Author Archives: Dr. Malcolm Kendrick

About Dr. Malcolm Kendrick

Malcolm Kendrick is a Scottish doctor and author of The Great Cholesterol Con (2008). He has been a general practitioner for over 25 years and has worked with the European Society of Cardiology.

Cholesterol lowering – proven or not?

Repatha

Just before I head off on holiday for a couple of weeks, I thought I should make a quick comment on the Repatha trial (PCSK9- inhibitor). I have written much about this new class of cholesterol lowering drugs, and I have been highly skeptical that they would have any benefits on cardiovascular disease. [Mainly on the basis that I don’t believe raised LDL causes CVD, and these drugs have one action – to lower LDL].

As many of you will be aware, the data from a clinical trial on Repatha has just been released. It was reported by the BBC thus

‘Huge advance’ in fighting world’s biggest killer.’

An innovative new drug can prevent heart attacks and strokes by cutting bad cholesterol to unprecedented levels, say doctors. The results of the large international trial on 27,000 patients means the drug could soon be used by millions.

The British Heart Foundation said the findings were a significant advance in fighting the biggest killer in the world. Around 15 million people die each year from heart attacks or stroke. Bad cholesterol is the villain in the heart world – it leads to blood vessels furring up, becoming easy to block which fatally starves the heart or brain of oxygen.

It is why millions of people take drugs called statins to reduce the amount of bad cholesterol . The new drug – evolocumab – changes the way the liver works to also cut bad cholesterol. “It is much more effective than statins,” said Prof Peter Sever, from Imperial College London.

He organised the bit of the trial taking place in the UK with funding from the drug company Amgen. Prof Sever told the BBC News website: “The end result was cholesterol levels came down and down and down and we’ve seen cholesterol levels lower than we have ever seen before in the practice of medicine.”

And so on, and so forth. So, the Repatha trial was a huge success. Obviously, it certainly lowered LDL to levels never seen before. Or, maybe it was not quite such a huge success. Michel de Logeril, a professor of cardiology in France – who set up and ran the famous, and successful, Lyon Heart Study sent me this comment.

‘This is just junk science.

The calculated follow-up duration required to test the primary hypothesis was 4 years as written by the authors themselves (but only in the second last paragraph before the end of discussion…) but the actual median duration of follow-up has been 2.2 years; it is thus a biased trial (a similar bias as in JUPITER: 1.9 years instead of 4 years): early stop!

In addition, contrary to the misleading claims in the medias, there was no effect on both total [444 deaths with evolocumab vs. 426 with placebo] and cardiovascular [251 vs. 240] mortality; which is not unexpected with a so short a follow-up.

They pretend that they are differences for non-fatal AMI and stroke but there is no difference in AMI and stroke mortality… Very strange… It would be critical to get access to the raw clinical data to verify the clinical history of each case in both groups.

Well, in my opinion and given the present state of consciousness among US doctors, FOURIER is a flop!

Best

Michel’

What he is saying, is that there was a reported reduction in non-fatal heart attacks and stroke. And less need for revascularization procedures e.g. PCI/stents. As you may gather Professor de Logeril would like to see the raw data to verify this. There is very little chance that this will be made available.

Anyway, that was the upside.

The downside is when you look at cardiovascular deaths.

  • The total number of deaths from cardiovascular disease in the Repatha group was 251
  • The total number of deaths from cardiovascular disease in the placebo group was 240
  • So, 11 more people died of cardiovascular disease in the Repatha group

The overall mortality data

  • The total number of, overall, deaths in the Repatha group was 444
  • The total number of, overall, deaths in the placebo group was 426
  • So, there were 18 more deaths in those taking Repatha.

The differences here are not large enough to be statistically significant. However, there were more, not less, deaths in the Repatha group, and more, not less, CV deaths. This study was also terminated early, which is extremely bad news for any clinical trial, and casts enormous doubt on any findings. It was supposed to last four years, but was stopped at 2.2 years. Why? Were the mortality curves heading rapidly in the wrong direction.

Alongside this, should be set the knowledge the Pfizer also had a PCSK9-inhibitor undergoing clinical trials, and they pulled the plug, right in the middle of it all.

Pfizer Ends Development Of Its PCSK9 Inhibitor

‘November 1, 2016 by Larry Husten

Immune issues and diminishing efficacy doomed the new drug.

Pfizer announced on Tuesday that it was discontinuing development of bococizumab, its cholesterol-lowering PCSK9 inhibitor under development.

“The totality of clinical information now available for bococizumab, taken together with the evolving treatment and market landscape for lipid-lowering agents, indicates that bococizumab is not likely to provide value to patients, physicians, or shareholders,” the company explained.

Pfizer said that it would halt two very large ongoing cardiovascular outcome studies with bococizumab, the 17,000 patient SPIRE 1 trial and the 10,000 patient SPIRE 2 trial. The trials were fully enrolled.’

Pulling the plug when 27,000 patients had been fully enrolled. What on earth did they see. Something more than slightly worrying. I guess we will never really know, but that is one hell of a write off.

It is also interesting to note that Amgen – the company selling Repatha, has announced that:

‘Amgen to refund cholesterol drug if patients suffer heart attack

Pledge aims to convince insurers to pay for $14,000-a-year medicine.2

As reported in the Financial Times.

This is a big vote of confidence … not! I think, perhaps, we are looking at a doomed drug. Probably a doomed class of drugs. Has the cholesterol hypothesis been verified, or contradicted? I know I am biased, but I know what I think.

1: http://cardiobrief.org/2016/11/01/pfizers-ends-development-of-its-pcsk9-inhibitor/

2: https://www.ft.com/content/34154cdc-0a86-11e7-ac5a-903b21361b43

What causes heart disease part XVIII

Viagra

For those who have read my endless series of blogs on cardiovascular disease, you may know exactly where I am going at this point.

Some time ago, Pfizer were developing a drug to treat angina. It blocked an enzyme called phosphodiesterase type-5. [Although I believe that its exact mechanism of action was not known at first]. To put it another way, this drug was a phosphodiesterase type-5 inhibitor (PDE5i).

The moment Pfizer found out what enzyme this drug blocked, they tried to patent the pathway that blocked this enzyme. Pharmaceutical companies trying to patent biological pathways. Perhaps I should try to patent the Krebs cycle, and charge everyone on the planet for having such a thing. Kerchingggg!

‘The U.S. patent office appears to have granted Pfizer a patent covering any drug that blocks this enzyme, meaning that it can sue all of its potential competitors.’1

Luckily, this time they were rebuffed.

Anyhoo, back to the drug. During phase one clinical trials, where humans are given the drug for the first time to see what effects it may have, many of the volunteers were hanging on to their medication, rather than handing them back. This was very unusual. Almost unknown in fact.

When researchers went out to find out why this was happening it was discovered, not quite sure who admitted to this, that sildenafil/Viagra improved erectile function. Thus, Viagra, the first PDE5i, was born. The first drug that worked simply and effectively to improve erectile dysfunction (ED). As for treating angina… that piffling indication was rapidly shelved as the dollar signs appeared in the sky above Pfizer HQ. Sex, as they say, sells.

In truth, it is actually one of the best drugs ever. Not only does is treat ED, but it can also be used by mountaineers to prevent pulmonary oedema (fluid filling up in the lungs), which is one of the major symptoms of altitude sickness. It does this by reducing the blood pressure in the pulmonary vessels (blood vessels in the lungs).

To explain a little further. If you climb very high, and the oxygen level drops, the heart pumps blood harder and harder through the lungs to get as much oxygen as possible into the system. This can result in fluid leaking out of the vessels and into the lung tissue, so they fill up with fluid. At which point you effectively drown, so you die. Viagra stops this happening, by lowering the blood pressure in the lungs.

Unsurprisingly, Viagra is used to treat people who have pulmonary hypertension (high blood pressure in the blood vessels in the lungs) at sea level. It is sold under the name Ravatio, for this indication – but we know that it is just Viagra. In addition, Viagra can be used to treat Raynaud’s disease, where the small blood vessels supplying the fingers and toes constrict, leading to painful cold fingers.

So, here we have a drug that can treat angina, pulmonary hypertension, erectile dysfunction and Raynaud’s disease at the same time. Thus, you can have great sex at twenty thousand feet above sea level, not get chest pain, or breathless, and stay warm at the same time. What more could a man ask for?

How does it do all these things? The answer is that it increases Nitric Oxide (NO) synthesis in endothelial cells. When it does this in the penis, it stimulates erections. In the heart, it opens up coronary arteries. In the lungs, it dilates the blood vessels, in fingers and toes it opens up arteries. So, all of the many different effects, are all due to exactly the same process – increased NO synthesis. Viagra also lowers blood pressure – as you would expect.

At the risk of blowing my own trumpet, I talked about this in my book ‘Doctoring Data,’ under the heading ‘Viagra and the drugs of unintended consequences.’ I posed the question. ‘If we were to prescribe Viagra as an antihypertensive, which is entirely possible, and it were found to reduce the risk of heart disease and stroke, which effect do you think would be responsible for the benefit? The blood pressure lowering effect, or the anticoagulant effects? Or something else.

Since I wrote those words, someone has actually looked at the impact of PDE5is on cardiovascular disease. Researchers at Manchester University, in the UK, studied the use of Viagra in people with diabetes – who often have erectile dysfunction. Here is what they found:

‘Viagra could prevent heart attacks, according to research. Patients taking the male impotence drug were found to have a lower risk of having a heart attack or dying from heart failure than those not on the medication. The lead scientist told the Daily Express the findings are “incredibly exciting”.2

The research paper was published in ‘Heart’, a BMJ journal. Actually, this paper was published last year, but only seems to have hit the press in the last few days. I spotted it in the Times a few days ago.

Here are the main results (for those readers who like their statistics)

‘Results: Compared with non-users, men who are prescribed PDE5is (Viagra, Cialis and the likemy words) (n=1359) experienced lower percentage of deaths during follow-up (19.1% vs 23.8%) and lower risk of all-cause mortality (unadjusted HR=0.69 (95% CI: 0.64 to 0.79); p<0.001)). The reduction in risk of mortality (HR=0.54 (0.36 to 0.80); p=0.002) remained after adjusting for age, estimated glomerular filtration rate, smoking status, prior cerebrovascular accident (CVA) hypertension, prior myocardial infarction (MI), systolic blood pressure, use of statin, metformin, aspirin and β-blocker medication. PDE5i users had lower rates of incident MI (incidence rate ratio (0.62 (0.49 to 0.80), p<0.0001) with lower mortality (25.7% vs 40.1% deaths; age-adjusted HR=0.60 (0.54 to 0.69); p=0.001) compared with non-users within this subgroup.’3

For those who don’t like their statistics quite as much as me (shame on you). I shall attempt to simplify.

