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

What causes heart disease part XXXIV (part thirty-four)

9th August 2017

Looking for the contradictions

Here was my mantra. ‘If I can find an absolute contradiction to any hypothesis, I shall discard it, and start again.’ I have to tell you that this shiny, bright eyed scientific idealism has had to bite the dust. Primarily, because it can be very difficult to know what a contradiction looks like – for sure.

If Newton had found that every so often apples did not fall from a tree, instead they accelerated upwards and into space, the theory of gravity would not have been born – because it would have been wrong. If your hypothesis is that all swans are white, then the finding of a single black swan immediately negates your hypothesis.

However, in science, refutations are rarely so clear cut. In biological science, there are so many things going on, so many variables to consider, that we are more in the world of weather forecasting, rather than Newtonian physics. There are few absolutes, no completely hard and fast rules.

This, of course, has allowed those who believe in the ‘cholesterol hypothesis’ to shape shift, twist and turn, and adapt the hypothesis to fit any facts. Never, ever, can they be pinned down. Never, ever, can the hypothesis be refuted by any single fact, or even a combination of facts. Believe me, I have tried. It is like attempting to nail mercury, firmly, to the table.

Take the hypothesis that a raised cholesterol level causes heart disease. Already, I imagine, you can see this fragmenting before your very eyes. What do you mean by a high cholesterol level. Total cholesterol? Low density lipoprotein (LDL) level? The ratio of LDL to HDL? Are you looking at LDL-C or LDL-P. Are you considering VLDL levels, what about oxidised LDL, or small dense LDL, or light and fluffy LDL.

That, without trying, is nine ‘cholesterol’ variables. And the possible combination of nine variable is nine factorial. This allows 362,880 possible combinations of ‘cholesterol’ that could be tested. In truth, I didn’t really try very hard there with ‘cholesterol’. I could add in at least sixteen variants of HDL (that I am aware of), including apoA-1 Milano (the super-protective form of HDL – allegedly). Which give us another sixteen ‘cholesterol variable).

9 + 16 = 25 variables (assuming they act independently)

The factorial of 25 is 1.55×1025   or: 15,511,210,043,330,985,984,000,000.00

As you can see, there is not the remotest possibility, ever, of trying to work out how all the forms of ‘cholesterol’ may interact. Even if you created theoretical models and fed them into a computer, you would be there for a very, very, long time.

Equally, there is no possibility of refuting the causal impact of any single cholesterol factor. And, if you did manage to pin anything down, the broader issue of ‘definition’ will simply be altered.

Just trying to look at the apparently simple concept of a high total cholesterol level itself. You would think it would be possible to say that there is an average level, a high level and a low level. This would allow you to say that the average total cholesterol level of everyone in the world (who has had their cholesterol level tested) is five point three (5.3mmol/l). [I just made this figure up]

Thus, anyone above this figure could be said to have a cholesterol level above average. Or high. And vice-versa. Just as you could measure the height of everyone in the world, and find an average. However, this cannot be done. Well, it could be done, but it has not been done, and I suspect it never will be done. Because, in the case of cholesterol levels, average is most definitely not considered ‘normal.’

Here, for example, is what is said about cholesterol levels on the Benecol website:

‘The government recommends that healthy adults should have a total cholesterol level below 5 mmol/L. In the UK, three out of five adults have a total cholesterol level of 5 mmol/L or above, and the average cholesterol level is about 5.7 mmol/L, which can be a risk factor in the development of coronary heart disease.’1

Thus, the average cholesterol in the UK is not normal. It is ‘high’ enough that it is a risk factor for heart disease. So, average is not normal. Is 5mmol/l normal? Well, Heart UK (The UK cholesterol charity – funded almost entirely by the pharmaceutical industry), makes this statement:

‘Total Cholesterol (TC) – this is the total amount of cholesterol in your blood. Ideally it should be 5 mmol/L or less.’

Which would suggest that anything below 5mmol/l is fine and normal? But if you have diabetes, you should have a cholesterol below 4.0mmol/. Diabetes UK lists the following blood lipid (cholesterol) targets as a guide for people with diabetes:

  • Total cholesterol: under 4.0 mmol/l
  • LDL levels: below 2.0 mmol/l2

Which means that four is actually better than five – thus five is high? And if you have had a heart attack it is recommended to get cholesterol levels below 4.0mmol/l. Ergo, a level of 5.0mmol/l must be causing the developing of heart disease. So, five is not actually normal. It is high.

The general consensus, though never very clearly stated, is that, whatever your level of cholesterol, you will gain benefit from lowering it. Which, logically, means that any level of cholesterol increases the risk of heart disease. Thus, there is no optimal level. I have seen it argued that the optimal level for cholesterol is 1.5 mmol/l. 3

Setting the level at this point means that, apart from a vanishingly small number of people, everyone in the western world has a ‘high’ cholesterol. Therefore, you can never argue that a high cholesterol does not cause heart disease, because everyone who suffers from heart disease has a high cholesterol level. In contrast, no-one with a ‘normal’ cholesterol level suffers from heart disease.

With cholesterol levels, we have the following situation:

 

High                                                                                           = high

Average                                                                                     = high

Low                                                                                            = high

Very low                                                                                    = high

Very, very low                                                                          = high

So low that you cannot find anyone with this level*        = normal

When confronted with logic like this, the cholesterol hypothesis is perfectly protected from attack. It is a non-refutable hypothesis. As Karl Popper said, if you cannot construct your hypothesis in such a way that it can be refuted, it is not science a.k.a. nonsense.

Which is why, in the end, I decided on another approach entirely. Replace the cholesterol hypothesis with something that actually fits the facts without the need for endless distortion of facts, and reality. Also, to try to create a hypothesis whereby data could be found to refute it.

At present, just to repeat myself for the final time, the cholesterol hypothesis is that a high cholesterol level causes CVD. This cannot be refuted, because there is no such thing as a normal cholesterol level. All levels are high. Res Ipsa Loquitir.

1: http://www.benecol.co.uk/cholesterol/understanding-your-number

2: http://www.diabetes.co.uk/diabetes-health-guidelines.html

3: http://www.onlinejacc.org/content/43/11/2142

*or at least, so few people exist that no study could ever be done

What causes heart disease part XXXIII

29th July 2017

Viagra…. again

When I began this long and winding series on cardiovascular disease (CVD) I already knew a few things that I thought were critically important to the processes underlying CVD.

The first was that, in order to get atherosclerotic plaques started, you needed to damage the endothelium in some way [the endothelium being the layer of cells lining blood vessels]. The second was that blood clot formation was the next key event – thrombogenesis.

Therefore, if you could protect the endothelium and/or stop blood clots from forming, you would most likely see some significant benefits on the risk of CVD. Mainstream medicine is fully in agreement that drugs that reduce the risk of blood clotting will usually have some benefit on CVD risk. Drugs such as aspirin and Clopidogrel – and suchlike.

In addition, most of the acute management of strokes and heart attacks is focussed on getting rid of the blood clot causing the acute event. We have clot busters and stents and other interventions to remove, squash, blow apart and bypass the clot. I often describe interventional cardiologists as ‘blood clot managers’ – obviously not to their faces. They like to think it is all far more cleverer than that.

In short, the importance of blood clotting in CVD is beyond any dispute. Which is why CVD sometimes sits under the umbrella term of ‘atherothrombosis.’

However, the role of the endothelium garners far less attention. If it is ever mentioned, it is towards the end of the process of atherosclerotic plaque development, where it has been noted that in advanced plaques the endothelium is often completely missing. Or if not missing, significantly dysfunctional.

The reason for this, never openly stated, is that to promote the idea that atherosclerotic plaques start with endothelial dysfunction, completely undermines the cholesterol hypothesis. The current hypothesis is that low density lipoprotein (LDL) a.k.a. ‘bad cholesterol’ leaks past/through the endothelium, and into the arterial wall behind.

This in turn triggers the inflammatory processes that creates the plaque (I am paraphrasing madly here). Once the plaque has grown to sufficient size, the overlying endothelium is: weakened, damaged, dysfunctional – choose the word you like best, or add your own. This, in turn makes it more likely that a blood clot will form, as a dysfunctional endothelium no longer represent a powerful anti-coagulant surface, which in my mind I like to think of as a brand new ‘Teflon non-stick frying pan.’

However, if you believe that endothelial dysfunction is the first step, then an entirely different process opens. One that goes like this: The endothelium is damaged/dysfunctional, so a clot forms at that point. The clot is then drawn into the arterial wall and becomes the core of an atherosclerotic plaque which can then grow through repeated blood clots forming at the same point.

This, as I think I have explained many times, fits all the observed phenomena far better than the current cholesterol hypothesis. However, it does knock LDL off its perch as the key factor causing CVD. It can only have a bit part, amongst many other players, in this particular game.

Currently whilst all other conjectures on CVD are allowed to change shape, and swirl around in a massive multifactorial dance, one idea lies beyond challenge, which is that LDL is the conductor, the key player, the factor without which nothing else happens:

Three Rings for the Elven-kings under the sky,
Seven for the Dwarf-lords in their halls of stone,
Nine for Mortal Men doomed to die,
LDL for the Dark Lord on his dark throne
In the Land of Mordor where the Shadows lie.
LDL to rule them all, LDL to find them,
LDL to bring them all and in the darkness bind them
In the Land of Mordor where the Shadows lie.

