(Part 2 of an occasional series about what really causes heart disease)
One of the greatest strengths of the cholesterol hypothesis is that there is no obvious alternative to replace it with. Stress? Well I believe that, in fact, stress is the number on cause of premature cardiovascular disease (although there are many provisos attached to this statement).
But if stress does cause heart disease, how does it do this? With the cholesterol hypothesis you have the massive advantage of superficial simplicity
- You eat too much cholesterol
- The level of cholesterol in your blood rises
- The excess cholesterol is deposited in the artery wall, causing narrowings/thickenings (plaques)
- Eventually these block the circulation, causing heart attacks and strokes
Of course, when exposed to the harsh light of critical thought, each link in this neat and tidy causal chain crumbles to dust. But it is such a seductive hypothesis that the mind is drawn back to it again and again, like moths to candlelight. It seems so perfectly simple that it must be true.
On the other hand, as I write this, I am also studying the cover of a recent British Medical Journal (BMJ). The headline is ‘Cardiovascular Disease and Aircraft Noise.’ You may have heard about this research in the mainstream media. It seems that living near an airport raises the risk of stroke by 24%, and the risk of heart disease by 21%. It is suggested this is due to the noise pollution. Okay, nice idea, but how?
How can aircraft noise cause your arteries to thicken and narrow?
I believe that this can be explained, but only if you completely discard the cholesterol hypothesis of cardiovascular disease, and look afresh at what heart disease may actually be, and how it is caused.
At this point I am going to introduce a relatively arcane term, ‘atherothrombosis’. No, I have not just made this word up. Nor is it recent. In fact, the basic idea has been kicking around for the last one hundred and sixty years. The concept of atherothrombosis was first proposed by Karl Von Rokitansky in 1852. He believed that thickenings in arteries, or plaques, were the end result of thrombosis (blood clots) forming on the arterial wall. Mainly because plaques looked exactly like blood clots, and seem to contain the same materials e.g. fibrin (a key ingredient of blood clots).
Virchow, another doctor and researcher, who lived during the same era, and who was significantly more influential, argued that this was nonsense. He had noted that plaques were to be found underneath the lining of the artery (endothelium). He argued that it was not possible for a clot to form within the artery wall itself. Frankly, a pretty good argument in the light of their knowledge at the time.
It was also Virchow who noted that plaques contained a lot of cholesterol, and so he hypothesised that cholesterol in the blood irritated the lining of the artery and then entered the arterial wall. Thus began the cholesterol hypothesis.
Although Virchow won the argument, the atherothrombosis hypothesis has sprung back into life at various point over the years, only to die back again. A fellow Scot called Duguid promoted the idea heavily around the second world war, and just after. Various other researchers have also supported the concept that heart disease is primarily due to blood clotting (thrombosis) – in some way.
Interestingly, at one point Pfizer also started to promote atherothrombosis as the cause of heart disease. For sentimental reasons I have kept hold of an educational booklet produced by Pfizer in 1992. On page four it states
‘Several features of mature plaques, such as their multi-layered pattern, suggest that the platelet aggregation and thrombus formation are key elements in the progression of atherosclerosis. Platelets are also known to provide a rich source of growth factors, which can stimulate plaque development.
Given the insidious nature of atherosclerosis, it is vital to consider the role of platelets and thrombosis in this process.’ [Well, quite]
There is little point in referencing this document, as I probably have the only copy left in existence. It is called ‘Pathologic triggers. New insights into cardiovascular risk.’ Produced by Medi Cine Inc. For Prizer Inc Copyright 1992, All rights reserved etc. etc.
It is interesting that when Pfizer did not have a statin, they were looking away from cholesterol as a cause of cardiovascular disease. It will come as no surprise to you that this was not through some altruistic attempt to discover the truth about the true cause of heart disease. It was to help market their drug doxazosin (a BP lowering drug) which had some additional anticoagulant properties.
Of course, as soon as atorvastatin arrived on the scene, no more was heard from Pfizer about the ridiculous concept of atherothrombosis. It was cholesterol, cholesterol, all the way, and fifty billion dollars in profit from atorvastatin.
Pity, really, because in my view, Pfizer had it right in 1992. C’est la vie.
Perhaps I am straying from the issue here. What is atherothrombosis? Or, what is the hypothesis of atherothrombosis?
It goes something like this:
- The lining of the artery (endothelium) is damaged
- A thrombus (blood clot) forms over the area of damage
- After a very short time the blood clot stops growing – and stabilises
- Blood cells called endothelial progenitor cells (EPCs) are attracted the surface of the clot
- The EPCs grow bigger, join together at the edges, and form a new endothelial layer on top of the thrombus [so the thrombus is now present inside the artery wall]
- Various repair systems go into action, to clear away the thrombus from within the artery wall
Rokitanksy did not know there were such things as EPCs, so he had no explanation as to how the thrombus could be found underneath the endothelium (single later of cells lining artery walls). The answer is, of course, that the endothelium was not there when the thrombus occurred. It reformed on top of the thrombus. Yes, simple when you know how.