  • Over a seven year period, those men taking PDE5is (Viagra Cialis and the like) had a 4.7% reduction in overall mortality – compared to men who did not.
  • Those taking Viagra were 38% less likely to have a myocardial infarction
  • If you did have a myocardial infarction, those who were taking PDE5is had a 25.7% death rate. Those who were not taking PDE5is had a 40.1% death rate. So, if you were unfortunate to have a heart attack, you were 14.6% less likely (absolute risk reduction) to die if you were taking PDE5is.

Or, to shorten this even more

  • 4.7% reduction in overall mortality
  • 38% reduction in MI (relative risk reduction)
  • 14.6% reduction in death after an MI

Whilst the first figure of a 4.7% reduction in overall mortality may not sound terrible exciting, it knocks all antihypertensives and cholesterol lowering medication into a cocked hat. Even if you add them together and multiply by two – on their best day. Because 4.7% is an absolute risk reduction. [Absolute mortality reduction in the Heart Protection Study (HPS), the most positive statin trial, was 1.8% over five years]

The benefits of Viagra are even more startling when it comes to having a heart attack (MI). The current ‘gold standard’ treatment of choice is Primary Percutaneous Coronary Intervention (PCI), which basically means popping a stent into a blocked coronary artery to open it up again.

It has been estimated that PCI results in a 2% absolute reduction in mortality4. On the other hand, Viagra gives you, very nearly, a 15% reduction in overall mortality. Or, to put it another way, Viagra may be seven and a half times as effective as PCI.

But it does not end here. it was also found that men with heart failure were 36% less likely to die if they took a PDE5i.

‘In the other subgroups, there was an inverse association between PDE5i use and all-cause mortality. Those with a recorded history of congestive cardiac failure, TIA and PVD had 36%, 40% and 34% lower risk, respectively.’ [A TIA is a transient Ischaemic attack/small stroke. PVD is peripheral vessel disease.]

Congestive cardiac failure is usually shortened to heart failure. [This 36% is a relative risk reduction, and I could not work out what the absolute risk was from the paper. I am probably too thick].

The effect on heart failure is almost certainly because another benefit of increasing NO is that you increase ‘angiogenesis’, otherwise known as, ‘the creation of new blood vessels’. If a coronary artery does completely block, this often leads to heart failure, as not enough oxygen and other nutrients can get into the heart muscle downstream.

However, if collateral blood vessels develop, the blood will be directed around the blockage and back into the artery downstream, through these newly created blood vessels. Although collateral circulation is not as effective as a fully patent coronary artery, it will create a significant flow of oxygen and nutrients once more. Thus, heart failure will be greatly improved.

Louis Ignarro, who identified nitric oxide (NO) as the key chemical messenger that dilated blood vessels, and won the Nobel Prize for doing so, decided to start treating people who have end stage heart failure with l-arginine. He had been looking for a substance that would, naturally increase NO, and found l-arginine did the job best. He has had some amazing results. Perhaps he should start using Viagra instead.

This study, I must add, was not interventional, it was observational. However, it strongly supports the hypothesis that increasing NO synthesis is just about the most important thing you can do. If you want to avoid dying from CVD.

Do I think everyone should take Viagra? Well, if you have heart failure, diabetes and a high risk of CVD – probably. Will you get a doctor to prescribe it for you, for CVD prevention? Absolutely no chance. Will anyone ever fund a study on this? With the drugs now off patent – no chance.

Oh, the joys of modern medicine. Unless someone does a controlled randomised double blind study on a medication, doctors will not prescribe – are not allowed to prescribe. However, virtually the only people with the money to do such studies are pharmaceutical companies. If the patent life of a drug has expired, no money can be made. So, no trial will be done. So, drugs that are almost certainly beneficial wither on the vine.

Unusually, for me, I do not blame the pharmaceutical companies for this. They are not charities. They need to make money or they die. You cannot expect them to spend hundreds of millions on a clinical study, without any possible means of gaining a return on their investment. We live in a funny old world.

In the meantime, look to other things that can increase NO synthesis. L-arginine/L-citrulline does this. Potassium does this. Sunlight does this. Exercise does this. Meditation does this. Vitamin D does this, as does Vitamin C. What are you waiting for? Go for a walk in the sun and eat an orange – you will live forever.

 

1: https://www.forbes.com/2002/10/23/cx_mh_1023pfizer.html

2: http://www.independent.co.uk/life-style/health-and-families/health-news/viagra-could-lower-heart-attack-risk-and-risk-of-dying-from-heart-failure-a7082801.html

3: http://heart.bmj.com/content/early/2016/07/26/heartjnl-2015-309223.full

4: https://www.ncbi.nlm.nih.gov/pubmed/12517460?access_num=12517460&link_type=MED&dopt=Abstract

What causes heart disease part XXVII

Lumen: The lumen of the artery is the hole in the middle that the blood flows through.

The artery wall: The artery wall is made up of three layers: Endothelium/intima, media and adventitia

The endothelium: Usually thought of as a single layer of endothelial cells than line the lumen of the artery. [The layer may be more than one cell thick]. This layer of endothelium acts as a barrier to blood, or anything in the blood, leaking from the lumen into the artery wall. There is a bit of space, sometime called the intima just under the endothelial cells.

The media: This layer is mostly made up smooth muscle cells and elastic tissue. The muscle can contract or relax, depending on circumstances

The adventitia: This outermost layer is mainly made up of collagen. It is very strong and keeps the artery in shape.

The atherosclerotic plaque: The areas of thickening and narrowing of arteries (in heart disease). These are usually found between the endothelium and the media – smooth muscle layer. They lie beneath the endothelium – within the artery wall itself. The area often referred to as the intimal layer of the artery.

The elevator pitch

Various people who work in business tell me of something called the ‘elevator sales pitch’. So-called, because of a (highly unlikely) situation whereby you find yourself in an elevator (which we in the UK call a lift) with a rich, famous, person. You have a short space of time to outline your idea to them, what it is, what it means, and why it is of value. They then hand over a hundred million dollars to invest in you, and your idea. Or something like that anyway.

Whilst the elevator pitch is clearly a mythical beast, the general point is reasonable. You should be able – or you should at least attempt – to condense your ideas into a very short space of time, before people get bored and walk away. Well, clearly I have miserably failed on this, as I am now writing part twenty-seven of my idea(s) on heart disease. In truth, I am planning on the elevator breaking down for about ten hours between floors to give me the time needed.

Recently, though, I have been speaking to a number of people who have successful careers in business, music, the arts and suchlike. I have been trying out my elevator pitch on them. Admittedly the elevator I am thinking of is in the Burj Khalifa in Dubai, but I am trying. So, here goes. Doors close on the elevator. Me and Bill Gates…

Me. ‘Forget diet, forget cholesterol, the real cause of heart disease is blood clotting.’

Bill Gates looks at his watch. ‘You have one minute.’

Me. ‘Blood clots can form and stick to the inside of artery walls. They then get absorbed into the artery wall itself where, normally, they are cleared away by specialised white blood cells. But if blood clots keep forming rapidly, at the same point, or the blood clots are bigger and more difficult to shift when they form, they cannot be cleared away quickly enough and so end up stuck inside the artery wall. This leads to a build-up of blood clot residue, and remnants, in the artery wall itself. Which means that repeated episodes of clotting, over time, build into thickenings, and narrow the larger arteries, mainly in the heart and the neck, growing somewhat like tree rings. These areas of damage are usually called atherosclerotic plaques.

In time, the process of blood clotting, over a vulnerable area, leads to heart attacks and strokes as the final, fatal blood clot forms over an area of the artery that is already thickened and narrowed. In short, atherosclerotic plaques are the remnants of blood clots. Heart attacks and strokes are the end result of the same processes that caused plaques to form in the first place. Heart disease is a disease of abnormal blood clotting. It is as simple as that. The end.’

Ping. Elevator door opens and Bill Gates walks out.

Do you think he believed me? Of course not. Heart disease is caused by cholesterol, end of.

Bill Gates: ‘Who was that complete idiot in the lift, make sure he never gets the chance to speak to me again.

Man in black suit: ‘OK boss.’

I should point out that I have never spoken to Bill Gates, and almost certainly never will. I merely used his name as an example of someone that you might try to convince using an elevator sales pitch.

I also know that my sales pitch will just seem like the most complete nonsense to most people. How can I possibly claim that atherosclerotic plaques are blood clots, when no-one else in the entire world is saying it? Am I not simply a flat-Earther? Indeed, am I not a lonely flat-Earther baying at the moon. At least the moon currently passing overheard, to join all the other moons that clearly fall into a big basket on the other side of the Earth – to be returned from time to time by an enormous dung beetle.

I like to think not, because the ‘blood clotting’ hypothesis fits all known facts about cardiovascular disease. In fact, many people have proposed the ‘blood clotting theory’ of CVD over, what is now, hundreds of years. From Rokitansky to Duguid to Smith – and many more. Here, from a paper written in 1993 called ‘Fibrin as a factor in Atherosclerosis’, co-authored by Elspeth Smith.

[Just to first remind everyone that Fibrin is a critical element of blood clots (along with platelets). Fibrin is made up of short strings of a protein called fibrinogen. When the clotting system (clotting cascade) is activated, the end result is that fibrinogen is stuck together end to end, in order to create long sticky strands of fibrin that entangle themselves around the clot and bind it all together.]

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.

Infusion of recombinant tissue plasminogen activator (rt-PA) into healthy men with no evidence of thrombotic events or 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 provides 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. It should be noted that these observations are based on the human and not just the animal model.

In 1852 Rokitansky discussed the “atheromatous process” (sic) 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 of haemostatic factors in coronary heart disease.

Unfortunately, since that paper was written the emphasis on cholesterol and lipoproteins has become even more overwhelming, and research into blood clotting and atherosclerosis has faded to almost nothing. It appears that the vast sums of money to be made from cholesterol lowering has completely distorted research into this area. All the funding, and all the international experts, have charged into the blind-alleyway that is the cholesterol hypothesis.

In a kind of supreme irony, in 1992 Pfizer were also travelling down the blood clotting route. I have (mentioned before) possibly the only remaining copy of a small booklet entitled ‘Pathologic Triggers New Insights into cardiovascular risk.’ And I quote:

‘Several features of mature plaques, such as their multi-layered patterns, suggests that platelet aggregation and thrombus formation are key elements in the progression of atherosclerosis. Platelets are also known to provide a rich source of growth factors, which can stimulate plaque development.

Given the insidious nature of atherosclerosis, it is vital to consider the role of platelets and thrombosis in the process, and the serious events that may be triggered once plaque are already present.’