 

Or something of the sort.

Currently, it is certainly true that the dark lord rules Mordor, and the ever-seeing eye seeks out all those who criticise the cholesterol hypothesis. Here, for example, is a recent missive from Mordor:

Statin Denial: An Internet-Driven Cult With Deadly Consequences (Editorial JAMA 25th July 2017)

‘We are losing the battle for the hearts and minds of our patients to websites developed by people with little or no scientific expertise, who often peddle ‘natural’ or ‘drug-free’ remedies for elevated cholesterol levels,” adds Steven Nissen. This “Internet-driven cult” denies statins’ benefits and whips up fears of side effects, then profits from the resulting confusion by peddling snake oil.’1

I think I need to shout ‘House’ at this point. Nissen has manage to get in the full set of insults. ‘Denier’, ‘cult’, ‘deadly’, ‘whips up’, ‘fears’, ‘profit from selling snake oil’. What’s missing. Mass murderers…child killers.

Would this be the same Steven Nissen who stated the following, when the new cholesterol guidelines came out in 2013:

“The science was never there for the LDL targets.’ He said. ‘Past committees made them up out of thin air.’ He added.”2 Make your mind up Steven. Either there should be LDL targets or not.

Where was I. Oh yes, just explaining that anyone who dares criticize the cholesterol hypothesis – which is basically interchangeable with statin worship – can find themselves under significant attack. As you can imagine, those working in mainstream research are going to make sure they never do such a silly thing. Grants have a nasty habit of drying up. Tenure can be whipped from under your feet at any time. Do not attract the interest of the ever-seeing eye, my precious.

However, facts have this nasty habit of coming along that cannot be fitted within the LDL hypothesis, and are completely supportive of the ‘endothelial damage/clotting’ hypothesis. A few blogs ago I wrote of a study demonstrating that men with diabetes, who used Viagra, or other PDE5 inhibitors e.g. Cialis, were far less likely to die from CVD.

We know that Viagra/sildenafil has, as a primary mode of action, increasing nitric oxide synthesis in endothelial cells. This is how it maintains erections in erectile dysfunction. It also reduces blood pressure, particularly reducing blood pressure in the lungs. Nitric oxide is also the most powerful anti-coagulant agent known to man. Furthermore, it protects the endothelium from damage, and stimulates the production of endothelial progenitor cells in the bone marrow.

What effect does it have on LDL? None.

What effect does it have on cardiovascular and overall mortality? Well, very recently I was sent this paper: ‘Association between treatment for erectile dysfunction and death or cardiovascular outcomes after myocardial infarction.’

This was a study on over forty-three thousand men over a six-year period, who had previously had a myocardial infarction (MI). Just over forty thousand did not have medication dispensed for erectile dysfunction (ED) (40,077), three thousand did (3,068). They were split into three groups: lowest number of ED scripts, medium and highest number.3

For the sake of brevity here I am just looking at the highest script group.

 

 

Well, well, well. Perhaps a couple of other well, wells for luck.

Yes, this study was observational. Yes, this means that other factors that may be at play. For example, those men requesting Viagra and other PDE5 inhibitors, may have been healthier than those who did not. But it is hard to believe they were over five times as healthy. The simple fact is that, when you see an effect as massive as this, it can generally be considered that you are looking at a causal relationship.

To put it another way, this is 81% relative risk reduction in overall mortality. Compare this with statins, in secondary prevention (using best figures possible), statins achieved a 15% relative risk reduction in overall mortality. But statins lower cholesterol levels…right? That is how they work…right? So, LDL does have an impact?

Well, it is of course true that statins lower the LDL level. However, they also do some other things as well. Now, in general I am not a great fan of animal studies. However, I am just presenting one study, done on atorvastatin, looking at the impact on many factors (including NO synthesis) that have nothing whatsoever to do with LDL lowering.

The study was called:

Atorvastatin enhanced nitric oxide release and reduced blood pressure, nitroxidative stress and RANTES levels in hypertensive rats with diabetes.’

A quick summary:

  • Atorvastatin had no effect on blood glucose or cholesterol levels
  • Blood pressure was reduced by 21% (in diabetic rats)
  • RANTES levels were reduced by 50% (RANTES is a ‘chemokine’ associated with endothelial damage)
  • Nitric Oxide (NO) was increased
  • ONOO (peroxynitrate) was decreased. (ONOO is a potent inhibitor of NO).

Summary: ‘These findings provide insights into mechanisms of restoration of endothelial function and vascular protection by atorvastatin in diabetes and hypertension.’ 4

When statins first emerged, they swept all before them. Included the discussion on what causes CVD. Cholesterol skeptics, such as, Professor Michael Oliver, were completely bowled over, and admitted they had been wrong, when statins were shown to lower CVD risk (the true magnitude of the benefits was massively over-hyped, but that is a discussion for another day).

Statins were designed to lower LDL/cholesterol and lower CVD risk and they did. End of argument.

Well, perhaps not quite.

If you decide to look more closely at the process of CVD, and more closely as the actions of statins, a different picture emerges. One which fully supports endothelial damage as the first step in plaque formation. Because statins do many more things than LDL lowering. It could be said that statins are simply the poor man’s Viagra (other PDE5 inhibitors are available).

 

1: http://www.latimes.com/science/sciencenow/la-sci-sn-statin-denial-20170724-story.html

2: http://www.nytimes.com/2013/11/13/health/new-guidelines-redefine-use-of-statins.html

3: https://www.ncbi.nlm.nih.gov/pubmed/14692706

4: https://www.ncbi.nlm.nih.gov/pubmed/25716966

Diabetes Unpacked – a new book

Last year I was asked if I would contribute to a book on diabetes. Any money made from royalties would go to The Noakes Foundation in South Africa, a non-profit organisation which aims to advance understanding of the low carb high fat (LCHF) diet, in order to help people eat more healthily. Mainly in South Africa, but also spreading the ideas around the world.

I told the publishers that my ideas on diabetes were not necessarily shared by anyone else, because my brain was turned inside-out at birth by a careless midwife, and I can never see things the same way as everyone else.

In truth, despite my in-built ‘outside in’ way of thinking, I am in (virtual) full agreement with this project, and the view that if you want to avoid diabetes, the correct diet is low carb, high fat (LCHF). If you are unfortunate enough to have diabetes, it is critically important to eat a LCHF diet.

Unfortunately, for reasons that I have discussed before, mainstream medical thinking has got this matter twisted through one hundred and eighty degrees. They tell us we must eat a high carb low fat diet. This is completely bonkers. It makes no sense from any aspect of human physiology, or science, or logic. But, there we go. To quote the film Inception. ‘The most resilient parasite is an idea planted in the unconscious mind.‘ Quite

The most resilient idea in medical science appears to be that fat, particularly saturated fat, is bad for us. Carbohydrates, on the other hand, are good for us. This idea cannot be shifted by facts, logic, science, or any argument that I have yet managed to find, at least not in the minds of most people – and all mainstream experts.

The parasitic resilience of this idea would not matter, if this idea were not underpinning the massive increase in obesity and diabetes that we are seeing in the Western World. If it were not an idea that is damaging, and killing, millions of people. But it is, so it does matter.

And so, in another attempt to change thinking, and to educate, many brilliant thinkers (including me, of course), I have contributed to the book ‘Diabetes Unpacked’. This is what the blurb says:

Diabetes used to be rare and clear. One boy in the school had type 1 and a friend of a friend’s granny had Type 2. We now see adults being diagnosed with type 1 and children growing up with Type 2. There are over 400 million diabetics world-side – 4 times are many as in 1980. The vast majority of these have Type 2 – sometimes judged as a ‘lifestyle’ disease.

The traditional view of diabetes is that it is a ‘chronic and progressive’ condition and that nothing can be done about it. Serious complications include loss of eyesight, amputations and death.

This book has gathered together some of the finest minds working in the field of diabetes and diet. The result is a collaboration of chapter by thought leaders, academics and doctors addressing the big issues. What is diabetes? What are the different types? What causes is? Who gets it? Why do we eat so much carbohydrate? Why do diabetics die of heart disease? Why do athletes commonly get Type 2 diabetes?

The writers in this book approach diabetes from many different angles, but they all share one common belief: Diabetes does not need to be ‘chronic and progressive.’ Both Type 1 and Type 2 can be substantially alleviated and the latter can be put into remission. Let us tell you how…’

The Authors are: Professor Tim Noakes; Ivor Cummins, Dr Robert Cywes, Dr Jason Fung, Dr Jeff Gerber, Mike Gibbs, Dr Zoë Harcombe, Dr Ian Lake, Lars-Erik Litsfeldt, Nina Teicholz, Dr David Unwin, Dr Neville Wellington, Jen Whitington (‘Fixing Dad’), Dr Caryn Zinn and me.

Whatever your interest – overall health, weight loss, diabetes – the importance of diabetes on heart health, I would urge you to buy this book and help The Noakes Foundation to spread the word.

