Category Archives: Cardiovascular Disease

The Lancet Study

11th December 2019

Several people have asked me to comment on a recent Lancet paper ‘Application of non-HDL cholesterol for population-based cardiovascular risk stratification: results from the Multinational Cardiovascular Risk Consortium.’ which made headlines around the world. Here – for example – from the BBC website:

What did the researchers find?

People should have their cholesterol level checked from their mid-20s, according to researchers. They say it is possible to use the reading to calculate the lifetime risk of heart disease and stroke.

The study, in The Lancet, is the most comprehensive yet to look at the long-term health risks of having too much “bad” cholesterol for decades. They say the earlier people take action to reduce cholesterol through diet changes and medication, the better.

They analysed data from almost 400,000 people from 19 countries and found a strong link between bad-cholesterol levels and the risk of cardiovascular disease from early adulthood over the next 40 years or more.

They were able to estimate the probability of a heart attack or stroke for people aged 35 and over, according to their gender, bad-cholesterol level, age and risk factors such as smoking, diabetes, height and weight, and blood pressure.

Report co-author, Prof Stefan Blankenberg, from the University Heart Center, Hamburg, said: “The risk scores currently used in the clinic to decide whether a person should have lipid-lowering treatment only assess the risk of cardiovascular disease over 10 years and so may underestimate lifetime risk, particularly in young people.” 1

The Daily Mail in the UK was a bit more excitable in its reporting

‘Adults ‘should have their cholesterol checked at 25’ because slashing it in the mid-30s can drastically reduce the risk of heart attacks and strokes

Researchers predicted huge 30-year risk profiles for heart disease and stroke, they found higher cholesterol in under-45s is more dangerous than in over-60s Even young people with healthy lifestyles ‘may benefit from knowing their risk.’ 2

My first thought, as always, is to look for the conflict of interest statement, just so you know how independent the researchers may be and make an estimate of potential bias.

My second thought was that this study did not look at cholesterol levels, or HDL levels, it looked at non-HDL cholesterol. An interesting thing to study. This is every form of liver derived lipoprotein that is not HDL, otherwise known as ‘good cholesterol’ or simply high-density lipoprotein.

Part of the reason for not looking at LDL, is that LDL is very rarely measured, or reported. Because the only way to measure LDL accurately is through ultracentrifuge, which is time consuming and expensive. Normally, the LDL levels are simply estimated using the Friedwald equation. To quote from the UK GP Notebook

‘… the ultracentrifugal measurement of LDL is time consuming and expensive and requires specialist equipment. For this reason, LDL-cholesterol is most commonly estimated from quantitative measurements of total and HDL-cholesterol and plasma triglycerides (TG) using the empirical relationship of Friedewald et al.(1972).

[LDL-chol] = [Total chol] – [HDL-chol] – ([TG]/2.2) where all concentrations are given in mmol/L (note that if calculated using all concentrations in mg/dL then the equation is [LDL-chol] = [Total chol] – [HDL-chol] – ([TG]/5))3

*TG = triglyceride

This means that the researchers will not have had any data on LDL levels for most people. The difficulty of directly measuring LDL is the reason why the risk calculators used in the UK and US do not even include LDL. These calculators are Qrisk3 https://qrisk.org/three/ and cvriskcalculator http://www.cvriskcalculator.com/

So, it is important to note that this was not a study on LDL levels. Instead, it was a study on non-HDL levels. Which changes it into something completely different than was reported. Obviously, non-HDL levels bear some relationship to LDL, in that a higher LDL level will tend to raise the overall non-HDL cholesterol level.

However, and very importantly, non-HDL also includes the triglyceride (TG) level. Or at least the TG level divided by 2.2. This is important because a high triglyceride (TG) level, divided by 2.2 or not, is a strong indicator of insulin resistance, which leads to type II diabetes. Here is what WebMD has to say on the matter

‘High TG’s signals insulin resistance; that’s when you have excess insulin and blood sugar isn’t responding in normal ways to insulin. This results in higher than normal blood sugar levels. If you have insulin resistance, you’re one step closer to type 2 diabetes.’ 4

Insulin resistance, whether or not it has developed into type II diabetes, greatly increases your risk of both CVD and overall mortality, as outlined in the paper. ‘Triglyceride–to–High-Density-Lipoprotein-Cholesterol Ratio Is an Index of Heart Disease Mortality and of Incidence of Type 2 Diabetes Mellitus in Men.’

‘This study shows that a high TG/HDL-C ratio in men is a predictor of mortality from CHD and CVD. The TG/HDL-C ratio had a significant and higher HR [hazard ratio] for mortality from CHD and CVD than was found for the TyG index [fasting blood sugar]. These 2 measures, TG/HDL-C ratio and TyG index, similarly predicted incidence of type 2 diabetes, but the HR associated with a high TG/HDL-C seems to make the ratio a preferred single parameter of measurement.’ 5

You will get no argument from me that a high triglyceride level is going to indicate the underlying metabolic catastrophe that is insulin resistance. This, in turn, is going to greatly increase the risk of CVD and early death. But this will have nothing to do with the LDL level. So, it has nothing to do with ‘bad’ cholesterol. Instead is to do with triglycerides.

Therefore, this study is like looking at people who smoke, and who eat red meat, then stating that red meat consumption and smoking cause lung cancer. You have arbitrarily rammed two things together without making any effort to decided which causes what. Scientific nonsense.

There also some massive statistical problems with this study. Where, for example is overall mortality? Not mentioned. Not mentioned means it will not have been significant. Also, the use of a very wide and fuzzy ‘combined end-point.’ I have written about this many times, in many different places. It is a game played to claim statistical significance, where none really exists.

To try and explain as quickly as possible. The most powerful end-point is overall mortality i.e. how many people were dead in either group. Or, to be more positive, how many people were alive in either group.

After this come end-points of decreasing importance. For example, how many people died of CVD. This is clearly important, but if more people died of CVD in one group, yet they were less likely to die of cancer, the overall mortality could remain the same in both groups – even if CVD mortality were lower in one.

Group one

  • CVD deaths 150
  • Cancer death 150
  • Total deaths/mortality 300

Group two

  • CVD deaths 180
  • Cancer death 120
  • Total deaths/mortality 300

Net benefit = zero. But such results can often be hailed as a massive success for, say, a drug. For example, the ‘FOURIER’ study on Repatha (injectable LDL lowering agent) was hailed as a great success, despite overall mortality being higher in the Repatha arm. How, you may think, was this possible?

Well, the Fourier study had five end-points. Known as a ‘combined end-point’. [Mortality was not one of them.] The primary end point was the combined total of:

  • Cardiovascular death
  • MI (myocardial infarction)
  • Stroke
  • Hospitalization for unstable angina
  • Coronary revascularization

How can you have five different end-points as a primary end point? Well, you just can… apparently. 6

What you may notice, or maybe not, is that three of these are clinical events: cardiovascular death, MI and stroke. Two of them are clinical decisions. To admit someone to hospital for unstable angina, and to carry out a coronary revascularisation. Revascularisation is, essentially, putting in a stent to keep a coronary artery open.

So, the second two end-points are potentially subject to significant clinical bias. If someone has a low non-HDL cholesterol level, the decision may well be to not admit to hospital for unstable angina, and to not carry out coronary revascularisation. Why, because the physicians think they are protected by their low cholesterol.

[Guess which end-point dragged the FOURIER study into statistical significance.]

You think that clinical decisions are all objective. Then ask yourself why all clinical trials, wherever possible, are double-blinded (neither the patient or the doctor knows who is taking the drug, or the placebo)? This double blinding is considered essential to remove clinical bias. No blinding, bias introduced.

Even if you look at MIs and strokes, this diagnosis is less certain than you might wish. I have had many patients where it is entirely unclear if they have actually had a stroke or a heart attack. With a small stroke it is often, simply a guess. Low cholesterol, I guess not a stroke. High cholesterol, I guess that it is.

Just in case you think I am now talking nonsense, as I was writing this blog, I was sent a BBC report of a clinical trial done on stents in the US, which stated that stents were as safe as bypass surgery, with regard to MIs. However, the researchers decided to use a completely different system for diagnosing MI…

‘The trial called Excel started in 2010 and was sponsored by big US stent maker, Abbott. It was led by eminent US doctor Gregg Stone and aimed to recruit 2,000 patients. Half were given stents and the other half open heart surgery. Success of the treatments was measured by adding together the number of patients that had heart attacks, strokes, or had died.

The research team used an unusual definition of a heart attack, but had said that they would also publish data for the more common “Universal” definition of a heart attack alongside it. There is debate around which is a better measure and the investigators stand by their choice.

In 2016, the results of the trial for patients three years after their treatments were published in the prestigious New England Journal of Medicine. The article concluded stents and heart surgery were equally effective for people with left main coronary artery disease.

But researchers had failed to publish data for the common, “Universal” definition of a heart attack. Newsnight has seen that unpublished data and it shows that under the universal definition, patients in the trial that had received stents had 80% more heart attacks than those who had open heart surgery.

The lead researchers on the trial have told Newsnight that this is “fake information7

When is a heart attack not a heart attack? When it is measured by investigators in the clinical study – who have financial conflicts of interest.

Another problem is that, if you carry out a coronary artery revascularisation, there is a fifty per cent chance of triggering a heart attack. Usually pretty small and not clinically significant – but an MI, nonetheless. So, for each two additional revascularisations, you may get one more MI. Which further skews the statistics. [Not an issue in the FOURIER study where only the first event was counted].

Anyway, I hope you are getting the general message that a quintuple combined endpoint is, primarily, nonsense. Full of potential bias, particularly in an observational study. As the Lancet study was.

Finally, because I have run out of energy to spend another minute looking at this study, there is the issue of Lipoprotein(a). Otherwise known as Lp(a). This too forms part of the non-HDL cholesterol measurement.

Lp(a) and LDL are identical apart from the fact that Lp(a) has an additional protein attached to the side called apolipoprotein(a). This protein has a critical role in blood clotting and therefore Lp(a) can be viewed as a pro-coagulant agent – makes the blood clot bigger and more difficult to break down. Higher levels have long been linked to an increased risk of CVD.

Just to choose one quote from many thousands of studies about Lp(a): ‘Lipoprotein (a) and the risk of cardiovascular disease in the European Population: results from the BiomarCaRE consortium.’