Of course, this leaflet was promotional, for their product doxazosin. Doxazosin lowers blood pressure and also has effects on urinary retention. However, in this leaflet, they were trying to promote its effects on blood clotting factors. Basically, doxazosin reduces fibrinogen levels and plasminogen activator inhibitor – 1 (PAI-1). Plasminogen is activated by tissue plasminogen activator (tPA) which then becomes plasmin, an enzyme that slices fibrin apart, and breaks down blood clots. PAI-1 stops this happening, so makes clots more difficult to break down.

To quote, again.

‘These recent studies suggest that doxazosin may have a range of significant antithrombotic effects in many patients, in addition to its proven beneficial effects on hypertension and hyperlipidaemia. Following doxazosin treatment, a reduction of platelet aggregation and a tendency towards dissociation, together with a reduction in fibrinogen levels, might prevent excessive degrees of thrombosis at the site of vascular injury. In addition, reduced levels of PAI-1, and increased tPA capacity with doxazosin might stimulate fibrinolysis and early clot dissolution at these sites, and prevent the evolution of an acute coronary event.’

So there, couldn’t have put it better myself.

Then Pfizer bought Warner-Lambert, who made atorvastatin/Lipitor. The focus became Lipitor and lipids, lipids, lipids. Lo it came to pass that Pfizer never mentioned blood clotting ever again, lest it interfere with the LDL story. Pity really, because mighty Pfizer got it right in 1992. Smith got it right in 1993, Duguid got it right in the 1940s, and Rokitansky was right in 1852. Of course, there have been many others who got it right too. Many, sadly, lost to history.

At some point this, the blood clotting hypothesis, the correct hypothesis will win. Maybe that time will be now.

Postscript

I realise some people may still wonder (if they have not read what I have written before) how the blood clot ends up within the artery wall/beneath the endothelium.

The reason is as follows. If the endothelium is damaged, a clot will form, sitting on the inside of the arterial wall. Once the clot has stabilised, and been reduced in size by fibrinolysis, the remainder of the clot will be covered over by Endothelial Progenitor Cells (EPCs) that float around in the bloodstream and are attracted to areas of endothelial damage.

After a layer of EPCs has grown over the clot, and converted themselves into mature endothelial cells the blood clot will now, effectively, be sitting inside the artery wall. Underneath a new layer of endothelium. Thus, clot becomes plaque.

http://circ.ahajournals.org/content /92/5/1355.full

What causes heart disease part XXVI

[Hold the front page]

Last night I watched a you tube presentation which completely astonished me. It was given by Professor Salim Yusuf, who is as mainstream as mainstream can possibly be. Here, from Wikipedia:

‘Salim Yusuf (born November 26, 1952) is an Indian-born Canadian physician, the Marion W. Burke Chair in Cardiovascular Disease at McMaster University Medical School and currently the President of the World Heart Federation, a world-renowned cardiologist and epidemiologist. In 2001, he published a landmark study that proved the benefits of clopidogrel in acute coronary syndrome without ST elevation.

Here, from Forbes magazine in 2012:

‘McMaster University’s Salim Yusuf has tied for second place in the annual ranking of the “hottest” scientific researchers, according to Thomson Reuter’s Science Watch. Yusuf was a co-author of 13 of the most cited papers in 2011. Only one other researcher, genomic pioneer Eric Lander of the Broad Institute of MIT, had more highly-cited papers than Yusuf.’1

On February the 12th he gave a presentation at a cardiology conference in Davos, Switzerland which can be seen on YouTube. In this presentation, he makes the following points:

  1. Saturated fat does raise LDL, a bit, but has no effect on CVD – maybe slightly beneficial. Monounsaturated fats are slightly beneficial. Polyunsaturated fats are neutral.
  2. Carbohydrate intake is most closely associated with CVD
  3. Fruit and vegetable intake has little or no impact on CVD – nor does fish intake [He wonders where the five portions of fruit and vegetable intake recommendations actually came from]. Vegetables in particular have no benefit.
  4. Legumes – beans and suchlike – are beneficial.
  5. The recommendations on salt intake are completely wrong, and set far too low. For those who do not have high blood pressure, low salt intake increase mortality. On the other hand, high salt intake does no harm.
  6. He recommends higher potassium intake.
  7. He criticizes Ancel Keys and lauds Nina Teicholz [Author of big fat surprise].

Well, good for him. It seems to have taken him a long time to get there, but he did in the end. Of course, mainstream medicine will remain in shocked silence, so you will likely hear nothing of this in the mainstream media. But, hey, you get to see it here. Perhaps someone would like to send this presentation to the BHF and the AHA and ask them for a comment?

The YouTube presentation is here:

 

1: http://www.forbes.com/sites/larryhusten/2012/04/25/when-youre-hot-youre-hot-salim-yusuf-second-most-influential-scientist-in-2011/#6ac825575abe

What causes heart disease part XXV

Lead

I have been studying cardiovascular disease for well over thirty years now. I have come across a million different hypotheses about what causes it. There is almost no foodstuff, vitamin, infectious agent, chemical compound, atomic element or activity [lack of, or excess] that has not been proposed at some point.

Many of them can look very promising, and the underlying hypothesis is often elegant – very elegant indeed. But what you must do with any hypothesis is to hold it close to the unforgiving flame of mortality data, and see if it is tempered by the heat – or simply melts.

I resolved very early on in my long and winding study on cardiovascular disease that any hypothesis had to explain everything – not just some things. For example, as almost everyone in the entire world knows a raised cholesterol level is considered the most important cause of cardiovascular disease. But it is exceedingly easy to find facts that seem to completely contradict this.

Here, for example, is a little graph looking at only two countries. It compares the death rate from heart disease in Russia and Switzerland, in men under the age of sixty-five relation to the average cholesterol level in those two countries.

lead-post

in Russia, with an average cholesterol level of 5.1mmol/l (197mg/dl) had a death rate 834% higher than that in Switzerland, which had an average cholesterol level of 6.4mmol/l (248mg/dl). Yes, this graph is the right way around. Yes, these data come from the World Health Organisation, and can be found on the British Heart Foundation (BHF) website. These particular statistics are now very deeply buried, but can still be found here: https://www.bhf.org.uk/publications/statistics/european-cardiovascular-disease-statistics-2008

I sometimes wonder if anyone at the BHF actually looks at these data, but that is a question for another day. Of course, when presented with facts like this, the dismissals. and creation of ad-hoc hypotheses rapidly reach into the sky. The word ‘paradox’ will be used pretty heavily, that’s always a good, temporary, escape route. In reality these two figures represent a full-blown black swan. But, hey, facts are slippery things.

Anyway, in my quest to explain everything about heart disease, perhaps the hardest single thing to explain is the fact that the rate of cardiovascular disease (heart attacks and strokes) has been going down in pretty much every single Western country for decades. I would say ‘first world’ country, but my son (a geography graduate) informs me that this terminology is now virtually barred for being racist. I shall be considered an ancient, prejudiced reactionary for using such a term.

So, I will say, Western Europe, North American, Australia, Japan, New Zealand and suchlike.

Now, the decline in CVD did not start at the same time, in all these countries. At this point I will make myself a hostage to fortune and make some sweeping statements. The rate of CVD peaked first in the US, in the late 1950s and has been falling since. It peaked next in Finland in the 1960s. In most of the other countries CVD peaked in the 1970s, before falling. It is impossible to say that there was a uniform worldwide effect. [Today, some countries are on the way up the mortality curve e.g. China and India].

However, I will make the general statement that CVD has been falling in most ‘first world’ countries for decades. This started long before any effective medical interventions were available. In the US, in the 1950s, there were no effective blood pressure lowering agents, no stents, no CABG, no clot busters…. Nothing really.

Possibly the greatest single factor has been the reduction in smoking. At the end of the second world war virtually all men smoked. Nearly 90% in the UK in the 1950s. Since that time the number of smokers has fallen, and fallen.

In addition to this, during the 60s, 70s, 80s and onwards, medical interventions have also greatly improved. In-hospital survival from a heart attack or stroke has improved almost year on year. The figures are complex, but around 60% of those admitted to hospital with a heart attack used to die – it is now around 30%, maybe less.

Some of this is due to the fact that ‘strict bed rest’ following a heart attack, the key medical intervention for decades, was abandoned. A piece of medical mismanagement that killed millions and millions… and millions.

What else may have cause the fall? I think that in the UK, the clean air act has a significant effect. The Great Smog of London, in the early 1950s, killed tens of thousands in less than a week. Much of this was from respiratory complications, but also CVD. It is now more clearly established that air pollution, in general, increases the risk of CVD. Most Western countries have drastically reduced air pollution.

Now, I would like to consider something almost never mentioned. Lead. That is the element, not the verb. Or the noun, as in dog lead.

In the 1920s someone discovered that if you put lead in petrol/gasoline it had all sorts of benefits on engine performance and wear and tear – and so on. Unfortunately, lead also caused all sorts of problem for human performance, and wear and tear. It is a heavy metal and, like other heavy metals, a powerful human toxin.

Despite the fact that lead toxicity was known for decades, it took until the nineteen-sixties before countries starting banning it from fuel – and pipes in housing – and the like. Which reversed a long-term trend of lead building up inside human beings. It lasts for decades within bone – gradually leaking out.

With regards to lead and CVD, is there a link?

A researcher called Weisskopf looked at the amount of lead in bones, and the rate of CVD. He found that those with the most lead in their bones were 837% more likely to die from CVD (relative risk)1 than those with the least lead in their bones. Now, whilst that is a relative risk, it is of the magnitude where we can safely say we are looking straight at a direct cause of CVD.

How does lead cause CVD. Most likely through the following mechanisms

‘Lead causes endothelial dysfunction by binding and inhibiting endothelial nitric oxide synthase and decreasing nitric oxide production.’2

Yes, we are straight back to my old friends, endothelial dysfunction and decreased nitric oxide (NO) production. In the world of cardiovascular disease, if you know where to look, all roads lead to NO.

If lead does cause CVD, is there any evidence that removing lead from the body can reduce the risk of CVD? [‘Reversibility’ and ‘Experimental Evidence’, the two most powerful of Bradford Hill’s canons for causation]. Which brings me to TACT. A trial designed to look at the impact of chelation on CVD. A way of removing heavy metals from the body…

What I love about this trial is that it was set up primarily to prove that chelation was nonsense, to be laid alongside homeopathy, and suchlike – by mainstream researchers. To quote an article in Medscape:

‘The original TACT trial wrestled with enrolment, ultimately taking over a decade to yield results, in part because cardiologists were absolutely convinced that chelation was a load of horse hockey.’ 3

TACT stands for Trial to Assess Chelation Therapy. When I first heard about chelation, I too, dismissed it as horse hockey. However, it turns out that I done the thing that I always advise everyone else against doing. I placed it in the ‘impossible/horse hockey’ category without making the effort of trying to find out what it was really about.

