Adherence to statins saves lives

17th February 2019

[Adherence to placebo saves lives]

To an extent I am cursing myself for doing what I am about to do. I have been dragged, yet again, into reviewing a paper that has made headlines round the world which proved, yes proved, that adherence to statins saves lives. I am doing this review because a lot of people have asked for my opinion on the paper.

I do feel like saying. ‘Look, I wrote the book Doctoring Data so that you could read papers like this and work out why they are complete nonsense for yourselves’. Clearly, not enough people have read my book, and I would therefore heartily encourage another million or so people to do so. [Conflict of Interest statement – I will get lots of money if this happens, which I think of as “win, win”].

The paper, in this case was called ‘Association of statin adherence with mortality in patients with atherosclerotic cardiovascular disease.’ It was published in the New England Journal of Medicine (NEJM) a couple of days ago.

The main finding was:

‘Using a national sample of Veterans Affairs patients with ASCVD (atherosclerotic cardiovascular disease), we found that a low adherence to statin therapy was associated with a greater risk of dying. Women, minorities, younger adults, and older adults were less likely to adhere to statins. Our findings underscore the importance of finding methods to improve adherence.’ 1

First thing to say is that this was an observational study. So, it cannot be used to prove causality, especially as the improvement in outcomes that they observed was an increased mortality risk of 1.3 (HR) in those who were least adherent – compared to those who were most adherent.

As many people know… sorry I shall rephrase that… as many geeks like myself know, if the hazard ratio is less than two, in an observational study, the best thing to do with said paper is to crumple it up and throw it in the bin. Because it is almost certainly meaningless. To quote Sir Richard Doll and Richard Peto, two of the fathers of medical research and epidemiology:

“when relative risk lies between 1 and 2 … problems of interpretation may become acute, and it may be extremely difficult to disentangle the various contributions of biased information, confounding of two or more factors, and cause and effect.”2

Observational studies with relative risks between one and two, are the type of studies which find that drinking five cups of coffee protect against CVD – or would that be increase the risk of dying of CVD.  Or maybe it is tea, not coffee? [I apologise for mixing up odds ratios, hazard ratios and relative risk. For ease of understanding, think of them as the same thing].

For example, I was looking at this paper:

‘Tea and coffee consumption and cardiovascular morbidity and mortality’.

Where they found that drinking between three and six cups of coffee reduced CV mortality by 45%:

 ‘A U-shaped association between tea and CHD mortality was observed, with an HR of 0.55 for 3.1 to 6.0 cups per day.’3

That is a far better result than adhering to statins. After all it is a 45% reduction vs. 30% reduction. My advice therefore would be to stop the statins and have nice cup of tea instead. Life would be so much better, and you would live longer as well. Sorry, but I don’t know what sort of tea. English breakfast, Earl Grey, Darjeeling… So many questions. So many stupid studies to read. So much crumpling. So many bins to empty.

Leaving behind the nonsenses they are – the observational studies with a minute difference in hazard ratio – let us move on to the major confounder of this latest crumple, bin, paper. Which is that people who adhere to medications do far better than those who do not – even if that medication is a placebo.

This was first noted, with regard to cholesterol lowering medications, nearly forty years ago in another paper, coincidentally published in the NEJM. It was called:

Influence of adherence to treatment and response of cholesterol on mortality in the coronary drug project.

I have copied the abstract in full. In part because it is written in something akin to understandable English. Most unusual in any medical journal. In this study the researchers were looking at drugs used to lower cholesterol levels, prior to the invasion of the statins.

‘The Coronary Drug Project was carried out to evaluate the efficacy and safety of several lipid-influencing drugs in the long-term treatment of coronary heart disease.  Good adherers to clofibrate, i.e., patients who took 80 per cent or more of the protocol prescription during the five-year follow-up period, had a substantially lower five-year mortality than did poor adherers to clofibrate (15.0 vs. 24.6 per cent; P = 0.00011).

However, similar findings were noted in the placebo group, i.e., 15.1 per cent mortality for good adherers and 28.3 per cent for poor adherers (P = 4.7×10-16). These findings and various other analyses of mortality in the clofibrate and placebo groups of the project show the serious difficulty, if not impossibility, of evaluating treatment efficacy in subgroups determined by patient responses (e.g., adherence or cholesterol change) to the treatment protocol after randomization.’ 4

I think it is worth highlighting the main findings again.

Those who adhered to taking clofibrate               =          15% mortality

Those who had poor adherence to clofibrate     =          24.6% mortality

Those who adhered to taking placebo                 =          15.1% mortality

Those who had poor adherence to placebo        =          28.3% mortality

From this is can be established that it was worse for you to not take placebo regularly than it was to not take clofibrate regularly.

If we move forward in time, others have looked at adherence to taking statins. The first thing they noted was people who take their medication regularly are different in many, many, ways to those who have poor adherence.

The paper is called: ‘Statin adherence and risk of accidents, a cautionary tale.’ Published in the American Heart Association journal Circulation.

As they say in the introduction:

‘Bias in studies of preventive medications can occur when healthier patients are more likely to initiate and adhere to therapy than less healthy patients. We sought evidence of this bias by examining associations between statin exposure and various outcomes that should not be causally affected by statin exposure, such as workplace and motor vehicle accidents.’

As they conclude:

‘Our study contributes compelling evidence that patients who adhere to statins are systematically more health seeking than comparable patients who do not remain adherent. Caution is warranted when interpreting analyses that attribute surprising protective effects to preventive medications.’ 5

This takes us back to Hill and Peto:

“when relative risk lies between 1 and 2 … problems of interpretation may become acute, and it may be extremely difficult to disentangle the various contributions of biased information, confounding of two or more factors, and cause and effect”

In the case of this latest ‘nonsense’ paper on statins, it is not actually difficult to disentangle the various contributions of biased information.

We already know that people who take tablets regularly, and placebo regularly, are more health seeking than those who do not. We already know that if you take a placebo regularly, this almost halves your (absolute) mortality rate. These are both enormous confounders in the latest NEJM study.

In fact, the confounder effect unearthed in previous studies is far larger than the effect they found. Which, if you are going to be ruthlessly logical, would suggest you would be far better off regularly taking a placebo than regularly taking a statin. If you choose to do so, you could entitle their paper “Proof that statins have no beneficial effect”.

You sure as hell cannot use such data to suggest that adhering to statins is beneficial. Yet, the authors of this study have done so. I give their paper a mark of D-Fail, please try again.

Or else, I would say, please inform yourselves of the previous research done in this area before writing a paper. This will avoid wasting everyone’s precious time.


2: Richard Doll & Richard Peto, The Causes of Cancer 1219 (Oxford Univ. Press 1981).




Response to the Lancet paper

3rd February 2019

A number of people have asked for my views on the Lancet Paper ‘Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomized controlled trials.’

It was reported in various major newspapers.

The Times reported the study thus: “Everyone over the age of 75 should be considered for cholesterol-lowering statins, experts have urged, after an analysis found up to 8,000 lives a year could be saved.”1  

The Telegraph had this to say. “Researchers said up to 8,000 deaths a year could be prevented if GPs simply prescribed drugs costing pennies a day.”

This comes hot on the heels of a concerted effort to silence statin critics around the world by a coalition of ‘experts. I suspect the coordinated timing is more than a coincidence.

‘The editors of more than two dozen cardiology-related scientific journals around the world published an editorial Monday to “sound the alarm that human lives are at stake” because of medical misinformation.

These physicians describe regularly encountering patients hesitant to take potentially lifesaving medications or adhere to other prescribed treatments because of something they read online. Or heard from friends. Or saw on television.

“There is a flood of bad information on the internet and social media that is hurting human beings,” said Dr. Joseph Hill, the architect of the essay and editor-in-chief of the American Heart Association journal Circulation. “It’s not just an annoyance, this actually puts people in harm’s way.”

The primary example illustrated in the editorial is the use of statins, a cholesterol-lowering medicine that can reduce heart attack and stroke risk in certain people. But doctors say too many of their patients shun taking statins because of bad information they picked up – often from politicians, celebrities and others who lack medical expertise.’2

Essentially, they feel that certain issues, such as prescribing statins, are so vitally important that critics should be silenced. Perhaps all these editors should try reading this:

‘Congress shall make no law respecting an establishment of religion or prohibiting the free exercise thereof; or abridging the freedom of speech, or of the press; or the right of the people peaceably to assemble, and to petition the Government for a redress of grievances.

Yes, the US founding fathers knew the first thing tyrannies always wish to do is remove freedom of speech. From that, all else follows. If they don’t get that message, they should all be forced to read 1984 by George Orwell.

“Freedom is the freedom to say that two plus two make four. If that is granted, all else follows.”

Getting back to the Lancet paper. What do I think of it? The first thing to note is ‘who done it.’ Well, of course, it was the Cholesterol Treatment Triallists Collaboration (CTT) from Oxford. Run by Professor Sir Rory Collins and Professor Colin Baigent. They do almost all these meta-analyses on statins, because they hold all the data. So, no-one else can really do them.

The CTT is in this hallowed position because they made a pact with the dev… sorry … they made a pact with the pharmaceutical industry to take hold of all the data on statins from all the pharmaceutical companies that manufacture statins and collate the data.

The CTT are very closely associated with the Oxford Clinical Trials Service Unit (CTSU) which is run by, and has employed, most of those in the CTT. Collins and Baigent etc. The CTSU is a clinical trials unit which, last time I looked, had obtained nearly £300 million in funding from the pharmaceutical industry for running clinical trials on various cholesterol lowering medications.

A fact that needs to be emphasised is that the CTT will not let anyone else see the data they hold. Including all the data on adverse events [side-effects] and serious adverse events. It is kept completely secret. I have the e-mail exchange between an Australian journalist and Professor Colin Baigent where the journalist attempts to find out if it is true that the CTT will not let anyone else see the safety data.

