papers stating that raised cortisol/stress/anxiety/depression cannot be causes of CVD, because many people with CVD have low cortisol levels in the morning. Bong! Wrong answer. A low cortisol level in the morning is probably the single most powerful indication of HPA-axis dysfunction. [Look up Bjorntorp on Google]

Anyhoo. Getting back to depression. If you are depressed, your HPA-axis will become dysfunctional. You will have abnormal cortisol levels, and you will become insulin resistant (because cortisol is a direct antagonist to insulin at many sites). In fact, severe depression can actually cause type II diabetes. Yes, you can look that up too.

Even if you don’t develop frank diabetes, you will end up with a whole serious of metabolic abnormalities. For the sake of keeping this short, you will also end up with blood clotting abnormalities too. Just to give one example, depression increases fibrinogen level in the blood.

‘In cross-sectional analyses, a stepwise increase in fibrinogen percentile categories was associated with a stepwise increase in risk of psychological distress, use of antidepressant medication, and hospitalization with depression.’ 2

Another important clotting factor is Plasminogen Activator Inhibitor-1 (PAI-1). This stops blood clots getting broken down/repaired after they form. Another quick quote here from a paper called ‘Mental disorders and thrombotic risk.’

‘Patients with psychosis, severe depression, or chronic stress are at increased risk for thromboembolism. Evidence suggests that tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) imbalance may play an important role in pathophysiology of mental and thromboembolic disorders. tPA facilitates clot dissolution and participates in several brain functions, including response to stress, learning, and memory. Depression is characterized by high PAI-1 level.’ 3

Linking it together

I hope that, at this point, it has become very clear how depression can, should, and in fact does link directly to an increase in the risk of CVD. Depression causes creates HPA-axis dysfunction and abnormal cortisol secretion, leading to insulin resistance and even diabetes (in severe cases).

This, in turn, stimulates the over-production of various clotting factors, such as fibrinogen. In addition, there is an increase in PAI-1, which prevents the breakdown/repair of the blood clot. [It causes other things too, but I am trying to keep this as concise as possible]

Clearly all this links directly to the four step model. Diabetes/raised blood sugar levels are directly damaging to the endothelium. Raised fibrinogen and PAI-1 are very powerful risk factors for CVD, primarily because they make the blood more likely to clot, and the clot more difficult to clear up.

In short, it is extremely straightforward to link depression to CVD, through the four step process:

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

Next, I will try to demonstrate how a number of other apparently unrelated conditions link to CVD through the ‘four-step’ process. Finally, I will put together, what I believe, are the ten (or so) best things you can do to protect yourself from CVD. I suspect you will already have worked out a number of them for yourself.

Then, anyone who cares to, can attack the four step hypothesis of heart disease and, I trust, do their best to pull it apart. I welcome the debate.





P.S. For those who like this sort of thing. Here is a paper by Bjrontorp which outlines how the HPA-axis dysfunction actually happens, and how it can be measured.

P.P.S. Bjorntorp worked out the main cause of CVD many years ago

Sunbathing is good for you

News announcer: ‘We interrupt the series of blogs on ‘what causes heart disease’ to bring you (slightly delayed), breaking news from Sweden… Sunbathing is good for you. Shock horror etc.’

Someone sent me this news story today, and I thought I should share it with you. For many, many, years I have been telling people that lying in the sun, getting a nice tan, is one of the healthiest things you can do. Despite the howls of anguish from all dermatologists telling us that one photon of sunlight is one photon too many. ‘You will cause people to die from skin cancer.’ Ho hum:

Why do sunbathers live longer than those who avoid the sun?

New research looks into the paradox that women who sunbathe are likely to live longer than those who avoid the sun, even though sunbathers are at an increased risk of developing skin cancer.

An analysis of information on 29,518 Swedish women who were followed for 20 years revealed that longer life expectancy among women with active sun exposure habits was related to a decrease in heart disease and noncancer/non-heart disease deaths, causing the relative contribution of death due to cancer to increase.