As it turns out, I should have made more effort…

‘TACT found that patients randomized to a regimen involving up to 40 separate three-hour infusions of a chelation-therapy solution (disodium ethylenediaminetetraacetic acid [EDTA], ascorbic acid, magnesium chloride, potassium chloride, sodium bicarbonate, B vitamins, procainamide, and a small amount of standard heparin) experienced an 18% drop in the trial’s primary end point (all-cause death, reinfarction, stroke, revascularization, or hospitalization for angina) compared with patients randomized to a placebo infusion.’3

More extraordinary than this:

‘When we broke the composite down to look at our secondary end points, we found that we had about a 40% reduction in total mortality, a 40% reduction in recurrent MI, and about a 50% reduction in mortality [in patients with diabetes],”3

A 40% – 50% reduction in mortality. Well, well, well. Eat your heart out statins. In fact, eat your heart out every single pharmaceutical product ever tested. What has been the effect on mainstream thinking on CVD? As you would expect, absolutely nothing has changed in the slightest. Still TACT2 is now being set up – so we can all look forward to that being ignored in about seven to ten years’ time.

Anyway, in an attempt to bring some structure to this blog, I am going to return to the start. Why has the rate of CVD gone down in most first world countries over the last fifty years? One of the reasons, I believe, is that the level of heavy metal pollutants (in particular, lead) has been dropping since around the mid nineteen sixties.

I think it could be argued that the US was the first country to embrace the motor car. Thus lead toxicity would have hit the US before anywhere else. I am not going to argue this too strongly, but I place it before you, for your consideration.

I shall finish by saying that, if you want to look for reasons for the pattern on CVD over the last sixty years, or so, you really need to start looking outside the box. For there are more things in heaven and earth Horatio, than are dreamt of in your philosophy.

1: Weisskopf MG, Jain N, Nie H, et al. ‘A prospective study of bone lead concentration and death from all causes, cardiovascular diseases, and cancer in the Department of Veterans Affairs Normative Aging Study’. Circulation 2009;120(12):1056-64.

2: Natalia V. Solenkova et al: ‘Metal pollutants and cardiovascular disease: Mechanisms and consequences of exposure.‘ Am Heart J 2014;168:812-22

3: http://www.medscape.com/viewarticle/814643?pa=QYKVfN05tfWXqq6%2BfjZ30whyKyHVDGvMW4WYyHO8jprcrUBo6WRIR4VFzOaThtqB8SIvl8zjYv73GUyW5rsbWA%3D%3D

Vitamin C – an update

Of course, I am always – ahem – ahead of my time, but I just noted this study that came out very recently. It demonstrates that if you give Vitamin C (along with hydrocortisone and thiamine) for just over two days in patients admitted with sepsis (blood poisoning) the mortality rate falls from 40% to 8.5%. The mortality rate in low income countries is normally around 60%.

Now, this was a small study, but it seems robust. It represents an almost five-fold reduction in mortality, but I think it provides some pretty strong support for the benefits of vitamin C. The conclusions of the study, repeated below were that.

‘Our results suggest that the early use of intravenous vitamin C, together with corticosteroids and thiamine may prove to be effective in preventing progressive organ dysfunction including acute kidney injury and reducing the mortality of patients with severe sepsis and septic shock.’

Hydrocortisone, Vitamin C and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study

Paul E. Marik, MD, FCCM, FCCP; Vikramjit Khangoora, MD; Racquel Rivera, Pharm D; Michael H. Hooper, M.D., MSc; John Catravas, PhD, FAHA, FCCP

Author and Funding Information

Chest. 2016. doi:10.1016/j.chest.2016.11.036

Abstract

Background:  The global burden of sepsis is estimated as 15 to 19 million cases annually with a mortality rate approaching 60% in low income countries.

Methods:  In this retrospective before-after clinical study, we compared the outcome and clinical course of consecutive septic patients treated with intravenous vitamin C, hydrocortisone and thiamine during a 7-month period (treatment group) compared to a control group treated in our ICU during the preceding 7 months. The primary outcome was hospital survival. A propensity score was generated to adjust the primary outcome.

Findings:  There were 47 patients in both treatment and control groups with no significant differences in baseline characteristics between the two groups. The hospital mortality was 8.5% (4 of 47) in the treatment group compared to 40.4% (19 of 47) in the control group (p < 0.001). The propensity adjusted odds of mortality in the patients treated with the vitamin C protocol was 0.13 (95% CI 0.04-0.48, p=002). The SOFA score decreased in all patients in the treatment group with none developing progressive organ failure. Vasopressors were weaned off all patients in the treatment group, a mean of 18.3 ± 9.8 hours after starting treatment with vitamin C protocol. The mean duration of vasopressor use was 54.9 ± 28.4 hours in the control group (p<0.001).

Conclusion:  Our results suggest that the early use of intravenous vitamin C, together with corticosteroids and thiamine may prove to be effective in preventing progressive organ dysfunction including acute kidney injury and reducing the mortality of patients with severe sepsis and septic shock. Additional studies are required to confirm these preliminary findings.

What causes heart disease part XXIV

In my long and winding road around cardiovascular disease I have often visited the same themes a few times. In part, this is because we are not dealing with Newtonian physics here. If billiard ball A strikes billiard ball B, at five metres per second, at an angle of 45 degrees, billiard ball B will move off at angle C at velocity D, assuming perfect elasticity. This will always happen, every single time.

On the other hand, with CVD, the complexity of human physiology and psychology, environmental factors, genetics the time of day, even sunspot activity – can have an effect – so some people have reported.

‘Space proton flux and the temporal distribution of cardiovascular deaths.

The influence of solar activity (SA) and geomagnetic activity (GMA) on human homeostasis has long been investigated. The aim of the present study was to analyse the relationship between monthly proton flux (> 90 MeV) and other SA and GMA parameters and between proton flux and temporal (monthly) distribution of total and cardiovascular-related deaths. The data from 180 months (1974-1989) of distribution in the Beilinson Campus of the Rabin Medical Centre, Israel, and of 108 months (1983-1991) from the Kaunas Medical Academy, were analysed and compared with SA, GMA and space proton flux (> 90 MeV). It was concluded: monthly levels of SA, GMA and radiowave propagation (Fof2) are significantly and adversely correlated with monthly space proton flux (> 90 MeV); medical-biological phenomena that increase during periods of low solar and/or geomagnetic activity may be stimulated by physical processes provoked by the concomitant increase in proton flux; the monthly number of deaths related (positively or negatively) to SA are significantly and adversely related to the space proton flux (> 90 MeV).’1

Oh yes, I do cast my net far and wide when looking at cardiovascular disease, as I feel I must. Quite what we are all supposed to do when the space proton flux is greater than 90MeV, I am not certain. Perhaps a tin foil hat would become appropriately protective headgear. By the way, this paper can be found in the National Institutes of Health on-line library – Pubmed. Referenced, peer-reviewed, and everything.

The point being? The point being that if you are looking for ‘billiard ball’ certainty, you are not going to find it here. If you were to do absolutely everything that I believe to be protective against cardiovascular disease, you will shift the odds in your favour, but you could still get struck down by a heart attack or stroke.

Anyway, with that proviso firmly in place, I shall move ahead, or maybe backwards. On the basis that some subjects need a second visit, I have decided to return to look at vitamin C again. First, because I have just been harangued by someone who believes that if you take high doses of vitamin C every day, you can reverse/cure heart disease completely and utterly. He also felt that I had completely ignored the work of G C Willis ‘The reversibility of atherosclerosis’, and also the research of Pauling and Rath on vitamin C.

It is true that I have not actually mentioned Willis before, but I have certainly written at length of Pauling and Rath. However, I realise that time passes, people forget things, and previous blogs settle to the bottom of the sediment layer. Therefore, it is not a bad idea to refresh things from time to time. I am also returning to vitamin C and the issues around it, because I have been getting a lot of correspondence about lipoprotein (a) (Lp(a)) recently. It seems this lipoprotein is gaining increasing attention. Of course, vitamin C and Lp(a) are tightly bound together.

Time, I think, for a quick refresher about this whole area. Particularly as it helps to confirm my central hypothesis that CVD is a disease of blood clotting, and you would struggle to explain the vitamin C/Lp(a) axis in any other way.

To begin. At some point in the distant past, our ancestors lost the ability to manufacture vitamin C. This happened, so I recently read, around sixty-one million years ago. Seems a long way back, but there you go. It has happened to some other animal groups, but not many. Quite why it occurred is unclear. You probably think you know, but I suspect you are wrong.

Interestingly, and as a bit of an aside, vitamin C is synthesized through a multi-step process, and the original molecule is glucose. Humans lack the last step in the process. Perhaps, because of this, glucose and vitamin C have some interesting interactions in the body. Mainly, it seems, that high levels of glucose prevent vitamin C from entering cells. Particularly immune cells, which need a lot of vitamin C to operate effectively. Make of that what you will.

Moving on, because humans cannot synthesize their own vitamin C, we must obtain it from within our diet. If we do not manage to eat enough, we will end up with scurvy. Scurvy presents with many different symptoms, but the one I am going to focus on in this blog is bleeding.

Bleeding occurs, because vitamin C is essential for collagen synthesis – a critical building block of supportive tissue throughout the body. Loss of collagen leads to break down of various structures in the body. For example, the walls of blood vessel walls which, start to break down and ‘crack.’

As blood vessel walls crack, they leak, and bleed. This leads to the best known symptom of scurvy, which is bleeding gums. This was well recognised several hundred years ago, mainly in sailors who had a highly-restricted diet during long voyages. In scurvy there is also bleeding in many other blood vessels, but you can’t easily see it. The usual cause of death in severe scurvy is internal bleeding.

On the positive side, after sixty-one million years, or so, evolution came up with a partial solution to the early stages of scurvy. Namely, the synthesis of a substance to block the cracks in the blood vessel walls, and control the bleeding. This substance is, or course, lipoprotein (a).

Lipoprotein (a) (Lp(a)) is synthesized in the liver, and it travels around in the bloodstream, looking for any cracks in blood vessels walls a.k.a. damaged endothelium. When a crack is spotted Lp(a) is attracted to the area and sticks very firmly, and cannot easily be removed. Of course, the rest of the blood clotting system also moves into action, so all hell breaks loose. Therefore Lp(a) becomes mixed up with platelets, red blood cells, fibrin, and almost everything else in the blood, including all the other lipoproteins.

However, Lp(a) has a very special trick up its sleeve. It mimics plasminogen.

After a blood clot forms, anywhere in the circulation, it has to be broken down, and removed – once the blood vessel underneath it has repaired. I liken this (not very accurately) to road works. If the road surface is damaged, the repair team comes in, sets up barriers and traffic lights and suchlike, then they repair the road. Then all the barriers, and traffic lights, and suchlike, must be removed.