(publishers’ note: Book is available as limited edition hardback and to pre-order here. General release is end August when it will be available through usual book channels as paperback and eBook)

What causes heart disease part thirty-two (XXXII)

Stress and heart disease

I have drifted around the issue of stress and cardiovascular disease (CVD) for some time. For many years I pursued the idea that stress was the cause of CVD. Indeed, I had it all worked out, fitting all facts about CVD within this model. But…

I was at a conference in Saudi Arabia a few years ago, giving my ‘How stress causes CVD’ lectures, to great acclaim, or so I thought. However, Paul Rosch, who was also attending said to me, one evening at dinner. ‘It is all very well to show that stress is associated with heart disease, but you have not really established a mechanism.’

This, I realised, was true. I could show things such as the fact that severe depression can cause insulin resistance, even type II diabetes. Also, that depression is associated with a much higher rate of CVD, as are almost all metal health diseases. On average, someone with a mental illness can expect to die around twenty years earlier than those in the surrounding population.

I could show that psychosocial stress lead to Hypothalamic Pituitary Adrenal-axis [HPA-axis] dysfunction, which then drove the metabolic syndrome, with a much higher rate of CVD. The HPA-axis is the conductor of the entire ‘stress’ system.

At one stage I became very interested in spinal cord injury, and CVD. I discover that, the level the spinal cord injury occurred, made very significant differences to the rate of CVD. This, in turn, seemed almost entirely dependent on whether the autonomic nervous system was spared, or damaged.

The autonomic sympathetic/parasympathetic nervous system co-ordinates the ‘flight or fight’, stress, response. It runs down the spinal column before fanning out to link up to all of the organs in the body. You have little conscious control over it, which is why it is often called the ‘unconscious’ nervous system.

The sympathetic part of the autonomic system does such things as, speeding up the heart rate, constricting the bladder, redirecting blood to the muscles. Also stimulating the release of stress hormones, such as cortisol, to increase blood clotting and raise blood sugar levels – all good things in preparation for a fight.

I figured, along with many others, that if the fight or flight response was chronically activated, this would have severe and potentially damaging effects on the body. A chronic ‘dysfunctional stress response’ if you like. It appeared that much of the damage caused by a dysfunctional stress response centred around the stress hormone cortisol.

This idea was further strengthened by the looking at Cushing’s disease, a condition whereby the adrenal glands produce too much cortisol – for various reasons. People with Cushing’s disease have a spectrum of biochemical and physiological abnormalities, from raised blood pressure to severe insulin resistance, raised blood clotting factors, and suchlike.

Those with Cushing’s almost always develop the metabolic syndrome, and often frank type II diabetes. They have a vastly increased risk of dying of CVD. Around 600% (relative increase in risk). Last week I was sent a paper, looking at Cushing’s, called ‘Markers of atherosclerosis in patients with Cushing’s syndrome: a meta-analysis of literature studies.’

The authors found: ‘Cushing’s disease is associated with an increased intima-media thickness (IMT), higher prevalence of carotid plaques, and lower flow-mediated dilation as compared with controls. These data consistently suggest the need for a strict monitoring of early signs of subclinical atherosclerosis in Cushing’s patients.’1

In fact, the prevalence of atherosclerotic plaques was 988% higher (relative risk), than in controls. This is, basically, a ten-fold increase in the risk of plaques, and that moves Cushing’s Disease from association to causation.

I have also looked at people who used steroids for various medical conditions and found that they had a greatly increased risk of CVD. It is estimated that regular steroids use increases CVD risk by around 400% (relative increase in risk). For those who do not know, steroids are often called corticosteroids, because they all used cortisol as the building block. [Cortisol is also called a ‘steroid’ hormone].

CORTISOL

PREDNISOLONE – A commonly prescribed ‘steroid’

Whilst everything was, of course, rather more complex that this, with far more strands of evidence to gather together. I had worked my way towards a pretty clear causal chain that looked something like this:

Negative psychological and/or physical stress → HPA-axis dysfunction → abnormal cortisol secretion → metabolic syndrome/type II diabetes → atherosclerosis → increased risk of CVD

Now, I think that this model is still perfectly usable, and it explains a lot. However, although I drew a simple arrow from metabolic syndrome/type II diabetes → atherosclerosis, this is the bit that Paul Rosch was talking about. What is actually happening here? It is all very well to state that something causes something else, but you still need to explain how.

I realised that I did not know how, other than in general terms. I also realised that there were many other things that ‘cause’ CVD, that are not stress related e.g. smoking, omeprazole, Kawasaki’s disease, air pollution, Avastin etc. etc. How could all these be fitted into that one small arrow. That is when I ripped up the stress hypothesis, to start again. Pretty painful, but necessary.

 

1: https://www.ncbi.nlm.nih.gov/pubmed/27763781

British Society of Lifestyle Medicine Conference

On the weekend of the 1st July I am giving a talk at the British Lifestyle Conference in Bristol UK.

This is a great grassroots movement of people, and many doctors, who are trying to achieve a more holistic approach to health. I hope some of you can come along. Here is what the organiser, Dr Rob Lawson, has put together for a mention on my blog.

Vital optimism at work – and play.

Lifestyle Medicine has been shaped by the natural evolution of Medicine. It is an established approach that focuses on improving the health and wellbeing of individuals and populations. It combines the broad facets of modern healthcare practices with the deeper understanding of being human. In the 21st century it has never been more important as a concept. And that is to create a society and an environment, from cell to community, which nurtures healthy longevity.

It requires an understanding and an acknowledgement of the physical, emotional, environmental and social determinants of disease and wellbeing. Hence the LM practitioner will engage with us as patients and operate within a boundary of evidence-informed medicine. A boundary in which our ideas, values, mind-set and social context blend not only with the clinicians’ expertise but also with clinical research outcomes.

Importantly, Lifestyle Medicine has a wider responsibility to recognise upstream determinants of disease and to promote population health, to protect ecological health and to reduce health inequity. This requires a realistic team approach and recognition that not one discipline or profession alone can meet our health needs.

On 1st July 2017 in Bristol Dr Malcolm Kendrick will be joining other world renowned speakers in Bristol at the inaugural Conference of the British Society of Lifestyle Medicine, the Science and Art of healthy longevity, https://bslm.org.uk/event/vital-optimism/, to which you are warmly invited. If you have never heard him speak – this is your chance! No better way to spend a Saturday in July

What causes heart disease – part thirty one (XXXI)

What is the final event?

(The upside down*)

The final event in most heart attacks, and strokes, is the development of a large, and often fatal, blood clot. If this happens in an artery in the heart, a coronary artery, it cuts off blood supply to an area of heart muscle and can lead to a myocardial infarction (MI) [myocardium = heart muscle, infarction = death of tissue due to lack of oxygen].

There is a related, but different mechanism of action, in most, strokes. In this case a blood clot that has formed in an artery in the neck (carotid artery), breaks off and travels to the brain where it gets stuck, blocking an artery. This leads to a cerebral infarction. There are other forms of stroke, with other causes, but this is the most common.

These are generally accepted models, and for the sake of brevity, it is also the model I am using here. Although I accept that it is not that simple. For example, you can have an MI with no blood clot found. Here, from a paper entitled: ‘Acute myocardial infarction with no obstructive coronary atherosclerosis: mechanisms and management’:

‘Myocardial infarction (MI) with no obstructive coronary atherosclerosis (MINOCA) is a syndrome with different causes. Its prevalence ranges between 5 and 25% of all MIs.’1

A heart attack with no blood clot. In truth, I think this can be easily explained, within the ‘obstructive’ model, but it would take too long for this blog. I will cover it at some point.

Anyway, to get back on track. It is generally accepted that the final event in cardiovascular disease is the formation of a large blood clot. This is the thing that causes both fatal, and non-fatal, strokes and heart attacks. Which is why atherosclerosis, as a disease, is often referred to as atherothrombosis. The idea being that atherosclerotic plaques gradually build up, over decades. In the final stage, the plaque ‘ruptures’ triggering the formation of a large and deadly clot.

The suggestion here, never ever explicitly stated, is that we have two different processes in operation. Plaque formation, then the blood clot. Or maybe you could look at this as one process, in two parts. Plaque growth, then plaque rupture – causing thrombus formation.

However, it is perfectly possible for thrombi to form with no underlying plaque, so the two processes need not be associated with each other. People with Hughes’ syndrome, for example, can die of strokes and heart attacks quite suddenly, caused by blood clots, with no plaque to be seen. [Hughes syndrome causes the blood to be highly likely to clot – hypercoagulable].

Which leaves the question hanging somewhat. Do we have one process – or two? I believe that the main reason for using the term atherothrombosis, is because this allows mainstream thinking to draw everything together as different manifestations of the same underlying process. Raised cholesterol causes plaques, these rupture, then a clot develops (which would not have formed had the plaque not been there). This allows clear wiggle room, but at some point you must decide, one process or two. This is not quantum physics.

In my world, it is far simpler. There is only one process. Atherosclerotic plaque are simply blood clots, in various stages of growth and/or repair. Plaque growth represents the formation of a new blood clot, at the same point, which is not cleared away properly. The final ‘thrombotic’ event is just a big enough clot forming to do real damage.

The first time I started to think about this seriously, was when I was reading a paper called ‘A Definition of Advanced Types of Atherosclerotic Lesions and a Histological Classification of Atherosclerosis. A Report From the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association.’ The things I do for fun … clearly, I am just a geek.