It starts quite well and the tone is amiable. Eventually Professor Colin Baigent clams up and refuses to answer any further questions. I have promised said journalist to keep this exchange under wraps, but almost every day I am tempted to publish it. It is toe-squirming.

Anyway, my point here is that the CTT is a horribly conflicted organisation, and has been paid, directly, or indirectly, a great deal of money by the pharmaceutical industry. Here are the conflicts of interest of those involved in writing the Lancet paper:

Conflicts of interest of statement from the Lancet paper: Commercial organisations in bold.

RO’C, EB, IF, CW, and JS have nothing to disclose. JF reports personal fees from Amgen, Bayer, Pfizer, Boehringer Ingelheim, Sanofi, and AstraZeneca, outside the submitted work; and non-financial support from Amgen, Bayer, and Pfizer, outside the submitted work. BM reports grants from the Medical Research Council, British Heart Foundation, and the National Institute for Health Research Oxford Biomedical Research Centre during the conduct of the study, and grants from Merck outside the submitted work. CR report grants from the Medical Research Council and British Heart Foundation during the conduct of the study; and grants from Merck, outside the submitted work. JE reports grants from the Medical Research Council and the British Heart Foundation during the conduct of the study, and a grant from Boehringer Ingelheim outside the submitted work. LB reports grants from the Medical Research Council and the British Heart Foundation during the conduct of the study. MK is an employee of a company that has received study grants and consulting fees from manufacturers of PCSK9 inhibitors and treatments for lipid disorders, outside the submitted work. AT reports personal fees from Amgen and Sanofi, outside the submitted work. PR reports a research grant from AstraZeneca during the conduct of the study; and research grants from Novartis, Pfizer, and Kowa, outside the submitted work. CP reports a grant from Merck, outside the submitted work; and personal fees from Merck, Pfizer, Sanofi, Amgen, and Daiichi-Sankyo, outside the submitted work. EL reports grants from AstraZeneca, Bayer, Boehringer Ingelheim, Amgen, and Merck, outside the submitted work; and personal fees from Bayer, Amgen, Novartis, and Sanofi, outside the submitted work. WK reports grants and non-financial support from Roche, Beckmann, Singulex, and Abbott, outside the submitted work; and personal fees from AstraZeneca, Novartis, Pfizer, The Medicines Company, GlaxoSmithKline, Dalcor, Sanofi, Berlin-Chemie, Kowa, and Amgen, outside the submitted work. AG reports personal fees from Aegerion Pharmaceuticals, Arisaph Pharmaceuticals, DuPont, Esperion Therapeutics, Kowa, Merck, Roche, Vatera Capital, ISIS Pharmaceuticals, Weill Cornell Medicine, and Amgen, outside the submitted work. SY reports a grant from AstraZeneca, outside the submitted work. RC reports support from the Nuffield Department of Population Health, during the conduct of the study; grants from the British Heart Foundation, Cancer Research UK, Medical Research Council, Merck, National Institute for Health Research, and the Wellcome Trust, outside the submitted work; personal fees from the British Heart Foundation and UK Biobank, outside the submitted work; other support from Pfizer to the Nuffield Department of Population Health (prize for independent research); and a patent for a statin-related myopathy genetic test licensed to University of Oxford from Boston Heart Diagnostics (RC has waived any personal reward). CB reports grants from the Medical Research Council and British Heart Foundation, during the conduct of the study; and grants from Pfizer, Merck, Novartis, and Boehringer Ingelheim, outside the submitted work. AK reports grants from Abbott and Mylan, outside the submitted work; and personal fees from Abbott, Amgen, AstraZeneca, Mylan, and Pfizer, outside the submitted work. LB reports grants from UK Medical Research Council and the British Heart Foundation during the conduct of the study.

As to the study itself. I wrote this as a ‘rapid response’ to an article Colin Baigent wrote in the BMJ about the study. It may be published, it may not be.

I would like to ask Colin Baigent one question on this study – at this time.  He claims that the Lancet study was a meta-analysis of twenty-eight RCTs. The study was called. ‘Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials.’

However, in the Appendix to the Lancet paper it is made clear that five of the studies are a comparison of high dose vs. low dose statins. PROVE-IT, A to Z, TNT, IDEAL and SEARCH. They cannot be used to test the hypothesis that statins are beneficial in the over 75s vs. placebo, as they were not done to answer this question.

Also, in nine of the RCTs used in the meta-analysis there were 0% participants over the age of 75 at the start of the study. These were 4S, WOSCOPS, CARE, Post CABG, AFCAPS/TexCaps, ALERT, LIPID, ASPEN and MEGA.

Which means that five of the studies could not address the question of statins vs placebo in the over 75s, and nine of the studies had no participants over the age of 75, which leaves fourteen studies that would be relevant to the issue of prescribing statins in the over 75s.

My question is, why did you call this study ‘Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials.

Yes, they claimed to have done a meta-analysis of twenty-eight studies, yet they could only use data from fourteen to make their claims. The largest of which was the Heart Protection Study (HPS), carried out by, guess who, Rory Collins from the CTSU and CTT.

As for the actual data, it is the usual obfuscation, skirting as close to the direct lie as possible without crossing that line. I am just going to look at one issue. The main claim was that “statin therapy or a more intensive statin regimen produced a 21% (RR 0·79, 95% CI 0·77–0·81) proportional reduction in major vascular events per 1·0 mmol/L reduction in LDL cholesterol.”

A 21% reduction in major vascular events. That sounds terribly impressive. However, if you have read my book Doctoring Data you will know that what is most important here is not what is said, it is what is not said.

Do you see any mention of overall mortality here? No, you don’t. Which means that it did not change. Also, you may note this wording ‘reduction in major vascular events.’ What is a major vascular event? Well, it is mainly a non-fatal heart attack or a non-fatal stroke. There are other CV events, but they are much less common.

Note again, no mention of fatal CV events. If there had been a reduction here, it would have been trumpeted from the rooftops. Which means that we have no reduction in mortality and no reduction in fatal CV events. Of course, it is worth preventing non-fatal heart attacks and strokes, as these can be extremely damaging and harmful things.

However, there is something worth mentioning here that I have not really covered before. There are heart attacks and heart attacks, and strokes and strokes. A heart attack (MI) can be a crushing near-death event, leaving the heart severely weakened and liable to trigger into a fatal heart arrythmia at any time. The patient can be left a cardiac cripple.

Alternatively, a heart attack can be diagnosed by a marginal rise in cardiac enzymes with no symptoms at all, and no residual problems. Yet, both of these events, so completely different in their impact, will be listed as a non-fatal heart attack, with precisely the same weighting.

Equally, a stroke can leave the person virtually paralysed down one side, incontinent, unable to speak, eat, or move. Or, it can be a half hour strange sensation with slight facial weakness that fully resolves. Again, both these events will be listed with precisely the same weighting.

That is a problem in itself, in that these trials list events of completely different severity as being equivalent. It also leads into another problem, who is going to make the diagnosis of a mild heart attack or stroke – and on what grounds?

It will most likely be a doctor, and that doctor will have prior knowledge of whether or not the patient was on a statin – or placebo. Yes, I know, clinical trials are supposed to be double-blinded, which means that neither the participant, nor the investigator, should know who is taking the drug, or the placebo.

However, in reality, they both know full well.

I was at a meeting a while back where one of the investigators for the PCKS-9 drug Repatha was talking about the study. At one point he mentioned that a trial participant had told him that he knew he was not taking the cholesterol lowering agent. When questioned how he knew this, the participant said – because my cholesterol level is the same as it always was.

He still wanted to continue on the trial, because he thought we was doing a ‘good’ thing and helping to move medicine forward – and suchlike. I feel it may be considered churlish to point out that the only thing he was helping to move forward was the profit margins for Amgen.

The reality is that when you have a medication that has a significant effect, e.g. lowering cholesterol by 40%, this is a very difficult to thing to hide from the patient, or the doctor. They can see the figures on a computer screen in front of them. And when you are on a clinical trial, and you enter hospital, the doctors have to be told you are in a clinical trial, and what it is.

So, these double blinded studies on statins are not effectively, or even remotely, double-blinded. Which means that bias in clinical decision making is now an option. Was it a heart attack, or not? Well, they are on a statin – so probably not. Or, they are taking a placebo, so it probably is. Bias, the very thing you are trying to remove has crept straight back in the side door.

Another issue with an event is that there are many different sorts of clinical event. Death would be one – obviously. Breaking your leg another. Kidney failure would also count as one, as would a severe rash, or emergency admission to a hospital for almost any reason.

So, when a study states, as this one does ‘reduction in major vascular events.’ My mind, as it is now trained to do, thinks to itself: “ What about other events, what happened to them? Were they also reduced, did they say the same, or did they go up?”

Because if you reduce major vascular events, but other serious events go up, then you have achieved exactly and precisely nothing. This is a variation on pushing people off cliffs to stop them dying of heart attacks.

Results: ‘Pushing one hundred people prevented all trial participants from suffering a fatal heart attack. We therefore recommend pushing everyone off a cliff to reduce the incidence of heart attacks in the general population.’ A.N. Idiot et al.

Statins reduce major vascular events. [A major non-fatal vascular event could also be called as Serious Adverse Event (SAE)]. But do they reduce all serious adverse events (SEAs). If not, you are simply replacing a major vascular event with something equally nasty.

Which leads on to the next question, do we know from the statin trials if statins do reduce SAEs in total? The answer is that we do not know this, for sure, because the CTT has these data, and refuses to let anyone else see them. However, some data has not been censored by big brother. The Cochrane collaboration (before they started the sad slide to bias and corruption) looked at this issue – way back in 2003.