Elevated Lp(a) was robustly associated with an increased risk for MCE (major cardiovascular events) and CVD in particular among individuals with diabetes. 8

Yes, you will have spotted the link with diabetes a.k.a. insulin resistance. So, a higher triglyceride level, added to raised Lp(a), further increases the risk of CVD.

So, with non-HDL cholesterol and Lp(a) we have another massive confounding factors built into the measurement. Again, I absolutely cannot disagree that raised Lp(a) increases the risk of CVD. I have written about it many, many times. Non-HDL cholesterol is a measure that contains Lp(a) within it…. You probably get the drift by now.

The whole paper, in my opinion, is complete nonsense. Assumptions, built on bias, built on a measure that has nothing much to do with LDL, or ‘bad’ cholesterol. Zoe Harcombe did a more forensic dissection of the paper. I like her ending:

‘The researchers assumed that a 50% reduction in non-HDL cholesterol could and would be achieved. The researchers assumed that a mathematical formula for risk reduction could be applied to that assumed 50% reduction in non-HDL cholesterol. The researchers’ assumed formula included the variable “number of years of treatment” and hence the formula produced a higher number, the earlier treatment started. The assumptions made it so.

The final paragraph of the paper stated: “However, since clinical trials investigating the benefit of lipid-lowering therapy in individuals younger than 45 years during a follow up of 30 years are not available, our study provides unique insights into the benefits of a potential early intervention in primary prevention.”

No, it doesn’t.’

Yet, there was no controlled clinical trial data to back this all up. There are only models and assumptions. Yet it made headlines around the world, as such stuff always does. Not only that, it made the wrong headlines.

As the BBC website stated: ‘The study, in The Lancet, is the most comprehensive yet to look at the long-term health risks of having too much “bad” cholesterol for decades’ Bad cholesterol is the bonkers, unscientific term that is used to describe LDL. This study did not look at ‘bad’ cholesterol… Scientific journalism at is finest.

My analysis. Crumple, throw, bin… forget.

1: https://www.bbc.co.uk/news/health-50648325

2: https://www.dailymail.co.uk/health/article-7751603/People-cholesterol-checked-25-lowering-slash-heart-disease-risk.html

3: https://www.gpnotebook.co.uk/simplepage.cfm?ID=x20030114211535665170

4: https://www.webmd.com/cholesterol-management/diabetes#1

5: https://jim.bmj.com/content/62/2/345

6: https://ahajournals.org/doi/10.1161/CIRCULATIONAHA.118.034309

7: https://www.bbc.co.uk/news/health-5071515

8: https://academic.oup.com/eurheartj/article/38/32/2490/3752512

What causes heart disease – part 67 – The Blood Brain Barrier

10th November 2019

The Blood Brain Barrier

Here I am going backwards in time and space to try and explain, from a different angle, a fundamental problem with the LDL/cholesterol hypothesis. In doing so I hope to again make clear why I am certain the entire process of cardiovascular disease (CVD) requires a complete re-think.

In a medical school long, long ago, on a planet far, far, away, I was part of a small group teaching session on cardiology… Aberdeen 1980, actually. I have mentioned this event before, a critical moment in my life. The tutor was Dr Elspeth Smith, who was researching heart disease at the time. Research that, to my chagrin, I knew little about until several years later, when I began more detailed research into cardiovascular disease.

At one point in the tutorial, Dr Smith stated that LDL (low density lipoprotein) cannot get past, or through, the endothelium. At that time, I hadn’t much of a clue what LDL was, and very little idea about the endothelium. However, something about the intensity of her comment created an itch, one that I have spent very nearly forty years scratching.

I say this because, if LDL cannot get past the endothelium, then the widely accepted, and supposedly primary causal mechanism of heart disease, must be wrong!

Just to remind you that the central mechanism underpinning the ‘cholesterol hypothesis’ has always been that LDL leaks out of the blood past, or through, the endothelium, and into the arterial wall behind.

This then stimulates a whole series of downstream processes whereby you end up with thickenings in the artery wall narrowing the artery – known as atherosclerotic plaques. The higher the LDL level, the faster the leakage? I put a question mark there, because I don’t think I have ever seen this stated explicitly – I suppose it is implied as self-evident.

Clearly, however, if LDL cannot pass through the endothelium – the single layer of cells that lines all artery walls – then the ‘cholesterol hypothesis’ is a busted flush. Which is sort of interesting in a ‘hold the front page’ sort of fashion. ‘LDL hypothesis completely wrong – shock horror.’ Dr Elspeth Smith explains that LDL cannot get through the endothelium. Experts around the world, agree, and look for other explanations for heart disease.

This is a headline that I must have missed.

At this point you may be thinking, how do we get from LDL, and the endothelium, to the Blood Brain Barrier (BBB), which is the title of this blog. Well, are you sitting comfortably? Then I shall begin, at the end, with the blood brain barrier itself.

All doctors are taught there is a barrier between the bloodstream and the brain called the Blood Brain Barrier (BBB). Very few know what it actually consists of, other than that there is a barrier, of some kind, that prevents various things from entering the brain at will.

A barrier between the blood and the brain is critical because the brain is a highly delicate organ, which copes very badly with noxious substances, such as bacterial toxins. Which makes the BBB essential for life. However, it can become a problem if you have, for example, a brain tumour and the doctors want to give you chemotherapy. Because most anti-cancer drugs cannot get past the BBB. Some drugs can, most can’t.

However, a certain number of things must enter our brains, or we would almost instantly die. Glucose, for example. If our brain cannot get enough glucose, we go into a coma, then die. We also need amino acids (the building block of proteins), some fats and vitamins and suchlike.

Clearly, therefore, the BBB needs to be a selective barrier. It must block some things, but allow entry – and exit – of those substances that are required for brain function. Ethanol from malt whisky, for example, distilled from glucose. Well it is essential for my life anyway – in moderation obviously … obviously.

At this point you may be thinking, we are getting further and further away from LDL and heart disease, but please bear with me on this, because it does all come together at the end.

Next question, what is the BBB? The answer is that it is comprised of endothelial cells that are tightly bound to each other, and have a strong support structure underneath called the basement membrane. This membrane keeps the endothelial cells wrapped even more closely, further protecting them from any possible disruption.

This ‘tight’ binding of endothelial cells means that anything that wants to get into the brain must first pass through an endothelial cell. As you may imagine, this is an extraordinarily complicated and tightly controlled process. Substances in the blood cannot flow down a concentration gradient and straight through an endothelial cell.

LDL, for example, can only enter a cell, if there is an LDL receptor on the cell wall. The LDL links onto the receptor and then LDL and the receptor (the ‘LDL receptor complex’) is dragged inside the cell in a process known as ‘endocytosis.’

It does not matter what the concentration of LDL in the blood is – without a receptor, LDL is unable to gain entry to a cell. If it cannot get in, it cannot pass through. This is why the concentration of LDL becomes very high in Familial Hypercholesterolaemia (FH).

In this condition there is a lack of LDL receptors on all cells in the body, so LDL cannot easily enter cells, therefore the concentration in the blood rises very high.

Proof, if proof were needed, that LDL cannot ‘escape’ from the bloodstream and find refuge in the artery wall, or any other tissue. No matter what the concentration in the blood. Osmosis and/or diffusion of LDL through any cell is biologically impossible.

Therefore, getting back to the BBB, for substances to move through the BBB they first must be ‘endocytosed’ and then need to be shuttled through the cell via an active transportation system. This is known scientifically as ‘transcytosis.’ Literally, transport through the ‘cytoplasm’ where cytoplasm is the name for the jelly-like substance that fills up cells.

Once the substance has been transcytosed through the cell it must be ejected out through the cell membrane on the opposite side. Another complex process known as exocytosis.

Not everything needs a receptor to enter a cell. However, nothing gets in without the cell controlling the entry and exit. Even individual ions (charged atoms), tiny as they are, must pass through ‘gates’, or channels, to get into a cell. Calcium, sodium, potassium etc.

Their passage is carefully monitored and controlled. If this were not the case, you would instantly die. If a cell loses control of its internal environment it is either dying – or dead. See under, hyponatremic encephalopathy (for those with a scientific bent).

It has been argued that LDL molecules do not need to pass through endothelial cells, they can simply slip through the ‘cracks’ between endothelial cells. I have seen this argument used as to why ‘small dense LDL’ can cause CVD because, in this form, it is small enough to get through the cracks between the endothelial cells.

The problem with this hypothesis is that, first, small dense LDL is almost exactly the same size as normal LDL. Second, and most important, there are no cracks, or gaps, between the endothelial cells in our arteries – or the BBB. Endothelial cells in large arteries are bound together very tightly indeed. They are linked together by zips, buttons, and super-glue, then welded to create what is called a ‘tight junction’.

You can Google ‘tight junctions’ under ‘images’ to see how complex they are. There are over twenty protein bonds, sealing any gap shut. Tight junctions are so tight that they, too, can prevent the entry and exit of single ions. So, there is absolutely no way through for LDL here, either. For a quick size comparison, if a human were the size of an ion, an LDL molecule would proportionately be around the size of a super tanker.

In short, the idea that LDL can simply leak through the endothelium and into the artery wall behind requires that several key mechanisms – required for life – do not exist.

As I hope you can now see, Elspeth Smith was quite correct. LDL cannot pass through the endothelium. At least it cannot pass through a healthy endothelium, and nor can anything else either. Unless, unless the endothelium enables its passage.

Complication number one – yes, there is always a complication.

As blood vessels get smaller and smaller, like the branches on a tree, the endothelium changes dramatically. As arteries shrink down to became arterioles, then capillaries, the endothelium is no longer an impenetrable barrier.

In these very small blood vessels, the endothelium develops holes (fenestrations). Gaps also appear between individual endothelial cells, and the supporting basement membrane becomes loose. What you have is more like a sieve than a castle wall.

This ‘sieve like’ quality allows substances to move in and out of arterioles and capillaries, almost at will. Which, of course, makes perfect sense. There is little point in blood arriving at, say, the kidneys, where various waste products are removed, if it was all stuck behind an impenetrable endothelial barrier. The blood would flow into your kidneys, then flow out again, unchanged. This is not a good recipe for life.

So, yes, in the very small blood vessels, the endothelium allows the free passage of substances. But absolutely not in the larger blood vessels. If the blood simply leaked out as it passed through larger blood vessels, it would never reach the smaller blood vessels, nor get back to the heart again. It would be like having a garden hose that was full of holes along its entire length. Nothing would reach the sprinkler head.

