Lumen: The lumen of the artery is the hole in the middle that the blood flows through.
The artery wall: The artery wall is made up of three layers: Endothelium/intima, media and adventitia
The endothelium: Usually thought of as a single layer of endothelial cells than line the lumen of the artery. [The layer may be more than one cell thick]. This layer of endothelium acts as a barrier to blood, or anything in the blood, leaking from the lumen into the artery wall. There is a bit of space, sometime called the intima just under the endothelial cells.
The media: This layer is mostly made up smooth muscle cells and elastic tissue. The muscle can contract or relax, depending on circumstances
The adventitia: This outermost layer is mainly made up of collagen. It is very strong and keeps the artery in shape.
The atherosclerotic plaque: The areas of thickening and narrowing of arteries (in heart disease). These are usually found between the endothelium and the media – smooth muscle layer. They lie beneath the endothelium – within the artery wall itself. The area often referred to as the intimal layer of the artery.
The elevator pitch
Various people who work in business tell me of something called the ‘elevator sales pitch’. So-called, because of a (highly unlikely) situation whereby you find yourself in an elevator (which we in the UK call a lift) with a rich, famous, person. You have a short space of time to outline your idea to them, what it is, what it means, and why it is of value. They then hand over a hundred million dollars to invest in you, and your idea. Or something like that anyway.
Whilst the elevator pitch is clearly a mythical beast, the general point is reasonable. You should be able – or you should at least attempt – to condense your ideas into a very short space of time, before people get bored and walk away. Well, clearly I have miserably failed on this, as I am now writing part twenty-seven of my idea(s) on heart disease. In truth, I am planning on the elevator breaking down for about ten hours between floors to give me the time needed.
Recently, though, I have been speaking to a number of people who have successful careers in business, music, the arts and suchlike. I have been trying out my elevator pitch on them. Admittedly the elevator I am thinking of is in the Burj Khalifa in Dubai, but I am trying. So, here goes. Doors close on the elevator. Me and Bill Gates…
Me. ‘Forget diet, forget cholesterol, the real cause of heart disease is blood clotting.’
Bill Gates looks at his watch. ‘You have one minute.’
Me. ‘Blood clots can form and stick to the inside of artery walls. They then get absorbed into the artery wall itself where, normally, they are cleared away by specialised white blood cells. But if blood clots keep forming rapidly, at the same point, or the blood clots are bigger and more difficult to shift when they form, they cannot be cleared away quickly enough and so end up stuck inside the artery wall. This leads to a build-up of blood clot residue, and remnants, in the artery wall itself. Which means that repeated episodes of clotting, over time, build into thickenings, and narrow the larger arteries, mainly in the heart and the neck, growing somewhat like tree rings. These areas of damage are usually called atherosclerotic plaques.
In time, the process of blood clotting, over a vulnerable area, leads to heart attacks and strokes as the final, fatal blood clot forms over an area of the artery that is already thickened and narrowed. In short, atherosclerotic plaques are the remnants of blood clots. Heart attacks and strokes are the end result of the same processes that caused plaques to form in the first place. Heart disease is a disease of abnormal blood clotting. It is as simple as that. The end.’
Ping. Elevator door opens and Bill Gates walks out.
Do you think he believed me? Of course not. Heart disease is caused by cholesterol, end of.
Bill Gates: ‘Who was that complete idiot in the lift, make sure he never gets the chance to speak to me again.’
Man in black suit: ‘OK boss.’
I should point out that I have never spoken to Bill Gates, and almost certainly never will. I merely used his name as an example of someone that you might try to convince using an elevator sales pitch.
I also know that my sales pitch will just seem like the most complete nonsense to most people. How can I possibly claim that atherosclerotic plaques are blood clots, when no-one else in the entire world is saying it? Am I not simply a flat-Earther? Indeed, am I not a lonely flat-Earther baying at the moon. At least the moon currently passing overheard, to join all the other moons that clearly fall into a big basket on the other side of the Earth – to be returned from time to time by an enormous dung beetle.
I like to think not, because the ‘blood clotting’ hypothesis fits all known facts about cardiovascular disease. In fact, many people have proposed the ‘blood clotting theory’ of CVD over, what is now, hundreds of years. From Rokitansky to Duguid to Smith – and many more. Here, from a paper written in 1993 called ‘Fibrin as a factor in Atherosclerosis’, co-authored by Elspeth Smith.
[Just to first remind everyone that Fibrin is a critical element of blood clots (along with platelets). Fibrin is made up of short strings of a protein called fibrinogen. When the clotting system (clotting cascade) is activated, the end result is that fibrinogen is stuck together end to end, in order to create long sticky strands of fibrin that entangle themselves around the clot and bind it all together.]