They got as much data as they could from the five major primary prevention statin trials at the time. Here was their conclusion on Serious Adverse Events:

‘In the two trials where serious adverse events are reported, the 1.8% absolute reduction in myocardial infarction and stroke should be reflected by a similar absolute reduction in total serious adverse events; myocardial infarction and stroke are, by definition, serious adverse events. However, this is not the case; serious adverse events are similar in the statin group, 44.2%, and the control group, 43.9%.

This is consistent with the possibility that unrecognized serious adverse events are increased by statin therapy and that the magnitude of the increase is similar to the magnitude of the reduction in cardiovascular serious adverse events in these populations. This hypothesis needs to be tested by analysis of total serious adverse event data in both past and future statin trials. Serious adverse event data is available to trial authors, drug companies and drug regulators. The other measure of overall impact, total mortality, is available in all five trials and is not reduced by statin therapy.’ 3

What does this mean in reality? Well, gathering it all together. Statins (in the over 75s) do not reduce mortality. They do not prevent fatal Mis and strokes. Whilst they reduce serious cardiac events, previously published results demonstrate they do not reduce total serious adverse events.

Which means that they are, wait for it, absolutely and completely useless.

Two plus two does equal four. Always bear that fact in mind.





What causes heart disease part 62

19th January 2019

I suppose it is gratifying to see things I write very strongly supported a few days later. After telling everyone that a high cholesterol level is not a risk for stroke, out comes a study almost straight away, demonstrating that a low cholesterol level increases mortality in patients who have already had a stroke.

This was in a population – and I would highlight this fact – in a population who have high grade carotid artery stenosis. Which mean a high degree of atherosclerosis on the carotid arteries (supplying blood to the brain). The paper is called:

‘Lower cholesterol tied to increased mortality in ischaemic stroke patients with carotid artery stenosis.


In patients with acute, first-ever ischaemic stroke with high-grade internal carotid artery (ICA) stenosis and post-stroke functional dependence, lower total cholesterol level was associated with increased risk for 5-year mortality.

Why this matters:

Recent treatment guidelines of hyperlipidaemia suggest more aggressive treatment for reducing risk for atherosclerotic cardiovascular diseases and ischaemic stroke.

However, these findings suggest a careful consideration of aggressive treatment of hyperlipidaemia in patients with acute, first-ever ischaemic stroke with high-grade ICA stenosis and post-stroke functional dependence.

Study design:

Study prospectively evaluated 196 patients with acute ischaemic stroke with high-grade ICA stenosis and modified Rankin Scale score ≥3.

Patients were divided into 2 groups based on total cholesterol level at admission: ≥200 or <200 mg/dL.

Patients were followed-up for 5 years after initial assessment.

Key results:

After adjusting for established clinical predictors of adverse outcomes, lower total cholesterol level (aHR, 1.88; 95% CI, 1.09-3.23; P=.023) was a significant risk factor for 5-year all-cause mortality.

The prevalence of diabetes mellitus (P=.013) was significantly higher and that of atrial fibrillation (P=.011) was significantly lower in patients with high vs low total cholesterol level.

Patients with lower cholesterol level had significantly lower value of haemoglobin (P=.001), whereas glycohaemoglobin was significantly higher in patients with higher total cholesterol level (P=.001).

Funding: None.

Four most annoying words in the English language. ‘I told you so.’

Of course, this study will be dismissed out of hand. “We should still be prescribing statins to people who have had ischaemic strokes” we will be told. “Studies like this are purely observational” we will be told. “A high cholesterol level still needs to be lowered” we will be told. Nothing to see here, please move along!

I do become increasingly weary of finding evidence that directly and absolutely contradicts the cholesterol hypothesis. It never makes the slightest difference – to anything. Hopefully a few people are out there listening, whose minds are not made of reinforced concrete.


Lung YJ, Weng WC, Wu CL, Huang WY. Association Between Total Cholesterol and 5 year Mortality in Patients with Carotid Artery Stenosis and Poststroke Functional D ependence. J Stroke Cerebrovasc Dis. 2019 Jan 11 [Epub ahead of print]. doi: 10.1016/j.jstrokecerebrovasdis.2018.12.030. PMID: 30642665

What causes heart disease part 61 – strokes

15th January 2019

In this never-ending story on heart disease, I have tended to use the terms “heart disease” and “cardiovascular disease” almost interchangeably. Well, everyone else does it, so why not me? However, in this blog I shall be splitting cardiovascular disease into its two main components, heart attacks and strokes, and concentrating mainly on strokes.

The first thing to say is that there are three main causes of strokes.

  • Atrial Fibrillation (ischaemic)
  • A burst blood vessel in the brain (haemorrhagic)
  • A blood clot (ischaemic)

[There are also cryptogenic strokes (no known cause), strokes due to a hole in the heart, strokes due to antiphospholipid syndrome, strokes due to sickle cell disease etc. etc.)

Atrial Fibrillation (AF) is a condition where the upper chambers of the heart (atria) do not contract and relax smoothly every second or so. Primarily because there is a disruption in the electrical conduction system, causing the atria to spasm and twitch in a highly irregular fashion.

When this happens, blood clots can form in the left atrium then break off and head up into the brain and get stuck. Causing a stroke. They can also travel elsewhere in the body causing a blockage to an artery in the kidneys, the leg, the arm and suchlike. If they form in the right atrium, they will end up stuck in the lungs.

These clots are usually quite small, about the size of a large grain of rice, but this is still big enough to do quite considerable damage. The treatment for AF is either to try and reverse the fibrillation or, if this does not work, to give anticoagulants such as warfarin to stop the clots forming.

A haemorrhagic stroke is when a blood vessel in the brain bursts. Blood is then forced into the brain and causes a lot of damage – leading to a stroke. Haemorrhagic strokes are usually quite severe, as you can imagine. The treatment is to NOT give an anti-coagulant of any sort. Haemorrhagic strokes are often/usually caused by a thinning of the artery wall, causing a ballooned area (aneurysm), which then bursts.

An interesting question, and I have seen different views on this is whether a small blood clot travels to the brain where it gets stuck, but does not completely block the artery, so it does not cause a stroke, but it creates an area of damage – which is then repaired – that leaves a weakness in the artery that balloons out – an aneurysm.

Anyway, the most common cause of a stroke is that large atherosclerotic plaques form in the main arteries that supply blood to the brain (carotid arteries). These plaques usually form around the base of the neck. A blood clot then forms on top of the plaque, then breaks off and travels to the brain, where it gets stuck – as with atrial fibrillation – causing a stroke. The effect is the same as with AF, but the underlying causing is completely different.

According to the American Stroke Association 87% of strokes are ischaemic.

Which means that the vast majority of strokes are caused by atherosclerotic plaques in the neck. Just as the vast majority of heart attacks are caused by atherosclerotic plaques in the coronary arteries. Therefore, you would expect that the risk factors for stroke would be exactly the same as the risk factors for heart attacks, as the underlying process is the same.

Well, many of the standard risk factors are the same. Smoking, diabetes, high blood pressure and suchlike. However, a raised LDL most certainly is not. There is a research study called the Simon Broome registry, started in the UK, that tracks the health outcomes of people diagnosed with familial hypercholesterolaemia (FH).

It is a fascinating resource which, if you decide to interpret their data through a different prism, virtually rules out the raised LDL in familial hypercholesterolaemia as a cause of CVD. One of the earlier papers in the BMJ, on the findings of the Simon Broome registry, found that:

‘Familial hypercholesterolaemia is associated with a substantial excess mortality from coronary heart disease in young adults but may not be associated with a substantial excess mortality in older patients.1

For ‘may not be’, replace, ‘is not’. In fact, what the Simon Broome registry has found repeatedly is that, after the age of, about fifty, FH does not increase the risk of coronary heart. Thus LDL is a risk factor before the age of fifty, and not after? Which means that it cannot be a risk factor at all [the thing that kills young people with FH before the age of fifty is clotting factor abnormalities – not raised LDL]

Which is something covered in the magnificent and insightful paper: ‘Inborn coagulation factors are more important cardiovascular risk factors than high LDL-cholesterol in familial hypercholesterolemia.2 Yes, as you may have guessed, I was a co-author.

However, if we move away from heart disease, to strokes. FH has never been found to be a risk factor for stroke – at any age. Here, for example is a study done in Norway, and published in the Journal Stroke. It was called ‘Risk of ischaemic stroke and total cerebrovascular disease in familial hypercholesterolaemia.’

A total of 46 cases (19 women and 27 men) of cerebrovascular disease were observed in the cohort of people with FH, with no increased risk of cerebrovascular disease compared with the general population (standardized incidence ratio, 1.0; 95% CI, 0.8–1.4). Total number of ischemic strokes in the cohort of people with FH was 26 (9 women and 17 men), with no increased risk compared with the general population (standardized incidence ratio, 1.0; 95% CI, 0.7–1.5).3

In 2010 the Lancet published a major study looking at risk factor for stroke in the non-FH population3. They used the term population attributable risk factors (PAF), which ‘weights’ the factors, depending on how prevalent they are (i.e., how many people have got the various risk factors). Their list of PARs for stroke was as follows:

  • 51.8% – Hypertension (self-reported history of hypertension or blood pressure >160/90mmHg)
  • 18.9% – Smoking status
  • 26.5% – Waist-to-hip ratio
  • 18.8% – Diet risk score
  • 28.5% – Regular physical activity
  • 5% – Diabetes mellitus
  • 3.8% – Alcohol intake
  • 4.6% – Psychosocial stress
  • 5.2% – Depression
  • 6.7% – Cardiac causes (atrial fibrillation, previous MI, rheumatic valve disease, prosthetic heart valve)
  • 24.9% – Ratio of ApoB to ApoA (reflecting cholesterol levels)

You will see that LDL is not in that list. The ratio of ApoB to ApoA is. However, this is primarily the ratio of VLDL (triglycerides) to HDL (‘good’ cholesterol), which is an accurate reflection of ‘insulin resistance’ and bears no relationship to LDL. As I always say to people who ask me for advice on reviewing clinical research…’the most important thing to focus on is not what is there, it is what is not there.’