Anyway, this paper rambled on and on, and on. Until, whilst propping my eyelids open, my interest suddenly sharpened as I came across the section on the definition of Type V(a) atherosclerotic plaques – don’t ask. For those who enjoy a bit of scientific jargon, here it comes. If you don’t care for jargon, just look at the text I have put in bold at the end.

‘Sequential histological studies of the lesions of large populations indicate that reparative connective tissue forms in and around regions of the intima in which large accumulations of extracellular lipid (lipid cores) disarrange or obliterate the normal cell and intercellular matrix structure. Sometimes the new fibrous tissue accounts for more of the thickness of the lesion than does the underlying lipid accumulation.

The new tissue consists of substantial increases in collagen and smooth muscle cells rich in rough-surfaced endoplasmic reticulum. In cases in which this tissue is particularly thick, some or much of it may be the remnant of thrombi that were incorporated and organized. Capillaries at the margins of the lipid core may be larger and more numerous than in type IV lesions, and they may also be present in the newly formed tissue. Lymphocytes, monocyte-macrophages, and plasma cells are frequently associated with the capillaries, and microhemorrhages may be present around them.

Type Va lesions may be multilayered: several lipid cores, separated by thick layers of fibrous connective tissue, are stacked irregularly one above the other. The term multilayered fibroatheroma can be applied to this morphology. The lipid core that is deepest and closest to the media may have formed first. Mechanical forces may play a role in the modeling of such lesions.

Additional lipid cores in locations and planes different from the first could be induced as asymmetric vascular narrowing and changes in lumen configuration modify hemodynamic and tensile forces, creating a redistribution of the regions of predisposition for lesion formation.

The architecture of some multilayered fibroatheromas could also be explained by repeated disruptions of the lesion surface, hematomas, and thrombotic deposits. Organization (fibrosis) of hematomas and thrombi could be followed by renewed accumulation of macrophage foam cells and extracellular lipid between the newly formed fibrotic layer and the endothelial surface.’ 2

In layman’s terms what does it mean? It means that a number of plaques look exactly as if they were created by the repeated formation of blood clots, one on top of another. A concept further reinforced, when the paper looked again at thrombosis.

‘Thrombosis

‘It has been reported that advanced atherosclerotic lesions containing thrombi or the remnants of thrombi are frequent from the fourth decade of life on. In 1975 Chandler and Pope compiled and reviewed studies that reported the frequency and nature of lesions with incorporated thrombi.

In a recent study of a population aged 30 to 59 years, 38% of persons with advanced lesions in the aorta had thrombi on the surface of a lesion. These thrombi ranged in size from minimal (microscopic) to grossly visible deposits, and some consisted of stratified layers of different ages. Immunohistochemistry revealed wavy bandlike deposits related to fibrin within the advanced lesions of an additional 29% of persons. Because of their structure, these were thought to represent the remnants of old thrombi. Similar data were reported by other authors.

The fissures and hematomas that underlie thrombotic deposits in many cases may recur, and small thrombi may reform many times. Repeated incorporation of small recurrent hematomas and thrombi into a lesion over months or years contributes to gradual narrowing of the arterial lumen. Some thrombi continue to enlarge and occlude the lumen of a medium-sized artery within hours or days.’

Perhaps the key sentence here, from my point of view, is the following:

‘Repeated incorporation of small recurrent hematomas and thrombi into a lesion over months or years contributes to gradual narrowing of the arterial lumen.’

Here, right here, is proof of the concept that plaques definitely do grow through repeated thrombus formation at the same point on the artery. Do all plaques do this? My own belief is that they do, but in many cases the repair mechanisms and other factors disrupt a clear picture of layered plaque growth. Essentially, the core of the plaque turns into mush (known as a lipid core) which obliterates evidence of how the plaque actually grew.

What else supports the idea that plaques are, in reality, blood clots? Well, very early on in their development, rather than in the third or fourth decades of life, you can find high levels of fibrin and fibrinogen, which are key components of blood clots. Here from a paper ‘Lipids and plasma fibrinogen: early and late composition of the atherosclerotic plaque.’

The precursor of large fibrous plaques appears to be the gelatinous lesion, which is characterized by oedema, accumulation of large amounts of low density lipoproteins and fibrinogen in the expanded interstitial fluid space, deposition of fibrin, and smooth muscle cell proliferation. It is postulated that deposition of fibrin may be a key event, stimulating smooth muscle cell proliferation by providing a scaffold for migration, a source of fibrin degradation products which are mitogenic, and binding thrombin. Fibrin may also be a factor in lipid accumulation because it binds lipoprotein (a) with high affinity, and may also bind low density lipoprotein.’3

In short, early plaques contain a lot of fibrin (key component of a blood clot), also lipoprotein (a), which is LDL with a different protein attached. Fibrin binds to Lp(a) forming very stable, and difficult to remove, blood clots. So, it is not just in type V(a) plaques that we find evidence of blood clotting. We find it very early on as well.

Sorry, If I am getting a bit jargonified at this point – if that is indeed a word. But I am aware that some highly trained scientific people do cast their eyes over this blog, and I do not want to make this too broad brush. Also, here, I am discussing the very core of my ideas about CVD, and I want to be as accurate as I can be. Equally, I do not want to put people off by delving too deep.

So, at this point, I shall only look at one more highly scientific study, which I think is important. One of the things I always tend to do, is to look at extremes. By which I mean populations with the highest rates of CVD, or medical conditions that accelerate CVD, and suchlike.

I believe answers are to be found at the extremes. To that end I became very interested in people who received heart transplants. For they, unfortunately, develop atherosclerosis at a very high rate. It tends to be called vasculopathy, as it is not exactly the same as atherosclerosis, but that may simply be a result of how fast it develops.

Cardiac allograft vasculopathy (CAV) is the major cause of long-term mortality after heart transplant (HTx). Cardiac allograft vasculopathy has heterogeneous pathologic features characterized by vascular wall inflammation, fibrous intimal thickening, and atherosclerosis.’

I believe that, because it is developing quickly, it is possible to see ‘plaques’ forming and growing in a way that is very difficult in the rest of the population. Or, to put it another way, we have an accelerated model of CVD, where things are revealed that may normally be hidden.

Here is the key section from the paper: ‘Repeated episodes of thrombosis as a potential mechanism of plaque progression in cardiac allograft vasculopathy.’

‘Conclusions

In conclusion, our observations demonstrate that a finding of ML (multi-layered) appearance, which may be indicative of repeated episodes of mural thrombosis, is not infrequent in asymptomatic cardiac transplant recipients. These findings may contribute to progression of cardiac allograft vascolopathy (CAV). The current study gives new insight into the potential role of coronary thrombosis in plaque progression in CAV.’4

Once again, repeated thrombus formation and plaque growth, causing multi-layered plaque progression.

I shall finish here by quoting myself in a previous blog:

‘Interestingly, at one point Pfizer also started to promote atherothrombosis as the cause of heart disease. For sentimental reasons I have kept hold of an educational booklet produced by Pfizer in 1992. On page four it states:

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

Given the insidious nature of atherosclerosis, it is vital to consider the role of platelets and thrombosis in this process.’ [Well, quite]

There is little point in referencing this document, as I probably have the only copy left in existence. It is called ‘Pathologic triggers. New insights into cardiovascular risk.’ Produced by Medi Cine Inc. For Pfizer Inc Copyright 1992, All rights reserved etc. etc.

It is interesting that when Pfizer did not have a statin, they were looking away from cholesterol as a cause of cardiovascular disease. It will come as no surprise to you that this was not through some altruistic attempt to discover the truth about the true cause of heart disease. It was to help market their drug doxazosin (a BP lowering drug) which had some additional anticoagulant properties.’

Of course, I have not answered all questions here. But I wanted to give you some insight as to my core thinking on CVD. Having jumped around for years I decided to start at the end, the final blood clot, and then worked backwards.

Was it possible, I asked myself, that blood clotting was not just responsible for the final clot, but also for the entire process of atherosclerosis? I believe that the evidence is out there, and clearly supportive, if you choose to look at it this way round.

I suppose you could say that I do not believe in atherothrombosis. I believe in thromboatherosis (you’re right, I just made that word up). In thromboatherosis, plaques start, and grow, through repeated thrombus formation at the same spot in an artery. In the end, a clot gets big enough to cause a stroke or heart attack. Sometimes the clot can be big enough to kill, without any underlying plaque, but normally it will form over an already existing plaque – where plaque rupture can be the trigger.

In short, there is only one process in CVD. It is the development of atherosclerotic plaques through repeated thrombus formation, followed by the final thrombus formation. As you can see this is actually very close to mainstream thinking. The only difference is that you have to flip your thinking through one hundred and eighty degrees, to see it upside down.

 

1: https://academic.oup.com/eurheartj/article/36/8/475/496887/Acute-myocardial-infarction-with-no-obstructive

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

3: https://www.ncbi.nlm.nih.gov/pubmed/7634262

4: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3787274/

*for those who enjoyed Stranger Things

P.S. Pop quiz. Why do plaques never develop in the heart itself? Here the pressure is highest, damage to endothelium must be greatest and yet, and yet, no plaques – ever.