Within a blood vessel, removal of barriers, and traffic lights, is a tricky exercise. Where does the blood clot go? Once a large blood clot has formed, over a ‘crack’ in the wall, it cannot stay there forever, restricting, or totally obstructing, blood flow. On the other hand, if the entire clot simply broke off, and travelled down the artery, it would get stuck as the artery narrowed – causing a complete blockage. Not a good idea.

Ergo, there is a need for a process that removes blood clots that have formed within blood vessels. It is called thrombolysis, or fibrinolysis. To ‘lyse’ means to break down.

The main player in thrombolysis is plasminogen. It becomes incorporated into (almost) all blood clots that form. It is activated by tissue plasminogen activator (t-PA). This turns plasminogen into plasmin, the ‘active’ enzyme that slices fibrin apart [fibrin is a long, and very strong, string of fibrinogen molecules that wraps round blood clots and binds them together].

t-PA can be manufactured and given to people who have heart attacks and strokes, to break apart the blood clots that are blocking the arteries in the brain, or the heart. You may have heard of t-PA referred to as a ‘clot-buster.’ Great stuff, but not so good if your stroke is due to a bleed in the brain, rather than a blood clot. In which case….

t-PA has been around for a while now and, with heart attacks at least, has mainly been superseded by angioplasty. Which is to open up the blocked artery, and stick a metal support (stent) into the artery. T-PA is still use in ischaemic strokes. That is, after you have had a brain scan to work out what sort of stroke you are having.

Sorry to appear to be going off in different directions here, but the systems of blood clotting are highly complex, and I think that explaining where Lp(a) fits in, is important.

Lp(a) is actually a lipoprotein, just like LDL. In fact, it is exactly like LDL, because it is basically LDL. It is the same size and shape, it contains triglyceride and cholesterol. However, it differs in one important aspect. Whilst LDL has a protein stuck to it called apolipoprotein B-100, Lp(a) has another protein stuck to it called apolipoprotein (a). Which is why it is called lipoprotein (a).

The fascinating thing about the protein, apolipoprotein (a), is that is has almost exactly the same chemical structure as plasminogen. So close, that you could hardly tell it apart. However, apolipoprotein (a) is completely unaffected by t-PA. It does not convert to plasmin, it is inert. So, when you want to break down a clot (fibrinolysis), the parts that have Lp(a) incorporated into it, cannot be broken down.

Which means that if you have a high Lp(a) level, you will develop bigger and more difficult to break down blood clots. Exactly what evolution had in mind for creatures that cannot manufacture vitamin C, and need to plug cracks in artery walls when the vitamin C level falls. However, not so good, if you want to stop atherosclerosis from developing.

Because these Lp(a) rich blood clots have to go somewhere, and the only place that they can go is to be absorbed into the artery wall itself, and then broken down. However, these clots are more difficult to break down, so, with repeated clots over the same area of artery wall, bigger and bigger plaques will grow.

That, anyway, is the theory.

What G.C. Willis did in 1957 was to study guinea pigs. Guinea pigs are another animal that does not synthesize vitamin C. He made them scorbutic (vitamin C deficient a.k.a. scurvy). Actually, he did not make them all scorbutic. He had a control group of twelve guinea pigs that he put on a vitamin C deficient diet, then injected them with vitamin C. None of these twelve guinea pigs developed any measurable atherosclerosis.

On the other hand, those guinea pigs on a scorbutic diet rapidly developed atherosclerosis. When I say rapidly, I mean within days. I think this point is worth repeating. If you make a guinea pig scorbutic, it will develop plaques, identical to those found in human arteries within days.

Willis then started feeding his guinea pigs vitamin C, and he found that the lipid filled plaques quite rapidly disappeared. He describes what he saw happening to the guinea after they were fed vitamin C.

‘The results of this investigation indicate that early lesions of atherosclerosis are quickly resorbed. The stages of this process are first a fading of lipid staining in the region of the internal elastic membrane with later a disappearance of all extracellular fat. Active phagocytosis of lipid by macrophage occurs, and when these macrophages finally disappear no evidence of the lesion remains.’ 2

I shall translate that passage for those with a non-science background.

What Willis found was that if you remove vitamin C from the guinea pig diet, they develop fat filled atherosclerotic plaques within days. If you then add vitamin C to the diet again, the plaques rapidly disappear (within days). The process of removal appears to be that the fat/lipid is ingested (phagocytosed) by white blood cells – known as macrophages.

However, if you let the plaques grow for too long, it is far more difficult to get rid of them.

‘More advanced lesions are considerably more resistant to reversal. Extensive lipid deposits clear in some parts of plaque but islands of intensely staining lipid persists in other parts. The macrophage response to such areas is only slight.’

It seems that if you don’t get rid of the plaque pretty much straight away, you don’t get rid of it at all. [Or maybe he didn’t wait long enough to see what happened over months, or years. Although my childhood memory of guinea pigs is that they tend to drop dead at the slightest excuse].

Of course, this was guinea pigs, not humans, so we must be careful not to extrapolate too far. However, previously, Willis had studied humans. Not many, only sixteen. Ten people with identified plaques were given vitamin C, six were not. In those ten treated with vitamin C, the plaques got bigger in three, stayed the same in one, and reduced in size in six. In those six not given vitamin C, three remained the same, and in three the plaques got bigger. Interesting, but hardly cast-iron proof of anything.

At this point there are a number of strands to gather together. We now know that humans cannot synthesize vitamin C, so we need to eat it. Without enough vitamin C, our blood vessels crack and bleed, and in severe cases we bleed to death.

In order to provide a degree of protection against vitamin C deficiency (scurvy), we produce lipoprotein (a) to fill up the cracks the blood vessels. However, unsurprisingly, a high level of lipoprotein (a) Lp(a) is associated with a higher rate of CVD.

‘In summary, elevated Lp(a) levels associate robustly and specifically with increased CVD risk. The association is continuous in shape without a threshold and does not depend on high levels of LDL or non-HDL cholesterol, or on the levels or presence of other cardiovascular risk factors.’ 3

This raises two inter-connected questions. Does vitamin C supplementation lower Lp(a) levels, and does it reduce the risk of CVD? It is of course entirely possible that vitamin C could reduce CVD risk by protecting blood vessels from ‘cracking’ without having any effect on Lp(a) levels.

Now you would think that this would have been an area of research interest to someone…. Anyone. However, the only people who seem to have looked at this area in any details are Linus Pauling (double Nobel prize winner, now dead) and Matthias Rath. A man whose reputation within the mainstream medical profession makes that of Andrew Wakefield look like mother Teresa. This from Wikipedia:

‘The Sunday Times (Johannesburg) has described Rath as an “international campaigner for the use of natural remedies” whose “theories on the treatment of cancer have been rejected by health authorities all over the world.”

On HIV/AIDS, Rath has disparaged the pharmaceutical industry and denounced antiretroviral medication as toxic and dangerous, while claiming that his vitamin pills could reverse the course of AIDS. As a result, Rath has been accused of “potentially endangering thousands of lives” in South Africa, a country with a massive AIDS epidemic where Rath was active in the mid-2000s. The head of Médecins Sans Frontières said “This guy is killing people by luring them with unrecognised treatment without any scientific evidence”; Rath attempted to sue him.

Rath’s claims and methods have been widely criticised by medical organisations, AIDS-activist groups, and the United Nations, among others Former South African President Thabo Mbeki and former Minister of Health Manto Tshabalala-Msimang have also been criticised by the medical and AIDS-activist community for their perceived support for Rath’s claims According to doctors with Médecins Sans Frontières, the Treatment Action Campaign (a South African AIDS-activist group) and a former Rath colleague, unauthorised clinical trials run by Rath and his associates, using vitamins as therapy for HIV, resulted in deaths of some participants. In 2008, the Cape High Court found the trials unlawful, banned Rath and his foundation from conducting unauthorised clinical trials and from advertising their products, and instructed the South African Health Department to fully investigate Rath’s vitamin trials.’

Matthias Rath even managed to fall out with Linus Pauling, before Pauling’s death, and law suits ensued. Rath has also successfully sued the BMJ, received £100,000 in damages. So, as you can see, not really a poster boy for mainstream medical research.

I include this information, as I think it is critical to the entire Vitamin C discussion. Because Matthias Rath is viewed as absolute scientific poison this has made the whole area of vitamin C supplementation a complete no-go area for any respectable scientist. If, as a doctor, you try to suggest that vitamin supplementation may be a possible treatment for, say, CVD, you might as well hand you licence over to the authorities at the same time – to save them the trouble of striking you off the medical register (almost a joke, but not quite).

So, essentially, we have a huge void here. The only research that I have ever seen (maybe I missed some) to establish if vitamin C supplementation does actually lower Lp(a) levels was done by Matthias Rath. And, according to him, it does. More so, in those with higher levels to start with. I am not referencing this research, but I would suggest you have a look around Rath and Pauling and vitamin C and Lp(a). See what you think. I think the research is robust.

With regard to the critical question, does vitamin C reduce the risk of CVD [with or without lowering Lp(a)]. I would say, case currently unproven. This does not mean that it does not (in fact I believe that it probably does). What I mean by ‘case currently unproven’ is that no-one has done a large scale interventional study using vitamin C to find out if it really reduces CVD.

The problem here is that such a study is almost certainly never going to be done. There is no way anyone can make money from doing such a study. Vitamin C cannot be patented, so if a company spend several hundred million ‘proving’ that vitamin C reduced CVD death, they would never get any money back.

You would have to find a Governmental organisation, tax payer funded, to do such a study. And with Matthias Rath around, that just ain’t going to happen. No-one would touch it.

However, there is one way to definitely reduce Lp(a) levels, and that is to take l-carnitine. Here, from a study called ‘L-carnitine reduces plasma lipoprotein(a) levels in patients with hyper Lp(a)’

‘L-carnitine, a natural compound stimulating fatty acid oxidation at the mitochondrial level, was tested in a double blind study in 36 subjects with Lp(a) levels ranging between 40-80 mg/dL, in most with concomitant LDL cholesterol and triglyceride elevations. L-carnitine (2 g/day) significantly reduced Lp(a) levels… the reduction being more dramatic in the subjects with the more marked elevations. In particular, in the L-carnitine group, 14 out of 18 subjects (77.8%) had a significant reduction of Lp(a) vs only 7 out of 18 (38.9%) in the placebo group. In a significant number of subjects the reduction of Lp(a) resulted in a return of this major cardiovascular risk parameter to the normal range.’ 4

Does this then result in a reduction in CVD risk? The answer is that I do not know, for sure. A meta-analysis of L-carnitine supplementation has been done. This consisted of five trials on three thousand people. L-carnitine supplementation did show some benefit – which did not reach statistical significance, but came very, very close.