Any study on CVD will be examining LDL levels very closely. If a relationship were found it would be shouted from the rooftops. The fact that you hear nothing about LDL in this paper means that there was no correlation – at all.

You can, if you wish, try to find some evidence that the risk of stroke is increased by a raised LDL level. I must warn you that you will look for a long time, because there is no evidence, anywhere – at all. It has interested me for many years that this issue is simply swept under the carpet.

Now, write out one hundred times:

  • Raised LDL is not a risk factor for stroke
  • Raised LDL is not a risk factor for stroke
  • Raised LDL is not a risk factor for stroke….

Then, ask yourself the question. How can a raised LDL be a risk factor for heart disease and not stroke – as the two conditions are, essentially, the same condition? Atherosclerotic plaques in medium sized arteries with the critical/final event being the formation of a blood clot – on top of the plaque.

Then, ask yourself another question. If a raised LDL is not a risk factor for stroke, how can lowering the LDL level provide any benefit? The correct answer is that… it cannot. Yet statins do provide benefit in stroke (Usual proviso here. Not by a great amount in absolute terms, but the benefit does appear to exist).

‘A meta-analysis of randomized trials of statins in combination with other preventive strategies, involving 165,792 individuals, showed that each 1-mmol/l (39 mg/dl) decrease in LDL-cholesterol equates to a reduction in relative risk for stroke of 21.1 (95% CI: 6.3-33.5; p = 0.009)’ 4

Just to repeat the main point here. A raised LDL is not, and has never been, a risk factor for stroke. Yet it is claimed that lowering the LDL level reduces the risk of stroke? In reality, the evidence from the statin trials prove, beyond any doubt, that any benefit achieved by statins cannot be through lowering the LDL level.

The logic stripped down is, as follows:

  • A raised level of factor A does not cause disease B
  • Thus lowering factor A cannot reduce the risk of disease B
  • Thus, you cannot claim that lowering factor A can have any possible effect on disease B

However, every single cardiovascular expert seems delighted to inform us, in all seriousness, that lowering factor A does, indeed, reduce the risk of disease B. Despite this breaking the very fabric of logic in two.

“Alice laughed: “There’s no use trying,” she said; “one can’t believe impossible things.”

I daresay you haven’t had much practice,” said the Queen. “When I was younger, I always did it for half an hour a day. Why, sometimes I’ve believed as many as six impossible things before breakfast.” Alice in Wonderland.





What causes heart disease part 60 – prediction

2 January 2019

It is difficult to make predictions, particularly about the future.’ Old Danish proverb

The hallmark of a great scientific hypothesis is prediction. Einstein’s theory of special relativity predicted that gravitational fields could be demonstrated to bend light – and he was proven right during observations made during a total eclipse of the sun.

Unfortunately, things are rarely as black and white as that. Even if you understand almost all of the factors at play, it can be extremely difficult to predict certain events, particularly the timing. Earthquakes, hurricanes, which flu virus will be active next year? There are so many variables interacting with each other that things get very complex. When will San Francisco suffer the next major earthquake? According to the best predictions – about twenty years ago.

Chaos theory can also play its part. A very small change in one part of a system can trigger massive downstream effects. A butterfly flaps its wings in Africa, and two weeks later a hurricane devastates Florida.

So, what of predicting your future risk of cardiovascular disease? How good are the current models? Are they of any use at all?

In the US, the calculator that is most widely used was put together by the American Heart Association and American College of Cardiology.(AHA/ACC). It is called the ‘cvriskcalculator’ It can be found on-line here It asks you to provide data on ten different parameters:

  • Age
  • Sex
  • Race
  • Total cholesterol
  • HDL (good) cholesterol
  • Systolic blood pressure
  • Diastolic blood pressure
  • Treated for blood pressure: yes or no
  • Diabetes: yes or no
  • Smoker: yes or no

After you input your data, an algorithm kicks into action to work out your cardiovascular future. If it calculates that your risk of suffering a CV event is greater than 7.5%, within the next ten years, you will be recommended to start on a statin. This, you will have to take for the rest of your life.

One word of warning, all men by age of fifty-five – even men with no other risk factors at all – will have a risk greater than 7.5%. At least they will, using ‘cvrisk’. Because age is by far the most powerful risk factor of all – at least it is on ‘cvrisk’.

In the UK, a more complex risk factor calculator has been developed. In truth, it is only more complex in that it has an additional ten risk factors to consider. It is called Qrisk3. It uses twenty different factors to calculate risk   They are, in no particular order:

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

How good are they at predicting a future event? A study was carried out in the US to analyse, in retrospect, how accurate the cvriskcalculator had been. They looked at the historical risk scores of several thousand people, then tracked forward in time to see what actually happened.

In the study they looked at CVD over five years, not ten, so all figures should be doubled to establish the ten-year risk that is used in most calculators:

‘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. Go1

What this means is that you carefully input your parameters into a risk calculator, which took many years of painstaking work to develop, using data carefully gathered by experts from the world of cardiology, and it overestimates your risk by five to six-fold. (I.e., 400 – 500% exaggeration!)

Excellent. Just for starters, this means that millions upon millions of people have been told to take a statin based on a calculation that is so wildly inaccurate as to be virtually meaningless. How so, Dr Go?

On a similar note, a group of researchers in the UK decided to look at data gathered on 378,256 patients from UK general practices. They wanted to establish which factors were most important in predicting future risk. The paper was called ‘Can machine-learning improve cardiovascular risk prediction using routine clinical data?’ 2

If the ACC/AHA and Qrisk3 calculators truly are looking at the most important variables, then we should see all the same factors appearing in this UK study. Below, just to remind you, are the ten factors used in the ACC/AHA calculator:

  • Age
  • Sex
  • Race
  • Total cholesterol
  • HDL (good) cholesterol
  • Systolic blood pressure
  • Diastolic blood pressure
  • Treated for blood pressure: yes or no
  • Diabetes: yes or no
  • Smoker: yes or no

Here is what the UK researchers found to be the top ten risk factors for CVD, in order, with number one being highest risk and number ten lowest risk:

  1. Chronic Obstructive Pulmonary Disease (usually a result of smoking)
  2. Oral corticosteroid prescribed
  3. Age
  4. Severe mental illness
  5. Ethnicity South Asian
  6. Immunosuppressant prescribed
  7. Socio-economic-status quintile 3
  8. Socio-economic status quintile 4
  9. Chronic Kidney Disease
  10. Socio-economic status quintile 2

Compare and contrast, as they say. Do these lists look remotely the same? As you can see, there are only two factors on the ACC/AHA list that were replicated by the UK researchers. One of them is age – which you can do nothing about, and the other is ethnicity – which you can do nothing about. As for the rest. Where have they gone?

What of cholesterol, and sex, and blood pressure, and smoking, and diabetes. Well, out of a total of forty-eight factors analysed, here is where they ranked in importance. In this analysis factors could either be ranked protective, or causal:

Smoking                                  = 18

Sex/female                              = 19 (protective)

Total cholesterol                    = 25

HDL cholesterol                      = 28 (protective)

Systolic blood pressure          = 29

Diabetes                                  = 31

LDL ‘bad’ cholesterol              = 46

Yes, LDL ranked 46th out of 48 factors, well, well, who’d a thunk. The only things that scored lower than LDL were FEV1 and AST/ALT ratio. Factors that, unless you are medically trained, you will never have heard of. The first one, FEV1 stands for forced expiratory volume (from your lungs), measured over one second. The other is the ratio of two liver enzymes.

At present, it is true to say that the established risk factors, and the risk calculators, are almost completely useless. Not only that, they get more useless if you try to use them across different countries. If I took Qrisk3, or ‘cvrisk’ to France, whatever risk it calculated, I would then have to divide whatever figure I got, by four.

This is because, for exactly the same set of risk factors, someone in France will have one quarter the rate of CVD as a man in the US, or UK. Which means that the ‘cvrisk’ would actually overestimate risk by twenty-fold in France. Five times too high a calculated risk in the US, multiplied by four times too high a calculated risk in France. 5 x 4 = 20.

So, what should you measure? What can help you to predict your risk of CVD? Coronary calcium score (CAC)? That is, looking at the amount of calcium in your arteries. This is probably the most accurate way to establish your burden of atherosclerosis.

However, a high(er) CAC score does not mean that you are at risk of CVD, it means you have already got CVD, it is already there. The CAC score is just telling you how far along the CVD path you have traveled. So, it is not really predictive, it is more of a historical record.

What you really want is to stop the calcium forming in your arteries in the first place. Or then again, do you? A ‘calcified’ plaque is not, necessarily, a dangerous plaque. A dangerous plaque has an almost liquid core, which is in danger of rupturing. A dangerous plaque is often called a vulnerable plaque, and they don’t show up well, if at all, on a CAC scan.

If you have lots of vulnerable plaque what should you do?

Take a statin. Statins accelerate calcification.

Take warfarin. Warfarin accelerates calcification

Both reduce the risk of dying of CVD – if only by a small amount (at least small with statins). So, you could both increase calcification and reduce your risk of a CV event – simultaneously. What then to make of your CAC score? If you find it is zero, great. If you find it is four hundred?

Logically, a high score only tells you that you have CVD, and already having CVD means you are at higher risk of dying of a CV event. Which comes as no great surprise. What you really need to be able to do is to accurately predict what your CAC score would be – before you did it. And if you could do that, you really would have a scientific hypothesis worthy of the name.