Whether the positive effect of sun exposure demonstrated in this observational study is mediated by vitamin D, another mechanism related to UV radiation, or by unmeasured bias cannot be determined. Therefore, additional research is warranted.

“We found smokers in the highest sun exposure group were at a similar risk as non-smokers avoiding sun exposure, indicating avoidance of sun exposure to be a risk factor of the same magnitude as smoking,” said Dr. Pelle Lindqvist, lead author of the Journal of Internal Medicine study. “Guidelines being too restrictive regarding sun exposure may do more harm than good for health.”1

There is a point here I think I should repeat… avoiding the sun is as risky for your overall health and life expectancy, as smoking. Which is pretty damned amazing? It has been estimated that smoking reduces life expectancy by six, on average. Thus, if you sunbathe regularly, it seems you can expect to live six years longer.

If I may indulge myself by quoting from my book ‘Doctoring Data’ on this very topic:

‘How about frightening people to stay out of the sun, or slap on factor 50 cream at the first suspicion that a deadly photon may sneak through 10 layers of protective clothing. Not necessarily a good idea, because without vitamin D synthesis in the skin, from exposure to the sun, there is significant danger that we can become vitamin D deficient, which can lead to all sort of other problems.

Here are just two stand-out facts from a major study in the Annals of Epidemiology entitled ‘Vitamin D for Cancer prevention.’

  • Women with higher solar UVB exposure had only half the incidence of breast cancer as those with lower solar exposure
  • Men with higher residential solar exposure had only half the incidence rate of fatal prostate cancer

To put that in simple English. If you spend longer in the sun, you may be far less likely to die of breast and prostate cancer. But what about the increased risk of dying of skin cancer! I have you cry. Well, what of it. Around 2,000 people a year die of malignant melanoma in the UK each year. It increased sun exposure were to double this figure we would have 2000 more cases.

On the other hand, breast cancer kills around 20,00 a year, as does prostate cancer. If we managed to halve the rate of breast and prostate cancer, we would reduce cancer deaths by 20,000 a year. Which is ten times as great as any potential increase in deaths from malignant melanoma.’

To what I wrote in Doctoring Data, I would further add that sun exposure is the best known way of increasing NO synthesis throughout the body. This protects the endothelium and, as you would expect, lowers blood pressure (the natural way). So, you are far less likely to die from CVD.

What this study highlights, once again (as with all advice on diet), what we are told to do by mainstream medical research, turns out to be actively damaging to health. Will advice on sun exposure now change? There is not the slightest, tiniest, possibility of this happening. Evidence has no impact on the pronouncements of the medical profession (at least not over the average human lifespan).

The only possible change I can see is that, whilst we will continue be hectored to stay out of the sun, at all possible costs, we will be advised to take vitamin D supplementation to make up for lack of sun exposure (even though there is little or no evidence that it actually does any good).

My advice is, and has always been. Sunshine is good for you. I have been saying this for twenty years. Ten years ago, whilst writing for Pulse Magazine in the UK I wrote an article called ‘Sunshine is good for you.’ I finished with the following:

Ponder this

I shall leave you to ponder the results of a study looking at people diagnosed with malignant melanomas, and then followed for five years.

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

‘Conclusion: Sun exposure is associated with increased survival from melanoma.2

Did I say that sunshine is good for you? It even prevents malignant melanoma.




The full study is: Avoidance of sun exposure as a risk factor for major causes of death: a competing risk analysis of the Melanoma in Southern Sweden cohort, P. G. Lindqvist, E. Epstein, K. Nielsen, M. Landin-Olsson, C. Ingvar and H. Olsson, Journal of Internal Medicine, doi: 10.1111/joim.12496, published online 16 March 2016.

2: Berwick M et al: Sun exposure and mortality from melanoma. J Natl Cancer Inst: 2005 Feb 2, 973(3):195-9

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.