Anyway, bringing some strands together here, the endothelium lining the large arteries has the same impenetrable structure as the endothelium lining the BBB, and therefore represents a barrier. Substances just cannot leak through this – and that includes LDL.

But can things be transcytosed through? More specifically, can LDL transcytose through it? Because, if it can, this would be a possible mechanism in support of the cholesterol hypothesis. Although, once again, you have to ask the question, why would the body have a system for actively transporting LDL through the endothelium and into the artery wall underneath. What would be the purpose of such a system? To cause atherosclerosis?

The mystery of this question is further deepened by the fact that the larger blood vessels in the body are supplied with nutrients via their own, small, blood vessels known as vasa vasorum. Literally, blood vessels of the blood vessels. These are arterioles, and capillaries, that penetrate/permeate the vessel wall.

These very small blood vessels, lying within the artery wall, have fenestrations (holes) and loose junctions that allow the free movement of LDL – in an out of artery walls. So, any LDL in the bloodstream can quite easily enter the artery – and exit the artery (and the veins) – without having to cross any barrier at all.

Which raises a further conundrum for the cholesterol hypothesis. Why would LDL that enters the artery wall, via the vasa vasorum, cause no problems. Whilst the LDL – that is claimed to enter the artery wall by forcing itself past the endothelium – creates atherosclerotic plaques. Same artery wall, same LDL.

Which then raises another question. Why do atherosclerotic plaques only form in artery walls? Why not everywhere else, within every other organ and tissue in the body. If LDL, once it leaves the bloodstream, is so destructive, acting as the focus for plaque development, why doesn’t it cause plaques within the liver, or the kidneys, or the muscles, or the gut. Only, it seems, in artery walls. [Please don’t say xanthelasma, until you have thought very carefully about it]

Strange…

But to get back on track. I wanted to see if I could answer a final question. We know that LDL cannot simply flow through endothelial cells, nor can it squeeze between non-existent gaps. But can it be actively transported through? Because, if it cannot, then this is the final nail in the cholesterol hypothesis. There is, literally, no way past. Elspeth Smith was quite correct.

[Other than via the vasa vasorum, obviously. However, veins have more vasa vasorum than arteries, so this if this is the route for LDL to enter blood vessel walls, then veins should have more atherosclerosis than arteries, which they do not. In fact, veins never develop atherosclerosis – ever.]

So, deep breath.

I wanted to know if LDL could get past the BBB. If not, then it could not get past the endothelium in the larger arteries either, end game. This is the sort of question to which you would think there should be a straightforward, yes or no answer. It took me a long time to find a definitive answer.

I did know that the brain manufactures its own cholesterol, because cholesterol is absolutely vital for brain function. Neurones are wrapped in myelin/cholesterol sheaths. New synapses have a very high proportion of cholesterol in them, and animal work has shown that – without cholesterol – new synapses cannot be made.

‘Brain cholesterol accounts for a large proportion of the body’s total cholesterol, existing in two pools: the plasma membranes of neurons and glial cells and the myelin membranes  Cholesterol has been recently shown to be important for synaptic transmission, and a link between cholesterol metabolism defects and neurodegenerative disorders is now recognized.’ 1

This ‘brain’ cholesterol is synthesized in support cells, known as glial cells. These cells surround neurones and nourish neurones, and the cholesterol is transported about in its own lipoprotein called Apo E.

So, on initial analysis, it did seem unlikely that the brain would have developed its own, specific, cholesterol manufacturing capability if it could simply absorb it from the bloodstream. As it turns out, and as I eventually discovered, the brain cannot absorb LDL from the bloodstream.

‘… the blood brain barrier (BBB) prevents the uptake of lipoprotein-bound cholesterol from the circulation.’ 1

In quick summary here, the brain requires cholesterol, yet the BBB prevents it from entering the brain. Which means that an intact endothelium can completely block the passage of LDL Which means that LDL cannot get past, or through, the endothelium. Elspeth Smith was quite right.

But what did she think caused CVD, or atherosclerosis, or atherosclerotic plaques – or whatever term is currently in vogue? Well, this is one thing that she wrote about the matter:

‘After many years of neglect, the role of thrombosis in myocardial infarction is being reassessed. It is increasingly clear that all aspects of the haemostatic (blood clotting) system are involved: not only in the acute occlusive event, but also in all stages of atherosclerotic plaque development from the initiation of atherogenesis to the expansion and growth of large plaques.’ 2

She believed, as I have been trying to outline for a few years now, that to start atherosclerosis, you need to damage the endothelium, then a blood clots forms, then we are on the pathway to the final occlusive thrombosis (a blood clot that completely blocks an artery).

She believed, as I believe, that LDL has no part to play in this process. It does not, because it cannot. If you believe in the ‘thrombogenic’ hypothesis, you cannot believe in the LDL hypothesis, and vice-versa.

Which hypothesis is correct?  Well, it is certainly true that the LDL hypothesis is currently in the ascendancy. But science is not, thankfully, a popularity contest like Strictly Come Dancing. Science is built on facts. Well, it is eventually. The fact is that the LDL hypothesis requires a central fact to be true but which can be proven to be wrong.

Elspeth Smith proved it to be wrong over fifty years ago, but no-one was listening. She was a hero, and I intend to do all that I can to ensure that it is her name, not that of Ancel Keys, that will echo through the history of CVD research. Because she was a true scientist. Whereas he….

Next time, why LDL also cannot damage the endothelium.

1: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4837572/#:~:text=The%20CNS%20cholesterol%20is%20transported,%2C%2039%20kDa)%20and%20lipids.&text=Lipid%2Dpoor%20particles%20(for%20example,ApoE%20levels%20in%20the%20brain.

2: https://www.sciencedirect.com/sdfe/pdf/download/eid/1-s2.0-0049384894900493/first-page-pdf

What causes heart disease – a summary

9th October 2019

But not by me

Following a podcast by Ivor Cummings, where I bored him for an hour and a half on what causes CVD*, a journalist that I know well, Jerome Burne, had a go at summarising the ‘thrombogenic’ hypothesis. I thought this was brave of him. I consider him a friend and an ally.

Of course, this is the Readers Digest version and, by necessity, misses out a great deal of the detail. However, I would be grateful if readers of this blog, go have a look on Jerome’s site and see what you think. Leave comments if you feel the urge.

I told him that I could not really comment on it, because I know this whole are so well that I cannot look at it the way a naïve reader could. Or, to put it another way, does it make any sense to an interested and intelligent reader coming across these ideas for the first time.

The blog can be found here: http://healthinsightuk.org/2019/10/08/cholesterol-is-innocent-how-the-real-killers-were-tracked-down/

*Ivor Cummings/Fat emperor podcast:

Or you can view it on Ivor’s site here

What causes heart disease part 66

5th October 2019

How does lead cause CVD?

Following my last blog, several people asked the question. How does lead cause CVD – or atherosclerotic plaques? What is the mechanism of action? It’s a good question, one that I think I have answered before, at least in part. However, I think there is real value in going over it again.

First, I want to highlight some of the more general thinking about causes of CVD, I believe this is important as well, in order to see how lead fits in, and where my interest in lead came from.

For many, many, years now I have been trying to create a unified hypothesis about cardiovascular disease. A journey I thought I would never finish. Mainly, I now realise, because I kept coming across ever more ‘factors’ that had a role in CVD. This meant that – although I couldn’t quite work out why at first – I was running into the impossible, and unsolvable, problem.

246 factorial

The unsolvable problem is a direct result of the number of possible interactions between all the risk factors that have been identified.

To try and explain this further, I shall start with the latest UK risk factor calculator which is called Qrisk3. The previous one was Qrisk2. Qrisk3 can be found on-line here https://qrisk.org/three/ You can play with it to your heart’s content. Qrisk3 has moved on considerably from Qrisk1 and 2. It now incorporates twenty different factors.  If you strip them out of the algorithm they are, in no particular order:

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

As a quick side-track, it amuses me that LDL is not in there – yet HDL is.

Now, you may think that this appears to be a relatively short list. At first sight it does not appear a complex task to fit these factors together into a coherent model. A twenty-piece jigsaw puzzle – at most?

Not so. The reality is that, if you view the model of CVD as twenty independent and unconnected risk factors, the number of possible interactions, or pieces, you need to analyse becomes mind-boggling.

Just to give you an idea of the scale of the maths involved here. You have twenty different risk factors, and you do not know how the connections between them work. Every risk factor can, potentially, interact with all the others – independently. This means that the possible combinations you must analyse is twenty factorial.

Calculating factorials is, on one hand, very straightforward. You simply multiply each factor, by all of the other factors, in turn. Thus, twenty factorial = 20 x 19 x 18 x 17 x 16 etc.

The result of multiplying 20 x 19 x 18 x 17 x 16 etc. is you end up with the following number: 432,902,008,176,640,000. Which is the number of different possible combinations between twenty factors. Rounding this figure up slightly, that equates to four hundred and thirty-three quadrillion. Which is a lot. And it gets far worse than that.

As far back as 1981, a paper was published outlining 246 different risk factors involved in CVD 1. Today, there would be far more, several thousand at least. However, even by 1981 the number of possible combinations was already incomprehensibly huge. I say this because 246 factorial is:

980360372638941007038951797078339359751464353463061342202811188548638347461066010066193275864531994024640834549254693776854464608509281547718518965382728677985343589672835884994580815417004715718468026937051493675623385569404900262441027874255428340399091926993707625233667755768320823071062785275404107485450075779940944580451919726756974354635829128751944137276448671023801110260206915547825809239994946405007360000000000000000000000000000000000000000000000000000000000

Yes, to my amazement, there is a website which will calculate factorials for you. You don’t think I worked that out myself do you? I would have definitely got bored and made several mistakes on the way. Therefore, I have no idea if this figure is right or wrong, but it seems to be in the right sort of ballpark.

There is no way to even describe a number that big, and it would certainly make for some jigsaw puzzle. In truth what we have here represents a figure so huge that you cannot possibly do anything with it. It has fifty-seven zeros before you even get to another number. At least I think it is fifty-seven, I may have lost count.

How long would it take to feed in the data on all these risk factors, run the combinations, and see if you can establish how they all fit together? That would take as close to an infinite amount of time as makes no practicable difference. Even with the latest Google quantum computer.