The LDL hypothesis for example. If you could find you someone with an extremely high LDL level, say four to five times average, and a CAC score of zero – at the age of seventy-two then you would remove it as a factor for prediction.

So, here you go – I have blogged about this before – from a paper called: ‘A 72-Year-Old Patient with Longstanding, Untreated Familial Hypercholesterolemia but no Coronary Artery Calcification: A Case Report.’

The subject has a longstanding history of hypercholesterolemia. He was initially diagnosed while in his first or second year as a college student after presenting with corneal arcus and LDL-C levels above 300 mg/dL [7.7mmol/l] 3

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

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

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

Prediction, prediction. The risk factor calculators cannot do it. LDL levels don’t do it. I cannot do it with perfect accuracy either. I cannot say to anyone that you will not die of CVD. I cannot say to anyone that you will die of CVD. I can only help you to change the odds.

If you are an elderly, depressed, diabetic South Asian man with Chronic Obstructive Pulmonary Disease, taking steroids, with chronic kidney disease, living in a small council house in the UK then your odds of dying of CVD in the next year are pretty damned high. What should such a person do? Write a will, I would think.

Not many of us are at such high risk. Few of us are in such a bleak situation. What can the average person do to shift those odds in your favour? If you have read this blog from start to finish, I would imagine that you already know. If not, I am going to tell you next time. I am going to tell you how to change the odds, but I am unable to tell you how to get them to zero.




Wikipedia a parable for our times

18th December 2019

As readers of this blog know I was obliterated from Wikipedia recently. Many have expressed support and told me not to get down about it. To be perfectly frank, the only time I knew I was on Wikipedia was when someone told me I was going to be removed. So it hasn’t caused great psychological trauma.

In fact my feelings about this are probably best expressed on a Roman tombstone. It has been translated in different ways, but my favourite version is the following:

I was not
I was
I am not
I care not

However, in the greater scheme of things, whilst my removal from Wiki is completely irrelevant, in another way it is hugely important. As Saladin said of Jerusalem, whilst he was battling with the Christians during the crusades. ‘What is Jerusalem? Jerusalem is nothing; Jerusalem is everything.’

My removal from Wikipedia is nothing. My removal from Wikipedia is everything. Not because it is me, but because of what it represents. Not to beat about the bush, there is a war going on out there between scientific enlightenment, and the forces of darkness.

You think that is too dramatic? Well, this is what Richard Horton – editor of the Lancet for many years – has to say about the current state of medical science.

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

Science has taken a turn towards darkness? Of course science cannot really turn anywhere. It is not an entity. Science is simply made up of people. The scientific method itself is simply an attempt to discover what is factually true, by removing human bias. It is, like everything humans do, imperfect. Bias is always there.

What Horton means is that the methods used to pursue science have increasingly moved from the pure Olympian ideal, a disinterested quest for truth, to something else. Distortion, manipulation and bias. In some cases downright lies. I hesitate to use the term ‘fake news’, but that is what it is. What it is becoming.

As John Ioannidis had to say in his seminal paper ‘Why most published research findings are false’

‘Moreover, for many current scientific fields, claimed research findings may often be simply accurate measures of the prevailing bias. It is more likely for a research claim to be false than true.’1

I think, in truth, this very much depends on the area of science you are looking at. Someone examining the food intake of the fruit bat is probably working away free from any pressure to make their findings fit with pre-existing ideas. Whilst they could be wrong, they will not been working to any agenda.

Some areas are highly contentious, where truth becomes the first casualty. For example, global warming, where you can see dreadful science being done on all sides, as people desperately try to prove their point. I watch on, in scientific despair. I have no idea what to believe, or who to believe, anymore.

Moving back to medical scientific research, which is more my area. Much of what is going on here is a complete disaster, but nutritional science is particularly awful. A complete mess. I have virtually given up reading any paper in this area as they just annoy me so much. I simply look at the authors involved, and I know what the paper is going to say. This does save time.

Ioannidis has turned his attention to nutritional science, in some detail. To quote from The American Council on Science and Health:

Dr. Ioannidis bluntly states that nutrition epidemiology is in need of “radical reform.” In a paragraph that perfectly captures the absurdity of the field, he writes:

“…eating 12 hazelnuts daily (1 oz) would prolong life by 12 years (ie,1 year per hazelnut), drinking 3 cups of coffee daily would achieve a similar gain of 12 extra years, and eating a single mandarin orange daily (80 g) would add 5 years of life. Conversely, consuming 1 egg daily would reduce life expectancy by 6 years, and eating 2 slices of bacon (30 g) daily would shorten life by a decade, an effect worse than smoking. Could these results possibly be true?”

The answer to his rhetorical question is obviously no. So, how did this garbage get published?

How did this garbage get published? How does the garbage get published? On the other hand how did a major study on replacing saturated fat with polyunsaturated fat (The Minnesota Coronary Experiment) NOT get published?

Because it found that polyunsaturated fat did lower cholesterol levels, but the more it lowered the cholesterol level, the greater the risk of death! That is in the results, and you can read that for yourself – this was the conclusion:

Available evidence from randomized controlled trials shows that replacement of saturated fat in the diet with linoleic acid effectively lowers serum cholesterol but does not support the hypothesis that this translates to a lower risk of death from coronary heart disease or all causes. Findings from the Minnesota Coronary Experiment add to growing evidence that incomplete publication has contributed to overestimation of the benefits of replacing saturated fat with vegetable oils rich in linoleic acid. 2

The results of this study were, eventually found in the garage of the son of one of the lead investigators. It was recovered and published forty years later in the British Medical Journal. Long after one of the lead investigators, Ancel Keys, had died. Yes, indeed.

I wrote the book “Doctoring Data” to try and shine some light on the methods used to distort and manipulate data. I try, as best as I can, to follow the scientific method. That includes discussion and debate, to test ones ideas in the furnace of sustained attacks.

However, if you try to do this, the forces of darkness come after you, and they come hard. Especially if ever dare to suggest that animal fats, saturated fats, are not in the least harmful. At which point you waken the vegan beast, and this beast is not the least interested in science, or the scientific method, or discussion or debate.

It has one aim, and that is to silence anyone, anywhere, who dares to question the vegan philosophy. Aided and abetted by the Seventh Day Adventist church. Below is a short list, non-exhaustive list, of those who have suffered their wrath:

Prof Tim Noakes – South Africa
Dr Maryanne Demasi – Australia
Dr Gary Fettke – Australia
Professor John Yudkin – UK
Dr Aseem Malhotra – UK
Dr Uffe Ravnskov – Sweden
Dr Andreas Eenfeldt – Sweden
Dr Zoe Harcombe – UK
Dr Robert Atkins – US
Nina Teicholz – US
Gary Taubes – US
Dr. Anna Dahlqvist – Sweden

Several of these doctors have been dragged in front of the medical authorities, usually by dieticians, who claim that patients are being damaged. So far, they have all won their cases – often after prolonged and expensive legal hearings. Luckily, the courts recognise logic when they see it.

Uffe Ravnskov has his book, the Cholesterol Myths, questioning the cholesterol hypothesis burned, live on air. All of the brave souls on this list have been accused of ‘killing thousands’ at one time or another. Maryanne Demasi lost her job with the Australian Broadcasting Company.

Now, it seems, the attacks have moved into a different area, such as a determined effort to remove everyone from Wikipedia. When the vegans find someone they don’t like, they work tirelessly to extinguish them from the record. They call them kooks and quacks – but they never ever reveal who they truly are. They exist in the shadows.

They got rid of me from Wikipedia; they are currently attacking Aseem Malhotra, Uffe Ravnskov, Jimmy Moore, and the entire THINCS network. (The International Network of Cholesterol Sceptics). There are even worse things going on, that I cannot speak about yet.

Yes, this is science today. At least it is one part of science – which is not science, and it has definitely turned to the darkness. You can be accused of being a kook and a quack by someone who hides behind anonymity and never dares to show their face. In truth, I know who it is. Someone found out for me. Yes MCE, it is you.

You want a debate, come out into the open, and reveal yourself, your motives and your arguments to the world. Then we can do science. Until then please expect me to hold you in the contempt that you deserve.





Dr Malcolm Kendrick – deletion from Wikipedia

I thought I should tell you that I am about to be deleted from Wikipedia. Someone sent me a message to this effect. It seems that someone from Manchester entitled User:Skeptic from Britain has decided that I am a quack and my presence should be removed from the historical record.

I have no idea who this person is, perhaps it is possible to find out? It seems a bit harsh as I recently contributed money to Wikipedia to keep it going. Was this a terrible mistake?

To be frank, I am not entirely bothered if I no longer appear on Wikipedia, but I am increasingly pissed off that self-styled anonymous ‘experts’ can do this sort of thing without making it explicit why they are doing it, what their motives are, and if they have any disclosure of interest.

Perhaps user Skeptic from Britain would like to reveal himself and provide some information as to why he is so interested in trying to wipe me out? Perhaps one or two of you here could join in the discussion and see what emerges.

His reasons for trying to get rid of me are the following

Malcolm Kendrick is a fringe figure who agues(sic) against the lipid hypothesis. He denies that blood cholesterol levels are responsible for heart disease and in opposition to the medical community advocates a high-fat high-cholesterol diet as healthy. Problem is there is a lack of reliable sources that discuss his ideas. His book The Great Cholesterol Con was not reviewed in any science journals. Kendrick is involved with the International Network of Cholesterol Skeptics, I suggest deleting his article and redirecting his name to that. Skeptic from Britain (talk) 20:29, 2 December 2018 (UTC)

Come out, come out, whoever you are.

What causes heart disease – part 59

27th November 2018

A number of people have written to me asking how to read all the articles I have written on cardiovascular disease. I understand it is not exactly easy to do this. So, here I am going to attempt a short summary of everything I have written up to now.

