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.

A talk by Aseem Malhotra to the European Parliament

15th April 2018

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

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

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

Statins and Amyotrophic Lateral Sclerosis

9th April 2018

Primum non Noncere’ – first do no harm.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

INCREASED RISK OF AMYOTROPHIC LATERAL SCLEROSIS

WITH DIFFERENT STATINS

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

 

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

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

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

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

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

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

Number of people                                                        = 50,000,000

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

What causes heart disease part forty-eight (48)

22nd March 2018

A year ago, I wrote a blog suggesting that lead – as in the element – could have caused/causes a great deal of cardiovascular disease. I went further, to propose that the removal of lead as an additive in petrol (gasoline) may have been responsible for a significant percentage of the decline in cardiovascular disease in the Western World, over the last forty or fifty years.

Last week a paper was published suggesting that excess lead was responsible for as many deaths as smoking 1. So, there you go, it turns out I was right. Once again. Yes, yes, I know, Nobel prize on the way. Or perhaps not.

In fact, what cheered me most about this study is that my hypothesis that endothelial damage is the trigger for CVD, was strongly supported. Some time ago I set about looking for factors/things that were capable of damaging the endothelial cells that line arteries. I tend to do this by going to Google and typing in the words endothelial damage ‘and’ copper, or lead, or mercury, or glucose, or smoking, or sickle cell anaemia etc. etc.

Then I see what pops up. At which point I switch to PubMed to look for the associated papers in the area. As it turned out when you hit lead and endothelial damage there was not a great deal, but it is fascinating, and it is clear that lead does damage endothelial cells, in various ways. It also damages many other things in the body – but that is another story.

This relatively unstructured searching system is how I ended up looking at chelation therapy. This form of treatment is/was supposed to remove heavy metals, such as lead, from the body. I had written it off as ‘woo-woo medicine’ (a phrase I actually hate, but I thought it was appropriate here). So, you use drain cleaner in arteries and this makes you better. Yes, right, pull the other one. Bong, next.

Oh well, you live and learn. Turns out that chelation actually works2.

The second thing about the latest paper demonstrating the impact of lead on CVD is that the endothelial damage conjecture had proven ‘predictive’. The best scientific hypotheses are those you can use to predict what is going to happen in the future or better explain the facts of what happened in the past.

As an example of a good predictive hypothesis, we know that if we stand in a specific place, at a specific time, we will see an eclipse of the sun. We know this because we have been told that it will happen by people, who get this right 100% of the time.

If, on the other hand, someone says global temperature will rise by two degrees in the next twenty years, and it does not, we should be rightly sceptical that the scientists predicting this have got their ideas properly nailed down. We should also be sceptical when people alter their hypothesis to fit the facts. Global Warming has become Climate Change. Which some, like me, would say has changed their hypothesis from one that can be disproven, to one that cannot. ‘We predicted the Climate would change, and look it has. Told you so.’

Well gee whizz that was just so extremely helpful. Thanks.

Anyway, to get back to endothelial damage. My conjecture is that, if you can find a factor that damages the endothelium, you will find that it increases the risk of CVD. It is not enough to say that most things that damage the endothelium increase the risk of CVD, or that almost everything that damages the endothelium increases the risk of CVD. It has to be everything.

There are, of course, provisos. We know that smoking increases the risk of lung cancer. We also know that some people who smoke never get lung cancer. So, on an individual basis, there can be protective things going on. Ergo, I would not expect everything that causes endothelial damage to cause CVD, in everyone.

Equally, we know that the tuberculous bacillus causes TB. However, not everyone that is exposed to the bacillus gets TB. We also know that people who carry the gene for CCR5 delta 32 mutation cannot be infected with HIV or Ebola. Why not? Because their cells do not code for the protein that allows these viruses to gain entry to cells. Just thought I would throw that one in. I am not just interested in CVD, you know.

In reality, there is almost nothing that is both necessary and sufficient to cause disease, or death – in everybody. Some people have survived falling out of aeroplanes without a parachute. Not many, but it has happened. Ebola kills up to 80% of those it infects, but some survive.

So, what I spend a lot of time doing is attempting to establish is whether or not endothelial damage is ‘necessary’ for CVD to develop [not that it is sufficient in everyone]. Or as someone told me on the blog ‘If and only if.’ As in, CVD will develop if, and only if, endothelial damage has occurred.

So, are there contradictions to the endothelial damage hypothesis? Well, if there are, I have yet to find them. Which does not mean that they do not exist. The closest I have come to a contradiction is with thalidomide. Everyone has heard of this drug, and the terrible malformations it caused. I suspect not many people know why it caused limb malformations.

It is because it interferes with the production and growth of endothelial cells. Because these cells did not grow and develop, blood vessels did not develop and grow in the unborn child, so there was no blood supply to support limb growth. So, the limbs were terribly shortened. I suspect that if thalidomide had been given at an earlier stage of the pregnancy the heart, brain, lungs etc. would have failed to develop and the foetus would have been non-viable – with spontaneous abortion.

Because thalidomide interferes with the formation of new blood vessels (angiogenesis) it is now used to treat cancer, and leprosy, and a few other things as well. Cancers need their own blood supply to grow, and if you stop them triggering new blood vessel growth and development the shrivel up and die. At least, that is the plan.

Other drugs have been developed to stop angiogenesis. One of the first was Avastin. Technically, it is a Vascular Endothelial Growth Factor (VEGF) inhibitor. It inhibits the growth of new endothelial cells. It is also widely used in macular degeneration, where the growth of new blood vessels in and around the macula (the main bit of the retina you use to see with), destroys the vision.

Unfortunately, Avastin has a significant adverse effect. You can probably guess what it is. Yes, it increases atherosclerotic plaque growth, and significantly increases the risk of death from CVD. In high doses, over two years, up to a 1,200% increase in heart attacks3.

Now thalidomide is not exactly the same as Avastin, but it definitely has a negative impact on endothelial cells in some way. But I can find no evidence for thalidomide increasing CVD risk. I can find evidence that, if you give thalidomide to pregnant animals, they too demonstrated limb deformity in offspring. However, if you give Viagra this eliminates the deformity. So, we know that inhibition of nitric oxide (NO) must be a key mechanism of endothelial dysfunction with thalidomide.

Therefore, it should increase CVD risk. Does it, or does it not? Well, you can read this paper ‘Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications.’4 And try to decide if it does, or it does not. Personally, I cannot figure it out at all. I am kind of hoping that it does, or else my theory is in danger of hitting the waste bin.

Until next time.

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

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

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

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

What causes heart disease part forty-seven

13th March 2018

Before putting cardiovascular disease to bed for a while and talking about other things – such as diabetes – I thought I should highlight a fact that is almost never remarked upon yet is extremely important. At least it is, if you trying to bring down the cholesterol hypothesis. The fact is this. A raised cholesterol level, or LDL level, is not a risk factor for stroke. Not even in familial hypercholesterolaemia (FH) is a raised cholesterol level a risk factor for stroke.

Here, I am quoting from a study published in the Lancet called ‘Cholesterol, diastolic blood pressure, and stroke: 13,000 strokes in 450,000 people in 45 prospective cohorts. Prospective studies collaboration.’

‘After standardization for age, there was no association between blood cholesterol and stroke except, perhaps, in those under 45 years of age when screened. This lack of association was not influenced by adjustment for sex, diastolic blood pressure, history of coronary disease, or ethnicity (Asian or non-Asian). 1

I think that this was a big enough study to demonstrate that, if there is any effect, it can only be tiny. Yes, the study is over twenty years old, but it was done before statins came along to distort the entire area. By which I mean after the mid-nineties, a large number of people with raised cholesterol were being put on statins, thus making any interpretation of the impact of different cholesterol levels, on stroke, almost impossible.

As for Familial Hypercholesterolaemia. The findings of the Simon Broome registry (set up in the UK to study the health impact of FH) were, as follows

‘The data also confirm our earlier findings that FH patients are not at a higher risk of fatal stroke.’ 2

Thus, a raised cholesterol level is not a risk factor for stroke, even at very high levels found in FH – even in homozygous FH (where both the subject’s genes are faulty so leading to more severe FH). Yet, and yet, statins reduce the risk of stroke. Not by much, and not to the extent that I consider the benefits to outweigh the harms, but they do. Here, plucked from a million possible articles is something from the American Heart Association

‘Millions more people worldwide may benefit from cholesterol-lowering statins after a global study showed the drugs help reduce heart attacks and strokes in people at moderate risk. The risk fell slightly further when patients also took blood pressure drugs.’ 3

The absolute figures wobble about, depending of which of the myriad studies and meta-analyses you choose to look at, but the reduction in stroke risk is about the same as the reduction in the risk of heart attacks/myocardial infarctions.

When I see facts like this, I try to use logic. The logic, in this case, goes something like this:

  • Factor A (raised LDL) is not a risk factor for disease B (stroke)
  • However, if you lower factor A, the risk of disease B falls

Conclusion. Something other than the lowering of Factor A is causing the reduction in the risk of disease B. If you take this thought one step further, the beneficial effect of statins on the risk of stroke, flatly contradicts the cholesterol hypothesis.

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

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

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

Meeting in London

4th March 2018

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

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

Other guests/speakers will be

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

Here is some of the blurb

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

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

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

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

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

I hope some people can get along.

Vendetta – The Tim Noakes affair

20th February 2018

[The high fat low carb conspiracy]

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

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

The tweets were:

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

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

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

Question One: does this constitute a medical consultation?

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

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

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

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

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

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

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

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

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

Yes, really. Yes…really.

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

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

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

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

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

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

What causes heart disease part 46

14th February 2018

The mind

The final big-ticket item on my list, of how to avoid CVD and live longer, is poor social interactions, and the strain caused by them, or whatever you want to call this rather difficult to define area. Here we have a whole range of different, interconnected, issues. Childhood abuse, family breakup, abusive partner, financial difficulties, abusive and bullying boss at work, social isolation, mental health issues, loneliness, no sense of being part of a supportive family or group – religious or otherwise.

The simple fact is that we humans are social animals. We require nurture and support by others. We need a sense of belonging, a sense of value and purpose. We need to be loved, not hit, or shouted at, or bullied, or treated with contempt.

When I first started looking at CVD, this was the area that I focussed on. It seemed obvious to me, that there was an enormously important mind/body connection that was simply being ignored by mainstream research into heart disease – and all other diseases. Despite the complete lack of interest by most researchers, whenever and wherever you look, if you chose to see, psychological/mental health issues were standing right there, waving their arms about and shouting me, me, me, me. Look at ME!

The full impact of negative stressors was highlighted in a study that was sent to me a few months back. Researchers found that people who suffer from significant money worries are thirteen times more likely to suffer a heart attack. Yes, thirteen times more likely, or 1,300%. Now that is the level of increased risk where I tend to prick up my ears and pay attention. Relative risk, or not1.

It is also clear that mental health, or mental illness, plays a massive role in overall health and life expectancy, as highlighted by researchers from Oxford University.

‘Serious mental illnesses reduce life expectancy by 10 to 20 years, an analysis by Oxford University psychiatrists has shown – a loss of years that’s equivalent to or worse than that for heavy smoking….

The average reduction in life expectancy in people with bipolar disorder is between nine and 20 years, while it is 10 to 20 years for schizophrenia, between nine and 24 years for drug and alcohol abuse, and around seven to 11 years for recurrent depression.’2

Yes, when your mind goes wrong, your body follows, with disastrous consequences for overall health. Of course, there is overlap between mental illness, drug use, smoking and suchlike. However, you can strip out all the other things, and you are left with the ferocious power of the mind/body connection. The power to nurture, and the power to destroy.

I usually tell anyone, still listening after I have bored them on various other issues, that health is a combination of physical, psychological and social wellbeing. Three overlapping sets. The holy trinity of wellbeing. You must get them all right, or nothing works. As Plato noted, a few years back “the part can never be well unless the whole is well.”

Who are the shortest-lived peoples in the world? Are they the poor? Not necessarily, although poverty can be a clear driver of ill-health. The shortest-lived people in the world are people who live in the places of greatest social dislocation and disruption. Or, to put it another way, people who have had their societies stripped apart. Australian aboriginals, NZ Maoris, North American aboriginals, the Inuit.

‘Indigenous Australians have the worst life expectancy rates of any indigenous population in the world, a United Nations report says. But it’s not news to Aboriginal health expert. They say it simply confirms what Australian health services have known for years.

Aboriginal Medical Services Alliance of the Northern Territory (AMSANT) chief executive officer John Paterson said the findings of the report, which examined the indigenous populations of 90 countries, were no surprise. The UN report – State of the World’s Indigenous Peoples – showed indigenous people in Australia and Nepal fared the worst, dying up to 20 years earlier than their non-indigenous counterparts. In Guatemala, the life expectancy gap is 13 years and in New Zealand it is 11.’ 3

Twenty years earlier. I think that figure is worth repeating. I cannot find anything else, from anywhere, that gets close to that sort of impact on health – on a population basis.

Or, to put it another way, do not be a stranger in your own land. It kills you. The differences in life expectancy in the US or the UK mirror these findings, albeit less dramatically. There are areas, within deprived inner-cities in the UK, where people do almost as badly as Australian aboriginals.

It does not take a genius to guess where they might be. Inner city Glasgow, Manchester, Liverpool. The same thing can be seen in ghetto areas in virtually all cities in the US. Where the marginalised poor live – but not for terribly long.

‘The differences between places [in the US] are sometimes stark. For example, the average person in San Jose (California District 19) lives to 84 years compared to just 73 years for someone from Kentucky District 5, in the rural south east of that state.’4

On a more positive note, living in supporting and positive environments, is exceedingly good for you. The Blue Zones are areas of the world where people live longer than anywhere else. For example: inland Sardinia, Loma Linda California, Nicoya (Costa Rica), Okinawa, Ikaria (Greece), and a couple of others. [I think I should point out here that they are also, sunny, something not mentioned in the book].

The most important factor was a sense of well-being, community, a connection with other people, a sense of purpose, and good relationships with friends and family. As a slight aside, the author of the book “The Blue Zones”, Dan Buettner, was very focused on the benefits of a high vegetable, low meat diet. He tried hard to promote the idea that diet was the primary driver of good health.

For example, in Sardinia, he wrote the following about the food that was eaten there:

‘It’s loaded with homegrown fruits and vegetables such as zucchini, eggplant, tomatoes, and fava beans that may reduce the risk of heart disease and colon cancer. Also on the table: dairy products such as milk from grass-fed sheep and pecorino cheese, which, like fish, contribute protein and omega-3 fatty acids.’

The Sardinians themselves, however, have a completely different view of what they eat, and they protested the misrepresentation of their diet:

‘In 2011, Sardinians called for formal recognition of their diet insisting that “the secret to a long life can be found in their traditional diet of lamb, roast piglet, milk and cheese.”’5

In fact, many years earlier, researchers studied another Italian community that defied all dietary expectations. This was in the town of Roseta in Pennsylvania. This community had moved, virtually lock stock and barrel, from Roseta in Italy, to a new Roseta in the US. It was noted that they had an extraordinarily low rate of CVD. Why? Here, once again, I quote an article from the Huffington Post:

‘What made Rosetans die less from heart disease than identical towns elsewhere? Family ties. Another observation: they had traditional and cohesive family and community relationships. It turns out that Roseto was peopled by strongly knit Italian American families who did everything right and lived right and consequently lived longer.