What causes heart disease – part XXX

Inflammation – or not

Over the last few years there has been a significant shift, from many researchers, towards the idea that atherosclerosis is an inflammatory process, to a greater or lesser extent. Below is a quote from a cardiac surgeon. A man who admits he was wrong about cholesterol being the main underlying cause CVD, so I can applaud him for that. He goes on to say:

‘Simply stated, without inflammation being present in the body, there is no way that cholesterol would accumulate in the wall of the blood vessel and cause heart disease and strokes. Without inflammation, cholesterol would move freely throughout the body as nature intended. It is inflammation that causes cholesterol to become trapped.

Inflammation is not complicated — it is quite simply your body’s natural defence to a foreign invader such as a bacteria, toxin or virus. The cycle of inflammation is perfect in how it protects your body from these bacterial and viral invaders. However, if we chronically expose the body to injury by toxins or foods the human body was never designed to process, a condition occurs called chronic inflammation. Chronic inflammation is just as harmful as acute inflammation is beneficial.’1

And so on and so forth. More recently, a friend and fellow cholesterol sceptic, Aseem Malhotra, was lead author on an article in the British Journal of Sports Medicine entitled: ‘Saturated fat does not clog the arteries: coronary heart disease is a chronic inflammatory condition, the risk of which can be effectively reduced from healthy lifestyle interventions.’

A major statin study called JUPITER, was designed to look at lowering C-reactive protein with rosuvastatin, to see if this would lower the risk of CVD – in those with low or normal cholesterol levels. C-reactive protein (CRP) is a non-specific marker of inflammation. To quote the lead investigator:

The recent JUPITER trial demonstrated that potent statin therapy reduces by 50 % the risk of heart attack and stroke among men and women with low levels of low-density lipoprotein (LDL)-cholesterol who are at increased vascular risk due to elevated levels of C-reactive protein (CRP), a biomarker of low-grade systemic inflammation. In JUPITER, both absolute risk and the absolute risk reduction with statin therapy were related to the level of CRP, whereas no such relationship was observed for LDL-C.’2

I could find another ten thousand papers all stating that CVD is caused by inflammation. Case proven? Well, the case is certainly proven, beyond doubt, that atherosclerosis is strongly associated with inflammation in the arterial wall. To which my response would be… and so what exactly?

If you twist your ankle, and tear ligaments, you will also find a great deal of inflammation in the surrounding area. You would, however, be stretching reality to suggest inflammation is the underlying cause of ankle ligament damage. I suppose you could try.

In my simple little world, inflammation is a result of underlying damage. It is not, and cannot be the underlying cause. Inflammation is a manifestation of the body attempting to heal itself. In fact, whenever I see the word inflammation, I mentally replace it with the word ‘healing.’ For many years I have smiled enigmatically at the widely accepted advice following a badly sprained ankle. RICE (Rest, Ice, Compression, Elevation). These are all ways of reducing inflammation, sorry, healing.

Just looking at the ‘I’ in RICE. Ice:

Ice works by decreasing the blood flow to an area, thus temporarily diminishing the swelling and inflammation that accompanies most injuries —- (when the tissue re-warms … the inflammatory process resumes). But in the 1970s we knew very little about the healing process.   We did not understand that inflammation is actually a very important initiating event of the overall healing process.

When you are injured, the blood vessels to the area dilate. That causes the swelling and warmth you notice. The increase in blood flow brings with it very potent chemicals, proteins and cells.   Those chemicals and cells set off a cascade of reactions that we refer to as inflammation. More importantly, this is also what initiates the HEALING process.   Yes, inflammation is a necessary part of the healing process. The inflammation chemicals send a message to other cells to come to the injured area… they also wake up sleeping or dormant cells already residing in the area of the injury. Those cells in turn start to repair the ligament, muscle or skin at the site of injury.’3

Finally, conventional sports medicine catches up with Chinese traumatology. In Chinese medicine, we NEVER recommend ice for injuries. Simple physics will tell you that ice applications will constrict blood vessels which will reduce blood flow to the injury, meaning less waste products removed and less nutrition delivered therefore slower healing.’4

I say, reduce inflammation at your peril. You may reduce the swelling, and some of the bruising, and things will certainly look less ‘damaged’. But, again, so what. Two billion years of evolution have created some pretty effective healing processes, which we also call inflammation. Interfere with inflammation, and the results are predictable.

The most powerful anti-inflammatory agents known to man are corticosteroids, so called as they are all synthesized around the base compound, cortisol (a corticosteroid). Medically they are used in a number of auto-immune/inflammatory conditions, ranging from rheumatoid arthritis, ulcerative colitis, eczema, lupus, transplant organ rejection and suchlike [Asthma is a bit different].

In these conditions, there is a rationale for reducing inflammation. Here, we have the body ‘seeing’ various proteins as alien, and attacking them, through an ‘auto-immune’ response. Yes, there is inflammation. However, this is not the body trying to repair itself. This is the immune system causing damage, by attacking the body itself, with resulting inflammation. In short, do not confuse inflammation with inflammation.

However, if inflammation were the underlying cause of CVD, then corticosteroids should reduce the risk of CVD, as they are the most potent anti-inflammatories known to man. But they very much do not. A paper was published recently, called ‘Can machine-learning improve cardiovascular risk prediction using routine clinical data?’ A fascinating paper indeed. The purpose was, as follows:

‘Current approaches to predict cardiovascular risk fail to identify many people who would benefit from preventive treatment, while others receive unnecessary intervention. Machine-learning offers opportunity to improve accuracy by exploiting complex interactions between risk factors. We assessed whether machine-learning can improve cardiovascular risk prediction.’

I have not written about this paper before, although it identified LDL as completely irrelevant in predicting CVD risk, and the risks it did identify were almost completely different from those in the current risk calculators. In fact, the number one risk factor of cardiovascular risk was Chronic Obstructive Pulmonary Disease (COPD). I have never seen this on any risk calculator before, and I am trying to digest the implications.

However, getting back on track, the main point of interest here is looking at number three on the list of factors that can increase CVD risk:

Oral corticosteroid prescribed

At number eight:

Immunosuppressant prescribed

Immunosuppressants are also designed, effectively, to impair the inflammatory response. They are used in much the same sort of conditions as steroids. In fact, corticosteroids could also be termed immunosuppressants.

The highly damaging effect of corticosteroids, or other drugs designed to suppress the immune response, should not really come as any surprise. There is a medical condition called Cushing’s disease, in which too much cortisol is produced by the adrenal glands. The impact of Cushing’s disease on CVD is to increase the risk by, at least, 500%. 5

Other anti-inflammatory drugs have similar, if less spectacular effects, on CVD risk. The FDA recently increased the warning level on non-steroidal anti-inflammatory drugs (NSAIDs). Drugs such as ibuprofen, naproxen, diclofenac.

The FDA is strengthening an earlier warning about the cardiovascular safety of non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs), both prescription and non-prescription, the agency said Thursday. After a comprehensive review of new safety information, the FDA is requiring updates to the labels of all prescription NSAIDs to reflect recent information on risk of heart attack and stroke. Over-the-counter non-aspirin NSAIDs already contain some safety information, but the labels on these drugs will also require an update, said the FDA in its announcement posted online.

The new labels for prescription NSAIDs should contain the following information, according to the FDA:

  • The risk of heart attack can occur within weeks of starting an NSAID, and that risk may increase with longer use.
  • The risk seems to be higher at higher doses.
  • It’s not clear if the risk of heart attack and stroke is the same for all NSAIDs.
  • The drugs can raise the risk of heart attack or stroke in both patients with a risk of heart disease and patients without.
  • Patients with heart disease or risk factors for it are at a greater risk of heart attack or stroke following the use of NSAIDs, because they have a higher risk at baseline.
  • There is also an increased risk of heart failure for patients using NSAIDs.6

Of course, it can be argued, and it has, that steroids and non-steroidal anti-inflammatory agents have other potentially damaging effects on the CVD. Whilst this is undoubtedly true (to an extent), you would still not expect agents that are, primarily, anti-inflammatory, to vastly increase the risk of CVD. If CVD is an inflammatory disease.

Personally, think that the science here has been done. Agents designed to reduced inflammation all greatly increase the risk of CVD – from moderately to spectacularly*. Thus, whilst it is true that you can find inflammation within arteries where atherosclerosis is developing, this DOES NOT mean that the inflammation is causing the problem.

What you are seeing is the body trying to heal damage, and then getting cause and effect twisted through one hundred and eighty degrees. ‘That’s looks abnormal, let’s get rid of it’. A pretty good summary of a great deal of medical research over the last few hundred years, I suppose.

 

1: https://www.sott.net/article/242516-Heart-surgeon-speaks-out-on-what-really-causes-heart-disease

2: https://www.ncbi.nlm.nih.gov/pubmed/23225175

3: http://www.howardluksmd.com/orthopedic-social-media/ice-ice/

4: http://www.drmirkin.com/fitness/why-ice-delays-recovery.html

5: https://www.ncbi.nlm.nih.gov/pubmed/8187313

6: https://www.medpagetoday.com/publichealthpolicy/fdageneral/52530

*aspirin is the exception. However, aspirin has strong anti-coagulant effects. It stops platelets sticking together. In this way, the anti-coagulant effects of aspirin, outweigh the damaging anti-inflammatory effect.