Thrombogenic theory vs. LDL/cholesterol hypothesis

Since the mid-nineteenth century there have been two main, and almost entirely conflicting, hypotheses as to what causes cardiovascular disease. At present it may seem as if there is only one, the cholesterol or LDL hypothesis. Namely that a raised low-density lipoprotein is the underlying/primary/necessary cause.

I am not running through all the reasons why this hypothesis is wrong here. I will confine myself to one simple point. For the LDL hypothesis to be correct, it requires that LDL can travel past the lining of the artery, the endothelial cells, and into the artery wall behind. This is considered the starting point for atherosclerotic plaques to form.

The problem with this hypothesis is that LDL cannot get into any cell, let alone an endothelial cell, unless that cell wants it to. We know this, for certain, because the only way for LDL to enter any cell, is if the cell manufactures an LDL receptor – which locks onto, and then pulls the LDL molecule inside. There is no other passageway. This is an inarguable fact.

If LDL cannot enter a cell, unless allowed to do so, then it cannot pass through a cell, unless a cell wants it to. It most certainly cannot exit the other side of a cell, unless granted passage.

Others have argued that, oh well, the LDL simply slips through the gaps between endothelial cells and that is how it gets into the artery wall. Again, this is impossible. There are no gaps between endothelial cells. Endothelial cells are tightly bound to each other by strong protein bridges, known as ‘tight junctions.’

These tight junctions can prevent the passage of single ions – charged atoms – which makes it impossible for an LDL molecule to slip through, as it is many thousands of times bigger than an ion. This, too, is an inarguable fact.  Ergo, the initiation of an atherosclerotic plaque (the underlying problem in cardiovascular disease) cannot be triggered by LDL leaking into an undamaged artery wall.

Which means that, if you want to get LDL (or anything else) into the artery wall, you first must damage the endothelium/lining of the artery. This has been accepted by the mainstream medical world, although you wouldn’t really know it, because they don’t exactly shout it from the rooftops.

Here, however, is a quote from the National Heart Lung and Blood Institute in the US. An organisation which is as mainstream as it gets:

Research suggests that coronary heart disease (CHD) starts when certain factors damage the inner layers of the coronary arteries. These factors include:

  • Smoking
  • High levels of certain fats and cholesterol in the blood
  • High blood pressure
  • High levels of sugar in the blood due to insulin resistance or diabetes
  • Blood vessel inflammation
  • Plaque might begin to build up where the arteries are damaged

It has taken them a long time to admit that damage must come first, but it is inescapable when you think about it. For once, I am completely in agreement with the mainstream on this, the initial step.

However, it is what happens next, where we rapidly diverge in our thinking. The mainstream believes that, after damage has occurred, it is LDL, and only LDL, leaking into the artery wall that triggers a whole series of downstream reactions that lead to plaques forming.

However, once you have damaged the endothelium there is no longer a barrier to stop anything getting into the artery wall. So, why pick on LDL? You also have proteins, red blood cells, platelets and Lp(a) and VLDL. Indeed, anything in the bloodstream now has free entry.

It particularly makes no sense to pick on LDL, as there is already plenty of LDL in the artery wall to start with. It gets there via the vasa vasorum (blood vessels of the blood vessels) which supply the largest blood vessels with all the nutrients they need, and through which LDL can freely flow into, and out of, the artery wall.

Which begs a further question. Why should the LDL that gets into the artery wall, from the blood flowing through the artery, cause a problem, when the LDL that is already there – does nothing? The more you look at it, the more ridiculous the LDL hypothesis becomes.

A counter hypothesis is as follows.

If you damage the endothelium, the first thing that happens is that a blood clot forms at that point. This has been known for a long time. I was sent an article a while ago, written as far back as 1959. The findings stand today:

‘…any intimal injury can very easily precipitate a local process of coagulation, platelet agglutination and fibrin deposition.’1 [a.k.a. a blood clot]

You may wonder where the word ‘intima’ just appeared from. The endothelium, and the thin layer underneath the endothelial cells is sometimes called the ‘intima.’ Sometimes it is called the endothelial layer, some people call it the epithelium, or the epithelial layer. What you never get, in medicine, is people calling it the same thing… the same damned thing. Thank God these people don’t make aeroplanes, is all I can say.

Anyway, damage the endothelium, and a blood clot will form. This is the main mechanism the body uses to stop itself from bleeding to death. Damage the artery/endothelium → underlying artery wall exposed → blood clot forms → life continues.

What then happens? Well, most of the blood clot is shaved down in size by plasmin, an enzyme designed to break up (lyse) blood clots. Then a new layer of endothelium grows over the top of the remaining blood clot, and in this way, the clot becomes incorporated into the artery wall. Although I have added in a few extra bits, this is, essentially, the thrombogenic theory, first suggested by Karl von Rokitansky in 1852.

He proposed this because he noted that atherosclerotic plaques looked very much like blood clots, in various stages of repair. He further observed they contained red blood cells, fibrin and platelets, which are the main constituents of a blood clot. His ideas were then rubbished by Rudolf Virchow, who could not see how a blood clot could end up underneath the endothelium, and Rokitansky’s theory (almost) died a death.

However, from time to time, other researchers also noted that plaques do look awfully like blood clots. For example, a researcher called Elspeth Smith – who taught me at Aberdeen University. She had this to say

‘…in apparently healthy human subjects there appears to be a significant amount of fibrin deposited within arteries, and this should give pause for thought about the possible relationship between clotting and atherosclerosis.’ 2

As her paper went on to say:

‘In 1852 Rokitansky discussed the “atheromatous process” and asked, “In what consists the nature of the disease?” He suggests “The deposit is an endogenous product derived from the blood, and for the most part from the fibrin of the arterial blood”. One hundred years later Duguid demonstrated fibrin within, and fibrin encrustation on fibrous plaques, and small fibrin deposits on the intima of apparently normal arteries. These observations have been amply confirmed but, regrettably, the emphasis on cholesterol and lipoproteins was so overwhelming that it was another 40 years before Duguid’s observations had a significant influence on epidemiological or intervention studies.

Finally, for now, Dr Smith stated this in another paper:

‘After many years of neglect, the role of thrombosis in myocardial infarction is being reassessed. It is increasingly clear that all aspects of the haemostatic system are involved: not only in the acute occlusive event, but also in all stages of atherosclerotic plaque development from the initiation of atherogenesis to the expansion and growth of large plaques.’3

What she is saying here is that every step of CVD is due to various aspects of blood clotting. You damage the artery wall, a blood clot forms, it is then incorporated into the artery wall. A plaque starts, then grows. This description of how CVD starts and develops, is the process that I believe to be correct. With a couple of provisos.

The main proviso is that endothelial damage is going on all the time, in everyone’s arteries, to a greater or lesser extent. Therefore, we are not looking at an abnormality, or a disease, or a ‘diseased’ process.

The formation of blood clots following endothelial damage is also a healthy, normal, process. If it did not happen, then we would all bleed to death. As can happen in haemophilia, where blood clots do not form properly, due to a lack of clotting factors.

The next normal healthy process is that any blood clots that form must be incorporated into the artery wall. That is, after having been stabilised and shaved down. If clots simply broke off and travelled down the artery, they would get stuck when the artery narrows and cause strokes and heart attacks – and bowel infarctions and suchlike.

In short, the only way to repair any blood clot that forms on the lining of an artery wall, is to shave it down, then cover it over with a new layer of endothelial cells. Incorporating it into the artery wall.

At which point, repair systems swing into action. The main repair agents are white blood cells called macrophages. These break down and digest any remnant blood clot, before heading off to the nearest lymph gland where they too are broken down, with their contents, and removed from the body.

This ‘repair’ process leads to, what is referred to as ‘inflammation’ in the artery wall. Once again, however, this is not a disease process, it is all quite healthy and normal.

Problems only start to occur when the rate of damage, and resultant blood clot formation, outstrips the ability of the repair systems to clear up the mess.


damage > repair = atherosclerosis/CVD

repair > damage = no atherosclerosis and/or reversal of plaques.

What factors can lead to the situation where damage outstrips repair? First, we need to look at those factors that increase the rate of damage. There are many, many, things that can do this. Here is a list. It is non-exhaustive, it is in no particular order, but it may give you some idea of the number of things that can cause CVD, by accelerating endothelial damage:

  • Smoking
  • Systemic Lupus Erythematosus
  • Use of oral steroids
  • Cushing’s disease
  • Kawasaki’s disease
  • Rheumatoid arthritis
  • High blood pressure
  • Omeprazole
  • Avastin
  • Thalidomide
  • Air pollution
  • Lead (the heavy metal)
  • Mercury
  • High blood sugar
  • Erythema nodosum
  • Rheumatoid arthritis
  • Low albumin
  • Acute physical stress
  • Acute mental stress
  • Chronic negative mental stress
  • Chronic Kidney Disease
  • Dehydration
  • Sickle cell disease
  • Malaria
  • Diabetes/high blood sugar level
  • Bacterial infections
  • Viral infections
  • Vitamin C deficiency
  • Vitamin B deficiency
  • High homocysteine level
  • Chronic kidney disease
  • Acute renal failure
  • Cocaine
  • Angiotensin II
  • Activation of the renin aldosterone angiotensin system (RAAS) etc.

Blimey, yes, that list was just off the top of my head, I could get you another fifty without much effort. And no, I did not just make it up. I have studied every single one of those factors, and many more, in exhaustive detail. The extent of how many factors there are, should not really come as a surprise to anyone, but it usually does.

After all, the bloodstream carries almost everything around the body, and the endothelium faces the bloodstream, it is the first point of contact. If damaging things are being carried about in the blood, the lining of the artery is going to be directly exposed to enemy attack.