‘After many years of neglect, the role of thrombosis in myocardial infarction is being reassessed. It is increasingly clear that all aspects of the haemostatic system are involved: not only in the acute occlusive event, but also in all stages of atherosclerotic plaque development from the initiation of atherogenesis to the expansion and growth of large plaques.
Infusion of recombinant tissue plasminogen activator (rt-PA) into healthy men with no evidence of thrombotic events or predisposing conditions elicited significant production of crosslinked fibrin fragment D-dimer. Thus, in apparently healthy human subjects there appears to be a significant amount of fibrin deposited within arteries, and this should give pause for thought about the possible relationship between clotting and atherosclerosis.
It also provides in vivo biochemical support for the numerous morphological studies in which mural fibrin and microthrombi have been observed adherent to both apparently normal intima and atherosclerotic lesions. It should be noted that these observations are based on the human and not just the animal model.
In 1852 Rokitansky discussed the “atheromatous process” (sic) and asked “In what consists the nature of the disease?” He suggests “The deposit is an endogenous product derived from the blood, and for the most part from the fibrin of the arterial blood”.
One hundred years later Duguid demonstrated fibrin within, and fibrin encrustation on fibrous plaques, and small fibrin deposits on the intima of apparently normal arteries. These observations have been amply confirmed but, regrettably, the emphasis on cholesterol and lipoproteins was so overwhelming that it was another 40 years before Duguid’s observations had a significant influence on epidemiological or intervention studies of haemostatic factors in coronary heart disease.’
Unfortunately, since that paper was written the emphasis on cholesterol and lipoproteins has become even more overwhelming, and research into blood clotting and atherosclerosis has faded to almost nothing. It appears that the vast sums of money to be made from cholesterol lowering has completely distorted research into this area. All the funding, and all the international experts, have charged into the blind-alleyway that is the cholesterol hypothesis.
In a kind of supreme irony, in 1992 Pfizer were also travelling down the blood clotting route. I have (mentioned before) possibly the only remaining copy of a small booklet entitled ‘Pathologic Triggers New Insights into cardiovascular risk.’ And I quote:
‘Several features of mature plaques, such as their multi-layered patterns, suggests that platelet aggregation and thrombus formation are key elements in the progression of atherosclerosis. Platelets are also known to provide a rich source of growth factors, which can stimulate plaque development.
Given the insidious nature of atherosclerosis, it is vital to consider the role of platelets and thrombosis in the process, and the serious events that may be triggered once plaque are already present.’
Of course, this leaflet was promotional, for their product doxazosin. Doxazosin lowers blood pressure and also has effects on urinary retention. However, in this leaflet, they were trying to promote its effects on blood clotting factors. Basically, doxazosin reduces fibrinogen levels and plasminogen activator inhibitor – 1 (PAI-1). Plasminogen is activated by tissue plasminogen activator (tPA) which then becomes plasmin, an enzyme that slices fibrin apart, and breaks down blood clots. PAI-1 stops this happening, so makes clots more difficult to break down.
To quote, again.
‘These recent studies suggest that doxazosin may have a range of significant antithrombotic effects in many patients, in addition to its proven beneficial effects on hypertension and hyperlipidaemia. Following doxazosin treatment, a reduction of platelet aggregation and a tendency towards dissociation, together with a reduction in fibrinogen levels, might prevent excessive degrees of thrombosis at the site of vascular injury. In addition, reduced levels of PAI-1, and increased tPA capacity with doxazosin might stimulate fibrinolysis and early clot dissolution at these sites, and prevent the evolution of an acute coronary event.’
So there, couldn’t have put it better myself.
Then Pfizer bought Warner-Lambert, who made atorvastatin/Lipitor. The focus became Lipitor and lipids, lipids, lipids. Lo it came to pass that Pfizer never mentioned blood clotting ever again, lest it interfere with the LDL story. Pity really, because mighty Pfizer got it right in 1992. Smith got it right in 1993, Duguid got it right in the 1940s, and Rokitansky was right in 1852. Of course, there have been many others who got it right too. Many, sadly, lost to history.
At some point this, the blood clotting hypothesis, the correct hypothesis will win. Maybe that time will be now.
I realise some people may still wonder (if they have not read what I have written before) how the blood clot ends up within the artery wall/beneath the endothelium.
The reason is as follows. If the endothelium is damaged, a clot will form, sitting on the inside of the arterial wall. Once the clot has stabilised, and been reduced in size by fibrinolysis, the remainder of the clot will be covered over by Endothelial Progenitor Cells (EPCs) that float around in the bloodstream and are attracted to areas of endothelial damage.
After a layer of EPCs has grown over the clot, and converted themselves into mature endothelial cells the blood clot will now, effectively, be sitting inside the artery wall. Underneath a new layer of endothelium. Thus, clot becomes plaque.