Thinking about things in this way, I came to realise that unearthing risk factor, after risk factor, after risk factor, was not going to make it easier to work out the cause of CVD. It was making it impossible.

The other word for impossible, I came to realise, is ‘multifactorial’.

Multifactorial = a word commonly used by cardiologists to prevent any discussion as to the real causes of CVD. In conversation on this issue, I silently change the word multifactorial to ‘246-factorial’, just to remind myself what a stupid concept it is to call a disease multifactorial. Then to believe that, by doing so, you have explained anything. ‘So, how do the factors all fit together?’ I mutter, imaging a number so vast that it is beyond comprehension.

Then I may quote Poincaré at them.

Science is built up of facts, as a house is built of stones; but an accumulation of facts is no more a science than a heap of stones is a house.’ Henri Poincaré.

Because multifactorial also effectively = a pile of stones. Well done, you have found thousands of stones, and carefully piled them ever higher, but this gets no nearer to constructing a house. To build a house you need to know how all the stones join up. You need a plan my friend.

Which starts to bring me, in a roundabout way, back to lead.

As regular readers of this blog will know, I ripped up the multifactorial model of CVD and tried to replace it with a process model. The plan of the house, if you like. I was no longer interested in finding endless risk factors, then chucking them on the pile. I wanted to know the process – or processes – involved.

In the end I stripped it down to three main elements. Basement, walls, roof.

  • Endothelial damage (damage to the lining of artery walls)
  • Formation of a blood clot
  • Repair

Or at least I stripped it down to three main processes – going wrong. Because this triad is all quite normal, and healthy. It is only when endothelial damage and clot formation accelerate, or repair is sub-optimal, that CVD/atherosclerosis will develop.

So, the simplest possible model is: rate of damage > rate of repair = CVD

Using the three-process model I began a different search. Starting with things that could damage the endothelium. I cast the net far and wide. Of course, it is more difficult to do the searching this way. Where do I begin? Do you just start thinking of things that might be damaging, and hope for the best? You will find yourself wandering all over the place. At least I did. Although it is quite an interesting journey – for a geek.

Bringing some structure into my search strategy, I decided that heavy metals were something that could not be doing any good to the human body. Mercury, lead, cadmium, and suchlike. Gold? Gold doesn’t seem to do much, one way or another. It was used to treat rheumatoid arthritis at one time. As for the others – not great. Lots of damage to health.

But do they damage the endothelial lining of the artery wall? Well, yes, they do. Looking at lead, here is a passage from the paper: ‘Mechanisms of lead-induced hypertension and cardiovascular disease.’

I admit that it is far too jargon heavy for most people. But I enjoyed it and I reproduced it in full because, what we have here, is the perfect storm. Many mechanisms I have previously mentioned in my long and winding series on what causes heart disease can be found here. Including many I did not mention because they were just too technical. I have put in bold some of the more important mechanisms:

‘Lead is a ubiquitous environmental toxin that is capable of causing numerous acute and chronic illnesses. Population studies have demonstrated a link between lead exposure and subsequent development of hypertension (HTN) and cardiovascular disease. In vivo and in vitro studies have shown that chronic lead exposure causes HTN and cardiovascular disease by promoting oxidative stress, limiting nitric oxide availability, impairing nitric oxide signaling, augmenting adrenergic activity, increasing endothelin production, altering the renin-angiotensin system, raising vasoconstrictor prostaglandins, lowering vasodilator prostaglandins, promoting inflammation, disturbing vascular smooth muscle Ca2+ signaling, diminishing endothelium-dependent vasorelaxation, and modifying the vascular response to vasoactive agonists. Moreover, lead has been shown to cause endothelial injury, impede endothelial repair, inhibit angiogenesis, reduce endothelial cell growth, suppress proteoglycan production, stimulate vascular smooth muscle cell proliferation and phenotypic transformation, reduce tissue plasminogen activator, and raise plasminogen activator inhibitor-1 production.’ 2

So, there you go. Not just one mechanism of action, but twenty-one different processes that lead can cause CVD. Fifteen ways of damaging the endothelium, four that inhibit repair, and two mechanisms for making blood clots more difficult to get rid of, as highlighted in the final passage… reduce tissue plasminogen activator, and raise plasminogen activator inhibitor-1 production.’

Tissue plasminogen activator (TPa) is the enzyme that activates the breakdown of blood clots. TPa converts plasminogen to plasmin, and plasmin then chops fibrin to bits, thus shaving down blood clots. Plasminogen activator inhibitor-1 is a substance that inhibits the action of tissue plasminogen activator (TPa = the clot buster, often given to patients after a heart attack or stroke).

Clearly, if you reduce TPa, and increase TPa inhibition, you end up with a blood clot that is very difficult to get rid of and is thus more damaging.

So, when people ask, have you got a mechanism of action to explain how lead causes CVD I say (rather smugly), no, I have got twenty-one. In truth, I have found quite a few more, but twenty-one is probably enough to be getting on with. One thing I have found is that once you start looking at all the potential processes, there seems almost no end to this stuff. It stretches in all directions.

Big fleas have little fleas upon their backs to bite ’em,

And little fleas have lesser fleas, and so, ad infinitum.

And the great fleas, themselves, in turn, have greater fleas to go on;

While these again have greater still, and greater still, and so on

Anyway, getting back on track, I started to look for factors, causal agents, whatever is the best name for them, that can impact on one of three processes:

  • Endothelial damage (damage to the lining of artery walls)
  • Formation of a blood clot
  • Repair

This is how I got to lead, only to discover that there was a huge body of research linking lead to CVD… that I had been completely unaware of. My analogy was that of a round the world sailor bumping into Australia and wondering why no-one had bothered to tell him it was there. ‘It’s pretty big, you know.’

Looking at things, by starting with one of the three processes, is also how I came across the evidence on sickle cell disease (SCD). I reasoned that sharp pointy red blood cells (sickled cells) hammering through the blood vessels would create serious damage to endothelial cells.

When I started looking, I found that, in some studies, SCD increases the (relative risk) of CVD by fifty thousand per cent. Yes, you did read that right. Fifty thousand per cent. With none of the other ‘established’ risk factors present.

Which makes SCD a ‘sufficient’ cause of CVD. In fact, it is the only sufficient cause I have ever found – in that it can lead to atherosclerosis in the blood vessels in the lungs, where the blood pressure is pretty low.

Which means that, with SCD, you don’t even need a high blood pressure. SCD can cause CVD all by itself. If you can find any other factor that can do that – let me know. For a more in-depth discussion on causation, and the concept of ‘sufficient’ see this article: https://jech.bmj.com/content/55/12/905.long

Then, I thought, what else causes damage to the endothelium. I ended up looking at a group of diseases known as ‘vasculitis’. Itis means, inflammation, as in tonsillitis, appendicitis. So, vasculitis means inflammation of the vascular system, by which I mean inflammation of the lining of the blood vessels. By which I mean, damage (and repair) to the lining of the blood vessels. Remember, inflammation = repair.

There are many different forms of vasculitis, most of which are not really thought of as being ‘vasculitis.’ For example, Rheumatoid arthritis, and Systemic Lupus Erythematosus. These conditions cause inflammation in many different places, but they also cause vasculitis. You may have noticed that both also appear on the Qrisk3 calculator.

Other forms of vasculitis, or diseases where vasculitis is an important part of the spectrum of abnormalities include:

  • Scleroderma
  • Sjogren’s
  • Erythema nodosum
  • Takayasu’s arteritis
  • Kawasaki’s disease

I think they all have great, evocative names:

All these forms of vasculitis are associated with a greatly increased risk of CVD. You can look this up yourself, if you want. In fact, children who suffer Kawasaki’s can die of myocardial infarctions (MIs), aged five. They have a brief, super-accelerated, form of endothelial damage that lasts a few weeks. Some can then end up with large aneurysms (balloon-like swellings) in their coronary arteries. These can burst, causing a MI.

So, not an entirely conventional MI. Nor conventional atherosclerosis. However, if you think of an aneurysm as a late stage abnormality in atherosclerosis [which most are] then in Kawasaki’s we can get from endothelial damage, to an aneurysm, in a month. Something that normally takes about sixty years to develop.

Three stones to make a wall

Lead, sickle cell disease, vasculitis.

In one sense it could be said that I have been discussing three completely unrelated things here. Lead, sickle cell disease, vasculitis. In another sense I hope you can see that these three ‘factors’ are related to CVD. Not by what they are, but by what they do. The damage they cause… the process.

They all fit very neatly into the walls of the house that are called ‘endothelial damage’. How else can you explain how three such disparate things can possibly cause exactly the same disease.

I must admit that this breakthrough in my thinking, from causes to process, was not mine. It was entirely due to one man. Professor Paul Rosch. We were discussing stress (strain) and CVD and he was critiquing a presentation I had given.

I shall paraphrase his comment. ‘Very good, you have given us the what, but not the how.’ Yes, very simple, when you think of it that way. What he was really asking was, what is the process? Since then, I have often wondered why have others not gone down this route?

I then realised that the problem, the great problem in all research into CVD, is that very early on it was decreed that LDL/cholesterol causes CVD. Therefore, all thinking, and any hypothesis on CVD required that LDL sat at the centre.

To my mind this is like opening a two-thousand-piece jigsaw puzzle and deciding, straight away, that one big piece – LDL/cholesterol – sits at the centre, and the other pieces must be made to fit around it.

Well, perhaps it does have a (small role) to play in CVD, but it most certainly does not sit and the centre. But if you keep it there, you distort the entire puzzle and make it impossible to complete. The pieces must be forced into place. Hammered down, or twisted into extreme shapes.

This, though, is where CVD research currently sits. Thousands of pieces are lying about the board. A few of them have been fitted together, here and there. As for the whole puzzle, it is doomed to failure, because the wrong piece is taking up the key position. Unfortunately, if you are a ‘serious’ CVD researcher, who wants to get grants for research, you can’t move it.

What I found if that you chuck that piece away, and start again, then everything becomes clear. The puzzle can be made to fit into one of these three processes:

  • Endothelial damage (damage to the lining of artery walls)
  • Formation of a blood clot
  • Repair

Lead, for example. Lead makes no sense as a significant risk factor using conventional thinking. It doesn’t raise BP, it doesn’t raise LDL, it doesn’t cause diabetes, it simply does not fit. So, it has become, essentially, ignored. But how can you ignore something that may be responsible for four hundred thousand deaths per year, in the US alone? Most of them CVD deaths?