Moving on, we need to look at factors that make the blood more likely to clot and/or make blood clots that are more difficult to shift. Again, in no particular order here and non-exhaustive:

  • Raised fibrinogen levels
  • High lipoprotein (a)
  • Antiphospholipid syndrome (Hughes’ syndrome)
  • Factor V Leiden
  • Raised plasminogen activator inhibitor 1 (PAI-1)
  • Raised blood sugar levels
  • High VLDL (triglycerides)
  • Dehydration
  • Stress hormones/cortisol
  • Non-steroidal anti-inflammatory drugs (NSAIDs)
  • Acute physical stress
  • Acute mental stress.

For good health, you want to maintain a balance between the blood being too ready to clot, and the blood not clotting when you need it to. If you turn down the blood clotting system, bleeding to death can be a problem. This can happen if you have haemophilia, or if you take warfarin – or any of the other drugs used to stop blood clots forming in Atrial Fibrillation. Aspirin can also lead to chronic blood loss, and anaemia.

Looking at it from the other angle. You do not want your blood to clot too rapidly, or else equally nasty problems can occur. Antiphospholipid syndrome (APS), is a condition where the blood is highly ready to clot (hyper-coagulable). It greatly increases the risk of CVD:

Patients with APS are at increased risk for accelerated atherosclerosis, myocardial infarction, stroke, and valvular heart disease. Vascular endothelial cell dysfunction mediated by antiphospholipid antibodies and subsequent complement system activation play a cardinal role in APS pathogenesis.’4

Just to look more closely at one other factor on the list, which is fibrinogen. This is a short strand of protein that is made in the liver. It floats about in the blood doing nothing very much. However, if a clot starts to form, or the clotting system is activated, fibrinogen ends up being stuck end-to-end to form a long thin, sticky protein strand called fibrin. This is a bit like the strands that make up a spider’s web.

Fibrin wraps around everything else in a blood clot and binds it all very tightly, creating a very tough plug. You would guess that if you have excess fibrinogen in the blood, more fibrin will form, creating bigger and more difficult to shift blood clots.  I was first alerted to the dangers of having a high fibrinogen level by the Scottish Heart Health study.

‘This large population study confirms that plasma fibrinogen is not only a risk factor for coronary heart disease and stroke, but it is also raised with family history of premature heart disease and with personal history of hypertension, diabetes, and intermittent claudication.’ 5

To my surprise, a raised fibrinogen was found to be the most potent risk factor in the Scottish Heart Health Study, ranking above smoking. Because I don’t want to make this blog too long, I will simply say that all the other things in the list above both increase the tendency of the blood to clot and increase the risk of CVD.

Finally, we can look at factors that impair the repair systems. There are two basic parts to the repair systems.

  • Formation of a new layer of endothelium, to cover the blood clot
  • Clearing away of the debris left by the blood clot within the artery wall

What sort of things stop new endothelial cells being created?

  • Avastin
  • Age – which reduces endothelial progenitor cells (EPC) synthesis
  • Thalidomide
  • CKD – reduces EPC synthesis
  • Diabetes
  • Omeprazole
  • Activation of the renin-angiotensin aldosterone system (RAAS)
  • And drug that lowers nitric oxide synthesis
  • Lack of exercise.

What sort of things damage the clearance and repair within the artery wall?

  • Steroids
  • Age
  • Immunosuppressants
  • Chronic negative psychological stress
  • Certain anti-inflammatory drugs
  • Many/most anti-cancer drugs.

Knowing this, it seems counter intuitive that there has been a great deal of interest lately in using anti-inflammatory drugs to reduce the risk of CVD. My response to the idea that inflammation may cause CVD has always been that, the most potent anti-inflammatory agent known to man is cortisone/cortisol. This is one of the stress hormones, and it vastly increases the risk of CVD. As do immunosuppressants – which are also used to dampen down the inflammatory response.

On the other hand, inflammation is not always a healthy thing. There are many chronic inflammatory conditions such as: rheumatoid arthritis, Crohn’s disease, asthma, Sjogren’s disease and suchlike where the bodies immune system goes wrong and starts to see proteins within the body as ‘alien’ and attacks them. This can cause terrible damage.

The way to best treat (if not cure) these conditions is to use immunosuppressant drugs. Cortisol/cortisone – and the many pharmaceutical variants that have been synthesized from cortisol – is still widely used. Hydrocortisone cream, for example, is widely used in eczema.

Immunosuppressants are also commonly used in transplant patients, to stop the organ from being attacked by the host immune system. This is a good thing to achieve, but longer-term problems with CVD are now widely recognised.

‘With current early transplant patient and allograft survivals nearly optimized, long-term medical complications have become a significant focus for potential improvement in patient outcomes. Cardiovascular disease and associated risk factors have been shown in renal transplant patients to be related to the pharmacologic immunosuppression employed.6

‘Taking high doses of steroids (glucocorticoids) seems to increase the risk of heart disease including heart attack, heart failure, and stroke, according to new research. Steroids fight inflammation and are often prescribed for conditions including asthma, inflammatory bowel disease, and inflammatory arthritis. Prednisone and hydrocortisone are two examples of steroids.

Yet well-known adverse effects of these potent anti-inflammatory medications can increase the risk of developing high blood pressure, diabetes, and obesity — risk factors for heart disease.’7

The question I suppose is, can CVD possibly be a form of autoimmune condition? It seems highly unlikely. Although the inflammatory system can go wrong in all sorts of way. You may have heard of Keloid scars. These happen when you damage the skin, and the resulting healing response can create a very large ‘hypertrophic’ and unsightly scar.

Perhaps if you damaged the lining of an artery, and this triggered the equivalent of a ‘keloid’ scar in the artery wall, then if you could dampen down this reaction, an atherosclerotic plaque would then be much smaller. In which case, an inflammatory could be of benefit.

However, as of today, the more potent the anti-inflammatory drug, the greater the increase in CVD. Which suggests that if you interfere with the healing response to arterial injury, you are going to make thing worse – not better.

In truth, the real reason why inflammation is being seen as a possible cause of CVD is because inflammatory markers can be raised in CVD. To my mind this just demonstrates that in people with CVD, lots of damage is occurring, therefore there is more repair going on, so the inflammatory markers are raised.

However, the mainstream has decided to look at this from the opposite side. They see a lot inflammation going on and have decreed that the inflammation is causing the CVD – rather than the other way around. Frankly, I think this is bonkers. But there you go.

Anyway, where has all this got us to. I shall try to achieve a quick summary.

The LDL hypothesis is nonsense, it is wrong, and it does not remotely fit with any other factors known to cause CVD.

The thrombogenic theory, on the other hand, fits with almost everything known about CVD. It states that there are three, interrelated, processes that increase the risk of CVD:

  • Increased rate of damage to the endothelial layer
  • Formation of a bigger or more difficult to remove blood clot at that point
  • Impaired repair/removal of remnant blood clot.

Any factor that does one of these three things can increase the risk of CVD. Although, in most cases, a few factors probably need to work in unison to overcome the body’s ability to heal itself. Which means that people who have only one or two risk factors, are probably not going to be at any greatly increased risk. You need to have three or four, maybe more, and then things really get going.

There are a few things that I have mentioned that will greatly increase the risk of CVD with no need for anything else to be present. They are:

  • Steroids/Cushing’s disease
  • Chronic Kidney Disease
  • Sickle cell disease
  • Antiphospholipid syndrome
  • Immunosuppressants
  • Avastin
  • Diabetes
  • Systemic Lupus Erythematosus
  • Kawasaki’s disease.

All of which means that – in most cases – CVD has no single, specific, cause. It should, instead, be seen as a process whereby damage exceeds repair, causing plaques to start developing, and grow – with a final, fatal, blood clot causing the terminal event. The next blog will be a review of the things that you can do to reduce your risk of CVD.

1: Astrup T, et al: ‘Thromboplastic and Fibrinolytic Activity of the Human Aorta.‘ Circulation Research, Volume VII, November 1959.







What causes heart disease part 58 – blood pressure

1st November 2018

A raised blood pressure, as a clinical sign, has always rather perturbed me. At medical school we were always taught – and this has not changed as far as I know – that an underlying cause for high blood pressure will not be found in ninety per cent of patients.

Ninety per cent… In truth, I think it is more than this. I have come across a patient with an absolute, clearly defined cause for their high blood pressure about five times, in total, and I must have seen ten thousand people with high blood pressure. I must admit I am guessing at both figures and may be exaggerating for dramatic effect.

Whatever the exact figures, it is very rare to find a clear, specific cause. The medical profession solved this problem by calling high blood pressure, with no identified cause, “essential hypertension”. The exact definition of essential hypertension is ‘raised blood pressure of no known cause.’ I must admit that essential hypertension certainly sounds more professional than announcing, ‘oh my God, your blood pressure is high, and we do not have the faintest idea why.’ But it means the same thing.

Doctors have never been good at admitting they haven’t a clue about something. Which is why we have a few other impressive sounding conditions that also mean – we haven’t a clue.

Idiopathic pulmonary fibrosis – progressive damage of the lungs – and we don’t know why

Cryptogenic stroke – a stroke caused by something – but we don’t know what

Essential hypertension – high blood pressure – we haven’t a clue why its high.

Can you turn something into a disease, simply by giving it a fancy Latin title? It appears that you can. Does it help you to understand what you are looking at? No, it most certainly does not.

So, why does the blood pressure rise in some people, and not in others. It is an interesting question. You would think that, by now, someone would have an answer, but they don’t. Or at least no answer that explains anything much.

Excess salt consumption has been blamed by some. However, even if you take the more dramatic figures, we are talking no more than 5mmHg. Indeed, the effect of reducing salt intake on people without high blood pressure is about 1mmHg, at most

‘Almost all individual studies of participants with normal blood pressure (BP) show no significant effect of sodium reduction on BP.’ 1

Which would mean that the effect of raising salt intake would be almost zero. So, if it is not salt, what is it? A magic hypertension fairy that visits you at night? Could be, seems as likely as anything else.