In short, Rosetans were nourished by people.

In all ways, this happy result was exactly the opposite expectation of well-proven health laws. The Rosetans broke the following long-life rules, and did so with a noticeable relish: and they lived to tell the tale. They smoked old-style Italian stogie cigars, malodorous and remarkably pungent little nips of a cigar guaranteed to give a nicotine fix of unbelievably strong potency. These were not filtered or adulterated in any way.

Both sexes drank wine with seeming abandon, a beverage which the 1963 era dietician would find almost prehistoric in health value. In fact, wine was consumed in preference to all-American soft drinks and even milk. Forget the cushy office job, Rosetan men worked in such toxic environs as the nearby slate quarries. Working there was notoriously dangerous, not merely hazardous, with “industrial accidents” and gruesome illnesses caused by inhaling gases, dusts and other niceties.

And forget the Mediterranean diets of olive oil, light salads and fat-free foods. No, Rosetans fried their sausages and meatballs in lard. They ate salami, hard and soft cheeses all brimming with cholesterol.6

The Okinawan’s, another of the Blue Zone populations are also known as the pig eaters. It is said that they eat every part of the pig, apart from the squeak. In short, you can focus on the diet of very long-lived people around the world, if you want, but you will find little or nothing here. Much in the same way, you can look at the French, with the highest consumption of animal fat in Europe, and the lowest rate of CVD.

Getting back to the main point in hand. What can we really learn about the Blue Zones is that social health is terribly, terribly, important. Perhaps the single most important factor of all. If your social health goes wrong, your psychological health will suffer, followed by your physical health. More recently it has been recognised, finally, that loneliness is a significant driver of ill health and early death.7

Be happy, be friendly, be healthy. Live long and prosper, my friend.

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

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

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

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

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

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

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

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

29th January 2018

Magnesium

Someone very wise once said. ‘When the facts change, I change my mind. What do you do, Sir?’ Actually, it was John Maynard Keynes (yes, I looked it up).

In my last blog I wrote about Magnesium, thus:

‘As for magnesium. Magnesium deficiency is increasingly recognised as a major health issue and can greatly increase the risk of sudden cardiac death. I now routinely test patients for magnesium levels, as does the rest of the health service, which has belatedly woken up to the importance of this chemical. Magnesium deficiency can also trigger atrial fibrillation (AF) which, in turn, vastly increases the risk of stroke.

But I feel I am running away with myself a bit. I need to stop and take stock. The last thing I want people to do, is to worry too much about the levels of this and that in the blood. I do not want you rushing to the doctor, or private lab, to have everything repeatedly checked.

 Magnesium level deficiency for example. This is almost unknown if you do not take an acid lowering drug such as omeprazole, or lansoprazole (both proton pump inhibitors (PPIs)). Unless you are taking one of these, of any other ‘zoles,’ long term, you are extremely unlikely to be magnesium deficient.’

Well, as it turns out I was wrong. Who me? Someone sent me links to a paper published in the BMJ Open, published this very day, 29th Jan 2018. As it turns out magnesium deficiency is far more common that I thought. The paper is entitled: ‘Subclinical magnesium deficiency: a principal driver of cardiovascular disease and a public health crisis.

‘Subclinical magnesium deficiency is a common and under-recognised problem throughout the world. Importantly, subclinical magnesium deficiency does not manifest as clinically apparent symptoms and thus is not easily recognised by the clinician. Despite this fact, subclinical magnesium deficiency likely leads to hypertension, arrhythmias, arterial calcifications, atherosclerosis, heart failure and an increased risk for thrombosis. This suggests that subclinical magnesium deficiency is a principal, yet under-recognised, driver of cardiovascular disease. A greater public health effort is needed to inform both the patient and clinician about the prevalence, harms and diagnosis of subclinical magnesium deficiency.’

The paper can be read in full, here. http://openheart.bmj.com/content/openhrt/5/1/e000668.full.pdf

So, when I said I don’t want people to rush about getting the levels of this and that checked, with regard to magnesium I was wrong. I do want people to rush about getting the levels of magnesium checked. [Although I suspect you will not get very far with your local GP].

What is the normal magnesium level?

  • Normal’ serum magnesium levels 0.75–0.95mmol
  • A serum magnesium <0.82mmol/L with a 24-hour urinary magnesium excretion of 40–80mg/ day is highly suggestive of magnesium deficiency.
  • Serum magnesium levels above 0.95mmol/L may indicate hypermagnesaemia

There are more complex tests that can be done, that may need to be done? Because the vast majority of magnesium is not in the blood, it is stored in cells/tissues/organs, you can be down to virtually your last drop, without the blood level being affected.

To find out how your magnesium stores are looking, you can give a magnesium infusion, and see how much is then excreted.

Thoren’s intravenous magnesium load test for diagnosing magnesium deficiency

Provide ~360–480mg of magnesium intravenously over 1hour

If <70% (less than 70%) of the magnesium load comes out in the urine over 16 hours, this is highly suggestive of magnesium deficiency

I have never heard of anyone having this test, ever. Most doctors will never have heard of it either. I only know about it, because I just read this article. Maybe someone can tell me who does it, and how it costs.

Anyway, funny how things turn out. Here I am writing a blog of vitamins and supplements and two days later, out pops a major review article on magnesium. I must be psychic. Or maybe not. But I thought it was important to make you aware of this research. I leave it up to you to decide how to act upon it.

What causes heart disease part forty-five

27th January 2018

Vitamins and supplements and suchlike

I did say I was going to talk about strain and mental health next, but so many people have commented on vitamins and supplements, that I thought I should cover this area. I must say that I do like vitamins, I like the idea of them – and my mother did make me take vitamin C tablets every morning. So, perhaps she is to blame for my early age mental programming.

However, there is very little good evidence that any vitamin supplement is beneficial. In large part this is because there are not huge profits to be made from selling vitamins, as they cannot be patented.

If a company did a major clinical trial on vitamin K, and found that it saved lives, there would be nothing to stop anyone else selling vitamin K, whilst claiming the newly discovered health benefits for themselves. The company that took the financial risk, and funded the trials, would be unable to recoup any research costs.

Another factor in play here is that the pharmaceutical industry is doing its level best to attack vitamins as damaging and dangerous, and lobbying madly to have vitamin supplements banned.1

Once they achieve this state of Nirvana, they can then invent new synthetic vitamins, patent them, and sell them back to us at hugely inflated prices, making massive profits. I just made that bit up, but I wouldn’t put it past them. What they are more likely to do is to add vitamins to various other drugs, to extend patent life. As Merck attempted to do with statins and niacin – and failed.

Another of the problems in trying to get a handle on the potential benefits of vitamins, is that it can be very unclear what the optimal dose, or blood levels, might be. This, I believe is because of the way that vitamins were first discovered.

Over many hundreds of years, it was noticed that some diseases occurred when ‘something’ was missing from the diet. Scurvy was the first of these diseases to be well documented. In 1753 a Scottish surgeon first proposed that lemons and limes could prevent and/or cure the condition. Obviously, he had no idea what it was in the limes and lemons that did the trick.

Other diseases such as pellagra and rickets were then identified as being due to a lack of a substance, of some sort. The term for theses missing substances was coined as ‘vital – amines’. Shortened to vitamins.

It took some time before the vitamins themselves were isolated. The first was vitamin B1, in 1910, the last was vitamin B12 in 1948. There are generally accepted to be thirteen vitamins, many of them are B vitamins, of one sort or another. However, in my opinion there are only twelve. Vitamin D is really a hormone.

I think vitamin D was only classified as a vitamin because no-one knew that it could be synthesized in the skin, from sunlight. Whilst people lived mainly outside, there was no vitamin D deficiency, it was only when the industrial revolution started, and people began to live and work indoors that rickets, (bent malformed bones) became an epidemic. A lack of vitamin D in the diet was identified as the cause.

Thus, Vitamin D looked and acted like a dietary vitamin deficiency, but it was not actually a dietary vitamin deficiency. Or at least only in part. To prevent rickets, children were given milk. Unfortunately, we are now seeing rickets again, because darker skinned Muslim women now fully cover up their skin, and some of them are becoming severely vitamin D depleted.

The reason for this ramble, is to make the general point that vitamins were only identified when major, immediate, and potentially life-threatening illness were identified. Which meant that the first task was the find the dose, or blood level, that prevented things like scurvy and rickets and pellagra. At the time researchers were not looking for longer term effects e.g. prevention of CVD, or cancer, or suchlike. Which means that there is no recommended daily allowance that takes optimal health into account.

I sometimes think of the recommended daily intake of vitamins as being just enough to keep you alive, but no more. A bit like having houseplant that is small and shrivelled. But if you give it some form of plant feed, it bursts into vigorous growth, and is far healthier.

Unfortunately, because we have these hallowed recommended daily intakes, vitamins are viewed by the medical profession as very simple things. You give the vitamin, make sure it gets above a baseline level in the blood, and that’s that. Nothing to see here, move along.

But if we look at just vitamin B12, the reference range (normal range), is all over the place. In the UK is set at 110 – 900ng/l [Itis higher in some regions]. In the US is it between 200 – 900ng/l, and in Japan 500 – 1300ng/l.

In Japan and the US, with a level of 110 you would immediately be given additional B12, in the UK you would be ignored. ‘Your level is fine, go away.’ I have seen many patients who strongly believe that they need additional Vitamin B12 injections, as they feel tired, depressed and suchlike. The NHS simply ignores, unless they have level below 110. Perhaps I should advise them to emigrate to Japan.

An additional problem with vitamin B12 is that the synthetic Vitamin B12 normally used is called hydroxocobalamin. This is then converted into the active form, methylcobalamin, in the body. However, some people cannot metabolise into methylcobalamin and need methylcobalamin injections. Which they cannot get on the NHS. Jolly good. Yes, the more you look into the area, the more complicated, and frustrating, it gets.

Vitamin D is the vitamin most in the news at present. The debate and arguments about vitamin D are becoming quite vitriolic. Some doctors refuse to believe that anyone has a true vitamin D deficiency, others think that the entire population needs to be dosed with added vitamin D during the winter months. I am very much in the latter group.

For example, it has only recently been discovered that that vitamin D has potent anti-cancer effects, and may reduce the risk of CVD. What level of vitamin D is needed to provide these benefits. Almost certainly a much higher level than that required to prevent rickets. Has this level ever been established…no. What about the risk of developing thin bones in old age? No.

Even more recently, a low level of vitamin D has been associated with a much higher level of hospital admission with acute asthma 2. What level is needed to prevent this happening? No idea. As the potential benefits of vitamin D continue to pile up, the minimum blood level remains unchanged and, it seems, unchangeable.

Moving to folate which, despite its name, is another B vitamin. Folate is known to be essential to prevent neural tube defects in the unborn child, and to produce red blood cells and suchlike. Again, the doses to stop these things happening has been established.

However, a recent study in Cambridge has shown that B vitamins, including folate, have significant benefits in reducing homocysteine levels, and if you give them in high doses, way above those currently recommended, they may delay, or even prevent, Alzheimer’s disease and reduce, or prevent, brain shrinkage 3.So, what is the correct dose of folate? Enough to stop neural tube defects, or anaemia, or enough to stop Alzheimer’s?

Can vitamin K prevent atherosclerotic plaques from becoming calcified? Who knows, they have never tested the correct formulation. Can vitamin C reduce the risk of CVD? Who knows? It was tested once in humans, at the wrong dose – at least the wrong dose according to Linus Pauling.

We haven’t the faintest clue about the correct doses, and blood levels of vitamins, required to achieve optimal health. What I do know is that you can take far more than the recommended daily dosage with no problems whatsoever. Vitamins are almost entirely safe. In the US, in 2010, for example, not a single person died from taking a vitamin 4.

On the other hand, you may be interested to read about the total burden of damage and deaths due to correctly prescribed pharmaceuticals. Here, from Harvard University:

‘Few know that systematic reviews of hospital charts found that even properly prescribed drugs (aside from misprescribing, overdosing, or self-prescribing) cause about 1.9 million hospitalizations a year. Another 840,000 hospitalized patients are given drugs that cause serious adverse reactions for a total of 2.74 million serious adverse drug reactions. About 128,000 people die from drugs prescribed to them. This makes prescription drugs a major health risk, ranking 4th with stroke as a leading cause of death. The European Commission estimates that adverse reactions from prescription drugs cause 200,000 deaths; so together, about 328,000 patients in the U.S. and Europe die from prescription drugs each year. The FDA does not acknowledge these facts and instead gathers a small fraction of the cases.5

Zero deaths, versus 328,000 per year. If I were truly looking for something dangerous to ban, it sure as hell would not be vitamins.

So, which vitamins would I recommend taking? My own view is, take vitamin D in the winter, vitamin C always, along with thiamine and Vitamin K2. About five to ten times recommended daily intake should be fine.

What of other supplements, such as: magnesium, co-enzyme Q10, potassium, L-arginine, L-carnitine, Omega-3 fatty acids, and suchlike. Well I am keen on potassium, very keen. I first noted that higher potassium consumption was associated with significantly reduced mortality in the Scottish heart health study.

This was not some minor difference either. We are talking more than a fifty per cent reduction in overall morality, in men 6. Lesser effect in women. This was far from an isolated finding. In study after study, potassium reduces blood pressure and, in turn, reduces the risk of CVD and overall mortality. Interestingly, the Mediterranean diet, such as it exists, tends to be high in potassium 7.

As for magnesium. Magnesium deficiency is increasingly recognised as a major health issue, and can greatly increase the risk of sudden cardiac death. I now routinely test patients for magnesium levels, as does the rest of the health service, which has belatedly woken up to the importance of this chemical. Magnesium deficiency can also trigger atrial fibrillation (AF) which, in turn, vastly increases the risk of stroke.8 But I feel I am running away with myself a bit. I need to stop, and take stock. The last thing I want people to do, is to worry too much about the levels of this and that in the blood. I do not want you rushing to the doctor, or private lab, to have everything repeatedly checked.

Magnesium level deficiency for example. This is almost unknown if you do not take an acid lowering drug such as omeprazole, or lansoprazole (both proton pump inhibitors (PPIs)). Unless you are taking one of these, of any other ‘zoles,’ long term, you are extremely unlikely to be magnesium deficient. As for potassium, get some lo-salt (a mixture of potassium and sodium chloride), or eat lots broccoli and bananas, and you will be fine. Other vegetables are available.

What of Omega-3 fatty acids, the fabled fish oil. There is some good quality evidence that they can be good for you. They seem to have beneficial effects on the conduction of electrical impulses in the heart. They are mildly anti-coagulant, a bit like aspirin with fewer downsides, such as causing blood loss from the stomach. They also have some benefits on brain function.

So, should you take an Omega-3 supplement? Easier, I think, to eat fish once a week. Sardines on toast is my favourite. But if you feel the need to buy Omega-3 supplements, go ahead. The only downside is cost.

A few years ago, I was contacted by a small company that wanted to create a combination pill to reduce the risk of CVD. They asked me to give them some medical input and support, which I did, but they ran out of money. Before going bust, they did produce a few thousand tubs of Prokardia. A tablet that contained:

  • Vitamin K2 5µg
  • Thiamine 7mg
  • Folic acid 7µg
  • Potassium 50mg
  • Magnesium 50mg
  • L-arginine 600mg
  • L-carnitine  50mg
  • L-citrulline 7mg
  • Co-enzyme Q10 3mg

The L-arginine and L-citrulline on that list are ‘co-factors’ for the production of nitric oxide (NO) in endothelial cells. Co-enzyme Q10 is something I have talked about at some length, and L-carnitine is an amino acid that has been found to have many benefits in CV health. I would have added vitamin D and vitamin C to this list, but you can only get so much stuff in one tablet before it becomes a meal in itself.