Mike Cawdery – a tribute

It is not often you are passed such terrible news. But sadly, Mike Cawdery, a regular and highly impressive contributor to this blog, was murdered along with his wife, on the 26th of May.

‘The devastated family of an elderly couple murdered in their home on Friday say they are struggling to understand what has happened. Michael and Marjorie Cawdery, both aged 83, were the victims of a brutal knife attack leaving them both with fatal injuries.

A family spokesperson said: “The awful and incomprehensible events of Friday 26 May have deprived our family of two wonderful people Michael and Marjorie who were our father, mother, brother, sister and grandparents. “We thank the police for their prompt response and professional actions. We also thank everyone who has expressed sympathy in whatever way and offered help.”

Mr Cawdery, a retired veterinary surgeon who trained at Trinity College Dublin, and his wife Marjorie, were attacked in their home and died at the scene.’ http://www.belfastlive.co.uk/news/belfast-news/marjorie-michael-cawdreys-family-say-13101196

I found out about this from his GP, who was kind enough to e-mail this news. He knew that Mike posted comments to this blog on a very regular basis, and he thought that I should know what had happened. Thank goodness, he did, otherwise I would have had no idea. I would have simply wondered why Mike Cawdery, our statistician par excellence, had fallen silent. [In truth, other people have since, e-mailed me with the news].

I never met him, I never spoke to him, but I believe that I – and other readers of this blog- knew him well. He seemed ferociously intelligent, and still driven to do what he thought was right. I felt he was an admirable man. Funny how the Internet brings people together into a ‘family’ that converses and argues and supports and occasionally falls out.

In the last month, Mike Cawdery posted 117 comments on the blog, all of them were worth reading. Here was one of his last ever posts.

‘May I plead with you all to keep a watch on the BMJ and to use their RAPID RESPONSE system just as one uses Dr Kendrick’s comment section. Many of the comments and references cited here are equally valid on some relevant editorials, news items and even reports. All one has to do is give name and rough address and answer a question or two. Open to all including doctors.

May I take this opportunity to suggest that any one, a patient, carer and particularly doctors as the ultimate carers sign up as “patient reviewers”. Interesting and gets patients and carers involved. Too long have patients been treated little better than pets (may be with less respect??). It is people like Dr Kendrick that have given patients an outlet to express their views and knowledge.’

At 83, he was still active, still getting involved, and still trying to make the world a better place. Mike, you will be missed, by us all.

Cholesterol lowering – the end of the beginning?

I have been somewhat silent over the last two or three weeks on this blog. The word ‘swamped’ springs to mind. The main swamping thing (alongside work and suchlike) that I have been doing is to analyse the Lancet paper which claimed that, basically, statins cause no adverse events. Professor Peter Sever (corresponding author), followed up the publication of this paper with statements such as:

‘While statins do have some potentially serious side effects, including a slightly raised risk of developing type II diabetes and, very rarely, a potentially fatal muscle condition known as rhabdomyolysis, Sever said that the Medicines and Healthcare Products Regulatory Agency (MHRA) should remove warnings of side-effects including muscle pain and weakness, sleep disturbance, erectile dysfunction and problems with cognitive function” (https://www.theguardian.com/society/2017/may/02/statin-side-effects-down-to-negative-expectations-not-the-drugs-nocebo).

In an interview with UK national newspaper, The Daily Telegraph, Peter Sever went on to say that:

‘There are people out there who are dying because they’re not taking statins, and the numbers are large, the numbers are tens of thousands, if not hundreds of thousands.

He said it was a “tragedy” akin to the MMR scandal that high risk patients had been deterred from taking drugs which could save their lives. Urging patients not to “gamble” with the risk of heart attacks and strokes, he said “bad science” had misled the public, deterring many from taking life-saving medication” (http://www.telegraph.co.uk/news/2017/05/03/statins-myth-thousands-dying-warnings-non-existent-side-effects/).

And so on and so forth. This paper, as you may expect, has been picked up with great enthusiasm by the mainstream medical media, and other doctors. Here is a Dr John Mandrola writing a Commentary in Medscape.

The frequency of muscle symptoms with statins is hotly debated. Randomized controlled trials (RCTs) in which patients don’t know whether they are taking the statin or a placebo report nearly identical rates of muscle-related adverse events. Observational studies, however, report higher rates of statin muscle complaints.

As a practicing doctor, I have always felt the truth lies closer to the observational data. A study published recently in the Lancet suggests I may be wrong. This new study, which has impeccable methods, suggests statin muscle complaints stem not from human muscles but from the human brain. In the Lancet paper, researchers took advantage of two distinct parts of the primary prevention ASCOT-LLA trial.

In the first part of ASCOT-LLA, more than 10,000 people were randomized to either atorvastatin 10 mg daily or placebo in a double-blinded fashion. After completion of the blinded phase of ASCOT-LLA, study participants were invited to take part in a nonblinded and nonrandomized extension study in which they could take atorvastatin open label.

The results turned on whether people knew they were on the statin. In the double-blinded phase of the trial, muscle symptoms occurred at the same rate—2.0% per year in both the statin and placebo groups. In the second phase of the trial, when people knew they were on the statin, side effects occurred at a higher rate (1.3% per year) in the statin group vs the placebo group (1.0% per year). This difference reached statistical significance (hazard ratio 1.41, CI 1.10–1.79; P=0.006).

These are remarkable observations, which are hard to dispute. In an accompanying editorial, two Spanish authors emphasized the obvious strengths of this paper: these were the same patients in both phases, and there was no run-in period in which patients intolerant to statins were excluded’ (http://www.medscape.com/viewarticle/879762_print).

So, this is a slam dunk. Right?

Well, I have taking a pretty forensic look at the Lancet Paper. It has the snappy title. ‘Adverse events associated with unblinded, but not with blinded, statin therapy in the Angle-Scandinavian Cardiac Outcomes Trial – Lipid Lowering Arm (ASCOT-LLA); a randomised double-blind placebo-controlled trial and its non-randomised non-blind extension phase.’ May 2nd 2017’.

You may not be surprised to know that Professor Sir Rory Collins was a co-author.

I believe it may have a weakness – or two – or three – or … you get the picture. However, if you are going to attempt to argue against such a paper, or pick holes in it, you need to study it with extreme care, to make sure that you have your facts absolutely right.

Then you need to look at all other associated papers around the entire ASCOT study. For example, I have been amusing myself, or not, by studying ‘Rationale, design, methods and baseline demography of participants in the Anglo-Scandinavian Cardiac Outcomes Trial’…. And a few other papers as well. I have also been speaking to some very bright people who understand exactly how clinical studies are done, how adverse events are reported and recorded. It is an arcane and opaque world indeed.

You need to try to understand comments such as this, in the paper:

Procedures

After randomisation, study participants were scheduled to be seen at 6 weeks and 3 months and then at 6 monthly intervals thereafter during both the blinding randomised and non-blinding randomised phases of the ASCOT-LLA (until the ASCOT-BPLA completed – yes this was two trials in one). At each study visit all adverse events (AEs) reported by participants were recorded by the study team in the case report form. Specific questions relating to any putative AEs were not asked at these visits.

Reports of AEs by the study participants were initially recorded verbatim and subsequently classified with use of the Medical Dictionary for Regulatory Activities into 26 separate system organ class (SOC) groups, 2288 unique preferred terms, and 5109 separated low-level terms…..’

Now, I defy anyone to make sense of that. [I had no idea what the word putative meant in this context. Having looked it up, I am none the wiser]. Either adverse reports were initially recorded onto a case report form, or comments were recorded verbatim and subsequently classified…. You can do one, or the other, not both. As for attempting to reclassify verbatim reports, in several different languages, fifteen years later…. Hmmmmm.

However, whilst trying to get my head around that, my interest was piqued by those involved in this data analysis. It turns out that the lead author, Ajay Gupta, was provided with financial support from the ‘Foundation for Circulatory Health’. I had never heart of this ‘charity’ before. So I tried to find out how it was funded – always tricky. You can usually find out who provides the dosh, but not how much.

Looking at their accounts, the foundation for Circulatory Health seems to be funded largely (almost entirely?) by the pharmaceutical industry. Companies which include, guess who, Pfizer, who funded the initial ASCOT study and who also funded the recent Lancet Nocebo paper.

Supporters (of the Foundation for Circulatory Health (http://www.ffch.org/supporters.html):

  • Pfizer
  • Sanofi-Aventis
  • Menarini
  • Novartis
  • Medtronic
  • Boston Scientific
  • Pulsecor
  • Patients attending the Hypertension and Cardiology Clinics

Digging further it then turned out that that Peter Sever and Neil Poulter (key authors on the ‘nocebo’ paper) are also directors of the Foundation for Circulatory Health, which Funded Dr Gupta to work on the Nocebo paper – supported by Pfizer. Well, who’d a thunk? [Well, me actually].