For those of you who like a bit of statistics, here we go

‘The interaction test yielded no significant differences between the effects of the four daily oral maintenance dosages of L-carnitine (i.e., 2 g, 3 g, 4 g, and 6 g) on all-cause mortality (risk ratio [RR] = 0.77, 95% CI [0.57-1.03], P = 0.08)’5

CI [0.57 to 1.03] – close, but no cigar.

To put this into figures anyone can understand. In the intervention groups (those taking L-carnitine) there were 83 deaths. In the control group (those not taking L-carnitine) there were 106 deaths. Total study population was 3108, split in two groups: control and intervention. This gets as close to statistical significance as you can get (virtually). In fact, if this had been a statin trial, you would never have heard the end of it. ‘Ladies and gentlemen a 22% reduction in overall mortality with L-carnitine supplementation.’ [Oh, what fun statistics are].

So, what do we know?

  • A high level of Lp(a) is associated with a higher risk of CVD.
  • There is a probable causal mechanism linking Lp(a) to CVD death
  • Lp(a) is synthesized in animals that cannot make their own Vitamin C
  • A lack of vitamin C causes blood vessels to crack open – and potentially leads to atherosclerotic plaques development
  • Animal models have shown that a lack of vitamin C does lead to rapid atherosclerotic plaque development, and that replacement of vitamin C causes rapid regression of atherosclerosis
  • Some evidence from humans suggest that vitamin C supplementation causes regression of atherosclerotic plaques
  • Vitamin C supplementation does seem to lead to a reduction in Lp(a) levels
  • L-carnitine supplementation does lead to a reduction in Lp(a) levels
  • L-carnitine supplementation may reduce overall mortality.

What would I now recommend? If you have a high Lp(a) level take lots of vitamin C and l-carnitine and see if your Lp(a) level falls. If it does, keep taking lots of vitamin C and l-carnitine for the rest of your life. If it does not fall? Not sure.

As for the rest of us? Well I have no idea how much vitamin C anyone should take, or how much l-carnitine is required. There is literally no area of medicine that is less clear than our true vitamin requirements. You can find a thousand shouty people supporting high vitamin supplementation – any or all vitamins.

My view. I do not think the RDAs for vitamins are remotely accurate, or useful. They were established in times of absolute deficiency. The agreed Vitamin B12 levels, for example, were based on seven people, over sixty years ago, and remain unchanged to this day. All seven had pernicious anaemia (caused by vitamin B12 deficiency).

So, I do not believe in the RDAs at all. They are often, I believe, too low for optimal health. I can see no harm coming to people from taking lots of vitamin C or lots of l-carnitine. So, supplement away. You will probably reduce your risk of dying from CVD.

 

References
1: https://www.ncbi.nlm.nih.gov/pubmed/9140214

2: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1823880/?page=3

3: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3295201/

4: https://www.ncbi.nlm.nih.gov/pubmed/11213533

5: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4223629/

What causes heart disease part XXIII

As 2016 draws to an end, I believe that a change is in the air. The dietary guidelines, or perhaps I should call them the ‘dietary misguidedlines’, are under a sustained attack. This, finally, may actually result in success. We will be able move on from believing that fat, or saturated fat, in the diet is responsible for cardiovascular disease or, indeed, any form of disease.

But where to then? The current dogma is that saturated fat in the diet raises cholesterol levels and this, in turn, leads to cardiovascular disease. However, as many of you may have spotted earlier this year, in the Minnesota Coronary Experiment (MCE), substituting saturated fat with polyunsaturated fat was effective at lowering cholesterol levels. However, it had absolutely no effect on deaths for heart disease, and greatly increased the overall risk of death.

The summary of this trial was, as follows:

  • It involved 9423 women and men aged 20-97
  • A cholesterol lowering diet was used, replacing saturated fat with linoleic acid (from corn oil and corn oil polyunsaturated margarine).
  • The low saturated fat group had a significant reduction in serum cholesterol compared with controls.
  • There was no evidence of benefit in the intervention group for coronary atherosclerosis or myocardial infarcts.
  • For every 0.78mmol/l reduction in serum cholesterol [Around a 20% reduction], there was a 22% higher risk of death [This is about a 30% reduction in cholesterol level]

Big deal, you might think. This is just one trial, so what difference does it make. However, this was no ordinary trial. It was absolutely pivotal for four main reasons:

  • It was the largest controlled trials of its kind ever done. That is, substituting saturated with polyunsaturated fats.
  • It was done by Ancel Keys (who started the entire diet-heart hypothesis in the first place)
  • It was finished, before the main clinical nutritional guidelines were developed
  • It was not published at the time, for reasons that have never been explained, by anyone.

As the authors of the re-analysis note.

Whatever the explanation for key MCE data not being published, there is growing recognition that incomplete publication of negative or inconclusive results can contribute to skewed research priorities and public health initiatives. Recovery of unpublished data can alter the balance of evidence and, in some instances, can lead to reversal of established policy or clinical practice positions.” 1

Which is a polite way of saying that a bunch of liars hid the results. Almost certainly because the results contradicted their self-promoted message that saturated fats are unhealthy. It is clear that these researchers, in particular Ancel Keys, did this quite deliberately, and then continued to promote their own dietary dogma.

I think it is almost impossible to overestimate the long-term impact of the non-publication of this trial.

  • For want of a nail the shoe was lost.
  • For want of a shoe the horse was lost.
  • For want of a horse the rider was lost.
  • For want of a rider the message was lost.
  • For want of a message the battle was lost.
  • For want of a battle the kingdom was lost.
  • And all for the want of a horseshoe nail.

Here is my updated version

  • For want of the MCE trial evidence the McGovern hearings were lost
  • For want of the hearings the guidelines were lost
  • For want of the guidelines the message was lost
  • For want of the message battle was lost
  • For want of the battle saturated fat was lost
  • All for the want of the MCE trial data.

The McGovern hearings which set the entire direction of nutritional thinking, and guidelines, took place in 1977. The MCE trial ran from 1968 to 1973. Had the data from this study been made available, the dietary guidelines in the US, the UK and the rest of the world (In their current form, demonising saturated fat) simply could not have been written.

If those guidelines had not been written, then the entire world of cardiovascular research would almost certainly have gone off in a different direction. The role of LDL in causing CVD would have been consigned to the dustbin history. Goldstein and Brown wouldn’t have done their research on Familial Hypercholesterolaemia, statins would never have been developed, and we not have been forced to endure fifty years of the damaging, destructive diet-heart/cholesterol hypothesis.

The fact that the diet-heart/cholesterol hypothesis is complete nonsense, has been clear as day to many people for many years. In 1977 George Mann, a co-director of the Framingham Study, writing in the New England Journal of Medicine called it ‘the greatest scam in the history of medicine.’ In my view, anyone with a moderately functioning brain, can easily see that it is nonsense.

So, if not fat and cholesterol, what does cause cardiovascular disease, and more importantly, what can be done to prevent it, or at least delay it? At last (some of you are thinking) I will state what I believe to be one of the most important things you can do to reduce the risk.

Returning to the central process of cardiovascular disease (CVD), for a moment. If you are going to reduce the risk of cardiovascular disease, you must do, at least, one of three things:

  • Protect the endothelium (lining of blood vessels) from harm
  • Reduce the risk of blood clots forming – especially over areas of endothelial damage
  • Reduce the size and tenacity (difficulty of being broken down) of the blood clots that develop

If you can do all three, you will reduce your risk of dying of a heart attack, or stroke, to virtually zero.

What protects the endothelium?

There are many things that that can do this, but the number one agent that protects the endothelium is nitric oxide (NO). Thus, anything that stimulates NO synthesis will be protective against CVD. Which brings us to sunshine and vitamin D.

  • Sunlight on the skin directly stimulates NO synthesis, which has been shown to reduce blood pressure, improve arterial elasticity, and a whole host of other beneficial things for your cardiovascular system, not least a reduction in blood clot formation.
  • Sunlight on the skin also creates vitamin D, which has significant impact on NO synthesis in endothelial cells, alongside many other actions. It also prevents cancer, so you get a double benefit.

Therefore, my first direct piece of direct advice for those who want to prevent heart disease, is to sunbathe. In the winter when the sun is not shining take vitamin D supplementation. Alternatively, go on holiday to somewhere sunny. Or get a UVB sunbed, and use it.

My only note of warning here is to say, don’t burn, it is painful and you don’t need to.

By the way, don’t worry about skin cancer. Sun exposure protects against all forms of cancer to a far greater degree than it may cause any specific cancer. To give you reassurance on this point, here is a Medscape article, quoting from a long-term Swedish study on sun exposure:

‘Nonsmokers who stayed out of the sun had a life expectancy similar to smokers who soaked up the most rays, according to researchers who studied nearly 30,000 Swedish women over 20 years.

This indicates that avoiding the sun “is a risk factor for death of a similar magnitude as smoking,” write the authors of the article, published March 21 in the Journal of Internal Medicine. Compared with those with the highest sun exposure, life expectancy for those who avoided sun dropped by 0.6 to 2.1 years.

Pelle Lindqvist, MD, of Karolinska University Hospital in Huddinge, Sweden, and colleagues found that women who seek out the sun were generally at lower risk for cardiovascular disease (CVD) and noncancer/non-CVD diseases such as diabetes, multiple sclerosis, and pulmonary diseases, than those who avoided sun exposure.

And one of the strengths of the study was that results were dose-specific — sunshine benefits went up with amount of exposure. The researchers acknowledge that longer life expectancy for sunbathers seems paradoxical to the common thinking that sun exposure increases risk for skin cancer.

“We did find an increased risk of…skin cancer. However, the skin cancers that occurred in those exposing themselves to the sun had better prognosis,” Dr Lindqvist said.”2

In short, avoiding the sun is a bad for you as smoking. In my opinion ordering people to avoid the sun, is possibly the single most dangerous and damaging piece of health prevention advice there has ever been. The sun has been up there, shining down, for over four billion years. Only very recently have we hidden from it. If you believe in evolution, you must also believe that sunshine provides significant health benefits. It cannot be otherwise.

Happy, sunny, CVD risk reduced, 2017

I have just added a little poem that was just sent as a comment on my blog. Thanks for the laugh.

Ancel Benjamin Keys
Researched dietary disease.
When the facts turned out contrarian,
He simply up and buried ’em. [Martin Back]

1: http://www.bmj.com/content/353/bmj.i1246
2: http://www.medscape.com/viewarticle/860805

The diet heart hypothesis suffers another attack – hoorah!

[Go Canada go]

I was writing another blog, on another matter, when someone sent me an email containing a petition signed by over two hundred Canadian doctors. You can read more about it here https://www.facebook.com/photo.php?fbid=10103115611237481&set=a.10103115599810381.1073741857.58002911&type=3&theater

It begins

Re: Canada’s Food Guide Consultation

From: Group of concerned Canadian Physicians and Allied Health Care providers

For the past 35+ years, Canadians have been urged to follow the Canadian Dietary Guidelines. During this time, there has been a sharp increase in nutrition-related diseases, particularly obesity and diabetes.