When you have a problem that is difficult to solve, I always like to turn it inside out, and see what it looks like from the opposite direction. Presently, we are told that essential hypertension increases the risk of cardiovascular disease.

Looking at this from the other direction, could it be that cardiovascular disease causes high blood pressure. Well, this would still explain why the two things are clearly associated, although the causal pathway may not be a → b. It could well be b → a.

I must admit that I like this idea better, because it makes some sense. If we think of cardiovascular disease as the development of atherosclerotic plaques, leading to thickening and narrowing of the arteries then we can see CVD is going to reduce blood flow to vital organs, such as the brain, the kidneys, the liver, the heart itself.

These organs would then protest, leading to the heart pumping harder to increase the blood flow and keep the oxygen supply up. The only way to increase blood flow through a narrower pipe, is to increase the pressure. Which is what then happens.

Over time, as the heart is forced to pump harder, and harder, the muscle in the left ventricle will get bigger and bigger, causing hypertrophy. Hypertrophy means ‘enlargement.’ So, in people with long term, raised blood pressure, we would expect to see left ventricular hypertrophy (LVH). Which is exactly what we do see.

LVH is often considered to be a cause of essential hypertension. I would argue that LVH is a result of CVD. This is not exactly a new argument, but it does make sense.

Two models strongly support the idea that CVD causes high blood pressure. The first is a rare condition called renal artery stenosis. This is where an artery to one of the kidneys narrows, or starts life narrowed. This causes the kidney to protest at a lack of blood supply and increase the production of renin.

Renin converts angiotensinogen, a protein made in the liver that floats about in the blood, into angiotensin I. Then angiotensin converting enzyme (ACE) turns angiotensin I into angiotensin II. And angiotensin II is a very powerful vasoconstrictor (narrows blood vessels), this raises the blood pressure.

Angiotensin II also stimulates the release of aldosterone, a hormone produced in the kidneys. Aldosterone increases the reabsorption of sodium and water into the blood from the kidneys, simultaneously driving the excretion of potassium (to maintain electrolyte balance). This increases the volume of fluid in the body, which also increases blood pressure.

This whole system is called the Renin angiotensin aldosterone system (RAAS), sometimes shortened to RAS. Activate at your peril. Angiotensin II is, amongst other things, a potent nitric oxide (NO) antagonist. Which, as you might expect, can do very nasty things to endothelial cells and the glycocalyx (glycoprotein layer that protects artery walls).

If you discover that the patient with very high blood pressure has got renal artery stenosis, the artery can be opened, and the blood pressure will – in most cases – rapidly return to normal. Which proves that narrow arteries can, indeed, lead to high blood pressure.

The other model is the situation whereby a number of blood clots build up in the lungs, a condition known as chronic thromboembolic pulmonary hypertension. It is not nice. The arteries are effectively narrowed by blood clots – in order to keep the blood flow up, the heart must pump harder. In this case the right side of the heart because it is this side that pushes the blood through the lungs.

So, you usually end up with Right Ventricular Hypertrophy (RVH). Eventually the heart cannot pump any harder and starts to fail, leading to Right Ventricular Heart Failure (RVF). Shortly after this, you die.

There is an operation that can be done to remove all the blood clots from the lungs. It has a very high mortality rate. Basically, you open up the lungs and pull out a great big complicated blood clot, that looks a bit like a miniature tree. If the operation is not fatal (pulmonary endarterectomy), the blood pressure drops, the LVF improves rapidly, and the outcomes are excellent.

This is another example which demonstrates that a rise in blood pressure is caused by narrowed blood vessels. Again, if you open the blood vessels the pressure drops, the stress on the heart falls, and rapid improvement can take place.

So, if CVD causes high blood pressure, is there any point in trying to lower the blood pressure with drugs. After all, you are doing nothing for the underlying disease.

Well, you would be taking pressure off the heart, so you might be improving left ventricular hypertrophy, and/or left ventricular failure. But, of course, you also lowering the blood flow to important organs, which is not so good. Indeed, it is well recognised that, in the elderly, you can increase the risk of falls by lowering the blood pressure – which can lead to fractured hips, and suchlike.

Also, if you lower the blood pressure too much the kidneys start to struggle, another major problem in the elderly. In fact, I often tell nurses working with me in Intermediate Care that dealing with the elderly can turn into a battle between the heart and the kidneys. Get one under control and the other one goes off.

Then, if you lower the blood pressure you are in danger of triggering the RAAS system into action as the body tries to bring the pressure back up again, and the RAAS system can be quite damaging to the blood vessel themselves. You will definitely disrupt the control of blood electrolytes such as sodium and potassium as aldosterone kicks into action.

I am forever battling to keep sodium levels up and potassium levels down, or vice versa, depending on which anti-hypertensive are being used. All of these are reasons why I do not bother to treat high blood with drugs, until it is far higher than the current medical guidelines would recommend.

What I do recommend to patients is:

  • Increase potassium consumption
  • Go on a high fat, low carb diet
  • Use relaxation techniques: mindfulness, yoga, whatever floats your boat
  • Take exercise
  • Get out in the sun – this stimulates NO synthesis
  • Try L-arginine and L-citrulline – as above
  • Increase magnesium consumption

This will often, if not always, do the trick.

If you must take medication, I was a very strong supporter of ACE-inhibitors, in that they blocked angiotensin II, and increased NO synthesis. Both good things. However, some research has come out recently, suggesting they may increase the risk of lung cancer. Not by a great deal, but there you go. Best to take nothing at all, if you possibly can.


What causes heart disease – part 57

11th October 2018

Blood pressure

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

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

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

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

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

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

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

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

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

So, how is this figure arrived at?

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

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

(Or maybe that is just me).

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

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

From 110mmHg to 120mmHg another very slight rise

From 120mmHg to 130mmHg another very slight rise

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Low pressure – no atherosclerosis

High pressure – atherosclerosis

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

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

What causes heart disease part 56 – a new paper

23rd September 2018

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

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

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

The paper is called ‘Inborn coagulation factors are more important cardiovascular risk factors than high LDL-cholesterol in familial hypercholesterolemia.’ And you can see it here

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

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

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

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

Here is the abstract:

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

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

Peter Gøtzsche – a scandal

19th September 2018

As many of you now know, Peter Gøtzsche was recently expelled from the Cochrane Collaboration. I was going to write a blog on it, but Maryanne Demasi has already written an excellent blog which covers most of what I was going to say. I would recommend that everyone reads it.1

I would simply add that, when an organisation that I had a lot of time for, the organisation now known as Cochrane, which used to be the Cochrane Collaboration, loses its way, one wonders if the lamps truly are turning out across the world. Perhaps never to be turned on again.

President Dwight Eisenhower made this warning to the world in 1961:

On Jan. 17, 1961, President Dwight Eisenhower gave the nation a dire warning about what he described as a threat to democratic government. He called it the military-industrial complex, a formidable union of defense contractors and the armed forces.

Eisenhower, a retired five-star Army general, the man who led the allies on D-Day, made the remarks in his farewell speech from the White House.

As NPR’s Tom Bowman tells Morning Edition co-host Renee Montagne, Eisenhower used the speech to warn about “the immense military establishment” that had joined with “a large arms industry.”

Here’s an excerpt:

“In the councils of government, we must guard against the acquisition of unwarranted influence, whether sought or unsought, by the military-industrial complex. The potential for the disastrous rise of misplaced power exists, and will persist.” 2

Had Eisenhower been alive today, I am certain that he would have recognised another player had joined the party. The ‘pharmaceutical/medical device industry complex.’ His warning about ‘the potential for the disastrous rise of misplaced power exists, and will persist,’ is equally valid today.

In fact, it is not a ‘potential.’ It has happened.

‘The lamps are going out all over Europe, we shall not see them lit again in our life-time.’ Edward Gray.



What causes heart disease part 55 – albumin

17th September 2018

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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



What causes heart disease part 54

31st August 2018

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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


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

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

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

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

Bleeding                                                          2.96 (2.46–3.56), P<0.001

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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What cause heart disease part 53 – diabetes

21st August 2018

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

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

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

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

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

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

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

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

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

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

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

Main functions of the glycocalyx:

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

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

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





What causes heart disease part 52

16th August 2018

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

‘Tight Junctions prevent the passage of molecules and ions through the space between plasma membranes of adjacent cells, so materials must actually enter the cells in order to pass through the tissue.’2 Wikipedia ‘tight junction’.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

How can a blood clot form under the endothelium?

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

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

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

After many years of neglect, the role of thrombosis in myocardial infarction is being reassessed. It is increasingly clear that all aspects of the haemostatic system are involved: not only in the acute occlusive event, but also in all stages of atherosclerotic plaque development from the initiation of atherogenesis and growth of large plaques.

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

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

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

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

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

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

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

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

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

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





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

6th August 2018

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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


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

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

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

You heard it here first.





What causes heart disease – part fifty

23rd July 2018

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Analogy: The effect of similar factors may be considered.

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

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

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

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

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

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

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

It has twenty variable factors. These are

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

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

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

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

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

At least three items on the list are caused by CVD

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

One of them sits completely alone

  • Atrial Fibrillation

As for the others:

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

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

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

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

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

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

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

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

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

Why saturated fat cannot raise cholesterol levels (LDL levels)

3rd July 2018

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

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

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

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

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

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

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

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

I would call it monumental stupidity.

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

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

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

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

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

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

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

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

To quote him from a paper in 1956:

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

In 1997 Keys wrote this:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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











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

15th June 2018

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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


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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

There were no identifiable risk factors for atherosclerosis.

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

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

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

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

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

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

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