Neil Poulter is a very well-known researcher in CV medicine, well known to those who keep track of such things. His name turns up all over the place. Here was his declaration of interest statement in the Lancet paper:

Neil Poulter’s institution (Imperial College London) held a grant for the conduct of the Anglo-Scandinavian Cardiac Outcomes Trial in the UK and Ireland and he has also received a speaker’s honoraria from Pfizer outside the submitted work. He is also a recipient of the National Institute for Health Research Senior Investigator Award to Imperial College Healthcare NHS Trust.’

Sounds quite reasonable(ish) and above board. However, compare this with a conflict of interest statement from 2008: ‘Poulter disclosed receiving ad hoc payments to appear on advisory boards/deliver lectures for “all the major pharmaceutical companies that produce major agents in hypertension and CV medicine” and receiving grant income from Pfizer and Servier’(http://www.medscape.com/viewarticle/790044?t=1#vp_2).

Perhaps he just forgot that he had received money from all the major pharmaceutical companies that produce major agents in hypertension and CV medicine. Must be hard to keep track of what you have previously disclosed. Is there a time limit on conflicts of interest?

For now, I shall continue to dig. I shall continue to analyse the paper. Watch this space. It is all rather time consuming, but it may turn out rather well in the end. Although, I suppose, that rather depends on which side you are on in this debate.

It’s official, statins do not have any side effects

Some of you will have noted that researchers have now decided that statins do not have any side effects at all. To be pedantic, the correct term is not side-effects, it is drug related adverse events. A side effect can be positive, or negative.

In order to prove that statins cause no adverse events, a paper was published in the Lancet entitled: ‘Adverse events associated with unblinded, but not with blinded, statin therapy in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid-Lowering Arm (ASCOT-LLA): a randomised double-blind placebo-controlled trial and its non-randomised non-blind extension phase.’

A virtually impenetrable title which could mean almost anything. But the key message can be found here:

‘These analyses illustrate the so-called nocebo effect, with an excess rate of muscle-related AE reports only when patients and their doctors were aware that statin therapy was being used and not when its use was blinded. These results will help assure both physicians and patients that most AEs associated with statins are not causally related to use of the drug and should help counter the adverse effect on public health of exaggerated claims about statin-related side-effects.’

Funding: Pfizer, Servier Research Group, and Leo Laboratories

Statement by authors in original ASCOT study [The Lancet vol 361 April 5th 2003. Pp1149-1158] ‘The Anglo-Scandinavian Outcomes Trial (ASCOT) is an independent, investigator-initiated and investigator-led multicentre, randomised trial designed to compare two antihypertensive treatment strategies for the prevention of CHD events…

Funding of the original ASCOT study: Pfizer, Servier Research Group and Leo Laboratories

The ASCOT study was published over fifteen years ago.

There was a lot of noise about this study on the radio, newspaper and television. At least there was in the UK. Professor Peter Sever, one of the authors, and a key investigator, stated on the radio, that the inserts warning of drug related adverse effects should be removed from the packaging, as they simply encourage patients to believe that they are suffering from adverse effects. He also stated that statins caused muscle problems in less than one in ten thousand patients.

I tend to disagree with him. I was asked to be interviewed on various radio stations, including BBC radio Scotland, and to write a newspaper article for the Scotsman newspaper. It went as follows:

The Great Statin Con

Yesterday, I was asked to appear on various programmes to discuss a study ‘proving’ that statins cause no side-effects at all. Or, at most, they may cause muscle pains in around one in ten thousand people, no more. At the same time, statins save thousands of lives a year. Therefore, everyone should take them, and patients should ignore scaremongering doctors – such as me I suppose – who state that side-effects are common, and potentially serious.

On the radio, Professor Peter Sever, the lead author of the study, suggested that the leaflets warning of side effects should be removed, because once a patient reads that there may be side effects, they will be far more likely to suffer from them, and report them. The so-called ‘nocebo’ effect. The opposite of the placebo effect, whereby people taking medicines think they will get better, or that their pain will be reduced.

There is no doubt that the nocebo effect is real, although the placebo effect is also real, so do these two effects not just cancel each other out? This is a difficult area of medicine, disentangling what is real, from what is imagined.

However, I watched my father in law become unable to walk, whilst taking statins. We were pushing him around in a wheelchair until, eventually, he agreed to stop his statins. At which point he became able to walk a good distance again, and even climb stairs again. A ‘nocebo’ effect? All in the mind? No, of course not.

I had a patient with such severe abdominal pains that she was going to undergo an investigative laparotomy to establish what was causing them. No investigations had revealed anything. I suggested she stop the statins and the pains were completely gone in two days. All in the mind? I have spoken to many other GPs who have reported seeing side effects in many patients.

I suppose if you are trying to push statins as hard as possible, and you built your academic reputation on running trials on statins, you will naturally want to push them as hard as possible. Some ‘experts’ have even suggested putting statins in the water supply.

But this latest report pushes things to a completely ridiculous point. Can I, as a GP, simply tell patients reporting side-effect that ‘you do not have a side effect, they do not exist, it is simply in your mind.’ No, this would be completely ridiculous, and a total denial of your job, which is to listen to what patients tell you. Not to take a horribly, I know best, paternalistic position.

On the other hand, the benefits of statins have been hyped to an almost completely ridiculous degree. We are told that they reduce the risk of having a heart attack by 30%, which sounds highly impressive, if you, like almost everyone, including me, do not understand statistics.

The reality is, that unless you have had a previous heart attack, statins have no effect on overall mortality. To put that another way, they don’t save lives. They don’t even prevent heart attacks or strokes in women with no previous history of heart disease.

The statistic you really want to know about statins is the following. If you have had a heart attack, or stroke, and take a statin for five years, you will increase your life expectancy by 4.2 days. Balance that against a twenty per cent chance of having side effects, some of which are very unpleasant and long-lasting, and you can see why I am not a fan of statins.
Ends.

Currently I am sifting through the original ASCOT paper to find out exactly what they did study, and what they found, and suchlike. The problem with trying to get to grips with research like this is that there are figures, and more figures, and data and exclusion criteria, and things that are not fully explained. So, it is difficult to make any statement about this entire saga, without many hours of detailed research.

However, I can certainly comment on the key finding from the recent Lancet ‘nocebo’ paper. Key or not, it is the finding that they made the most noise about.

‘During the non-blinded non-randomised phase, muscle-related AEs (adverse events) were reported at a significantly higher rate by participants taking statins than by those who were not (161 [1·26% per annum] vs 124 [1·00% per annum]; 1·41 [1·10–1·79]; p=0·006).’

To translate 161 people (out of more than six thousand) complained of muscle pain whilst taking the statin, and 124 people taking a placebo complained of muscle pain. In total 37 more people complained of muscle pain on the statin. This is not, what I would call, a lot. It was an absolute increase, in the risk of reporting adverse effects, of 0.26%.

Compare and contrast this figure with the findings of the ‘Statin USAGE’ study. As far as I know, this was the largest study to look at why people take, then stop taking, statins:

‘The USAGE survey – “Understanding Statin use in Ama and Gaps in Education” – is the largest known cholesterol survey conducted in the U.S., involving more than 10,100 statin users. The USAGE survey explores patient perceptions, attitudes, behaviors and concerns about statins, the most commonly prescribed medications to treat high cholesterol.’ http://www.statinusage.com/Pages/about-survey-respondents.aspx

A number of things were found. The most important of which, is just how many people stopped taking their statins after one year. A pretty staggering 75%. Why did they stop?

‘More than six in ten respondents (62%) said they discontinued their statin due to side effects, with the secondary factor (17%) being medication cost. Only 12% of respondents cited lack of efficacy in cholesterol management as a reason for stopping their medication. On average, respondents who experienced side effects due to their statin stopped after trying two different statins.

Three out of ten respondents experienced side effects of muscle pain and/or weakness, and 34% stopped taking their statin because of these side effects without consulting with their doctor.’

So, on one hand, what the Lancet study found was that 0.26% extra patients reported muscle pain – when they knew they were on a statin. On the other hand, the Statin USAGE survey found that 30% of people experience muscle pain and/or weakness when on a statin. Now, try to get those two figures to match up.

You could argue that the nocebo effect can only account for 0.26% of adverse effects. Therefore, the other 29.74% (30% in the Statin USAGE study – 0.26% nocebo effects) represents the true rate of adverse effects. You could argue that randomised controlled clinical trials do not reflect the experience of taking medication in the real-world environment. You could say that you can believe one of these studies, but not both.

On the other hand, you could move sideways a bit, and wonder why researchers suddenly decided to ‘data dredge’ a twenty-year-old study – not set up to look at adverse effects as a primary end-point – to prove that statins do not have any adverse effects. You could then look at who funded that research and you could ask yourself why would a company currently being sued in the US for not highlighting the adverse effects of statins, decided to use a study to prove that statins do not have adverse effects.

Alternatively, you could ask people who have taken statins, whether they suffered adverse effects, and try to match the number who claim that they do, with the one in ten thousand figure of Professor Peter Sever. And good luck with that. It is hard, I find, not to think that ‘he who pays the piper calls the tune.’

Tim Noakes found not guilty – of something or other

Many years ago I started looking at research into cardiovascular disease. Almost as soon as I began my journey, I came to recognise that many facts I had been taught in medical school were plain wrong. This did not come as a great surprise. Anyone familiar with the history of scientific research will soon find out that widely established facts are often not ‘true’ at all. My mother still likes to tell me that when she was at school it was taught, with unshakeable confidence, that there are 48 human chromosomes. There are 46.