I would have been more than happy to promote Prokardia as a supplement. It could do no harm, and everything on that list was potentially beneficial for heart health. Unfortunately, Prokardia does not now exist. However, if you took these supplements, in these doses x4 (you were supposed to take four tablets a day) you would not go far wrong.

Having said all this, I do not want everyone to get too carried away with supplements. I have read articles supporting supplement after supplement, and every single vitamin that exists, in high doses. However, it can all get a bit ridiculous. Eat good, natural foodstuffs, and it should be possible to get everything you need in the diet. After all, that was what we were designed to do. Our ancestors did not go around searching for potassium supplements, or L-citrulline. It was all right there, in the nearest woolly mammoth. All you needed to do was catch it.

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

What causes heart disease part 44

12th January 2018

I’m going to try and draw some of the strands together at this point, in an attempt to provide some advice as to how to reduce the risk of CVD. Of course, there is massive overlap with other health issues. Smoking, for example, does not just cause CVD; it also causes lung cancer, chronic obstructive pulmonary disease (COPD) and many other unpleasant things.

So, you could call this instalment of the blog: “How to remain healthier and live longer”. Here I am only going to focus on the big-ticket items, the things that have been shown to make a real difference to life expectancy. For example, even if you believe that statins are effective in reducing CVD risk, when you look at the clinical trial data – assuming you believe it, one hundred per-cent – the average increase in life expectancy is around four days, if you take a statin for five years1.

Which means that, if you start taking a statin aged fifty, and keep taking it religiously for thirty years, you could expect to live for an extra: 6 x 4 days = 24 days. Or a bit less than a month. You may think this is worthwhile, you may not. This, by the way is the best-case scenario.

On the other hand, it has been estimated that if you take regular exercise, you could live for an extra four and a half years. Which makes exercise at least fifty-four times more effective than statins. Or, to put it another way 5,400% more effective.

As I hope that you can see, I am trying to give you a sense of the scale of benefits, or harms, that I am discussing here. Most of what is hyped by the pharmaceutical industry, and others, sits on the cusp of completely and utterly irrelevant. Is coffee good or bad for you? Who cares, the effect on life expectancy is in the order of a couple of days – either way.

Looking at preventative cardiovascular medications, the only ones that make a really major difference are anti-coagulants (blood thinners) such as warfarin, rivaroxaban, apixaban and suchlike. These are primarily used to prevent stroke in atrial fibrillation. Here, you can reduce the absolute risk of a stroke by around 50% over ten years. I am not sure how this can be re-calculated into increased life expectancy. I am sure it could be done, but it is complicated. However, this is still a massive benefit, and would mean years, not days, of extra life.

In short, if you have atrial fibrillation, you most definitely should take an anticoagulant. You might want to explore magnesium supplementation, particularly if you are taking an anti-acid PPI such as omeprazole, lansoprazole – or any of the other ’…prazoles.’ These lower magnesium levels. They also lower NO and, vitamin B12 levels and double the risk of CVD death. So, I would recommend never, ever, taking these long-term.

You might also want to try reducing weight, alcohol intake, stress/strain, and carbohydrate intake at the same time to see if you can flip out of atrial fibrillation naturally. It may work, it may not.

Moving away from that slight detour, what are the other real, big-ticket items? Perhaps the most obvious is smoking, or not-smoking. Smoking twenty cigarettes a day will reduce your life expectancy by around six years. Not only that, it will reduce ‘healthy life expectancy’ by far more. By which I mean you may well have ten or twenty years of such nasty things as: difficulty breathing, repeated chest infections, leg ulcers, angina, and suchlike, before you then die – early.

At this point you may be thinking, this is all incredibly conventional. Well, yes, it is. However, there is absolutely no doubt that exercise, and not smoking, have a massive and positive effect on health. Which means that they can hardly be ignored.

Of course, some people smoke and live to ninety, and some people take no exercise and live to ninety. So, what does that prove? Nothing at all. You can play Russian roulette for several rounds without blowing your brains out, but it is going to get you in the end.

My next big-ticket item, however, is not conventional at all. It is sunshine. If there is one piece of mainstream medical advice that I would vote as the single most damaging, it would be the current, ever more hysterical, advice to avoid the sun. If we dare expose ourselves to a stray photon, we are told, then we will vastly increase the risk of dying of skin cancer.

It is true that fair skinned people, living closer to the equator than their skin was designed for, can suffer superficial skin damage with excess solar exposure. There is also a significant increase in the risk of several types of skin cancer: basal cell carcinoma, squamous cell carcinoma and rodent ulcers (non-melanoma cancers). Whilst not pleasant, they can be easily spotted and fully removed. Which means that they are not a major health risk, and will have virtually no impact on life expectancy.

The type of skin cancer of greatest concern is malignant melanoma. Whilst melanomas can also be spotted early, and successfully removed, they can grow deeper into the skin. At which point cancerous cells will break off from the main melanoma ‘body’, and travel about in the blood stream, before getting stuck in various other places and growing (metastases). Five-year survival for metastatic melanoma is around 15 – 20%.

So, this truly is a cancer to be avoided, even if it is not common. But does sun exposure cause, or increase, the risk of, malignant melanoma? Here, from the Lancet:

‘Outdoor workers have a decreased risk of melanoma compared with indoor workers, suggesting that chronic sunlight exposure can have a protective effect. Further, some melanomas form on sun-exposed regions; others do not…

It has long been realised that indoor workers have an increased risk for melanoma compared with those who work outdoors, suggesting that ultraviolet radiation is in some way protective against this (melanoma) cancer. Further, melanoma develops most often on the back of men and on the legs of women, areas that are not chronically exposed to the sun.’3

Essentially states that the more sunlight areas of your skin are exposed to, the less likely you are to develop a malignant melanoma. How does this fit with the fact that there has been a steady rise in the incidence of malignant melanoma (incidence means number of newly diagnosed cases per year).

The first to question to ask is simple. Is this a real rise, or has it been driven by increased recognition and diagnosis? A study in the UK concluded that there has been no true increase in incidence. It is publicity, fear, and misdiagnosis that has created the apparent epidemic of melanoma. As noted in this article in the British Journal of Dermatology:

Melanoma epidemic: a midsummer night’s dream?’

‘We therefore conclude that the large increase in reported incidence is likely to be due to diagnostic drift which classifies benign lesions as stage one melanoma…The distribution of the lesions (melanomas) reported did not correspond to the sites of lesions caused by solar exposure. These findings should lead to a reconsideration of the treatment of ‘early’ lesions, a search for better diagnostic methods to distinguish them from truly malignant melanomas, re- evaluation of the role of ultraviolet radiation and recommendations for protection from it, as well as the need for a new direction in the search for the cause of melanoma.’4

In short, the rise in malignant melanoma is most likely an artefact, driven by diagnostic drift, and an increased recognition of early, benign lesions (‘lesion’ is just a word for an abnormal ‘thing’ found on the body). In fact, if you look at the evidence more closely, it seems that sunlight may, in fact, protect against melanoma. A study in the US looked at people who had already been treated for melanomas, to review recurrence and long-term survival:

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

The conclusion of the paper:

‘Sun exposure is associated with increased survival from melanoma.’5

Maybe not quite what you expected. But then again, vitamin D is synthesized by the action on sunlight on the skin. It converts cholesterol to vitamin D, and vitamin D has potent anti-cancer actions. Remove this from the skin at your peril.

Enough of the fear of the sun and malignant melanoma. I don’t wish to get dragged any further onto the playing field of the anti-sun brigade. Instead, here is a list of benefits that have been found from increased sun exposure. I am giving you the most positive figures here (these are relative risk reductions).:

  • 75% reduction in colorectal cancer
  • 50% reduction in breast cancer
  • Non-Hodgkin’s lymphoma 20 – 40% reduction
  • Prostate cancer 50% reduction
  • Bladder cancer 30% reduction
  • Metabolic syndrome/type II diabetes 40% reduction
  • Alzheimer’s 50% reduction
  • Multiple sclerosis 50% reduction
  • Psoriasis 60% reduction
  • Macular degeneration 7-fold reduction in risk
  • Improvement in mood/well-being.6,7

Well, what do you know. If you raise your gaze from malignant melanoma there is a world of benefits associated with greater exposure to the sun. With all these benefits, you would expect to see a real improvement in life expectancy. Does this happen?

Indeed, it does. There have been a series of studies in Denmark and Sweden looking at the benefit of sunshine. One of them, which looked at overall life expectancy, concluded that avoiding the sun was as bad for you as smoking.

‘Non-smokers who avoided sun exposure had a life expectancy similar to smokers in the highest sun exposure group, indicating that avoidance of sun exposure is a risk factor for death of a similar magnitude as smoking. Compared to the highest sun exposure group, life expectancy of avoiders of sun exposure was reduced by 0.6-2.1 years.’’8

This was a twenty-year study. If average life expectancy is around eighty years, we can safely multiply those figures by four, to work out that a decent amount of sun exposure can add somewhere between three, to eight years, to your life expectancy. Let’s call it five.

But it is not just cancer, diabetes and Alzheimer’s that are reduced by sunbathing. Sun exposure is also particularly good for the cardiovascular system, mainly because it increases nitric oxide levels. This, in turn, reduces blood pressure, and the risk of developing blood clots. It also protects the endothelium, and has significant benefits on lowering blood pressure and suchlike9.

Not only that, but lying in the sun is free and enjoyable. So, who could possibly ask for anything more?

At this point, you now know my first three big ticket items for living longer. More importantly, living longer with more ‘healthy’ and enjoyable years.

  1. Do not smoke
  2. Take exercise
  3. Go out in the sun – and enjoy it.

These three things alone can add around sixteen years to your healthy lifespan. Next, the impact of mental health. The biggest hitter of them all.

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

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

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

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

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

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

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

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

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

What causes heart disease part 43

29th December 2017

What is stress?

I have talked about stress quite a lot, but as many people have pointed out, the word itself is meaningless. Or perhaps it would be more accurate to say that is has too many meanings, or that it means different things to different people.

Paul Rosch, a very brilliant man1, told me that when he was first looking at stress soon after the Second World War, he was working with Hans Sayle, a Hungarian. Sayle often commented that, had he understood English better, he would have used the word strain, not stress. He fully understood that ‘stress’ is the thing that creates ‘strain’ on the body. It is strain that matters, not the stress.

This, I think, is absolutely critical. You can look at some people’s lives and they may seem highly ‘stressful’, whereas others appear to be relaxed, and avoiding stresses wherever possible. However, you have no idea at all who is under the greater strain.

I remember a cardiologist, many years ago, pointing to an elderly woman who had just had a heart attack. ‘She lives in an idyllic cottage in the middle of the country, married, with loving children. No stress at all. So, don’t tell me stress causes heart disease.’ I merely shrugged. How could the cardiologist possibly know what was going on under the surface?

Perhaps her husband came home and beat the living daylights out of her every Saturday night. I remember seeing another lady, a few years earlier, who was deeply upset because she had been in hospital for an operation, and whilst there her husband had her two, very large, dogs put down.

Yes, she loved the dogs, but her main anxiety was that she had bought them for protection. When her husband went out for an evening and drank, he would come home and beat her mercilessly. She had bought the dogs for to keep her safe, now they were gone.

This couple were upstanding members of the community. They were regarded as having a perfect marriage and a perfect life. He was a magistrate and a local businessman, she ran a couple of charities. Having heard her story, I later watched them together, smiling and a laughing at local events. This was after I knew what actually went on in the home. Superficially, I could not tell anything was amiss between them.

On the other hand, some people can appear to lead lives that are full of stressors, yet can cope very well. Probably because have good physical and psychological resources, and are highly resilient. They usually have many other supportive factors in their lives. A loving partner, friends, family, and suchlike.

I think we are all also guilty of deciding that what causes us strain, will also cause someone else strain, and vice-versa. In fact, identical stressors can create very different effects. I give a few lectures every year. I quite enjoy it, I feel in control, and confident that I am good at giving talks and I find the process positive and enjoyable. However, I know of people who find the idea of standing up in front of other people absolutely terrifying. To them, giving a lecture would create massive negative strain.

In short, we cannot know the strain that someone else is under by looking at what they do, or how they act. Even massive events, such as having a partner die, will not have the same impact. For most of us this would be shocking and terrible. However, if your partner has been an abusive bully for thirty years, their death may come as a relief. Yes, it is all complex stuff indeed.

The reality is that, if you want to know if someone has suffered a level of negative stress, sufficient to have damaged them, you have to measure it. Yes, the dreaded objective medical science. Of course, before measuring things you have to have a hypothesis to test.

The hypothesis here is reasonably straightforward. It is as follows. Long term negative stressors (or one overwhelming acute event) can create damage to the neuro-hormonal system that coordinates the physiological reaction to strain. This, in turn, has negative physiological effects that can lead to serious disease e.g. CVD, or diabetes, or both.

If a tiger walked in the room, we would all react in pretty much the same way. Sudden terror. This would activate a vast array of different responses, and this reaction starts in the hypothalamus – deep within the brain. When stimulated, the hypothalamus releases hormones that, in turn, activate the pituitary gland to release further hormones. These hormones travel to the adrenal glands where the stress hormones are synthesized. Cortisol, adrenaline (epinephrine) and suchlike. This is called the Hypothalamic-Pituitary-Adrenal axis (HPA-axis).

The stress hormones that are released, speed up the heart rate, release glucose into the bloodstream, dilate the pupils, shunt blood supply from the guts to the muscles, and suchlike. At the same time the unconscious nervous system, which is tightly interwoven with the HPA-axis, lights up, and this puts every other system in the body onto ‘fight or flight’ mode. The blood pressure goes up, sweat glands are activated, blood clotting factors are released, and so on and so forth.

This is all normal, and natural and, assuming you survive, after about twenty minutes, or so, all systems start to wind back down to ‘normal.’ If the fight or flight system switches on ‘accidentally’ due to a perceived threat, that is not a real threat, this is usually called a panic attack. Which is why some people go nuts on aeroplanes and try to open the doors at 35,000 feet. In the midst of a panic attack the conscious mind is over-ridden, as the persons ‘inner chimp’ desperately tries to flee the situation. [The ‘Inner chimp’ is the part of the brain fuelled on impulsive emotion and gut instinct].

Some people who suffer from post-traumatic stress disorder (PTSD) are far more likely to see threatening situations all around them, and trigger panic attack mode far more often than others. Their fight or flight system has been set to super-sensitive mode. A child shouting may trigger the memory of a battlefield attack. Ditto a plane passing overhead, or a car changing direction rapidly. Not easy to live in a state of hair-trigger fight or flight.

Children who have been physically, or sexually abused have much the same hair-trigger systems in place. They live life on high alert, and are ready for fight or flight at any time. Billy Connolly, a Scottish comedian, who was abused when he was a young boy, always said he did not like being touched. It brought back memories that setoff deep, negative reactions.