The answer is that you cannot.

1: https://www.atherosclerosis-journal.com/article/0021-9150(81)90122-2/abstract

2: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2519216/

What causes heart disease part 65 – Lead again

23 September 2019

Lead again

I am returning to lead, the heavy metal. Not the verb to lead, or a noun – such as a dog lead. Yes, English is complicated, with the same word meaning several different things, which can lead to confusion.

I am indebted to Leon Vd Berg for bringing my attention to another paper about lead that I had missed. Which is slightly surprising as I tend to look for such papers. However, such is the daily avalanche of medical publications that it is literally, impossible to keep up.

There are several things about the paper that I found fascinating. However, the first thing that I noticed was that…. it hadn’t been noticed. It slipped by in a virtual media blackout. It was published in 2018, and I heard nothing.

This is in direct contrast to almost anything published about diet. We are literally bombarded with stories about red meat causing cancer and sausages causing cancer and heart disease, and veganism being protective against heart disease and cancer, and on and on. Dietary articles often end up on the front page on national newspapers.

Here is one such headline from the Daily Mail 7th August 2019

‘Eating chicken instead of steak, lamb or sausages ‘slashes a woman’s risk of developing breast cancer by 28%’

Mind you, here is another headline from the Daily Mail 8th Sept 2019

Chicken ’causes cancer’: Oxford University scientists say people who eat poultry are at increased risk of developing deadly disease.’

Tricky thing eating chicken. It can cause and prevent cancer simultaneously. You read it here first.

However, the point I wish to make is not so much the utter nonsense and constant contradictions of dietary studies. Nor is it the fact that the increased, and decreased risk in such studies, is minute. Sitting well within the boundaries of reasonable chance. Which is why you keep getting contradictory studies.

Researcher one:      ‘I just threw a head – all throws of a coin must be heads.’

Researcher two:       ‘No, sorry, I just threw two tails – most throws of a coin end up tails

Researcher one:      ‘Hold on, forget your tails, I just go four more heads – in a row – most throws end up heads, not tails.’

The correct term for this is idiot research, and those who do it are – primarily – idiots. However, none of this nonsense is really important. The point I am trying to make here is that this type of dietary research hogs the limelight.

It seems that whatever else Ancel Keys did not achieve – scientific truth and accuracy, for starters – he most certainly did manage to convince almost everyone in the World that diet is the single most critical important factor for health.

In years gone by, people ate food because they enjoyed eating it. This still happens in France. Imagine that. Nowadays every meal comes with implied fearmongering, and high-level criticism. Are you destroying the world or not – you evil scum.

‘Hold on, it’s only a bacon sandwich. With a fried egg and a bit of cheese grated on top…. Yes, I suppose you’re right, I am personally responsible for the destruction of the Amazonian rain forest. Forgive me father, for I have sinned.’

Destruction of the planet is only one aspect of eating, it’s also destruction of your health – with added moral judgement. If you go to Slimming World, you can eat various tasteless stuff, but you are allowed ‘sins.’ A sin would be something you really like eating, but it is so deadly, that it is a sin to eat it. Chocolate, for example. Get thee behind me Satan.

I don’t understand how anyone manages to eat anything nowadays. I have almost given up eating salads because someone will always remark ‘Oooooh, that’s healthy.’

My reply used to be. ‘I am not eating it because it is healthy, I am eating it, because I enjoy it.’ Nowadays I just grunt in a vaguely non-threatening way. I do not say. ‘No, a healthy meal would be a full English breakfast with bacon, eggs, sausages, fried bread. a few more sausages and a bit of lard melted on top.

I do not say this because, in truth, almost all diets are perfectly healthy. Vegetarian, paleo, keto, vegan (with a few essentially nutrients thrown in, so you don’t die), HFLC, etc. In fact, the only non-healthy diet would be the one recommended by all the experts around the world.

Namely, High carb, low fat (HCLF). The ‘eat well plate’, ‘the food pyramid’ – whatever it is now called. Stay away from that, and you will be fine.

Rule one of diet.       Everything the ‘experts’ recommend, is wrong.

Rule two:                   Eat food you enjoy – and enjoy eating

Rule three:                Eat food that looks like food

Rule four:                   Cook your own meals – when possible

Rule five:                   Try fasting from time to time

Rule six:                     That’s it

Where was I? Oh yes, lead. The heavy metal. The thing that, unlike diet, makes no headlines whatsoever, the thing that everyone ignores. Here is one top-line fact from that study on lead, that I missed:

‘Our findings suggest that, of 2·3 million deaths every year in the USA, about 400 000 are attributable to lead exposure, an estimate that is about ten times larger than the current one. 1

Yes, according to this study, one in six deaths is due to lead exposure. I shall repeat that. One in six. Eighteen per cent to be exact, which is nearer a fifth really.

Of course, this study is observational, with all the usual caveats associated with such studies. Indeed, many people commenting on this blog have stated that correlation [found in such studies] does not mean causation. I think you will find that this does not include me – although I may have said it by mistake. It is true that correlation does not mean causation, up to a point. However, once that point has been reached, causation can be considered proven.

For example, in observational studies, smokers were found to have fifteen times the risk of lung cancer. That is a powerful enough correlation to prove causation – beyond any reasonable doubt. There is no point in setting up a controlled clinical trial to prove this. In fact, any such trial would be completely unethical.

The question is, at what level of increased risk/correlation can causality be accepted. There is no absolute clear-cut answer to this Life ain’t black and white. However, most epidemiologists will tell you that unless the odds ratio (OR) is above two, you cannot attempt to claim causality. Too much noise, too many possible confounders.

Which means (deep breath, waiting for statisticians to attack this mercilessly) you need to find that a ‘factor’ is associated with at least a doubling of risk, before you do not simply crumple up the published paper and throw it in the bin.

Most dietary studies get absolutely nowhere near two. We have risks such as one point one (1.10), or one point three. One point three (1.3) is a thirty per-cent increase in risk. Here for instance is a review of red meat and colo-rectal cancer

‘As a summary, it seems that red and processed meats significantly but moderately increase CRC risk by 20-30% according to these meta-analyses.’  2

Figures like this, from an observational study, mean only one thing. Crumple, throw, bin. Remember also, they are only looking at one form of disease colo-rectal cancer (CRC).  The impact on overall mortality (the risk of dying of anything) would be minuscule, if it could even be found to exist at all. Of course, overall mortality is not mentioned in that CRC paper. Negative findings never are.

So, on one side, we have papers (that make headlines around the world) shouting about the risk of red meat and cancer. Yet the association is observational, tiny, and would almost certainly disappear in a randomised controlled trial, and thus mean nothing.

On the other we have a substance that could be responsible for one sixth of all deaths, the vast majority of those CVD deaths. The odds ratio, highest vs lowest lead exposure, by the way, depending on age and other factors, was a maximum of 5.30 [unadjusted].

Another study in the US found the following

‘Cumulative lead exposure, as reflected by bone lead, and cardiovascular events have been studied in the Veterans’ Normative Aging Study, a longitudinal study among community-based male veterans in the greater Boston area enrolled in 1963. Patients had a single measurement of tibial and patellar bone lead between 1991 and 1999. The HR for ischemic heart disease mortality comparing patellar lead >35 to <22 μg/g was 8.37 (95% CI: 1.29 to 54.4).’ 3

HR = Hazard Ratio, which is similar, if not the same to OR = Odds Ratio. A Hazard Ratio of 8.37, means (essentially) a 737% increase in risk (Relative Risk).

Anyway, I shall repeat that finding a bit more loudly. A higher level of lead in the body leads to a seven hundred and thirty-seven per cent increase in death from heart disease. This is, in my opinion, correlation proving causation.

Looking at this from another angle, it is true that smoking causes a much greater risk of lung cancer (and a lesser but significant increase in CVD), but not everyone smokes. Therefore, the overall damage to health from smoking is far less than the damage caused by lead toxicity.

Yet no-one seems remotely interested. Which is, in itself, very interesting.

It is true that most Governments have made efforts to reduce lead exposure. Levels of lead in the children dropped five-fold between the mid-sixties and the late nineties. 4 Indeed, once the oil industry stopped blowing six hundred thousand tons of lead into the atmosphere from vehicle exhausts things further improved. Lead has also been removed from water pipes, paint, and suchlike.

However, it takes a long old time from lead to be removed from the human body. It usually lingers for a lifetime. Equally, trying to get rid of lead is not easy, that’s for sure. Having said this, chelation therapy has been tried, and does seem to work.

‘On November 4, 2012, the TACT (Trial to Assess Chelation Therapy) investigators reported publicly the first large, randomized, placebo-controlled trial evidence that edetate disodium (disodium ethylenediaminetetraacetic acid) chelation therapy significantly reduced cardiac events in stable post–myocardial infarction (MI) patients. These results were so unexpected that many in the cardiology community greeted the report initially with either skepticism (it is probably wrong) or outright disbelief (it is definitely wrong).3

Cardiologists, it seems from the above quotes, know almost nothing about the subject in which they claim to be experts. Just try mentioning glycocalyx to them… ‘the what?

Apart from a few brave souls battling to remove lead from the body, widely derided and dismissed by the mainstream world of cardiology, nothing else is done. Nothing at all. We spend trillions on cholesterol lowering, and trillions on blood pressure lowering, and more trillions on diet. On the other hand, we do nothing active to try and change a risk factor that kicks all the others – in terms of numbers killed – into touch.

Funny old world. Is it not?

Next time, back to diet, because everyone knows how important diet is…. Only joking.

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

2: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4698595/

3: https://www.sciencedirect.com/science/article/pii/S0735109716015989

4: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1240871/pdf/ehp0110-000563.pdf

Diet and heart disease – again!

April 25th 2019

Thank you to those of you enquiring after my health. I have had a horrible cough and cold and proper ‘man flu’ for the last couple of weeks, now settling. Before that, skiing, before that lecturing. But enough about me.

Over the last few weeks I have watched a flurry of activity from all directions, as the attacks on red meat and saturated fat intensify. Walter Willett must be writing up a new research paper every five minutes, such is the wealth of material he has cascaded down upon a grateful world in recent weeks (I suspect others may be doing much of the heavy lifting on his behalf).