In addition, it became clear that, not only were certain key facts wrong, there seemed to be a co-ordinated effort to attack anyone who dared to challenge them. One stand out example of such an attack was what happened to John Yudkin, the founder of the nutrition department at the University of London’s Queen Elizabeth College.

He did not believe that saturated fat was to blame for heart disease, the idea at the centre of the diet-hypothesis. At the time, this theory was being relentlessly driven by Ancel Keys, and it had gained widespread acceptance amongst the scientific community. In 1972 Yudkin wrote the book ‘Pure white and deadly’ in which he outlined why sugar was the probable cause of heart disease, not fat(s). He was then ruthlessly attacked. As outlined by the Telegraph:

‘The British Sugar Bureau put out a press release dismissing Yudkin’s claims as “emotional assertions” and the World Sugar Research Organisation described his book as “science fiction”. When Yudkin sued, it printed a mealy-mouthed retraction, concluding: “Professor Yudkin recognises that we do not agree with [his] views and accepts that we are entitled to express our disagreement.”

Yudkin was “uninvited” to international conferences. Others he organised were cancelled at the last minute, after pressure from sponsors, including, on one occasion, Coca-Cola. When he did contribute, papers he gave attacking sugar were omitted from publications. The British Nutrition Foundation, one of whose sponsors was Tate & Lyle, never invited anyone from Yudkin’s internationally acclaimed department to sit on its committees. Even Queen Elizabeth College reneged on a promise to allow the professor to use its research facilities when he retired in 1970 (to write Pure, White and Deadly). Only after a letter from Yudkin’s solicitor was he offered a small room in a separate building.

“Can you wonder that one sometimes becomes quite despondent about whether it is worthwhile trying to do scientific research in matters of health?” he wrote. “The results may be of great importance in helping people to avoid disease, but you then find they are being misled by propaganda designed to support commercial interests in a way you thought only existed in bad B films.”

And this “propaganda” didn’t just affect Yudkin. By the end of the Seventies, he had been so discredited that few scientists dared publish anything negative about sugar for fear of being similarly attacked. As a result, the low-fat industry, with its products laden with sugar, boomed.’1

Let us scroll forward some forty years or so, to Professor Tim Noakes. Regular readers of this blog will have heard of Tim Noakes who is, to quote Wikipedia.. ‘…a South African scientist, and an emeritus professor in the Division of Exercise Science and Sports Medicine at the University of Cape Town.

At one time he was a great supporter of the high carb low fat diet, and even helped to develop high carb energy foods for long distance runners. However, for various reasons (most importantly studying the science again) he completely changed his mind. He is now a very well-known proponent of the high fat, low carb (HFLC) diet, as a way to treat obesity and type II diabetes – and improve athletes’ performance.

A couple of years ago, he was dragged in front of the Health Professions Council of South Africa (HPCSA) after being charged with unprofessional conduct for providing advice to a breast-feeding mother in a tweet. “Baby doesn’t eat the dairy and cauliflower. Just very healthy high fat breast milk. Key is to wean [sic] baby onto LCHF.”

The case against him was obviously, and almost laughably, bogus. The HPCSA did not even (as I understand it) have any guidelines on what constitutes an on-line doctor patient relationship. You could make the case that it is difficult to find someone guilty of breaching rules, when there are no rules. Despite this, I thought they would get him on some technicality or other.

Just as happened to Gary Fettke in Australia

‘Prominent Launceston surgeon Gary Fettke has been banned from giving nutritional advice to his patients or the public for the rest of his medical career. He was recently notified by the Australian Health Practitioner Regulation Agency that he was not to speak about nutrition while he remained a medical practitioner.

Dr Fettke is a strong advocate for a low carb, high fat diet as a means to combat diabetes and ill-health. AHPRA told Dr Fettke “there is nothing associated with your medical training or education that makes you an expert or authority in the field of nutrition, diabetes or cancer”. It told him the ban was regardless of whether his views on the benefits of the low carbohydrate, high-fat lifestyle become accepted best medical practice in the future.’ 2

Lo, it came to pass that Gary Fettke cannot even talk about a high fat diet, even if it becomes accepted best medical practice…. Ho hum, now that really makes sense. At this point you may possibly, just possibly, see some parallels between Tim Noakes, an advocate of the high fat low carb diet in South Africa, and Gary Fettke, an advocate of the high fat low carb diet in Australia. Also, of course, John Yudkin, who was attacked and effectively silenced by the sugar industry many years ago.

This would be, I suppose, the very same sugar industry who paid Harvard researchers in the 1960s to write papers demonising saturated fat and extolling the virtues of sugar.

‘Influential research that downplayed the role of sugar in heart disease in the 1960s was paid for by the sugar industry, according to a report released on Monday. With backing from a sugar lobby, scientists promoted dietary fat as the cause of coronary heart disease instead of sugar, according to a historical document review published in JAMA Internal Medicine.

Though the review is nearly 50 years old, it also showcases a decades-long battle by the sugar industry to counter the product’s negative health effects.

The findings come from documents recently found by a researcher at the University of San Francisco, which show that scientists at the Sugar Research Foundation (SRF), known today as the Sugar Association, paid scientists to do a 1967 literature review that overlooked the role of sugar in heart disease.3

A pattern does appear to emerge does it not?

With my views on diet, and cholesterol, and heart disease, and suchlike, I have often been accused of being a conspiracy theorist – which is just another way of saying that I am clearly an idiot who should shut up. I simply smile at people who tell me this, and say nothing. However, my motto is that…‘Just because you’re paranoid, it doesn’t mean they are not out to get you.’ In the case of the High Fat Low Carb advocates, they are out to get you, and there truly is a worldwide conspiracy to attack any silence anyone who dares criticise sugar/carbs in the diet.

The attacks and distortions have not stopped with the ‘Harvard researchers’, or John Yudkin, or Gary Fettke or Tim Noakes, they continue merrily today. In the Sunday Times of April 23rd 2017 an article appeared, entitled ‘Kellogg’s smothers health crisis in sugar – The cereals giant is funding studies that undermine official warnings on obesity.’ Just to choose a few paragraphs.

One of the food research organisations funded by Kellogg’s is the International Life Sciences Institute (ILSI). Last year if funded research in the Journal Annals of Internal Medicine that said the advice to cut sugar by Public Health England and other bodies such as the World Health Organisation could not be trusted.

The study, which claimed official guidance to cut sugar was based on “low quality evidence”, stated it had been funded by an ILSI technical committee. Only by searching elsewhere for a list of committee members did it become clear that this comprised 15 food firms, including Kellogg’s, Coca-Cola and Tate and Lyle.

In 2013 Kellogg’s funded British research that concluded “regular consumption of cereals might help children stay slimmer.” The study, published in the Journal Obesity Facts relied on evidence from 14 studies. Seven of those studies were funded by Kellogg’s and five were funded by the cereal company General Mills.

And so on and so forth. Interestingly, no-one from the world of nutrition has suggested that Kellogg’s should be dragged into court for distorting data, trying to discredit honest researchers, and paying ‘experts’ to speak on their behalf. It is the Golden Rule, I suppose. He who has the gold, makes the rules.

This all has obvious parallels to the tricks the tobacco industry got up to over the years. They did everything they could to hide the fact that cigarettes cause heart disease and cancer. Now the sugar industry, and those selling low fat high carb products, are trying to hide the fact that sugar/carbs are a key cause of obesity and type II diabetes.

And the techniques used by the sugar/cereal/high carb companies are drearily familiar – and sadly still highly effective. As with Yudkin, Noakes and Fettke, go for the man, not the ball (discredit the person, not their data). Dismiss any damaging evidence that does manage to emerge as ‘weak’, pay your own experts to write bogus reports, and create uncertainty everywhere. Some people should be very ashamed of themselves indeed. Instead, I suppose, they are getting massive bonuses.

The nutrition society of South Africa said, in response to the Noakes judgement: “We are glad that the hearing has been finalised after almost three years, unless there is an appeal. The judgement, however, has absolutely no bearing on the current or future status of nutrition or the dietary guidelines in South Africa.’4 So there, nyah, nyah, nyah. Any apology to Tim Noakes? No. Any apology for wasting huge sums of money on a court case they lost? No. Just a threat that they may appeal. They are not going to change a thing.

So, whilst Tim Noakes won his case, any scientist looking on gets a very clear message. If you say things we don’t like, we will attack you and drag you through court and make your life a living hell for three years. Now, that is how you silence people, just as they silenced Yudkin nearly forty years ago.

 

1: http://www.telegraph.co.uk/lifestyle/wellbeing/diet/10634081/John-Yudkin-the-man-who-tried-to-warn-us-about-sugar.html

2: http://www.couriermail.com.au/news/national/surgeon-gary-fettke-banned-for-good-on-food-advice-by-regulatory-body/news-story/d973faa72dc64836f2209469a67592d5

3: https://www.theguardian.com/society/2016/sep/12/sugar-industry-paid-research-heart-disease-jama-report

4: https://www.pressreader.com/south-africa/the-sunday-independent/20170423/281681139761415