All this is well known, and widely accepted. What is less widely accepted is that repeated activation of fight or flight can, in time, lead to a breakdown/burn-out/dysfunction of the HPA-axis and the unconscious nervous system – usually called the autonomic nervous system. In part, this is because people have steadfastly measured the wrong things, at the wrong times.

Perhaps the single greatest ‘measurement’ problem is to look at cortisol levels only n the morning. Cortisol is a key ‘stress’ hormone that is released in response to stressful situations. It also naturally fluctuates during the day. It rises to its highest level in the morning, just before you wake up, then it drops. Then rises and falls during the day.

Researchers, looking to link ‘strain’ to heart disease, and diabetes, and suchlike, have made the mistake of only measuring early morning cortisol in those with CVD, and found it to be lower than normal. They have then stated that HPA-axis dysfunction cannot be an underlying cause of CVD and/or diabetes – or any other serious medical condition.

This, of course, is exactly the wrong interpretation. If the HPA-axis is damaged, the normal rise and fall of cortisol, will break down. Or, to put it another way. A burnt-out HPA-axis leads to ‘flat-line’ cortisol production. It gets pumped out at the same rate – no matter what is going on Therefore, if you measure the cortisol level in the morning, in those with HPA-dysfunction, it can appear to be low, not high.

The correct way to diagnose HPA-axis damage, is to take regular cortisol measurements over a twenty four hour period. This was known by a Swedish researcher called Per Bjorntorp, who used hourly measurements of cortisol, to see what the flexibility of the HPA-axis was in people suffering from ‘cardio-metabolic disease.’ That is, people who have the ‘metabolic syndrome.’

The metabolic syndrome is a group of abnormalities that are often found clustered together. Abdominal obesity, high blood pressure, raised blood sugar levels (sometimes high enough to be called type II diabetes), raised clotting factors, high triglycerides/low HDL, higher LDL levels, high insulin levels.

This syndrome is also (has also been) called: insulin resistance syndrome, pre-diabetes, syndrome X and Reaven’s syndrome. Whatever you call it, it is the same thing. It is associated with a greatly raised risk of CVD. Around six-fold in some studies a.k.a. 600%.

Per Bjorntorp did a series of studies looking at HPA-axis dysfunction, and the metabolic syndrome, and he concluded that the underlying cause of the metabolic syndrome was indeed HPA-axis dysfunction. Here, I quote from his paper. ‘The metabolic syndrome – a neuroendocrine disorder?’

‘Central obesity is a powerful predictor for disease. By utilizing salivary cortisol measurements throughout the day, it has now been possible to show on a population basis that perceived stress related cortisol secretion frequently is elevated in this condition. This is followed by insulin resistance, central accumulation of body fat, dyslipidaemia and hypertension (the metabolic syndrome). Socio-economic and psychosocial handicaps are probably central inducers of hyperactivity of the hypothalamic–pituitary adrenal (HPA) axis. Alcohol, smoking and traits of psychiatric disease are also involved. In a minor part of the population a dysregulated, depressed function of the HPA axis is present, associated with low secretion of sex steroid and growth hormones, and increased activity of the sympathetic nervous system. This condition is followed by consistent abnormalities indicating the metabolic syndrome. Such ‘burned-out’ function of the HPA axis has previously been seen in subjects exposed to environmental stress of long duration.’ 2

It shouldn’t really be a great surprise that if you damage the HPA-axis/autonomic nervous system that you will end up with the metabolic syndrome. The short-term effects of activating the flight or fight system are to: raise blood pressure, raise blood clotting factors, raise blood sugar levels, raise LDL, and direct energy stores out of subcutaneous fat.

If this becomes a chronic state, you will end up with chronically: raised blood pressure, raised blood clotting factors, insulin resistance/type II diabetes and increased abdominal fat/central obesity, as fat stores are moved from the subcutaneous to the central fat stores.

We have a perfect model confirming this sequence with Cushing’s disease. This is a condition where excess cortisol is produced in the adrenal glands (usually due to a small cortisol secreting tumour). The long-term effects of Cushing’s disease are:

  • Raised blood pressure
  • Raised blood clotting factors
  • Insulin resistance/type II diabetes
  • Raised VLDL, low HDL (dyslipidaemia)
  • Central obesity
  • Greatly increased risk of CVD, around 600%

In short, long term increased cortisol production, creates a severe form of the metabolic syndrome, and a very high rate of CVD.

I suppose the final link in the chain is to look at what happens if we prescribe people cortisol. In truth, we do not do this, not exactly. Instead, we prescribe them corticosteroids. These are often just called ‘steroids’. They are used to treat inflammatory conditions, such as asthma, Crohn’s disease, Rheumatoid arthritis and suchlike.

All the prescribed corticosteroids are synthesized from the basic cortisol template. Cortisol is also called a corticosteroid, because it is a steroid hormone manufactured in the ‘cortex’ of the adrenal gland. One commonly prescribed corticosteroid is prednisolone, and the chemical structure of cortisol and prednisolone can be seen in the two diagrams.

 

If you prescribe steroids long-term, they too cause insulin resistance, then the metabolic syndrome, then type II diabetes, and much higher risk of CVD. The risk of CVD is increased by, up to, 600%. 3

Personally, I see this whole issue as a bit of a ‘slam dunk,’ where all the evidence fits together in an almost perfect causal chain:

Bjorntorp, in a series of well controlled studies, demonstrated that environmental ‘stressors’ can lead to HPA-axis dysfunction/physiological strain. This, in turn, leads to the metabolic syndrome. The metabolic syndrome, in turn, leads to a vastly increased risk of CVD.

PTSD is also a condition where the HPA-axis is dysfunctional4, and the rate of CVD is vastly increased5. Equally those who are victims of childhood abuse demonstrate HPA-axis dysfunction6 and a greatly increased risk of CVD7. Severe depression is also associated with HPA-axis dysfunction8 and a greatly increased risk of CVD9.

The key hormone in this process appears to be cortisol, because a high level of cortisol, independently of HPA-axis dysfunction, also leads to the metabolic syndrome, and a very high rate of CVD. In addition, if you prescribe corticosteroids they, too, lead to the metabolic syndrome and a very high rate of CVD.

Which of the elements of the resultant metabolic syndrome are most important? This is not entirely clear. Is it the raised blood pressure, the clotting factors, the high insulin or sugar? To an extent it does not matter that much. If you can get rid of the underlying cause, they will all disappear.

Next blog. How to get rid of the underlying cause?

 

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

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

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

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

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

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

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

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

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

What causes heart disease part XLII (forty two)

9th December 2017

Stress/strain – again

It has been a long time since my last blog, but life can get in the way of other things. Three lectures to give, a deadline for my book and revalidations. The latter a complete pain that UK doctors have to go through every five years, which means gathering together evidence of all the things I have done, the learning I have learned, the hoops I have jumped through – and suchlike.

Then, my cousin dropped dead of a cerebral haemorrhage. At least he died doing something he enjoyed. He had just holed a putt on a golf course near Edinburgh, when his number came up in the great lottery of life. It reminds me that whatever we know, however much we learn, fate rules us all, and makes a mockery of our belief that we can control everything. ‘As flies to wanton boys are we to the gods.’

In this blog, I am going to return to stress, which I prefer to call strain.

Just after writing my last blog someone was kind enough to send me information about a study that had been done, showing that people who are under financial stress are thirteen times more likely to die of cardiovascular disease, and people in stressful jobs are six times as likely to have a heart attack. Not yet published research, but presented at a conference in South Africa. You may have read it1.

As those who have read my blog over the years will know, I have long argued that chronic negative stress is, from a population perspective, the single most important driver of cardiovascular disease. The mind/body connection is key to health, and thus, illness. This, I think I further emphasised by the point that mental illness is associated with the greatest impact on life expectancy.

‘Serious mental illnesses reduce life expectancy by 10 to 20 years, an analysis by Oxford University psychiatrists has shown – a loss of years that’s equivalent to or worse than that for heavy smoking….

The average reduction in life expectancy in people with bipolar disorder is between nine and 20 years, while it is 10 to 20 years for schizophrenia, between nine and 24 years for drug and alcohol abuse, and around seven to 11 years for recurrent depression.’2

Up to twenty years reduction in life expectancy.

Yes, when your mind goes wrong, your body follows, with disastrous consequences for physical health. Of course, there is overlap between mental illness, drug use, smoking and suchlike. However, you can strip all the other things out, and you are left with the ferocious power of the mind/body connection. The power to nurture, and the power to destroy.

I usually tell anyone, still listening after I have bored them on various other issues, that health is a combination of physical, psychological and social wellbeing. Three overlapping sets. The holy Trinity of wellbeing. You must get them all right, or nothing works. As Plato noted, a few years back, “the part can never be well unless the whole is well.”

Who are the shortest-lived peoples in the world? Are they the poor? Not necessarily, although poverty can be a clear driver of ill-health. The shortest-lived people in the world are people who live in the places of greatest social dislocation. Or, people who have had their societies stripped apart, with massive resultant stress. Australian aboriginals, NZ Maoris, North American aboriginals, the Inuit.

‘Indigenous Australians have the worst life expectancy rates of any indigenous population in the world, a United Nations report says. But it’s not news to Aboriginal health experts. They say it simply confirms what Australian health services have known for years.

Aboriginal Medical Services Alliance of the Northern Territory (AMSANT) chief executive officer John Paterson said the findings of the report, which examined the indigenous populations of 90 countries, were no surprise. The UN report – State of the World’s Indigenous Peoples – showed indigenous people in Australia and Nepal fared the worst, dying up to 20 years earlier than their non-indigenous counterparts. In Guatemala, the life expectancy gap is 13 years and in New Zealand it is 11.’3

I continue to find it absolutely amazing that mainstream medical thinking casually dismisses mental ‘stress’ as a cause of anything, other than mental health. The connection is always dismissed in the following way.

People who are depressed, anxious, suffering from PTSD and suchlike are more likely to drink and smoke and participate in other unhealthy lifestyles, and it is this that causes their higher rate of CVD and reduced life expectancy, and suchlike. There is a degree of truth to this, but some researchers have looked at this issue and found that the ‘unhealthy lifestyle’ issue explains very little.4

Underlying such an explanation, it has been noted that financial worries can increase your risk of heart disease by thirteen-fold (relative risk). Many of the arguments about CVD currently rage around diet, with people battling about HFLC vs LFHC, [high fat low carb vs low fat high carb].

In all the dietary studies I have seen, we are talking about increased, or reduced, risks in the order of 1.12, or 0.89. Which means a twelve per cent increased risk, or an eleven per cent reduced risk. These figures may just reach statistical significance, but they are so small as to be, to all intents and purposes, completely irrelevant.

On the other hand, a thirteen-fold increase in risk can be written another way. This is a 1,300% increase in risk. Compare this to anything to do with diet, or raised cholesterol, or blood pressure, or blood sugar or – any of the other mainstream risk factors. It is like comparing Mount Everest to a mole hill.

Yet, and yet, attempting to divert attention, and discussion, away from diet, or cholesterol, or sub-fractions of cholesterol, or suchlike seems an impossible task. People may say that they cannot see how stress can cause CVD. To which I say, every single step has been worked out, many times, by many different people.

Chronic stress → dysfunction of the hypothalamic pituitary adrenal axis (HPA-axis) → sympathetic overdrive + raised stress hormones → metabolic syndrome (raised BP, raised blood sugar, raised clotting factors, raised cortisol, raised all sorts of things) → endothelial damage + increased blood clotting → plaque formation and death from acute clot formation.

And if you want to close this loop further, stress also increases LDL levels, in some studies by over 60%5. So, when you see raised LDL, in association with increased CVD, it is not the LDL causing the CVD. It is stress, causing both.

 

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

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

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

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

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

What causes CVD part XL1 (Part forty-one)

12th November 2017

Another slight detour I am afraid. This is due to the recent publication of the ORBITA study. Reported in the British Medical Journal (BMJ), thus:

‘Percutaneous coronary intervention (PCI) is not significantly better than a placebo procedure in improving exercise capacity or symptoms even in patients with severe coronary stenosis, research has found.1

The ORBITA study, published in the Lancet, is the first double blind randomised controlled trial to directly compare stenting with placebo in patients with stable angina who are receiving high quality drug treatment.’ Compared to the sham-controlled group:

  • PCI did not significantly improve exercise time. The numerical incremental increase in average exercise time was 16 seconds (P=0.20).
  • PCI did not significantly improve measures on well-validated patient-centered angina questionnaires.
  • PCI did not significantly improve the Duke treadmill score or peak oxygen uptake.
  • PCI did significantly improve the dobutamine stress echo wall-motion index, indicating that stenting reduced ischemic burden.

In short, PCI did nothing at all. I can hear cardiologists across the US putting plans for new swimming pools on hold. 2

As many people know, the purpose of a stent is to open up obstructed coronary arteries, and then keep them open, using a metal framework ‘stent’, that sits within the artery. This procedure has been done on thousands, millions, of people. In an acute myocardial infarction (MI or heart attack to you) it provides benefits. However, in non-acute blockage it does nothing, apart from enrich interventional cardiologists.

Frankly, I was surprised that these researchers got ethical approval for this study. Carrying out a sham operation is a pretty major thing to do to a patient. I am further surprised they managed to get any volunteers, but they did. I very much take my hat off to these researchers. Bold, very bold, indeed. They must have been pretty damned certain they were going to see no benefit from stents.

Anyway, this study only proves what many people had suspected for some time. Stents, in the non-acute situation, do not work. Of course, this study has already been attacked and dismissed. Here is one review from SouthWestern medical centre, entitled ‘Stents do work: A closer look at the ORBITA study data.’:

ORBITA was small – too small, in fact, considered definitive evidence that cardiologists should change the role of stents in clinical practice.

I participate in a number of cardiology care guidelines committees and even wrote a piece about the ORBITA trial for the American College of Cardiology. In order for regulating bodies to change clinical practices, research studies must present data from a much larger pool, such as the 2007 COURAGE PCI study, which enlisted more than 2,000 participants. In general, larger trials present data that are more statistically significant and more appropriate to apply to specific patient segments.3

Too small? Wrong patient type, no doubt the wrong atmospheric pressure as well. Unlike the studies that were used when cardiologists first started doing stents, where the study size was precisely zero. In fact, if you read the entire article from the Southwestern medical centre, it is gibberish. But it will have the desired effect. The ORBITA study will have no impact stenting revenue. Like many other ideas in medicine, it is too seductive, and far too lucrative. The artery is blocked, it must be opened. End of.

Many years ago, Bernard Lown had precisely the same issue with Coronary Artery Bypass Grafting (CABG). Another massively lucrative intervention which rapidly became the operation – based on no evidence whatsoever. It was such an obviously brilliant idea that to question it was to defy ‘common sense.’ You have a blockage in an artery, bypass it with a graft.’

One thing that you find about good science is that it is usually very far removed from ‘pure common sense.’ It is counterintuitive. It is counterintuitive because it challenges established thinking a.k.a. prejudices. As Einstein had to say. ‘Common sense is nothing more than a deposit of prejudices laid down in the mind before age eighteen.’ He also said that ‘It is harder to crack prejudice than an atom.’