It also seems that the Lancet has given up any pretence of being an objective seeker of the truth. Instead, the Lancet appears to have become a mouthpiece for the vegan movement. Here is what the Lancet has to say about their new EAT-Lancet project.

‘Food systems have the potential to nurture human health and support environmental sustainability; however, they are currently threatening both. Providing a growing global population with healthy diets from sustainable food systems is an immediate challenge. Although global food production of calories has kept pace with population growth, more than 820 million people have insufficient food and many more consume low-quality diets that cause micronutrient deficiencies and contribute to a substantial rise in the incidence of diet-related obesity and diet-related non-communicable diseases, including coronary heart disease, stroke, and diabetes. Unhealthy diets pose a greater risk to morbidity and mortality than does unsafe sex, and alcohol, drug, and tobacco use combined. Because much of the world’s population is inadequately nourished and many environmental systems and processes are pushed beyond safe boundaries by food production, a global transformation of the food system is urgently needed.’1

Many out there probably agree with much of this statement, especially the parts about environmental sustainability and insufficient food to feed many people. However, even if you do, you have to ask what an investigative medical journal is doing in this space. There is no longer even an attempt to be mildly objective. The Lancet has simply taken sides. Which is the exact opposite of what any scientific journal should ever, ever, do. You may notice that Professor Walter Willett was the lead author of the article quoted above

Here is one statement that I would like to further highlight. Unhealthy diets pose a greater risk to morbidity and mortality than does unsafe sex, and alcohol, drug, and tobacco use combined.’

At this point I completely part company with Walter Willett. For it is the most complete and absolute nonsense. For a start, how did he calculate the figures? For example, sexually transmitted disease – and death. How many people die of this? How many people suffer, and by how much? Do we have any idea?

Well, we know that many children die from congenital syphilis. How many around the world? I checked the WHO publications on this, and there are only estimates to be had. HIV? Gonorrhoea? Hundreds of millions that are infected, and affected, but how many millions? How many deaths? Unknown really.

We can perhaps be a little clearer on the other things such as cigarette smoking. Just looking at one country, the US:

‘Cigarette smoking is responsible for more than 480,000 deaths per year in the United States, including more than 41,000 deaths resulting from secondhand smoke exposure. This is about one in five deaths annually, or 1,300 deaths every day.’ 2

The US population is around three hundred million. The population of the world around seven billion. If 480,000 deaths a year occur in the US, this would equate to eleven million deaths a year around the world.

Alcohol?

Around the world, about 1 in 5 adults were estimated to drink heavily in any given 30-day period. The burden of ill health for alcohol was less than for tobacco, but still substantial: 85.0 million DALYs [Disability adjusted life years]. Alcohol-related illness was estimated to cause 33.0 deaths per 100,000 people worldwide.3

Thirty-three deaths per 100,000 people worldwide is two point three million deaths each year from alcohol, worldwide. As for ‘illegal’ drug deaths.

‘Globally, UNODC estimates that there were 190,900 (range: 115,900 to 230,100) drug-related deaths in 2015, or 39.6 (range: 24.0 to 47.7) deaths per million people aged 15-64 years. This is based on the reporting of drug-related deaths by 86 countries.’4

This figure seems low, based on the CDC review of drugs deaths in the US

‘70,237 drug overdose deaths occurred in the United States in 2017. The age-adjusted rate of overdose deaths increased significantly by 9.6% from 2016 (19.8 per 100,000) to 2017 (21.7 per 100,000). Opioids—mainly synthetic opioids (other than methadone)—are currently the main driver of drug overdose deaths. Opioids were involved in 47,600 overdose deaths in 2017 (67.8% of all drug overdose deaths).’ 5

70,237 in the US would extrapolate up to 1.623 million deaths a year worldwide. Maybe other countries don’t hand out opiods like sweeties to everyone. Although, in the UK, we are certainly following suit.

So, we have some figures to go on. Somewhere in the fifteen to twenty million per year killed by unsafe sex, alcohol, drug and tobacco use each year. Who knows what the morbidity might be?

This is a gigantic figure, and we are supposed to believe that unhealthy diets are worse than this? I would challenge Walter Willett to find a single randomised controlled clinical study demonstrating that any dietary substance has significantly increased the risk of death in anyone, ever.

By unhealthy, of course, what the authors mean is animal fats/saturated fat, red meat, bacon, sausages and suchlike. Essentially, anything that is not vegan.

What of saturated fat? The last time it was possible to get an accurate assessment of saturated fat and deaths from CHD in individual countries was in 2008. After that, the figures mysteriously disappeared. Luckily Zoe Harcombe kept a copy and sent it to me.6

From these figures, I present you with a graph. Sorry, it is a bit complicated. So, please take a little time to study it, because it has two axes. The percentage of energy from saturated fat in the diet is the top axis, going from 0% up to 18%. As you can see from this, saturated fat intake is highest in France at 15.5%, and lowest in Georgia at 5.7%. Second lowest Azerbaijan, then Ukraine, then Russia.

The other axis looks at deaths from CHD. With the highest being Russia, then Georgia, then Azerbaijan, then the Ukraine.

The fact that stands out is that the countries with the lowest saturated fat intake had, on average, six times the rate of death from CHD, in comparison to the four countries with the highest saturated fat intake. I like to wave this graph at people who tell me that saturated fat in the diet is the single most important risk factor for CVD. I also like teasing vegans with it. Although they rarely respond well to teasing – as you may imagine.

I would also like to enquire of Walter Willett what he makes of data like this? I presume he would just ignore it, or point to the vegetarians of La Loma California, or suchlike. But, as any scientists know, you cannot just pick and choose populations you like and ignore those that you don’t. Nor would I dream of saying that, from this graph, we can prove that saturated fat intake protects against CVD. However tempting that may be.

But I know that this is what the EAT-Lancet are likely to do, along with all other researchers who simply ignore things they don’t like. In fact, the games played to prove that saturated fat is bad for you, twist the fabric of logic well beyond breaking point.

Which takes to me to favourite paper of all time. ‘Teleoanalysis: combining data from different types of study.’ Published in the BMJ more than fifteen years ago. 7

The paper makes this statement:

‘A meta-analysis of randomised trials suggested that a low dietary fat intake had little effect on the risk of ischaemic heart disease.’ Good, I like that. It seems astonishingly accurate. Randomised trials on dietary fat have had no effect. Which is the point where this paper should really have fallen silent.

But no, the authors decided that we should ignore these pesky studies a.k.a. evidence. Instead we should use teleolanalysis. I shall now quote directly, and heavily from the papers itself.

‘Once a causal link has been established between a risk factor and a disease it is often difficult, and sometimes impossible, to determine directly the dose-response relation. For example, although we know that saturated fat intake increases the risk of ischaemic heart disease, the exact size of the effect cannot be established experimentally because long term trials of major dietary changes are impractical. One way to overcome the problem is to produce a summary estimate of the size of the relation by combining data from different types of study using an underused method that we call teleoanalysis. This summary estimate can be used to determine the extent to which the disease can be prevented and thus the most effective means of prevention. We describe the basis of teleoanalysis, suggest a simple one-step approach, and validate the results with a worked example.

What is teleoanalysis?

Teleoanalysis can be defined as the synthesis of different categories of evidence to obtain a quantitative general summary of (a) the relation between a cause of a disease and the risk of the disease and (b) the extent to which the disease can be prevented. Teleoanalysis is different from meta-analysis because it relies on combining data from different classes of evidence rather than one type of study.

In contrast to meta-analysis, which increases the precision of summary estimates of an effect within a category of study, teleoanalysis combines different categories of study to quantify the relation between a causative factor and the risk of disease. This is helpful in determining medical practice and public health policy. Put simply, meta-analysis is the analysis of many studies that have already been done; teleoanalysis provides the answer to questions that would be obtained from studies that have not been done and often, for ethical and financial reasons, could never be done.

In so doing we can prove that saturated fat causes heart disease. ‘I say, Bravo. Bravo, sir. You are truly a genius.’

It is upon such foundations as this that the EAT-Lancet authors can say – in all seriousness – Unhealthy diets pose a greater risk to morbidity and mortality than does unsafe sex, and alcohol, drug, and tobacco use combined.’

Keep saying it and people will end up believing you. Even if you have not a scrap of evidence to support it. A phenomenon first noted by Lewis Carroll in his magical poem the Hunting of the Snark…

“Just the place for a Snark!” the Bellman cried,

   As he landed his crew with care;

Supporting each man on the top of the tide

   By a finger entwined in his hair.

 

“Just the place for a Snark! I have said it twice:

   That alone should encourage the crew.

Just the place for a Snark! I have said it thrice:

   What I tell you three times is true.”

Unfortunately for the EAT-Lancet crew, repeating nonsense as many times as you like cannot magically transform it from nonsense to truth. The biggest recent study on the impact of diet and heart health was the PURE study. Which was reported thus, last year:

‘Findings from this large, epidemiological cohort study involving 135,335 individuals aged 35 to 70 years from 18 low-, middle- and high-income countries (across North America, Europe, South America, the Middle East, South Asia, China, South East Asia and Africa) suggest that high carbohydrate intake increases total mortality, while high fat intake is associated with a lower risk of total mortality and has no association with the risk of myocardial infarction or cardiovascular disease-related mortality.

Furthermore, a higher saturated fat intake appeared to be associated with a 21% lower risk of stroke. Why might these results be in such contrast with current dietary advice? “The conclusion that low fat intake is protective is based on a few very old studies with questionable methodology,” explains Professor Salim Yusuf (McMaster University, Hamilton, Ontario, Canada), senior investigator for the PURE study. “The problem is that poorly designed studies performed 25–30 years ago were accepted and championed by various health organisations when, in fact, there are several recent studies using better methods, which show that a higher fat intake has a neutral effect,” he continues, citing the example of the Women’s Health Initiative trial conducted by the National Institutes of Health in 49,000 women that showed no benefit of a low-fat diet on heart disease, stroke or cardiovascular disease.’ 8

Anyway, I know that facts are pretty much useless against the diet-heart behemoth. It eats facts, turns them through one hundred and eighty degrees and spits them out again. I just felt the need to let people know that IT IS ALL COMPLETE AND UTTER RUBBISH. Gasp. Thud. I feel my man flu returning.