We are especially concerned with the dramatic increase in the rates of childhood obesity and diabetes. In 1980, 15% of Canadian school-aged children were overweight or obese. Remarkably, this number more than doubled to 31% in 2011; 12% of children met the criteria for obesity in the same reporting period. This has resulted in a population with a high burden of disease, causing both individual suffering, and resulting in health care systems which are approaching their financial breaking points. The guidelines have not been based on the best and most current science, and significant change is needed.

From the Report of the Standing Senate Committee on Social Affairs on Obesity in Canada, “Canada’s dated food guide is no longer effective in providing nutritional guidance to Canadians. Fruit juice, for instance, is presented as a healthy item when it is little more than a soft drink without the bubbles”

They have put together a list of things that they believe should happen

Points for Change

The Canadian Dietary Guidelines should:

  1. Clearly communicate to the public and health-care professionals that the low-fat diet is no longer supported, and can worsen heart-disease risk factors
  2. Be created without influence from the food industry
  3. Eliminate caps on saturated fats
  4. Be nutritionally sufficient, and those nutrients should come from real foods, not from artificially fortified refined grains
  5. Promote low-carb diets as at least one safe and effective intervention for people struggling with obesity, diabetes, and heart disease
  6. Offer a true range of diets that respond to the diverse nutritional needs of our population
  7. De-emphasize the role of aerobic exercise in controlling weight
  8. Recognize the controversy on salt and cease the blanket “lower is better” recommendation
  9. Stop using any language suggesting that sustainable weight control can simply be managed by creating a caloric deficit
  10. Cease its advice to replace saturated fats with polyunsaturated vegetable oils to prevent cardiovascular disease
  11. Stop steering people away from nutritious whole foods, such as whole-fat dairy and regular red meat
  12. Include a cap on added sugar, in accordance with the updated WHO guidelines, ideally no greater than 5% of total calories
  13. Be based on a complete, comprehensive review of the most rigorous (randomized, controlled clinical trial) data available; on subjects for which this more rigorous data is not available, the Guidelines should remain silent.

Oh, happy days. My sense of what is now happening is that the momentum against the very stupid and damaging nutritional guidelines that have dominated the Western World for the last forty years is reaching breaking point. This group even managed to throw ‘restricting salt intake’ into the dustbin. Oh, happy days.

If this carries on, I will have nothing left to blog about soon. Suits me.

High cholesterol low heart disease – The Sami

(Of course, it is a paradox…. Paradox number 112, or thereabouts)

As a nod to a regular contributor to this blog, who lives not far from the area, I thought I should write about the Sami. When I was younger we would probably have called the Sami ‘Eskimos’ – because anyone who lived north of the Arctic circle and dressed in fur was, clearly, an Eskimo. This term is now, I believe, a dread insult. A bit like calling a Scotsman an Englishman, or an Austrian a German. Or, I believe, a Canadian an American. Wars have been fought over less.

The Sami, unlike the Inuit, who reside mainly in North America, live in the North of Scandinavia: Northern Sweden, Norway and Finland and suchlike. In what used to be called Lapland. However, we now call the Lapps, the Sami (please keep up), so do they live in Samiland?

What I know about the Sami is that they obviously enjoy the cold, eating reindeer and smoking. They must do other things too, but I am not entirely sure what. This makes them very similar to the Inuit, who also enjoy: the cold, eating seals, caribou, and smoking. Neither the Sami, nor the Inuit, have the least interest in eating vegetables. I suppose there may be the occasional frozen carrot – or suchlike – from Iceland (that is a UK based joke).

Apart from not eating vegetables, smoking, and eating lots of fat, the Inuit and the Sami have one other thing in common. You can probably guess what it is. Yes, they both – those that live a traditional lifestyle anyway – have a very low rate of death from heart disease.

This came to my attention during an e-mail discussion I was having about whether the human brain required any glucose – at all. Those taking part were the usual suspects, Richard Feinman, Gary Fettke, Nina Teicholz, Jimmy Moore, Jason Fung, Tim Noakes etc. [Yes, good bit of name dropping there].

The consensus was that the human brain could use Ketone bodies for much of its energy requirement. However, there was an absolute need for about forty grams of glucose per day. The final statement on this matter, the one everyone seemed to agree on anyway, was as follows:

1)     The brain requires no dietary glucose. It has a requisite use of 40 grams/day, but these grams can easily be provided from glycerol, and normal ingestion of not particularly high amounts of protein in a high fat, zero carbohydrate diet.

2)     But this is a time dependent situation. Short term fasting will not be a problem for most otherwise healthy people. However, more prolonged starvation will eventually kill you as the brain will pirate 40 grams of glucose/day from protein and lipid, until you have neither fat stores, nor adequate diaphragm or heart muscle left to survive.

Don’t worry, there were about a thousand papers quoted in creating these statements, so the science seems robust. This discussion started because I had an interest in how hunter gatherers, who ate no carbohydrates, kept their brains going. What was the mechanism by which the Massai, Inuit and Sami, power their brains with glucose, if they don’t eat any carbohydrates?

Well, it seems that you can get a certain amount of glucose from fat. Fat is made up of triglycerides, and each triglyceride contains three fatty acids and one glycerol molecule. Two glycerol molecules stuck together (by the liver) makes one glucose molecule.

In short, pure fat does contain some glucose, which can be used to power the brain. However – assuming you are eating no carbs – the brain requires more glucose than can be provided by the glycerol held in triglycerides. Thus, you still need to convert some dietary protein into glucose. If you are not eating any food at all, the body will need to break down muscle to get at the protein required to synthesize glucose.

To cut a very long story short, the end point of the discussion was an agreement that you do not actually need to eat any carbohydrates to remain heathy. The body, and the brain, can get all the glucose it requires from glycerol and dietary protein.

The reason why I was interested in this issue was that ‘the absolute need for carbohydrates’ is a ‘fact’ that is thrown at me from time to time by ‘experts.’ I have always known they were wrong, because there are people e.g. the Massai, who never eat any carbohydrates, and remain far healthier than any expert I have ever cast my eyes upon. However, I wanted to be sure of the facts.

Anyway, time to return to the Sami. For, during this lively discussion, someone posted up two papers on the Sami that I had not seen before. Both papers noted that the Sami, despite having very high cholesterol levels, a high level of smoking, a high fat diet and almost zero carbohydrate intake – and suchlike – had a very low rate of cardiovascular disease.

This was particularly interesting for a couple of reasons. Firstly, most of the Sami live in Finland, and the Finns – at one time – had the highest rate of heart disease in the world. Not only that, but the Sami live in an area of Finland, North Karelia, which had the highest rate of heart disease in Finland. The worst of the worst.

In addition, the Sami had considerably worse ‘traditional’ risk factors for heart disease than the surrounding population. Higher cholesterol and LDL, high fat diet, far more smoking etc.

‘The finding of high cholesterol and high prevalence of smoking the Sami area are compared with the reference rate, and high cholesterol in the Samis and Finns in the north, conforms with similar observations. in studies performed previously. As the classic risk factors indicate a high risk of CHD in the north, other factors, possibly the antioxidants, are important in the low CHD mortality there.’1

[Antioxidants and their impact on CHD were studied in the Heart Protection Study (HPS), and found to have no effect on CHD whatsoever. Whilst this study was done by Rory Collins, and has many issues, the data on the lack of impact of antioxidants on CHD appear robust].

Other researchers have also tried to establish why the Sami have such a low rate of CHD/IHD. As noted in the paper ‘‘Low mortality from ischaemic heart disease in the Sami district of Finland’:

An exceptionally low mortality from IHD was found here in the Sami district of Finland and an exceptionally high mortality in a neighbouring Finnish area, a 2-3-fold contrast or even wider, depending on age and time. No difference in IHD of this magnitude between areas located so close to each other has previously been described in the literature.’2

Of course, they looked for the reasons.

‘Reasons for the rarity of IHD in the Sami district of Finland

Our current knowledge of cardiovascular risk factors cannot explain the low mortality from IHD in the Sami district of Finland. Serum cholesterol is, in fact, relatively high in the far north of Finland, and it is higher in the Sami than the Finns, the same being true of the prevalence of smoking, while the low blood pressure frequently found in the far north and among the Sami would be insufficient to cause any substantial reduction in the risk of IHD. Similar differences in serum cholesterol, blood pressure and smoking have also been found between Norwegian Sami and Norwegians of Finnish ancestry. Serum high density lipoprotein cholesterol (HDL)is usually similar in both ethnic groups, although a Finnish study found even lower HDL-total cholesterol ratios in the Sami, which would indicate an elevated risk of IHD… The high serum cholesterol in the Sami can be attributed to their fatty diet.’

In short, the Sami live in area of Finland that had the highest rate of heart disease in the world. Their risk factors were worse than the surrounding population (LDL 4.45mol/l on average), yet their heart disease rate remained very low. It was postulated that this was due to a high intake of antioxidants, but the impact of antioxidants on heart disease has been subjected to large double blind placebo controlled trial, and antioxidants were found to have no impact on heart disease.

At this point you may cry, enough of finding populations that eat a high fat diet, have high LDL levels and low rates of heart disease. It is like shooting fish in a barrel. Not that the experts pay the slightest attention to such contradictory facts. They merely label such findings a ‘paradox’ and move on. But I thought it was interesting. Another nice shiny nail in the cholesterol hypothesis. ‘You call it a paradox, I call it a contradiction… let’s call the whole things off.’

Next, my series on what truly does cause heart disease continues.

1: ‘High serum alpha-tocopherol, albumin, selenium and cholesterol, and low mortality from coronary heart disease in northern Finland’: P. V. LUOMA, S. NAYHA, K. SIKKILA & J. HASSI. Journal of lnternal Medicine 1995; 237: 49-54

2: Simo Nayha: ‘Low mortality from ischaemic heart disease in the Sami district of Finland.’ Soc. Sci. Med. Vol. 44 No. 1, pp. 123-131, 1997

P.S. I am feeling much better, thanks for those who were concerned over my welfare.

Those who promote a high fat low carbohydrate diet are silenced around the world

For various reasons, including a chest infection that just will not clear, I have been quiet recently. (When you are physically unwell, your brain doesn’t work. At least mine doesn’t). I have coughed more in the last six weeks than in the rest of my life put together x 10.

Anyway, my brain cleared enough to read an e-mail by Gary Fettke, who has promoted the high fat low carb lifestyle for a long time. He, like many others has been ruthlessly attacked for doing this. Professor Tim Noakes was accused of exactly the same thing, and the South African authorities dragged him to court in order to silence him (not yet sure of the verdict).