If you want a really good read, I recommend Bernard Lown [he is my hero]. He was the first to challenge the orthodoxy that CABG was an unquestioned good. For which he was of course, roundly attacked. His essay on this can be read here4. I include a particularly poignant section by Bernard Lown discussing CABG:

‘One might wonder why patients acquiesced to undergoing a painful and life-threatening procedure without the certainty of improving their life expectancy. I have long puzzled at such acquiescence. Surprisingly, patients not only agreed to the recommended intervention but commonly urged expediting it. Such conduct is compelled by ignorance as well as fear. Patients are readily overwhelmed by the mumbo-jumbo of medical jargon. Hearing something to the effect of “Your left anterior descending coronary artery is 75 percent occluded and the ejection fraction is 50 percent” is paralyzing. To the ordinary patient such findings threaten a heart attack or, worse, augur sudden cardiac death.

Cardiologists and cardiac surgeons frequently resort to frightening verbiage in summarizing angiographic findings. This no doubt compels unquestioning acceptance of the recommended procedure. Over the years I have heard several hundred expressions, such as: “You have a time bomb in your chest” and its variant “You are a walking time bomb.” Or, “This narrowed coronary is a widow maker.” And if patients wish to delay an intervention, a series of fear-mongering expressions hasten their resolve to proceed: “We must not lose any time by playing Hamlet.” Or, “You are living on borrowed time.” Or, “You are in luck — a slot is available on the operating schedule.” Maiming words can infantilize patients, so they regard doctors as parental figures to guide them to some safe harbour.’

The man is a genius and he can write far better than wot I can. I should hate him.

Some forty years later, or so, we find that CABG has been replaced by PCI/stenting. Exactly the same knuckle headed stupidity has driven stenting. The noise of sheep bleating ‘Narrow artery bad, open artery good,’ fills the air. My goodness, I think they’ve got it. Who could possibly argue with that? Kerching!

Those who have read my endless blog on the causes of on CVD will know I have long been highly sceptical of stenting as the answer to anything very much. Other than the removal of large sums of money from person A, to hospital B, and interventional cardiologist C.

Why does it not work? How can it possibly not work?

Because the heart is not simply a pump, arteries are not simply pipes, and humans are not inanimate objects whereby our function, or lack thereof, is purely dependant on some form of medical or surgical intervention. Thus endeth the lesson on stenting.

1: http://www.bmj.com/content/359/bmj.j5076

2: https://www.medscape.com/viewarticle/888115?pa=ItuYp8yggqEV0rOdozORa13VwlwcjMMn88tJMLYfucZ3N%2FNEihiaVx2Ypnp0WNqT8SIvl8zjYv73GUyW5rsbWA%3D%3D

3: http://www.utswmedicine.org/stories/articles/year-2017/stent-PCI-ORBITA.html

4: https://bernardlown.wordpress.com/2012/03/10/mavericks-lonely-path-in-cardiology/

What causes heart disease part XL (part forty)

27th October 2017

As readers of this blog will know, for many years I have pursued the idea that ‘stress’ was the primary cause of cardiovascular disease. Actually, it is strain. Stress is the force applied, strain is the effect that stress produces. For the sake of simplicity, I will just use the word stress.

This journey started when I began to take an interest in the rate of heart disease death in Scotland and France. Being Scottish born and bred, (OK, my father was English, but I forgive him) I felt I knew a bit about the lifestyle of the average Scot, aye Jimmy.

I had also travelled to France many times, so I felt I knew a bit about the French as well. The other reason for looking at France and Scotland was that, in my formative years, Scotland had one of the highest rates of heart disease in the world, perhaps the highest. I am talking primarily about death from myocardial infarction here. On the other hand, the French rate was very low, perhaps the lowest in the world, and has since then got lower.

Why such a massive difference? The conventional explanation was that the Scots had such a terrible diet. The famed deep-fried Mars bar is oft quoted. ‘How can a country that deep fries a Mars bar expect anything less.’ As if everyone in Scotland does nothing but stuff their faces with deep-fried Mars bars, all day, every day.

I do not have the statistics to hand, but I would be very surprised to find that even fifty per cent of Scots have eaten even one. Indeed, if you have made the mistake of eating a deep-fried Mars bar, you will never (unless very drunk) eat another. However, the Scottish ‘unhealthy diet’ meme is so firmly embedded in most people’s brain that it cannot be removed.

Ironically, a Mars bar contains almost no fat at all, it is made almost entirely from sugar a.k.a. carbohydrate. If you wrap it in batter, and stick it in a deep fat fryer full of vegetable fats, you have, according to current thinking, just made it significantly healthier. More carbs wrapped round the outside, and now dripping with vegetable/polyunsaturated fat. Mmmmm … you can just feel your arteries unclogging.

In reality, as with most other well-known facts about heart disease, when I started to look closely, the only significant difference that I could find about the diets in France and Scotland, was that the Scots ate slightly less saturated fat. They also ate fewer vegetables.

On the other hand, the French smoked more, took a bit less exercise and, at the time, had an identical BMI and blood pressure to the Scots. Rates of diabetes were also identical, as were average total cholesterol levels.

In short, I could find no significant difference in ‘classic’ risk factors. If anything, they slightly favoured the Scots over the French. Yet, and yet, age-matched, the French suffered one fifth the rate of deaths from heart disease. If you open up a risk calculator designed for a UK population, and use it to calculate risk for the French, you still have to divide the answer you get, by four. [Which might suggest that risk calculators are not capturing the major causes of CVD].

This gave me to think that there may be something else going on. Other than diet.

What? There have been many papers written about the ‘French Paradox’. The paradox being that they eat masses of saturated fat (highest consumption in Europe, probably the world), they have average to high cholesterol levels and a vanishingly low rate of heart disease.

Scientifically the French paradox should really be called the ‘French refutation of the diet-heart hypothesis and the LDL hypothesis, and all other hypotheses about cardiovascular disease you can think of’. Instead, a range of protective factors have been proposed. Eating garlic, drinking red wine, lightly cooked vegetables, and suchlike. But if you chase them down, and I have, they explain nothing – at all. Primarily, because they are just not true a.k.a. unsupported by evidence.

So, what was going on? What was the key thing that caused the Scots to die of heart disease in great numbers? One obvious and outstanding difference between the Scots and French was not what they ate, but the way that they ate. Scots saw, and in many cases still see, eating very much as a refuelling exercise. On the other hand, mealtimes, and eating, is a massive part of French life. Time is taken, food is appreciated, families tend to eat together – and suchlike.

Could it be, I thought, that the way food is eaten is more important that what is eaten?

If you eat whilst you are relaxed and socialising with friends and family, will your body deal with food in a different way? The answer is, of course, yes. Just to put it in the most basic terms. If you are highly stressed, either physically or psychologically, your fight or flight system will be activated. The sympathetic nervous system will be directing blood from the digestive system, to muscles, acid production in the stomach will be down, the heart rate will be up – and suchlike.

At the same time the stress hormone: adrenaline (epinephrine), growth hormone, glucagon, and cortisol levels will be high and surging round your bloodstream. This will be activating catabolism – the breakdown of energy stores – sugar levels will be up, free fatty acids circulating, blood clotting systems activated, insulin levels down, and on and on. This is not, it should be added, the perfect metabolic situation in which to eat food.

If you look at most animals, after they have eaten they like to lie down, relax and fall asleep. This allows the food that has been eaten to be digested. Humans seem happy to leap to their feet and rush about after eating. I started thinking about the fast food culture of the US. They began the trend for fast eating, fast living, eating and driving. Rush, rush, busy, busy, work, work, bang, bang. They were first to suffer a high rate of heart disease.

I began to study the effect of stress on metabolism. I looked at a condition known as post-aggression metabolism. The state the body finds itself in after trauma such as a car crash or major operation. In such cases the stress hormones are sky high, blood sugar moves into the diabetic level, insulin cannot achieve anything as it is battling against a catabolic system on full throttle. Not a good time to be eating food.

Then I looked at less dramatic situations. My attention drifted onto Cushing’s disease. A condition where the stress hormone cortisol is over-produced by the adrenal glands. Usually because of a cortisol secreting tumour. Cushing’s disease represents a form of chronic ‘fight or flight’, constant stress.

I discovered that, in Cushing’s there is a spectrum of metabolic, and other physiological, abnormalities such as:

  • High blood sugar level
  • High insulin level
  • High clotting factors
  • High VLDL (triglycerides)
  • Low HDL
  • High blood pressure
  • Abdominal obesity.

I also noted that, Cushing’s increases the risk of CVD by, at least, 600%.

I then realised that Cushing’s syndrome and the metabolic syndrome shared exactly the same set of metabolic and physiological abnormalities. So I began to think. ‘This is beginning to look interesting.’ Actually, I was thinking this before the term metabolic syndrome existed. At the time is was called either Reaven’s syndrome, or syndrome X. The term “insulin resistance syndrome” is now popular.

Then I was pointed to the work of Per Bjorntorp, who had been looking at the Hypothalamic Pituitary Adrenal axis (HPA-axis). This is the central control system for the stress/flight of fight response. It links together the sympathetic and parasympathetic nervous system, with the actions of the stress hormones, the adrenal glands, thyroxine, glucagon, insulin etc. etc. A complex beast of a thing.

Bjorntorp established that chronic psychological stress (chronic strain) creates a dysfunction of the HPA-axis that can be monitored, most easily, by looking at twenty-four-hour cortisol secretion. A dysfunctional HPA-axis leads to a flattened and unresponsive (burnt-out) cortisol release during the day. This does not mean cortisol levels are high, or low, they just flat-line.

He studied various populations e.g. Sweden and Lithuania, and found that the Lithuanians (at the time) were far more likely to have a dysfunctional HPA-axis than the Swedes, and their rate of CVD was four times as high as that in Sweden. A study done only on men at the time. I then started to look at other conditions where the HPA-axis is damaged. Depression, schizophrenia – in fact almost all psychiatric illness – PTSD, survivors of childhood abuse. In all cases the same pattern emerged. HPA-axis dysfunction, greatly increased risk of metabolic syndrome/insulin resistance syndrome and greatly increased risk of CVD death.

I detoured round spinal cord injury. Most people are probably unaware that spinal cord injury is associated with a very much higher rate of CVD. People who suffer spinal cord injury also have a damaged HPA-axis. Some more than others. It depends on the level of the damage, and whether or not the autonomic nervous system is damaged. [The autonomic nervous system is the name given to the network of nerve fibres that make up the sympathetic and parasympathetic nervous system. It travels down the spine, but not in the spinal canal].

I then had a look at corticosteroids. These are the drugs used in many diseases as anti-inflammatory agents. They are used in diseases such as asthma and rheumatoid arthritis and Crohn’s disease and systemic lupus erythematosus (SLE), all ‘auto-immune’ diseases where the body attacks itself. Corticosteroids dampen down the ‘inflammatory’ response.

Corticosteroids are synthesized from cortisol, which is one of the body’s own steroid hormones. Which is why they are called corticosteroids (steroids manufactured in the cortex of the adrenal gland). They are fantastic drugs, and widely used. However, if you take corticosteroids for a long time you will end up with the metabolic syndrome, and a greatly increased risk of CVD, around a 400% increase.

The more I looked, the more it seemed very clear that the unconscious neuro-hormonal system was the key player in CVD, both heart attacks and strokes. It also seemed that cortisol was probably the lynch pin. It still does. Which is why my favourite graph on CVD comes from Lithuania. I have used it before, and I make no bones about using it again.

The rate of heart disease in Lithuania was gradually falling during the 1980s, until the year 1989. At which point the Berlin wall came down, the Soviet Union broke apart and the structure of society was torn apart. It was a very, very, stressful time.

What happened to the rate of heart disease in men, under 65.

Latvia and Estonia showed the same pattern, as did Russia three years later when Gorbachov was deposed by Yeltsin. In non-Soviet European countries, nothing happened. Heart disease rates continued their gentle fall.

I had been looking for evidence that abrupt social disruption leads to stress which leads to CVD. The problem is that, normally, gigantic social disruption = war. During war medical statistics tend to get overlooked, or other causes of sudden death distort the picture.

For the first time in history, a gigantic social upheaval occurred right in front of our eyes. It was not war, and the WHO was there, recording away, as part of the MONICA project. [Myocardial infarction and coronary deaths in the World Health Organization]. Cause, and effect? I believe so.

Which takes me back to Scotland. Glasgow was a very big city, then it shrank. It shrank because social engineers decided to move people from the tenements, which were considered crowded and unhealthy, to wonderful new towns, and high-rise flats. Such as these shown below.

As you can imagine people very much enjoyed living in these inhuman monoliths. A great sense of community and fun developed. So much so that they have now all been demolished.

Whilst this great forced location of people was taking place, the rate of CVD in and around Glasgow exploded. Yes, Scotland as a whole had a high(ish) rate, but greater Glasgow, whilst all this was going on, had by far the highest rate of all. Cause, and effect?

So, my thought experiment that started in Scotland, ended up back in Scotland. I then looked around the world for populations with extraordinarily high rates of CVD. I hypothesized that populations that had suffered enormous social stress would have high rates. So I looked at Australian aboriginals, Maoris, migrant populations, native Americans, and suchlike.

What did I see. Well, pretty much the same things everywhere. Social upheaval followed by high rate of CVD. At present Australian aboriginals have, I believe, the highest rate of CVD in the world. A population where lifestyle and culture has been shredded. If you use a CVD risk calculator on a young aboriginal woman, you have to multiply the predicted ten-year risk by thirty.

Exceptions, of course, exceptions. The Rosetta community of Pennsylvania US. An immigrant population that had moved from Rosetta Italy to Rosetta US – en masse. They became famous for a very, very, low rate of heart disease. What made them different? Here is a section from a Huffington Post article:

‘What made Rosetans die less from heart disease than identical towns elsewhere? Family ties. Another observation: they had traditional and cohesive family and community relationships. It turns out that Roseto was peopled by strongly knit Italian-American families who did everything right and lived right and consequently lived longer.

In short, Rosetans were nourished by people.

In all ways, this happy result was exactly the opposite expectation of well-proven health laws. The Rosetans broke the following long-life rules, and did so with a noticeable relish: and they lived to tell the tale. They smoked old-style Italian stogie cigars, malodorous and remarkably pungent little nips of a cigar guaranteed to give a nicotine fix of unbelievably strong potency. These were not filtered or adulterated in any way.

Both sexes drank wine with seeming abandon, a beverage which the 1963 era dietician would find almost prehistoric in health value. In fact, wine was consumed in preference to all-American soft drinks and even milk. Forget the cushy office job, Rosetan men worked in such toxic environs as the nearby slate quarries. Working there was notoriously dangerous, not merely hazardous, with “industrial accidents” and gruesome illnesses caused by inhaling gases, dusts and other niceties.

And forget the Mediterranean diets of olive oil, light salads and fat-free foods. No, Rosetans fried their sausages and meatballs in…..lard. They ate salami, hard and soft cheeses all brimming with cholesterol.2

The tenements of Glasgow were filthy and rat infested and crowded and had poor sanitation. But if you speak to those who lived in them, their memories were of close family ties, strong community support, fun, playing football in the street. Then they were shifted to the Brave New World of sterile social engineering. Isolation, loneliness, breakdown of community. Death.

You want to know one of the most important ways to avoid dying of CVD?

 

1: 1https://www.researchgate.net/publication/13659734_Increased_Psychosocial_Strain_in_Lithuanian_Versus_Swedish_Men

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

Starting the conversation

19th October 2017

I am giving a presentation at this conference in London on the 25th of November, if any of the readers of this blog are interested in attending, it would be great to see you there. This is mainly in the area of cancer, but I am looking at how we have reached a situation where hugely expensive ‘pharma developed drugs’ are widely used, when many are completely ineffective. However, novel ideas, new ways of looking at cancer, are blocked at every turn.