Had Rokitansky known this, and won the argument, we would possibly never have heard of cholesterol ever again. Unfortunately, as he didn’t know that EPCs existed, Virchow kicked the idea of atherothrombosis into touch, and so cholesterol became the single molecule that has triggered more Nobel prize winning research than any other.
The role of endothelial Progenitor Cells
I recently asked a medical student who had the misfortune of being stuck with me for the day.
Me: ‘What happens in you scratch your skin.’
Medical student : ‘You bleed.’
Me: ‘Then what?’
Medical Student: ‘A scab forms.’
Me: ‘Then what?’
Medical student: ‘The scab falls off after your skin has healed.’
Me: ‘Good, so what happens if you scratch/damage the lining of your artery?’
Medical student: ‘A scab/thrombus forms.’
Medical student: ‘Then it falls off…..’
Me: ‘Then what happens?’
Medical student: ‘It….’
Me: ‘It travels down the artery till the artery narrows, and the blood clot gets stuck somewhere?’
Medical student: ‘Ummmm….’
Me: ‘Ummmm, indeed.’
Clearly, you cannot have blood clots breaking off and travelling down arteries to get stuck further down. This would be horribly damaging. Strangely, human physiology is a bit cleverer than that. Yes, if you scratch your skin the clot/thrombus falls off after the skin has healed. This causes no harm to anything. But a damaged blood vessel has to be able to get rid of the thrombus that forms without it breaking off and travelling to the nearest organ e.g. the brain, where it blocks a blood vessel and causes a stroke.
Also, the lining of the artery wall is nothing like the skin. The most superficial layer of the skin (the epidermis) is a single layer of cells. But this layer starts life deeper down, in the dermis. Cells formed in the dermis gradually move towards the surface where they then fall off.
However, the single layered of cells lining the artery walls do not start life deeper in the artery wall, and grow outwards (or inwards). These cells come from within the bloodstream itself. These are Endothelial Progenitor Cells (EPCs). They are formed in the bone marrow and float around in the bloodstream. They are attracted to areas of endothelial damage. They stick to these areas, grow into mature endothelial cells, and form a new layer of endothelium.
A neat and perfect system for ensuring that damage to blood vessels can be covered over, and the resulting thrombus does not end up jamming up the downstream blood vessels. Ask the average doctor about EPCs and I can guarantee they have never heard of them. Never, ever. Important little things though.
As you age, the production of EPCs falls. If you are stressed, the production of EPCs falls. If you take steroids the production of EPCs falls. If you have kidney disease, the production of EPCs falls. Guess what. All of these things are associated with a vastly greater risk of cardiovascular disease. Vastly greater.
For now just to look more closely at one of these risk factors, steroids. Steroids are used in a wide range of medical conditions such as asthma, rheumatoid arthritis, and inflammatory bowel disease. Essentially, they are the most potent anti-inflammatory agents known – and in any disease where inflammation is a major problem steroids work brilliantly (for a while at least).
Steroids can be more accurately called corticosteroids, because the basic building block of all steroids is cortisol. This is one of the natural steroid hormones made within the adrenal glands. It is a stress hormone, which will be produced in much greater amounts under a situation of threat/stress.
So, what happens if cortisol levels are chronically raised? Well, there is a condition called Cushing’s disease. The underlying problem in Cushing’s disease is excess production of cortisol, which can happen for various reasons….that I do not have the time to discuss here.
People with Cushing’s disease develop a range of metabolic problems: high blood sugar levels/type II diabetes, high levels of clotting factors, raised triglycerides, low HDL, high blood pressure, central obesity etc. Production of EPCs also falls. This abnormal metabolic pattern is also seen in those who take a high dose of steroids over a long period of time, where production of EPCs also falls.
Of greatest interest is the fact that people with Cushing’s disease suffer a greatly increased rate of heart disease. Relative risk increased by around 600% – 700% (Or more). People who take steroids long-term have a ~400% increased risk of dying of CHD.
These are not small increases in risk. They are far greater than any of the standard accepted risk factors for cardiovascular disease. In fact, we are talking molehills next to Mount Everest here.
For now, taking the discussion back to those who live near to airports. It is known from a great deal of research that people who suffer long-term negative stress exhibit abnormal cortisol production. Although it won’t be nearly as extreme as those with Cushing’s, or those taking steroids. They also have an increased risk of dying of heart disease and stroke.
It is known that noise pollution creates long-term negative stress. It is now known that people living next to airports suffer a high level of strokes and heart disease.
Try and use the cholesterol hypothesis to explain the increased risk, and you can’t. Try and use the atherothrombosis hypothesis to explain this phenomenon and, it all fits together without any trouble at all. So, who wins this argument? Virchow, or Rokitansky?
Of course it is not nearly as simple as: stress > increased cortisol secretion > reduce EPC production > atherothrombosis…… But it is one important link in the chain.
More on this, at some point.