Refs:

1: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)31788-4/fulltext

2: ‘https://www.cdc.gov/tobacco/data_statistics/fact_sheets/fast_facts/index.htm

3: https://www.nhs.uk/news/medical-practice/tobacco-alcohol-and-illegal-drugs-are-global-health-threat/

4: http://www.unodc.org/wdr2017/field/Booklet_2_HEALTH.pdf

5: https://www.cdc.gov/drugoverdose/data/statedeaths.html

6: European cardiovascular disease statistics 2008 edition. Steven Allendar et al: Health Economics Research Centre, Dept of Public Health, University of Oxford.

7: https://www.bmj.com/content/327/7415/616

8: https://www.escardio.org/Congresses-&-Events/ESC-Congress/Congress-resources/Congress-news/the-pure-study-understanding-the-relationship-between-nutrition-and-heart-disease

What causes heart disease – Part 63

17th March 2019

[Is stress the most important cause of cardiovascular disease?]

Forgetting for a moment attacks by various people, and newspapers, that shalI remain nameless [Mail on Sunday UK], I thought I would return to the more interesting topic of what actually does cause cardiovascular disease and. As I have done several times before, I am looking at stress/strain.

I know that, deep down, most people feel that stress can lead to illness. ‘Oh, I was terribly stressed, then I went down with the flu.’ Or ‘He has been under a lot of stress and had a heart attack.’ If we go back over a hundred years William Osler, a famous physician, described a man suffering from angina as ” … robust, the vigorous in mind and body, the keen and ambitious man, the indicator of whose engines are always at ‘full speed ahead’ “.

The idea that hard driving Type A personalities were more likely to die of heart attacks gained great popularity at one time. But you don’t hear so much about this anymore. It is all diet, and cholesterol, and blood pressure and diabetes and tablet after tablet. Measure this, monitor that, lower this and that.

I believe that the side-lining of stress to be a monumental mistake. Because it remains true that stress is the single most important cause of heart disease, and I intend to try and explain exactly how this can be. Once more into the breach dear friend.

I shall start this little journey by explaining that stress is the wrong word to use. In fact, the use of the word stress has often been more of a barrier than an aid understanding. This is because, when we talk about stress, we really mean strain.

Stress or strain

It was Hans Seyle who coined the term ‘stress’ to cover the concept of negative psychological events leading to diseases, specifically heart disease. Of course, this is a terrible oversimplification, but it will do for now. Seyle later admitted that, had English been his first language (he was born in Slovakia) he would have used the term strain, not stress.

This is because stress is the external force placed on an object, or a human being. Strain is the resulting deformation or damage that can occur. Therefore, it is the resultant strain that is the driver of ill health.

For example, being told you are a useless idiot by one or another parent would be considered a significant external negative ‘stressor.’ The resultant anxiety and upset then represents the strain. However, the two things do not necessarily match up very well.

If you are highly resilient, or perhaps deaf, being told you are a useless idiot may have absolutely no effect on you whatsoever. You will continue to whistle a happy tune, whilst skipping along the pavement.

If, on the other hand, you are a rather more sensitive soul, or perhaps being told you are a useless idiot is a daily occurrence, then the resultant strain/deformation may be quite severe. In this case, the same external stressor can result in completely different levels of internal strain – depending on the resilience of the individual.

To give another example, some people enjoy giving public talks, they look forward to it. Others would rather chew their own arm off rather than stand up and talk in public. Once again, we have the same external stressor, resulting in completely different levels of internal strain.

The death of a close relative, such as a husband, is a major negative stressor which, for most people would cause a significant burden of strain. However, if the husband was an abusive bully, who regularly beat his wife, the death may be a blessed relief and the levels of strain will be reduced greatly. Then again, the conflicting feelings of guilt, relief, happiness and grief can lead to immense strain.

In short, there is no point in saying that an individual is under a great deal of stress. That may or may not be true, but it is very difficult to define, or measure. What matters is their response to negative stressors – real or perceived. The internal strain.

Of course, this does not mean that you can discount external stressors. These can be very important on both an individual, and a population wide basis. So, before looking at strain in more detail, I am going to review external ‘population-wide stress(ors)’.

Population-wide stressors

Whilst this is a fascinating area, the terminology used is more than a little variable, and confusing. One of the problems is that the terminology swirls around, and people write about the same thing using different words or use the same words to describe different things. A bit like using IHD, CHD, CAD and CVD to describe much the same thing, I suppose.

To keep this simple, and stripping terminology down things down to basics, the concept I am trying to capture, and the word that I am going to use, here to describe the factor that can affect entire populations is ‘psychosocial stress’. By which I mean an environment where there is breakdown of community and support structures, often poverty, with physical threats and suchlike. A place where you would not really want to walk down the road unaccompanied.

This can be a zip code in the US, known as postcode in the UK. It can be a bigger physical area than that, such as a county, a town, or whole community – which could be split across different parts of a country. Such as native Americans living in areas that are called reservations.

On the largest scale it is fully possible for many countries to suffer from major psychosocial stress at the same time. This happened very dramatically after the breakup of the Soviet Union, which started in some countries earlier than others e.g. Poland. But the main event was the fall of the Berlin wall, and the collapse of communism across most of Eastern Europe. It was studied quite closely by a number of researchers. Here is one paper:

‘The mortality crisis in transition economies. Social disruption, acute psychosocial stress, and excessive alcohol consumption raise mortality rates during transition to a market economy.’ 1

As the paper states:

‘Acute psychosocial stress was one of the main drivers of the sharp mortality increase experienced by the former communist countries of Europe. In central Europe, the post-communist mortality crisis was quickly solved, while in much of the former USSR, life expectancy at birth did not return to 1989 levels until 2013.’

The splintering of the Soviet Union is something to be, generally, celebrated. However, it caused a massive surge in premature deaths, mainly from cardiovascular disease (CVD).

Below is a graph which tracks at CVD deaths in men under 65s in four former Soviet countries: Russia, Kazakhstan, Ukraine and Belarus. The graph starts in the year 1980 and goes on to 2015 2.

CVD was similar in all four countries and was pretty steady, perhaps gently falling. Then, Berlin wall fell in 1989, with major disruption hitting Russia by 1991 when Gorbachev was ousted by Yeltsin. At which point CVD took off in all country.

It may be easier to see a clear pattern if we look at a single country in the Soviet Union, Lithuania. This is a graph that I have used several times before. Figures are from Euro Heart Statistics.

In Lithuania CVD was gently dropping until 1989 then – Bam! Virtually a doubling of the rate in a five-year period. Then it dropped straight back down again.

If you want a comparator country in Europe, here is the UK during the same time period. A steady uninterrupted fall (completley undisturbed by the launch of statins in 1987) Every other country in Western Europe, the USA, Canada, Australia etc. show the same pattern as the UK – a steady fall.

Getting back to the Soviet Union, it is it interesting that the main increase in those who died was seen in men, mainly middle aged men. To quote from the social disruption paper again:

‘Looking back, it could have been expected that the European mortality crisis would primarily have affected children, pregnant women, the elderly, and the disabled. Yet, as shown.. men were much more affected than women in every transition country. The fastest relative upswing in mortality was recorded for 20−39 year olds, who experienced a marked rise in violent deaths, while the fastest absolute rise occurred among 40−59 year olds, who were mainly affected by a rise in cardiovascular deaths.’

It seems inarguable that extreme psychosocial stress, as experienced in ex-Soviet Union countries after 1989, drove a massive spike in CVD deaths, which is only now beginning to settle down in many of the countries.

As an important aside, you may notice that, in Russia, the rate of CVD rose quickly from 1990 until about 1995, then dropped. Then it jumped up again in 1998. You may ask, what happened in 1998? Well, this was the year of the collapse of the Ruble – known as the Ruble crisis. It resulted in massive financial chaos, and levels of poverty exploded.

‘Mobs trying to get their savings were barred from entering the banks, executives flew to London to get suitcases full of dollars and coup plans were discussed in the newspapers. The value of the stock market dropped to 10 percent of its value of the previous year, the value of Ruble tumbled by 75 percent, and 18 of Russia’s 20 major banks effectively collapsed under massive debts. Foreign investors, some of them calling Russia “Indonesia with nukes,” fled the country.

Some have said the damage to the economy was greater than that unleashed by Hitler’s armies in World War II. By the time of the 1998 Ruble crash ran its course the poverty level had increased from 2 percent of the population in the Soviet era to 40 percent.’  3

Moving away from the Soviet Union to the population that has undergone the single greatest and most extreme form of social breakdown and disruption, social stress and dislocation known. This is the Australian aboriginals. A group of people that has been subjected to an immense burden of negative stressors.

Here are a few bullet points from a study carried out by the Australian Government:

  • Stress is a significant factor of the lives of Aboriginal young people.
  • High levels of self-harming intent and behaviour. Feelings connected to loss of hope – high levels of anxiety and depression
  • Rapid social change in Aboriginal communities.
  • Interpersonal violence, accidents and poisoning, stress, alcohol and norms of violence as in male to male fighting.
  • Domestic violence and child abuse, as well as sexual assault, are further stressors and sources of mental ill health.
  • These behavioural outcomes reflect the impact of historical factors, colonisation and disadvantage.

What impact has this had, specifically on cardiovascular disease rates? A research study was done, called the Perth Aboriginal Atherosclerosis Risk Study (PAARS) population. The investigators looked at CHD (coronary heart disease), not CVD (cardiovascular disease) – which would also include strokes. Sorry for jumping about in the terminology, but everyone does. Indeed, it is hard to find two studies that use the same terminology, or end points.

Sticking to CHD, which basically means deaths from heart attacks, researchers found that the CHD rate in Austrailian Aboriginals was 14.9 per 1000/year versus 2.4 for the general population. This is 1,490 per 100,000 per year [this is metric most commonly used] and represents the highest rate I have ever seen in any population, in any country, at any time – ever. Although Belarus came pretty close at one point.

What also stands out is that the rate of heart attacks in Aborignal Australians was six fold higher than the surrounding population. However, if we separate the figures from men and woman, we can see something even more astonishing.

For Aboriginal men the rate of CHD was 15.0 versus 3.8 per 1000 per year. A four hundred per cent increase on men in the surrounding population. For aboriginal women the CHD was almost exactly the same as for the men, 15.0 per 1000 per year – which is highly unusual in itself – as men normally have a much higher rate than women.