What causes heart disease part XXXIX (thirty nine)

9th October 2017

In this blog I would like to highlight some of the evidence that is not there. The missing link, the lost chord. The thief that steals in, in the night. The thing that is not there when you look for it.

“As I was going up the stair

I met a man who wasn’t there!

He wasn’t there again today,

Oh how I wish he’d go away!”

 

When I came home last night at three,

The man was waiting there for me

But when I looked around the hall,

I couldn’t see him there at all!

Go away, go away, don’t you come back any more!

Go away, go away, and please don’t slam the door…”

 

There was a theory, indeed there still is, that a myocardial infarction starts with damage to the heart muscle (myocardium), and the blood clot forms afterwards. Carlos Monteiro, a Brazilian researcher with whom I often communicate, promotes and supports this, the ‘myogenic theory of heart disease’. He is not alone.

Now, superficially this idea may sound completely daft. However, there is a great deal of evidence that can be gathered to support it. First, in a significant number of myocardial infarctions, no blood clot can be found. Here, from a paper entitled ‘Myocardial infarction without obstructive coronary artery disease.’

‘A substantial minority of myocardial infarction (MI) patients have no obstructive coronary artery disease (CAD) at angiography. Women more commonly have this type of MI, but both sexes are affected.1

So, how can you have an MI, if there is no blood clot, and no blockage of a coronary artery? A very good question M’lud.

There is also an increasingly recognised form of ‘heart attack’ called Takotsubo cardiomyopathy, named after the Japanese octopus pot. This is where you have all the signs and symptoms of a myocardial infarction, but it is not a myocardial infarction. It is due to extreme levels of stress – both positive or negative. Here I quote from the British Heart Foundation:

Takotsubo cardiomyopathy

This condition is also called acute stress-induced cardiomyopathy, broken heart syndrome and apical ballooning syndrome.

Takotsubo cardiomyopathy was first reported in Japan in 1990. The word ’Takotsubo’ means ‘octopus pot’ in Japanese, as the left ventricle of the heart changes into a similar shape as the pot – developing a narrow neck and a round bottom.

The condition can develop at any age, but typically affects more women than men. The good news is that often the condition is temporary and reversible.

What are the symptoms of Takotsubo cardiomyopathy? The main symptoms of Takotsubo cardiomyopathy are chest pain, breathlessness or collapsing, similar to a heart attack. In some cases, people may also suffer palpitations, nausea and vomiting.’2

You can, in fact, die from Takotsubo cardiomyopathy. Another myocardial infarction that is not a myocardial infarction.

Equally, you can find that people can suffer from a myocardial infarction days, or even weeks, after a blood clot blocked the artery. Here is a paper entitled ‘Plaque Instability Frequently Occurs Days or Weeks Before Occlusive Coronary Thrombosis.’

‘In at least 50% of patients with acute STEMI, coronary thrombi were days or weeks old. This indicates that sudden coronary occlusion is often preceded by a variable period of plaque instability and thrombus formation, initiate days or weeks before onset of symptoms.’3

So, there you go. You can have four types of myocardial infarction:

  • A myocardial infarction with no obstructive arterial disease
  • A myocardial infarction cause by stress, with no obstructive arterial disease
  • A myocardial infarction that happens weeks after the thrombus forms
  • The ‘classic’ myocardial infarction with thrombus formation followed rapidly by infarction.

What are we to make of this gentle reader? Three forms of ‘myocardial infarction’ that cannot be linked in time, or in any other way, to thrombus formation. Or, to put it another way the infarction a.k.a. the bit where the heart muscle becomes seriously damaged, is not related to a blockage in the artery either immediately, or at all.

In addition to this, there is the observation of ‘the completely blocked coronary artery, without myocardial infarction’. Here is a case history from the British Medical Journal:

A 75 year old man was admitted because of stable angina pectoris without any history of myocardial infarction. His risk profile consisted of arterial hypertension and hypercholesterolaemia. At the time he was being treated with 100 mg aspirin, 100 mg metoprolol, 20 mg pravastatin, and 40 mg isosorbide mononitrate daily. ECG showed sinus rhythm, no Q waves, and slight T wave inversions at lead aVL and I. A bicycle stress test resulted in horizontal ST segment depression of 2 mm at 75 W. Coronary angiography was performed and revealed coronary artery disease with complete occlusion of the proximal part of the left coronary artery.4

At this point you could very reasonably argue that there truly is no consistent association between blood clots, arterial obstruction, and myocardial infarction. Or, to put it another way, the widely held view that the blood clot, and subsequent arterial occlusion, immediately precedes the infarction, is contradicted by evidence.

Which leads to the inevitable conclusion that something else must be going on. Perhaps it is true that the infarction, due to extreme stress and build of lactic acid does come first. Then, as a consequence, the clot forms in the artery.

Hmmmm. I don’t think so. However, in order to understand what is actually going on it is necessary, unfortunately, to dig even deeper, to find the man that isn’t there. Banksy, a man who paints on walls, is never seen, but we know he was there because, otherwise, you can’t explain the painting.

1: https://www.ncbi.nlm.nih.gov/pubmed/22941122

2: https://www.bhf.org.uk/heart-health/conditions/cardiomyopathy/takotsubo-cardiomyopathy

3: http://circ.ahajournals.org/content/circulationaha/early/2005/02/21/01.CIR.0000157141.00778.AC.full.pdf

4: http://heart.bmj.com/content/83/6/672

What causes heart disease part XXXVIII (part thirty-eight)

24th September 2017

‘The flow of rivers and streams in their boundaries . . . the circulation of the blood in our arteries and veins . . . the flight of the insect, the bird and the airplane; the movement of a ship in the water or of a fish in the depths . . . these are all, in major degree, varied expressions of the laws of fluid mechanics … Everywhere we find fluids and solids in reactive contact, usually in relative motion; and everywhere in this domain, the laws of fluid mechanics must control.

Application of the laws of fluid mechanics to the natural conditions in the circulatory system reveals a rational and demonstrable basis for the localization, inception, and progressive development of atherosclerosis.

Atherosclerosis does not occur at random locations. It does occur uniformly at specific sites of predilection that can be precisely defined, predicted, and produced by applying the principles of fluid mechanics. The areas of predilection for atherosclerosis are consistently found to be the segmental zones of diminished lateral pressure produced by the forces generated by the flowing blood.

Such segmental zones of diminished lateral pressure are characterized by tapering, curvature, bifurcation, branching, and external attachment. Serpentine flow in a relatively straight vessel also produces segmental zones of diminished lateral pressure.

Although these anatomic configurations occur in many variations of geometry, their common feature is a pattern of blood flow conducive to the production of localized areas of diminished lateral pressure. This is the initial stimulus.

Atherosclerosis may therefore be considered to be the biologic response of blood vessels to the effect of the laws of fluid mechanics, that is, the diminished lateral pressure generated by the flowing blood at sites of predilection determined by local hydraulic specifications in the circulatory system.’1

Not my words, and quite poetic I suppose. What does it mean. It means, if you accept what is written, is that atherosclerosis forms exactly where you would expect it to form – if the initial stimulus is ‘diminished lateral pressure’.

My last blog was primarily a looking at the primary stimulus for the initial formation of atherosclerotic plaques. I like to use the term biomechanical stress. I am not entirely certain if this means anything. But the general idea is that atherosclerotic plaques start at the points in blood vessels where there is the greatest ‘biomechanical stress.’

Several people who know far more about fluid dynamics questioned this. I think that they are all probably right in what they say, and the mathematics are well beyond my understanding. However, what I do know, and what are facts, are the following:

  • Atherosclerotic plaques inevitably occur where is there is tapering, curvature, bifurcation, branching and areas of external attachment.
  • Plaques never develop in veins, regardless of tapering, curvature and branding and suchlike.
  • Plaques never develop in the arteries and veins in your lungs – unless you develop pulmonary hypertension (raised blood pressure in the lungs) – though a caveat applies.
  • Plaques often appear on one side of an artery, and not the other (i.e., they do not encircle the artery).
  • If you take a vein from the leg, and use it as a coronary artery bypass graft, it will rapidly develop atherosclerotic plaques.

Therefore, whatever term you want to use, however, you wish to understand it, it is clear that in order to get a plaque to start, you need to apply some form of ‘stress’ to the blood vessel, and the blood pressure needs to be at a certain level – or else nothing will happen. This is true, no matter what the LDL level, or the blood sugar level, or whether you smoke, or [insert any one of eight thousand risk factors here].

Ergo, there must be some form of damage occurring at the point of high biomechanical stress, that triggers plaque development. Under biomechanical stress, the first part of the artery to suffer will be the endothelium – the layer of cells that lines the arteries. If endothelial cells are stressed, damaged, or dysfunctional, this is the trigger for plaques to start:

In view of the ever-increasing prevalence of ischaemic heart disease in the developed and developing world, it has become imperative to identify and investigate mechanisms of early, potentially reversible pre-atherosclerotic changes in the endothelium. To date, the most clearly defined and well-understood early precursor of atherosclerosis is Endothelial Dysfunction. In fact, Endothelial Dysfunction can be regarded as the primum movens of atherosclerotic disease.’2

I guess that primum movens is Latin for ‘the single most really important thing.’

In short, you damage the endothelium, and that releases the atherosclerotic dogs of war. What sort of things are known to increase endothelial stress/damage. Here is a list, off the top of my head, of a few factors that have been identified.

  • Smoking
  • Air pollution
  • Diabetes
  • Cocaine use
  • Dehydration
  • Infections/sepsis
  • Systemic Lupus Erythematosus (SLE)
  • Lead
  • Stress hormones
  • Avastin
  • Omeprazole
  • Cushing’s disease
  • Kawasaki’s disease.

I could go on, and on, but I think that is enough to be going on with. All of these factors have been demonstrated to cause significant damage to the endothelium – in different ways – and there is another thing that they all do. They all increase the risk of dying of CVD. Some of them enormously increase the risk. A young woman with SLE has an increased risk of dying of CHD of 5000% (relative risk increase).

When you are looking at a 5000% increase in risk you are, without the slightest shadow of a doubt, looking at a cause.

The only other increased risk I have ever seen to match this, or in fact beat this, is in young people with sickle cell anaemia where the increased risk of stroke is 33,000% (relative increase in risk). Yes, not many young people get strokes, but an increase of 33,000% is difficult to argue with.

Why do they get so many strokes? It is, in part, because the ‘sickle’ shaped red blood cells clump together more easily than normal shaped red blood cells. Once they clump together, they form clots, and these clots block arteries. Often in the brain – but also elsewhere. It is not as simple as this, but that will do for now.

There is another thing about sickle cells anaemia that I find of great interest. It is the only condition (at least the only condition I have come across), where atherosclerotic plaques can form in the lungs – at normal blood pressure.3

Why does this happen? Well sickle cells are not round and smooth. They are crescent shaped, and spiky at the ends, and stiffer than normal red blood cells, and they are more likely to cause mechanical damage to the endothelium.

‘A further mechanism of endothelial dysfunction is attributed to the rigidity of sickled erythrocytes (red blood cells) causing mechanical injury to the endothelial cells.’3

In addition:

‘The sickling process leads to vascular occlusion, tissue hypoxia and subsequent reperfusion injury, thus inducing inflammation and endothelial injury. This causes a blunted response to nitric oxide (NO) synthase inhibition.’3

Yes, our old friend Nitric Oxide again. Put simply, sickle cells crash into, and damage endothelial cells, which then stop producing as much NO. This endothelial dysfunction then leads on to atherosclerosis. All of this happens with no other risk factors present, and in arteries where atherosclerosis is normally never seen. Which means that we are looking very directly at cause, and effect. Physical damage to endothelial cells, no other factors required.

Now, I am aware that many people wonder why my series on what causes heart disease/cardiovascular has been so long and meandering. One major reason is that there is so much to try and find out, and explain. Also, and perhaps more critically, if you are going to try and understand cardiovascular disease fully, you must attempt to fit everything together, and that does take time.

For example, you must explain how: SLE, sickle cell anaemia, Kawasaki’s disease, omeprazole, diabetes, smoking and infections (to name but seven) can all cause CVD when, superficially, there is nothing to link them. Certainly none of the established, mainstream, risk factors.

There is no point in saying that, yes, they all cause heart disease, and that’s that, just add them to the list. There is a requirement to fit them within a single process, and it must make sense. It also has to be supported by the facts – as far as that is possible.

Equally, there is no point in saying CVD is ‘multifactorial’, which is the normal defence of the mainstream when pressed on why many people, with no risk factors for CVD, still get CVD. The word “multifactorial” explains nothing, it is just an escape route for those pressed to explain the many ‘paradoxes’ or refutations that keep on appearing.

If, for example, you cannot explain how sickle cell anaemia causes atherosclerotic plaque formation, in pulmonary arteries, this means you do not understand, or do not wish to understand, the underlying process. It fits nowhere within the accepted major risk factors, yet it increases the risk of stroke by 33,000%, and causes plaques to develop in the lungs. So, you cannot just ignore it, relatively rare though it may be.

So, where have we got to? Where we have got to, I believe is to demonstrate that the trigger factor for CVD is damage to the endothelium. If you don’t damage the endothelium nothing else happens. The damage happens at well recognised places where the biomechanical stress is at its greatest. Which means that, with no biomechanical stress, there can be no atherosclerotic plaques.

However, it takes more than just biomechanical stress. You also have to have, at least one, extra factor present to trigger endothelial dysfunction. Then … next episode.

References:

1: From Chapter 8 Coronary Heart Disease: The Dietary Sense and Nonsense: George V. Mann: 9781857560725: Amazon.com: Books

2: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3721957/

3: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2780857/

What causes heart disease part XXXVII (Part thirty-seven)

16th September 2017

Beginning at the end.

Whilst there is significant controversy about how atherosclerotic plaques may start, and grow, the final event in cardiovascular disease is, in most cases, pretty much accepted – even by me. The formation of a blood clot. Yes, there are many caveats here, and also a number of different processes that can occur, but I am not covering them in this blog. I am using the simple ending. The obstructive blood clot.

If a blood clot forms in the coronary arteries – blood vessels supplying blood to the heart – it can fully block the artery, jam up blood flow, vastly reduce oxygen supply, and cause a myocardial infarction (MI). The clot usually forms on the surface of a pre-existing atherosclerotic plaque.

If a blood clot forms in the carotid arteries – main blood vessels supplying blood to the brain – it can then break off, travel up into the brain where it gets stuck, jams up blood flow, reduces oxygen supply, and cause a cerebral infarction (ischaemic stroke). Again, blood clots in the carotid arteries almost always form on the surface of atherosclerotic plaques formed earlier.

What this means is that reducing the formation of blood clots will, or definitely should, reduce the risk of heart attacks and strokes. And, of course, it does. Aspirin, for example, has anticoagulant action, and it lowers the risk of CVD, although not by a huge amount.

However, recently, a study was published in the New England Journal of Medicine which demonstrated that if you add rivaroxaban – an anticoagulant, primarily used to prevent strokes in patients with Atrial Fibrillation – to aspirin, this further reduces the risk of CVD1.

The trial was reported thus, in the Daily Mail on the 11th of September:

‘Phenomenal’ pill slashes the risk of death from heart disease by 22% and could save millions of lives, ‘ground-breaking’ trial finds.’