Gary Fettke is an Australian orthopedic surgeon who has suffered the same fate as Tim Noakes. However, in Australia it seems you can be accused, tried and found guilty without having any chance to defend yourself in person. This is not a court of law, but the Australian Medical Board (AHPRA) who can – as with the General Medical Council (GMC) – strike you off being a doctor. Which for a doctor is a gigantic punishment.

Previously, Gary had been told that he could not comment on any area of nutrition for advocating a reduction in sugar intake (to what are now WHO guidelines). Of course, as with all such cases the ‘authorities’ changed the goalposts from a discussion on low carb high fat (LCHF) and turned the discussion into something else.

Namely, that Gary Fettke, as an orthopaedic surgeon should never give advice on dietary matters. “The fundamental fact ‘is’ that you are not suitably trained or educated as a medical practitioner to be providing advice or recommendations on this topic as a medical practitioner.”

This of course allows the AHPRA to silence him, without discussion any of the science, and no chance of any appeal. So, his suspension about discussing any matters of diet has now been turned into a lifelong ban. Please read Gary’s e-mail:

Hi everyone,

It is with frustration that I write to inform you that I have been ‘silenced’, forever, by the Australian Medical Board, known as AHPRA.

We have a draconian system here in Australia where anonymous notifications can go in and they are investigated for public safety. The accused can only submit material but never have right of reply. It is a star chamber.

I recently got to present that ‘opinion’ of the process and the fabricated evidence at a Senate Inquiry. My evidence on the failings of AHPRA was granted parliamentary privilege which allowed a tell all opportunity. Within a few hours I received an email final determination of the 2 ½ year investigation. Coincidence or just another kick in the guts?

My verbal submission and the whole issue of bullying and harassment in the hospital system is linked from http://www.nofructose.com/introduction/senate-inquiry-into-medical-complaints-process-in-australia/

My first notification in 2014 was from an anonymous dietitian for me advocating cutting back sugar intake to what is now the WHO recommendations. Behind closed doors, with no right of reply or appeal, the goal posts shifted and I was investigated for the whole LCHF concept, for being disrespectful to health professionals (the Dietitians Association of Australia and the Heart Foundation, but never an individual) on social media and for failing to disclose a conflict of interest (COI) in our Nutrition for Life Centre, whilst on social media.

The good news is that AHPRA have decided NOT to argue the LCHF concept. I submitted enough material for a thesis and they have accepted that LCHF may be that the benefits of the LCHF lifestyle become the accepted best medical practice.

The central issue for my silencing has been that my primary medical degree and my further qualifications as an Orthopaedic Surgeon are not satisfactory to give nutritional advice. “The fundamental fact ‘is’ that you are not suitably trained or educated as a medical practitioner to be providing advice or recommendations on this topic as a medical practitioner.”

If it wasn’t so serious it would be farcical. This decision is non-appealable under National Law. The determination is life long and by its wording, does not allow me to even do research in the area or gain further qualification because that would involve me communicating in the area of nutrition. The only thing I have not clarified is if it affects international boundaries.

We have put up the post this morning re the AHPRA decision and the launch of our community fund to keep the LCHF message going

The web page is

http://www.nofructose.com/introduction/help-be-a-voice-for-lchf-after-gary-is-silenced/

and the Facebook one is off Belinda Fettke No Fructose

https://www.facebook.com/belindanofructose/posts/1175659919195124

The other parts of the AHPRA decision I can live with.

I will not force anyone to eat LCHF, not that I ever did or ever could.

I will show respect to the medical profession (doesn’t stop me from thinking otherwise).

The COI allegation is unproven as I do declare my vested interest for all patients that I send to Nutrition for Life. I admit guilt for not doing that in social media but the doctor/patient relationship is not defined in that context. I pointed out to AHPRA that they shouldn’t be applying jurisdiction in an area that is undefined. That went down like a lead balloon.

I also pointed out that AHPRA don’t govern nutritional advice in Australia. Another lead balloon.

I had a recent notification, again from an anonymous dietitian, and have been investigated for ‘inappropriate’ reversal of someone’s Type 2 Diabetes and was also reported for what I was ‘about to say’ at a hospital food national conference. AHPRA actually asked me for a copy of my speech BEFORE I gave the talk. I refused as it was an infringement of the right of free speech.

AHPRA have just this week decided to close that investigation but have warned me that they will be observing me to see if a ‘pattern of behaviour’ continues, presumably in relation to reversing more patients’ diabetes.

I hear rumours that I have ‘attacked’ health professionals at a personal level – that is simply unfounded and I think started by some naysayers. Alas, I am having some sh!t thrown at me at times. If you hear something, then let me know please.

If this sounds like a horror story, it is. I honestly thought that this would just fade away but strange things do happen when you upset the ‘industry’. Just see what’s happening with Tim Noakes. The only thing in Tim’s favour is that it has gone to court. Mine is a closed process with no right of appeal, unless I can continue to have politicians assist.

My next step is to challenge the process via more closed groups and that will be years of tying me up. I am going the public awareness path as the finding lacks the common-sense conclusion. We are liaising with some media channels and politicians. It’s all we can do.

Any support would be appreciated. Happy to liaise. Feel free to forward this email as it is.

Cheers.

Gary

Gary Fettke
Orthopaedic Surgeon
M.B.,B.S.(University NSW), F.R.A.C.S.(Orthopaedic Surgery), F.A.Orth.A.

Science evolves by being challenged. Not by being followed. @thegaryscience

If you think this is all completely ridiculous, then please circulate widely, and make as much noise as possible.

Saturated fat and heart disease

The greatest scam in the history of medicine’ George Mann

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

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

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

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

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

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

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

Yes, indeed. Couldn’t agree more.

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

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

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

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

The GMC judgement has certainly been criticized:

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

The GMC responded thus:

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

Niall Dickson

Chief executive, General Medical Council

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

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

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

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

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

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

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

Shaken baby syndrome: saturated fat consumption.

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

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

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

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

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

Psychiatrist:       ‘Do dead people bleed?’

Patient:                                   ‘No, I guess not.’

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

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

 

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

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

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

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

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

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

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

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

The conclusion of the authors:

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

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

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

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

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

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

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

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

2: http://www.foodandnutritionresearch.net/index.php/fnr/article/view/31694

Buy this new book

Fat and Cholesterol Don’t Cause Heart Attacks

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

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

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

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

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

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

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

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

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

thincs-coverart-frontcover-sm

You can get a copy direct from the Publishers here…

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


Amazon.co.uk
Amazon.com

What causes heart disease part XXI

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

hdp21

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

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

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

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

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

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

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

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

Anyway, we now have a simple equation

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

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

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

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

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

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

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

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

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

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

To rearrange this jargon as simply as I am able.

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

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

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

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

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

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

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

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

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

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

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

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

 

References:
1: http://atvb.ahajournals.org/content/31/7/1462.full
2: Shah NH, LePendu P, Bauer-Mehren A, Ghebremariam YT, Iyer SV, Marcus J, et al. (2015) ‘Proton Pump Inhibitor Usage and the Risk of Myocardial Infarction in the General Population.’ PLoSONE 10(6): e0124653. doi:10.1371/journal.pone.0124653

Medical censorship in the twenty first century

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

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

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


A humiliating climb down – or a Machiavellian move?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

From: colin.baigent@xxxxxxxxxxx

To: maryannedemasi@xxxxxxxxxxxx

Subject: RE: URGENT COMMENT NEEDED PLEASE: ABC TV AUSTRALIA

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

Dear Maryanne

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

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

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

Colin Baigent.

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

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

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

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

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

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

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

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

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

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

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

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

1: http://www.forbes.com/sites/larryhusten/2014/08/02/no-retraction-for-you-review-panel-exonerates-medical-journal-in-statin-kerfuffle/

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


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

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

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

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

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

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

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

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

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

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

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

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

Anyway, you can read the editorial in full here (http://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(16)31583-5.pdf). In addition to the paragraph highlighted above, I would like to draw your attention to a couple of other very worrying statements in the closing parapgraphs:

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

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

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

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

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

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

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

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

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

What do other editors think of this latest paper? Well, we have the thoughts of Fiona Godlee (editor of the BMJ), and Rita Redberg (editor of the Journal of the American Medical Association). I will supply a few quotes from them in an article published in Medpage Today (http://www.medpagetoday.com/cardiology/cardiobrief/60122):

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

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

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

As they went on to say

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

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

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

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

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

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

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

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

pic1

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

Declaration of interests

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

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

 

1: http://www.thelancet.com Published online September 8, 2016 http://dx.doi.org/10.1016/S0140-6736(16)31357-5

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

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

4: http://www.thelancet.com Vol 385 April 11, 2015

5: http://www.medpagetoday.com/cardiology/cardiobrief/60122

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

Duane Graveline

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

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

Regards,

Kevin’

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

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

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

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

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

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

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

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

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

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

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

What causes heart disease part XX

Stress/strain

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

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

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

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

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

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

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

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

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

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

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

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

‘How do you know it is genetic?’

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

DR-Men-Lithuania

Exactly the same pattern can be seen in Latvia

DR-Men-Latvia

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

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

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

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

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

1: http://www.ncbi.nlm.nih.gov/pubmed/10889792

What causes heart disease part XVIIII

Diet?

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

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

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

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

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

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

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

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

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

Big fleas have little fleas,

Upon their backs to bite ’em,

And little fleas have lesser fleas,

and so, ad infinitum.

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

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

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

It is not.

What causes heart disease past XVIII

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

‘Native HDL prevents platelet hyperreactivity by limiting intraplatelet cholesterol overload, as well as by modulating platelet signalling pathways after binding platelet HDL receptors such as scavenger receptor class B type I (SR-BI) and apoER2′. The antithrombotic properties of native HDL are also related to the suppression of the coagulation cascade and stimulation of clot fibrinolysis. Furthermore, HDL stimulates the endothelial production of nitric oxide and prostacyclin, which are potent inhibitors of platelet activation. Thus, HDL’s antithrombotic actions are multiple and therefore, raising HDL may be an important therapeutic strategy to reduce the risk of arterial and venous thrombosis.’ 5

And what about VLDL?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

References:
1: http://www.ncbi.nlm.nih.gov/pubmed/3524931
2: http://europepmc.org/abstract/med/23199546
3: http://www.ncbi.nlm.nih.gov/pubmed/16877876
4: Br Heart j 1985; 53: 265-8
5: http://www.ncbi.nlm.nih.gov/pubmed/24891399
6: https://www.karger.com/Article/Pdf/93221
7: http://www.ncbi.nlm.nih.gov/pubmed/15569822
8: http://www.ncbi.nlm.nih.gov/pubmed/22278047

What causes heart disease part XVII

Epidemiology

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

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

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

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

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

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

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

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

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

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

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

Accurate at last? Certainly more accurate.

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

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

CVD17-1

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

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

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

CVD17-2

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

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

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

CVD17-3

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

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

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

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