The astonishing fact is that Australian Aboriginal women had a rate of CHD that was ten times the rate of the surrounding female population. Or, to put it another way. One thousand per cent higher. 4

A similar picture, though less extreme, can be seen in Native Americans. As outlined in this 2005 paper. ‘Stress, Trauma, and Coronary Heart Disease Among Native Americans.5

‘This study quantified exposure to trauma among American Indians, adding to the existing evidence that this population experiences a disproportional amount of trauma. We were intrigued by the statement “It may be that high rates of trauma exposure contribute to the increasing prevalence of cardiovascular disease among American Indian men and women, the leading cause of death among this population” and wanted to lend support to this assertion. Indeed, American Indians now have the highest rates of cardiovascular disease in the United States.

In a study similar to the AI-SUPERPFP study (American Indian Service Utilization, Psychiatric Epidemiology, Risk and Protective Factors Project (AI-SUPERPFP) Team). Koss et al. documented adverse childhood exposures among 7 Native American tribes and compared these exposures to levels observed in the Adverse Childhood Experiences (ACE) Study conducted by Kaiser Permanente and the Centers for Disease Control and Prevention in a health maintenance organization population. Compared with participants in the ACE study, not only did the American Indians have a significantly higher rate of exposure to any trauma (86% vs 52%), but they also had a more than 5-fold risk of having been exposed to 4 or more categories of adverse childhood experiences (33% vs 6.2%).’

Wherever you look, you can see that populations that have been exposed to significant social dislocation, and major psychosocial stressors, have extremely high rate of coronary heart disease/cardiovascular disease.

This can be supported if we look at the twenty countries in the world that have the highest rates of CVD – both men and women. Figures from WHO 2017 6.  Ex-soviet countries in bold

  • Turkmenistan
  • Ukraine
  • Kyrgyzstan
  • Belarus
  • Uzbekistan
  • Moldova
  • Yemen
  • Azerbaijan
  • Russia
  • Tajikistan
  • Afghanistan
  • Syria
  • Pakistan
  • Mongolia
  • Lithuania
  • Georgia
  • Sudan
  • Egypt
  • Iraq
  • Lebanon

I feel that some of these figures may not be entirely accurate. Such as the CVD rate in Syria, or Iraq in the last few years. As for the rest. I would not like to comment on the social and political situations in all of these countries in too much detail. However, we are not looking at peaceful and mature democracies here. Mainly dictatorships and countries riven by internal conflict.

Winding this back to the US, there is a pattern of CHD showing that certain counties suffer much higher rates than others. Figures taken from the CDC. On this graph darker means a higher rate of heart disease, lighter means less heart disease. These are deaths per 100,000 per year. You may discern a pattern.

The UK shows precisely the same sort of picture with inner cities and more deprived areas, having much higer rates than affluent suburbs.

Wherever and however you look it becomes apparent that higher levels of psychosocial stress are strongly associated with CVD/CHD. In some cases, very strongly indeed.

But how can psychosocial stress and factors such as childhood trauma, as seen in the Australian Aboriginals, or Native Americans, lead to a build up of atherosclerotic plaques in the arteries,the main cause of CVD?

Or to put it another way, how does a negative external stressor, lead to the internal physiological strain, that causes CVD? For that we need to turn to Sapolski, Bjortorp and Marmot. Which comes next!

 

1: https://wol.iza.org/uploads/articles/298/pdfs/mortality-crisis-in-transition-economies.pdf

2: https://www.bhf.org.uk/informationsupport/publications/statistics/european-cardiovascular-disease-statistics-2017

3: http://factsanddetails.com/russia/Economics_Business_Agriculture/sub9_7b/entry-5170.html

4: https://www.ncbi.nlm.nih.gov/pubmed/20427550

Adherence to statins saves lives

17th February 2019

[Adherence to placebo saves lives]

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

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

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

The main finding was:

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

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

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

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

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

For example, I was looking at this paper:

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

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

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

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

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

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

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

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

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

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

I think it is worth highlighting the main findings again.

Those who adhered to taking clofibrate               =          15% mortality

Those who had poor adherence to clofibrate     =          24.6% mortality

Those who adhered to taking placebo                 =          15.1% mortality

Those who had poor adherence to placebo        =          28.3% mortality

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

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

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

As they say in the introduction:

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

As they conclude:

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

This takes us back to Hill and Peto:

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

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

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

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

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

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

1: https://jamanetwork.com/journals/jamacardiology/article-abstract/2724695?fbclid=IwAR20HUGfxI9Cq8KVAgW0GY8Mu0MmK5goqGkqmErIb-hl5QZbcy_zahgNEvc

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

3: https://www.ncbi.nlm.nih.gov/pubmed/20562351

4: https://www.ncbi.nlm.nih.gov/pubmed/6999345

5: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2744446/

What causes heart disease part 62

19th January 2019

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

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

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

Takeaway

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

Why this matters:

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

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

Study design:

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

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

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

Key results:

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

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

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

Funding: None.

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

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

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

1: https://www.univadis.co.uk/viewarticle/lower-cholesterol-tied-to-increased-mortality-in-ischaemic-stroke-patients-with-carotid-artery-stenosis-651463

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

What causes heart disease part 61 – strokes

15th January 2019

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Now, write out one hundred times:

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

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

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

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

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

The logic stripped down is, as follows:

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

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

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

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

1: https://www.bmj.com/content/303/6807/893

2: https://www.ncbi.nlm.nih.gov/pubmed/30396495

3: https://www.ahajournals.org/doi/10.1161/STROKEAHA.118.023456

4: https://www.ncbi.nlm.nih.gov/pubmed/19814666

What causes heart disease part 60 – prediction

2 January 2019

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

For predicted risk less than 2.5 percent, actual incidence was 0.2 percent

For predicted risk between 2.5 and 3.74 percent, actual incidence was 0.65 percent

For predicted risk between 3.75 and 4.99 percent, actual incidence was 0.9 percent

For predicted risk equal to or greater than 5 percent, actual incidence was 1.85 percent

“From a relative standpoint, the overestimation is approximately five- to six-fold,” explained Dr. Go1

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

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

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

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

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

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

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

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

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

Smoking                                  = 18

Sex/female                              = 19 (protective)

Total cholesterol                    = 25

HDL cholesterol                      = 28 (protective)

Systolic blood pressure          = 29

Diabetes                                  = 31

LDL ‘bad’ cholesterol              = 46

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

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

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

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

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

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

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

Take a statin. Statins accelerate calcification.

Take warfarin. Warfarin accelerates calcification

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

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

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

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

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

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

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

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

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

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

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

1: https://www.eurekalert.org/pub_releases/2016-05/kp-crt042916.php

2: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0174944

3: https://www.cureus.com/articles/11752-a-72-year-old-patient-with-longstanding-untreated-familial-hypercholesterolemia-but-no-coronary-artery-calcification-a-case-report

What causes heart disease – part 59

27th November 2018

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

Thrombogenic theory vs. LDL/cholesterol hypothesis

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

A counter hypothesis is as follows.

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

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

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

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

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

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

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

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

As her paper went on to say:

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

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

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

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

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

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

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

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

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

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

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

Thus:

damage > repair = atherosclerosis/CVD

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

What sort of things stop new endothelial cells being created?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

2: https://www.sciencedirect.com/sdfe/pdf/download/eid/1-s2.0-0049384894900493/first-page-pdf

3; https://www.sciencedirect.com/sdfe/pdf/download/eid/1-s2.0-0049384894900493/first-page-pdf

4: http://www.onlinejacc.org/content/accj/69/18/2317.full.pdf

5: https://heart.bmj.com/content/heartjnl/69/4/338.full.pdf

6: https://www.ncbi.nlm.nih.gov/pubmed/12034401

7: https://www.webmd.com/asthma/news/20041115/steroids-linked-to-higher-heart-disease-risk

What causes heart disease part 58 – blood pressure

1st November 2018

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

What I do recommend to patients is:

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

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

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

1: https://www.cochrane.org/CD004022/HTN_effect-low-salt-diet-blood-pressure-and-some-hormones-and-lipids-people-normal-and-elevated-blood

What causes heart disease – part 57

11th October 2018

Blood pressure

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

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

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

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

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

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

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

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

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

So, how is this figure arrived at?

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

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

(Or maybe that is just me).

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

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

From 110mmHg to 120mmHg another very slight rise

From 120mmHg to 130mmHg another very slight rise

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Low pressure – no atherosclerosis

High pressure – atherosclerosis

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

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

What causes heart disease part 56 – a new paper

23rd September 2018

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

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

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

The paper is called ‘Inborn coagulation factors are more important cardiovascular risk factors than high LDL-cholesterol in familial hypercholesterolemia.’ And you can see it here https://www.sciencedirect.com/science/article/pii/S0306987718304729.

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

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

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

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

Here is the abstract:

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

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

What causes heart disease part 55 – albumin

17th September 2018

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

1: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4574825/

2: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5681838/

What causes heart disease part 54

31st August 2018

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

INCREASE IN CARDIOVASCULAR EVENTS WITH AVASTIN3

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

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

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

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

Bleeding                                                          2.96 (2.46–3.56), P<0.001

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

1: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4864131 /

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

3: http://jaha.ahajournals.org/content/6/8/e006278

What cause heart disease part 53 – diabetes

21st August 2018

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

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

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

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

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

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

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

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

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

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

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

Main functions of the glycocalyx:

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

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

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

1: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4127581/

2: https://www.medscape.com/viewarticle/584885_2

3: http://diabetes.diabetesjournals.org/content/55/2/480

4: http://diabetes.diabetesjournals.org/content/55/4/1127

What causes heart disease part 52

16th August 2018

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

How can a blood clot form under the endothelium?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

1: https://www.researchgate.net/figure/Schematic-diagram-of-the-structure-of-the-blood-brain-barrier-BBB-The-BBB-is-created_fig1_259386351

2: https://en.wikipedia.org/wiki/Tight_junction

3: https://www.sciencedirect.com/science/article/pii/0049384894900493

4: https://www.ncbi.nlm.nih.gov/pubmed/16614729

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

6th August 2018

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Discussion

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

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

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

You heard it here first.

1: https://www.ncbi.nlm.nih.gov/pubmed/7925507

2: https://www.nejm.org/doi/full/10.1056/NEJMoa035655

3: http://circ.ahajournals.org/content/71/4/699?ijkey=7c374f414cfa07f8668551aba66604e81cc54adc&keytype2=tf_ipsecsha

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