Oh yes, we do like a phenomenal pill, do we not. Mockery of such ridiculous hype aside, this was an impressive result. Far more impressive than any statin trial, it must be added – with no impact on LDL levels at all. Only one slight problem, it would be rather expensive to add rivaroxaban to everyone taking aspirin. Minimum cost, about £6Bn/years ($8Bn/year) in the UK alone.

Of course, there are other things that can reduce the risk of blood clotting. Omega 3 fatty acids, for example which reduce ability of platelets to stick together2 – an action almost identical to aspirin. Then there is Von Willibrand disease – a condition where people lack a key blood clotting element called the Von Willebrand factor. Patients with this condition have a 60% reduction in the risk CVD.

Those with haemophilia had – prior to the development of clotting factors to replace those that were missing –around 20% the risk of CVD of the surrounding population.

On the other hand, there are situations where the risk of blood clotting increases. Use of non-steroidal drugs e.g. brufen, naproxen, diclofenac etc. These increase the risk of clotting, and CVD. There are conditions, such as Hughes syndrome and Factor V Leiden where the risk of blood clotting goes up, and so does the risk of CVD and so on, and so forth.

In fact, I think it can be stated with complete confidence that any drug, condition, or anything else that reduces the risk of blood clotting, also reduces the risk of CVD, and vice-versa. Of course, if you reduce the risk of blood clotting, you can also increase the risk of serious bleeding. So, it is not all positive. All is balance. Yin and Yang, and suchlike. Even the relatively benign aspirin, in low doses, can lead to chronic blood loss, anaemia, and, in extreme cases, death.

What does this prove. Well it certainly proves that blood clotting and CVD are intimately related. So much so that the word ‘atherothrombosis’ is often used to describe the processes of CVD. ‘Athero-‘ = the atherosclerotic plaque growing then ‘-thrombosis’, the clot that forms top of the plaque that then kills you. That, at least, is the official Soviet party line.

However, I never liked the idea that we have two almost completely different processes going, that are linked together, but only at the final event. I wanted to explore the idea that a single process – blood clotting – could be responsible for plaque starting, growing and then ‘rupturing’ causing the whole spectrum of atherothrombosis. Blood clots, from start to finish.

This took me on a pretty amazing journey, a long and winding route indeed. I have come to believe that the system of blood coagulation must be, just about, the most complex physiological system in the body. It is beyond mind-boggling. Just when you think you have read about every factor involved, another one pops up. Indeed, I think I am forgetting facts about blood clotting faster than I can learn them. My brain is full.

However, the other day, I came across an expression that captured something about blood clotting that I have always struggled to put into words. It described the coagulation system as ‘idling’, as in sitting with the engine running. The blood coagulation system is never ‘off’ it is always turning over in the background, constantly producing small combination of substances that make up a full blood clot.

I suppose this is because, if you suffer a significant wound, or damage to a large blood vessel, the coagulation system cannot hang about. It must accelerate from zero to one hundred in the blink of an eye. Bang, go, stamp on the accelerator. At the same time, if it accelerates out of control, the clot will be too big, it will spread too rapidly, blocking blood vessels all over the place.

So, almost the moment you stamp on the accelerator, you are hammering on the brake. Accelerate, brake, accelerate, brake. Build up the clot, break down the clot. A fantastically dynamic system with feedback loop upon feedback loop. Too little clotting, you die. Too much clotting, you die. This is going on, all the time, in your body. A system constantly hunting, and hunting, to find equilibrium.

What is the greatest, the most powerful trigger, for a clot to form? It is a substance called Tissue Factor (TF). It is found almost everywhere in the body, but it is found in the highest concentrations within the walls of the larger arteries and veins. This, of course, makes perfect sense. If an artery, or vein, is damaged, the place you want a blood clot to form is exactly at that point. Bang, go.

Tissue factor is sometimes called extrinsic factor. It is called this because it does not float about (freely) in the bloodstream, it sits ‘externally/extrinsically’ to the blood. [In fact, platelets and white blood cells also contain TF, but it is inactive/not expressed unless other things are triggered first].

Other parts of the clotting system are often referred to as intrinsic factors that trigger the ‘intrinsic clotting system’. Factors you may have heard of, such as factor VIII, or factors IX and X and Xa etc. The intrinsic system tends to operate more slowly, and less powerfully, than the extrinsic (massive over-simplification warning).

Normally, the ‘intrinsic’ clotting factors, and the extrinsic system operate together to drive and amplify the clotting response once it is triggered. All of which means that, normally, you want to keep the blood well away from contact with TF, because the moment there is contact, all hell breaks loose and a blood clot will form, instantly, at that point.

The single most important barrier that keeps the blood separated from TF is the endothelium. Which means that an intact and healthy endothelium is the best protection against accidental blood clots forming. Yes, blood clots can form with no TF contact. A deep vein thrombosis (DVT) can develop in veins with intact endothelium. The process is different, the blood clot formed is also very different. It is mainly an intrinsic process.

Forgetting other types of blood clot that can form elsewhere in the body, the only way a clot will form in the larger arteries is due to endothelial damage. No endothelial damage, no clot. Once a blood clot has formed, then stabilised, what happens?

Well, normally the clot will not have been allowed to get too big, because all the feedback loops will kick into action to slow things down. So, most clots will not fully block an artery, nor even half block an artery. They also get shaved down in size quickly. Primarily through the action of Tissue Plasminogen Activator (TP(a)).

TP(a) is an enzyme floating about in the bloodstream that converts plasminogen into plasmin. Plasminogen is an inactive enzyme that is incorporated into all blood clots as they form. When TP(a) converts plasminogen to plasmin, it slices fibrin apart, chopping blood clots into small pieces. A process known as fibrinolysis. Two of the major components of a blood clot are platelets – small sticky cells that coordinate the clotting response – and fibrin – long sticky strands of protein that binds the clot together.

However, there will be always be a part of the clot that remains clamped to the artery wall. Because if all the clot was fully broken down/fibrinolysed, the bloodstream would be exposed to TF again, and the entire blood clotting process would simply kick off…. again.

Which means that once a clot has been formed, a part of it will always be left stuck to the artery wall. This then needs to be got rid of. How does this happen? Well, it is not like scratching your skin, whereby a clot (scab) forms, the endothelium re-grows underneath it, then the scab falls to the ground. If this were the process that happened in an artery, where do you think that clot would go? Down the artery, to get stuck where it narrows, to cause an infarction. Not a very good design feature, I would argue.

So, what happens is something far cleverer. A replacement endothelial layer is created from Endothelial Progenitor Cells (EPCs). These are synthesized in the bone marrow, and float about in the bloodstream. Chemicals released, when endothelium is damaged, attract EPCs to the area of damage/blood clot.

Once they arrive they stick to the surface of any remaining clot, then they grow into fully mature endothelial cells, forming a new endothelial layer. What this means is that any remaining blood clot now sits beneath the new endothelial layer, and within the artery wall itself. It cannot now break off and get stuck somewhere else in the body.

Even more clever is the fact that EPCs have the capability, to become something other than mature endothelial cells. They can travel down another road in the developmental pathway, to become monocytes. Monocytes, in turn, mature into macrophages.

Macrophages are white blood cells whose job it is to clear up all alien materials in the body. Dead cells, invading bacteria, any damaged tissue. They squirt nitric oxide out, oxidise dead and damaged material, such as anything found in a blood clot, then engulf it, before travelling off to the lymph glands. Here, the dead, damaged and alien materials are further broken down, before excretion from the body.

Thus, with EPCs, you have the entire repair and clearance system all in one package. Some of the EPCs that arrive on the scene, form the new endothelial layer. The rest turn into monocytes, then macrophages, which clear away the remnant blood clot.

This process of repair and clearance is what I call ‘healing’. Others choose to call it inflammation, and claim it is the underlying cause of CVD. Good for them. I suspect it may not be a fertile route to travel down.

The other thing to note here is that the substance which is most intimately bonded to the exposed endothelium, at least in humans, is lipoprotein (a) (LP(a). Lipoprotein (a) is Low Density Lipoprotein (LDL) with an extra protein attached to it. A protein called apolipoprotein A. This protein is fascinating, because it has an almost identical structure to plasminogen. Identical apart from a single amino acid.

However, this difference, though very slight, is critical, because it means that TP(a) cannot have any effect on apolipoprotein A. There can be no conversion to plasmin. Thus, any blood clot, or part of the blood clot, containing Lp(a) is extremely resistant to fibrinolysis. It cannot be broken apart, and so remains attached to the artery wall, and will be a major component of the remnant blood clot that is then drawn into the artery wall – and then broken down by macrophages.

This is where Linus Pauling, Mattias Rath, vitamin C, and guinea pigs come into play. I have discussed this area before, but I am going to discuss it again…. Soon.

Before fully signing off on this blog I shall leave you with another thought, which is this. Lp(a) is identical to LDL ‘bad cholesterol’ – apart from a single attached protein – apolipoprotein A. So, if you were closely studying the contents of an atherosclerotic plaque, it would be quite easy to think you were looking at LDL, when you were actually looking at Lp(a)?

Of course, what I have done here is to describe a process of clot formation, and repair, that is probably happening all the time. The next question is obvious. When, and how, can this process become ‘abnormal?’ When, and how, does it lead to CVD?

1: http://www.nejm.org/doi/full/10.1056/NEJMoa1709118#t=article

2: https://www.ncbi.nlm.nih.gov/pubmed/8925184?log$=activity

P.S. those interested in a great deal more complexity, this paper is a belter. http://onlinelibrary.wiley.com/doi/10.1111/j.1538-7836.2007.02515.x/full

Here is one section that explains a great deal in a few words. ‘Recent evidence suggests that ECs [endothelial cells] in regions of disturbed flow in arteries are primed for activation (they have increased levels of NF-κB in their cytoplasm) and that systemic imbalances (e.g. associated with sepsis or cardiac risk factors) may result in the translocation of NF-κB to the nucleus and increased expression of procoagulants such as tissue factor (TF) and adhesion molecules. TM, thrombomodulin; t-PA, tissue-type plasminogen activator; EPCR, endothelial protein C receptor; TFPI, tissue factor pathway inhibitor; VWF, von Willebrand factor.’ And there, I think you have it, in a nutshell. Although I realise that most people have never heard of any of those things.

What causes heart disease part XXXVI (part thirty-six)

5th September 2017

Wipe your mind clear of all previous ideas about CVD. About as easy as standing in the corner and not thinking about a tiger. In reality, once you have read about, and talked about, and researched, and thought about anything, patterns are created in your mind. Familiar landscapes develop, and well-worn pathways become the comfortable and easy routes to travel down.

Say what you like about Ancel Keys (and I had better not, for I would end up swearing a lot), he created the tightly patrolled mental box for everyone. Diet and cholesterol and cardiovascular disease. These are the great beacons that mark out, the map of the mind, where all thinking and discussion must take place. They illuminate all, and beyond them is darkness.

Now, blow out the beacons. Move out into darkness. We shall create a new landscape of thought. We have control of the vertical, and the horizontal, you are entering the Outer Limits. [I suspect some people may not get that reference]. We are breaking free of the box. In fact, there is no box, it no longer exists.

In the distance, there is a glimmer of light… it is our first fact. At least we hope it is a fact. We approach the glittering light and scrape way the grime that has been obscuring it for many years, to reveal…

Atherosclerotic plaques only develop in larger arteries.

Quite close to it, almost hidden away, lies another fact.

Atherosclerotic plaques never develop in veins.

There are two exceptions to the second fact – well, there are more, but these are the most obvious. First, if you take a vein, and use it to create a coronary artery bypass graft, it will develop atherosclerosis very rapidly. Secondly, if you create an arteriovenous fistula AV-fistula (fusing an artery and vein together) for dialysis patients, the venous section will develop atherosclerotic plaques.

Setting aside these exceptions, these two facts were as close to inarguable as I have been able to find. Inevitably, they lead to my first question. Why do plaques develop in arteries, and not in veins? Right now, I can see you doing what everyone does, searching for a simple answer, with thoughts such as:

  • There is less oxygen in veins, and oxygenation is damaging to arterial walls
  • The pressure is less in veins
  • The LDL level is lower in veins (it’s not, but I have heard a lot of people say this)
  • Arteries and veins have a different structure (they do not).

And so on, and so forth. Isn’t the search for a quick and simple answer fun…?

After exploring almost every avenue that I believed could possibly be involved in CVD, I found myself returning more and more often to the difference in blood pressure in veins and arteries as the place where the answers were most likely to be found.

However, I knew pressure, by itself, is not going to cause anything, unless you succeed in ‘bursting’ an artery, or ‘bursting’ the lining of the artery. I mean, this can be done. You can develop an aneurysm (thinned and ballooned area) in an artery, which can then rupture – usually with catastrophic consequences.

But before that, what can pressure do? Force things carried within the artery into the artery wall behind? No, that does not make sense. For that would mean everything carried in the bloodstream would simply be blasted into all artery walls, everywhere. The smallest molecules would go first, molecules such H20 to start with. Does this happen…. No, of course not. Our arteries, and the endothelial cells that line our arteries (and veins), are not leaky.

In short, differences in pressure cannot provide any sort of an explanation.

However, there is a law of fluid dynamics which says – words to the effect – if the pressure in a tube is higher, the velocity of the fluid flowing through a tube will also be higher. Which means that blood is travelling far faster in an artery than a vein. A veritable white-water maelstrom, compared to a meandering river as it approaches the sea.

Thus, it is easy to imagine that anything lining an artery is going to be exposed to far greater ‘forces’ than anything lining a vein. These forces, which I shall call biomechanical stresses, will be particularly intense in certain places. For example, where arteries branch (bifurcate) e.g. where the carotid arteries, that supply blood to the brain, branch off (bifurcate) from the aorta.

Another place of extreme biomechanical stress is within the coronary arteries. These arteries are exposed to a unique stress, in that they are compressed with great force when the heart contracts. Some have likened this to stomping on a hose every second. Indeed, blood cannot flow in coronary arteries during systole (ventricular contraction) because they are squeezed shut.

In general, if you look at where atherosclerotic plaques develop, you find that they most often occur at maximum biomechanical stress. Where carotid arteries (main arteries supplying blood to the brain) branch from the aorta, and also where other arteries branch from the aorta, and within the coronary arteries. It seems, therefore, that biomechanical stress is required for plaques to develop. This is not the same as high blood pressure, but it is closely associated with high blood pressure.

In truth, this idea is not in any way contentious. This is a highly jargon filled section from a paper called ‘Biomechanics of Atherosclerotic Coronary Plaque: Site, Stability and In Vivo Elasticity Modelling.’

Although the coronary and peripheral systems in their entirety are exposed to the same atherogenic cells and molecules in the plasma, atherosclerotic lesions form at specific regions of the arterial tree. Such lesions appear in the vicinity of branch points, the outer wall of bifurcations and the inner wall of curves. Pathologic studies, have shown that healed plaque ruptures are predominantly in the proximal portions of the left anterior descending (LAD), right coronary (RCA), left circumflex (LCx) and left main (LM) arteries. Investigations over the last decade have elucidated both fluid mechanical and most recently structural biomechanical factors that mediated the site of plaque formation.’1

Which is all fine and sensible. However, this very same paper states the following:

‘Plaque formation is now recognized as an inflammatory process triggered by high levels of serum LDL that enter the coronary wall, encounter oxygen reactive species, and become oxidized. The oxidization, in turn, stimulates the recruitment of monocytes that convert to macrophages to phagocytize oxidized LDLs. This forms a necrotic core with recruitment of smooth muscle cells from the media to seal over the fatty core.’

That is the official party line as to how CVD starts, and develops. But if you believe that, you immediately face a conundrum. How can you reconcile the hypothesis that raised LDL entering the artery wall initiates plaque development, with the observation that atherosclerotic lesions form at specific regions of the arterial tree? It is surely one, or the other, but it cannot be both. Sorry, but at this point I need to take you back into the landscape of raised LDL and CVD.

You may think, in fact you probably are already thinking: “Well, biomechanical stress damages the endothelial cells, allowing LDL to enter.” Now, that could be true. However, if that is true, then you have (if you believe in the cholesterol hypothesis), just made a move that will result in checkmate against you.

The argument goes like this:

If LDL can only leak into the artery wall at an area where the endothelial layer is damaged, and this is where plaques develop, this means it cannot leak through in areas where the endothelium is not damaged. Ergo, the first step in the development of plaques cannot be LDL ‘leaking’ into the artery wall past the endothelium, it is damage to the endothelium. Ergo, a raised LDL level is not the primary cause of CVD. Checkmate.

You don’t like that logic? If you prefer a few more facts, using a different approach.

If you think LDL is capable of, simply, transporting itself past the endothelium, then you need to define a mechanism. Is it simply osmotic pressure, with LDL travelling down a concentration gradient from the bloodstream into the artery wall? Is it actively transported through endothelial cells? Does it leak between the endothelial cells? These are the mechanisms that I have seen most commonly proposed – although they are often presented with so much surrounding jargon that it is almost impossible to work out what is being said.

In truth, I have spent years and years trying to establish if LDL can, or cannot, move into the arterial wall, past the healthy, undamaged, endothelium. If I had been organised enough, I could have gathered together ten thousand papers saying that it can, and another ten thousand saying that it cannot.

Having torn up twenty thousand papers, on the basis of complete uselessness, I began with, what may seem a simple question, a thought experiment if you like. Why would endothelial cells allow LDL to pass through them, to then allow LDL to be oxidised in the arterial wall behind? This process serves no physiological purpose, other than to kill you from cardiovascular disease!

The idea that endothelial cells simply cannot prevent this from happening is, frankly bonkers. Cells can quite easily control the passage of single atoms/ions through their cell membranes Indeed, this is one way that all cells function. To give one example, they can pump individual sodium ions out, and individual potassium ions in, to maintain an electrical action potential. They only lose the ability to control their own internal environment, within very tight parameters, when they die.

Therefore, the idea that an endothelial cell cannot prevent a relatively massive LDL molecule from entering the side facing the bloodstream, then passing straight though, then ejecting itself out the other side, is complete nonsense. Complete… nonsense.

Indeed, it has been well established that the only way LDL can enter a cell, is for that that cell to manufacture an LDL receptor, wave it about it the bloodstream to lock onto an LDL molecule, before dragging the receptor and the LDL back inside. Ergo, LDL does not get into an endothelial cell, unless the cell wants LDL to enter. It activates complex processes to allow this to happen.

The reason why some people have very high LDL levels is because they cannot manufacture enough LDL receptors, or the LDL receptors they manufacture are faulty. A lack of LDL receptors, or faulty receptors is, of course, the underlying problem in Familial Hypercholesterolaemia(FH). Proof, if proof were truly needed, that LDL cannot force its way into cells – no matter what the concentration in the bloodstream.

In short, even a superficial understanding of how cells control the passage of atoms and molecules, leads to the inescapable conclusion that LDL cannot possibly travel straight through an endothelial cell, without the activation of complex and highly controlled cellular process.

This problem has been duly noted by those who support the LDL/cholesterol hypothesis. So, the current thinking, although I have never seen it expressed clearly, is that there must be gaps between endothelial cells, wide enough for LDL to leak past.

Again, no. The fact is that, in a healthy artery wall, with healthy endothelium, there simply are no gaps between endothelial cells. Here, from a paper entitled. ‘Endothelial Cell Junctional Adhesion Molecules.’ [jargon alert].

‘Endothelial cells line the lumen of all blood vessels and play a critical role in maintaining the barrier function of the vasculature. Sealing of the vessel wall between adjacent endothelial cells is facilitated by interactions involving junctionally expressed transmembrane proteins, including tight junctional molecules, such as members of the junctional adhesion molecule family, components of adherence junctions, such as VE-Cadherin, and other molecules, such as platelet endothelial cell adhesion molecule.’2

At the risk of simply repeating what this paper says, there are no gaps between endothelial cells. Instead, there is a highly complex structure of proteins and other molecules between each endothelial cell ensuring that nothing gets past – unless the endothelial cells are instructed to let them past. This happens with white blood cells, they can open the junctions between endothelial cells, and move into the artery wall – then out again. Clever stuff.

Of course, if most things travelling in the bloodstream had to overcome complex barriers to get past the endothelium you would die, as your blood would simply circulate round and round, struggling to exchanging nutrients back and forth with the underlying tissue. Which kind of negates the point of having a circulatory system in the first place.

Nature, in the way that nature does, noted this potential problem, and came up with a solution. As blood vessels get smaller, and smaller, the endothelium develops holes – called fenestrations. These fenestrations allow almost everything present in the blood to flow freely in and out of the surrounding tissues/organs. Red blood cells would be one exception.

Why, you could ask, would endothelial cells have fenestrations in them to allow the free passage of molecules in and out, if things can freely pass in and out of non-fenestrated, tightly bound, endothelium?

At this point, I am overwhelmed with the need to make a quick summary:

1: It is impossible for LDL to pass straight through a living endothelial cell

2: Endothelial cells are tightly bound together, and will not allow anything to pass between them.

In addition, here are a couple of other facts to consider.

The first of which is that, in the brain, the endothelium never becomes fenestrated. There are no holes, even in capillaries (the smallest blood vessels in the body). Which means nothing can move into, or be removed from the brain, that the endothelial cells do not grant passage. This barrier function is usually referred to as the blood brain barrier (BBB):

‘Cholesterol is a major constituent of the human brain, and the brain is the most cholesterol-rich organ. Numerous lipoprotein receptors and apolipoproteins are expressed in the brain. Cholesterol is tightly regulated between the major brain cells and is essential for normal brain development. The metabolism of brain cholesterol differs markedly from that of other tissues. Brain cholesterol is primarily derived by de novo synthesis and the blood brain barrier prevents the uptake of lipoprotein cholesterol from the circulation.’ 3

To put this another way, if LDL could pass the BBB, then the brain would not need to synthesize its own cholesterol, and the brain does synthesize cholesterol within specialised glial cells. Which is further confirmation that an intact, non-fenestrated endothelium, blocks the passage of LDL.

Now here is a final fact (a final fact in this blog at least) that I would like you to ponder. Which is that large blood vessels have their own blood vessels, known as vasa vasorum. Literally, ‘blood vessels of the blood vessels’. Vasa vasorum surround and penetrate large arteries, and veins, supplying them with the required nutrients.

They are, of course, fully fenestrated (full of holes). Thus LDL, or anything else, can simply leak out of the vasa vasorum and into the artery wall if it so wishes – yes, even down a concentration gradient, if you like to think of it in this way.

Which means that there is absolutely no need for LDL, or anything else, to be absorbed through the endothelium lining the arteries, as it can get in from ‘behind’, so to speak. Which takes me back to my first question here. Why would endothelial cells transport LDL past themselves, and into the artery wall behind – if LDL can perfectly easily get into the artery wall from the vasa vasorum? This truly would be an exercise in pointlessness.

I could go on, as I have only touched upon a small part of the complexity involved here. But I hope to have given you enough food for thought. Yes, you easily can make statements such as ‘Plaque formation is now recognized as an inflammatory process triggered by high levels of serum LDL that enter the coronary wall’. Certainly, if you say it fast enough, and do not think about it, such a statement can seem reasonable.

However, if you start looking at the actual process required for LDL to travel into the arterial wall, you begin to realise that it is (with a healthy and intact endothelium) simply not possible. Or, if it is possible, it should be happening everywhere, in all arteries and veins. Not at discrete points.

At which point, you begin to realise that the cholesterol hypothesis, whilst is sounds superficially reasonable, requires mechanisms of action that just do not exist.

LDL cannot enter the arterial wall, at least not from the lumen of the artery, unless the endothelium has been damaged in some way. If you damage the endothelium, all hell breaks loose – and then we have a completely different story on our hands. One where LDL may have a role in plaque formation, or it may not, but it most certainly cannot be the primary role.

This is a conclusion that I arrived at a long time ago. Not, initially, because I set out to debunk the hypothesis. I simply wanted to understand how a raised LDL could cause atherosclerosis. ‘Because it does’, has never ever been a reply that I am happy to accept. In fact, nowadays I would translate this particular ‘because it does’ into ‘because it must.’ It must, because if LDL cannot pass through, or past, a healthy endothelium, the cholesterol hypothesis is wrong. And it can’t, so it is.

Now I have got that out of the system, I shall move on to look at what happens when you damage the endothelium. For that, logically, must be the first step in plaque formation.

1: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4722860/

2: http://atvb.ahajournals.org/content/36/10/2048

3: https://www.hindawi.com/journals/cholesterol/2012/292598/

What causes heart disease part XXXV (thirty five)

19 August 2017

Having spent many years smashing everything into pieces in an attempt to work out what is going on with cardiovascular disease, I am now going to attempt the amazing feat of bringing everything together in some sort of coherent structure. I have no idea how long this may take, so please bear with me while I first set the scene by making a couple of point that need to be made.

Point One:

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

Cardiovascular disease is best seen as a process. Attempts to find the key, single, cause has created the massive multifactorial monster we see before us today. Unfortunately, the trap of searching for a/the cause seems to be hard wired into our thinking. This approach has worked well for things such as infectious diseases and suchlike, but it does not work here. I have lost track of the number of times someone has come up with the new cause of CVD, then tried to crowbar all observations to fit. Or simply dismiss contradictory evidence.

  • It’s caused by infections
  • It’s all due to vitamin C deficiency
  • It’s all due to blood sugar
  • Its’ all due to inflammation etc. etc. etc. etc. etc.

It’s…….

In truth, I was as guilty of this as everyone else. I believed that ‘stress’ was the cause, and everything could be incorporated within this factor. This is not true. Stress/strain represents one factor that is capable of causing CVD – quite an important one – but it cannot explain everything.

Whilst there obviously are ‘causes’ of cardiovascular disease, they cannot be understood in isolation from process(es). What is going on, and why, and how can things that seem to cause cardiovascular disease be fitted into these processes.

It may seem intellectually unsatisfactory to move away from a simple, single, cause model. We all want the E=MC2 moment, or the untangling of the structure of DNA moment. Eureka! That was never going to happen here, or it would already have happened. If there truly were a single cause it would have been found by now – and it hasn’t.

Point Two:

The evidence base is flawed. In part because studying complex biological systems is, in itself, very difficult to do. The number of variables involved is mind-boggling, and the number possible interactions between those variables is mind boggling to the power one trillion. If you are looking for absolute certainty…. look elsewhere.

Just to give one example of how many potential factors there are. Here is part of a paper by researchers, who looked at geomagnetic disturbance and its impact on heart attacks and strokes (Russian paper):

‘It was shown statistically that during geomagnetic disturbances the frequency of myocardial infarction and brain stroke cases increased on the average by a factor of two in comparison with quiet geomagnetic conditions. These results are close to results obtained by (Stoupel, 1999), for patients suffering with acute cardiological pathology. Our recent study (with L.Parfeonova) revealed the relation between heart ventricular ectopic activity (VEA) and geomagnetic conditions in patients with CHD. On the average 1995 episodes of VEA having on one patient within 24 hours have been revealed in patients, whose records coincided with the periods of geomagnetic storms and 1440 VEA episodes for active conditions. Minimal quantity of VEA episodes was found for unsettled condition: 394. In a quiet geomagnetic condition VEA episodes appeared more often than in periods of unsettled conditions.’1

How many researchers have taken geomagnetic disturbances into account as a potential confounding factor in their research? I would suggest, none. Yet here is a factor that can (possibly) increase the risk of CVD events by 100%.

I chose this example, almost at random, to highlight the point that this stuff is complicated, and there any many, many, uncertainties involved. Can you control any study for all factors ever found to be associated (causally or otherwise) with CVD? No, you cannot.

Alternatively, you can do what many people do. Dismiss research that seems contradictory, or just daft. I can see many people automatically seeking to dismiss a Russian study about the effect of geomagnetic disturbance on CVD on the dual grounds that is a: Russian and b: bonkers. That would be unwise.

Of course, there is the other problem that much of medical research (especially in the highly lucrative area of CVD) has been funded by the pharmaceutical industry, resulting in the problem that most research findings are false:

‘There is increasing concern that most current published research findings are false. The probability that a research claim is true may depend on study power and bias, the number of other studies on the same question, and, importantly, the ratio of true to no relationships among the relationships probed in each scientific field. In this framework, a research finding is less likely to be true when the studies conducted in a field are smaller; when effect sizes are smaller; when there is a greater number and lesser preselection of tested relationships; where there is greater flexibility in designs, definitions, outcomes, and analytical modes; when there is greater financial and other interest and prejudice; and when more teams are involved in a scientific field in chase of statistical significance. Simulations show that for most study designs and settings, it is more likely for a research claim to be false than true. Moreover, for many current scientific fields, claimed research findings may often be simply accurate measures of the prevailing bias.2

This is a famous paper, one of the most cited and read in medical research history. It was written in 2005 and things have got worse, not better, since then.

Oh, but of course, peer review keeps everything on the straight and narrow:

‘The mistake, of course, it to have thought that peer review was 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.’ Richard Horton, editor of the Lancet.

In this morass, where does one turn?

This is a question that has no definitive answer. Shall I just choose evidence that suits my argument, and dismiss all else? To an extent, the difficulty in disentangling evidence was my spur to write the book Doctoring Data. In it, I attempted to determine what is valid and what is not. How to spot the biases and errors. How to know what it true, from the other stuff?

Answer… it cannot be done. Not for certain. Whatever evidence I choose, it can be criticised – in one way or another. Did the study I am quoting control for geomagnetic disturbance or not? As a general rule, any study – and I mean any study – can be pulled apart and dismissed, if you so wish. Which could leave most of what I do as a smoking ruin.

However, most of the research I look at has one major advantage. There is not much, if any, financial interest, behind it. Other than suppressing it, I suppose.

Yes, of course, I bring certain biases to the discussion. I am almost entirely anti-statin. I am not a great believer in blood pressure lowering – at least not at current levels. I do not believe in the cholesterol hypothesis and I think that the anti-saturated fat dogma is completely bonkers and has no evidence to support it – at all. I believe that salt is good for and, in most people, protects against CVD.

I believe that a high carbohydrate low fat diet is utterly bonkers – especially in those with diabetes. And suchlike. In short, I believe that almost everything we are told is good for you, is bad for you, and vice-versa. With the exception of smoking (bad) and exercise (good).

Having got that out of my system. Let us begin….. in the next blog.

1: http://adsabs.harvard.edu/abs/2014cosp…40E1114G

2: http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.0020124