4th November 2021
And so, after only thirty short years of research, my book on heart disease is finally finished, and is published today. Up to now my books, and blogs, have mainly consisted of telling people what does not cause heart disease. Or to be slightly more accurate, cardiovascular disease.
Hint, it is not cholesterol, or LDL, or LDL/cholesterol, or the good cholesterol/bad cholesterol ratio – or whichever term is in favour today.
So, what does cause cardiovascular disease? Those few, those happy few, who have read this blog over the years may already know a great deal of what is in the book. For others this will be a new and, hopefully, fascinating foray into a completely different way of thinking.
The first point I want to make, then emphasize, then re-emphasize, is that there is no ‘the’ cause of cardiovascular disease. By which I mean that there is not, and never has been, any one single factor that can be considered to be ‘the’ cause. Instead, there are many. They can work by themselves or combine with others.
So you can say that, for example, diabetes is ‘a’ cause of cardiovascular disease. But you cannot say that it is ‘the’ cause. Yes ‘a’ cause but not ‘the’ cause. This is not purely semantics. Whilst the difference may seem subtle, it is critical. A table, or the table. A man, or the man. An answer, or the answer.
If there is no ‘the’ cause, what does this mean in practice? It means that many different things, or factors, or whatever term you use to describe them, can lead to exactly the same disease. You may then ask; can they all be described as causes? Boy, oh boy, it all gets very complicated. I have found that the language used here has become perhaps the greatest barrier to understanding.
Laying that admittedly complex issue to one side for the moment, and trying to keep things concrete, rather than abstract, the inescapable fact is that many, many, different factors can increase the risk of/cause cardiovascular disease. So, how can they all be fitted together into a unified theory?
It has been tricky, very tricky.
Mainstream medicine has effectively stuck its fingers in its ears, yelled ‘la, la, la, I’m not listening,’ and run away from this entire issue. The current position is simply to state that cardiovascular disease is multifactorial. No need to think beyond that. Just find the important risk factors, then deal with each one separately. This works up to a point. Stop smoking, keep the blood pressure down, control diabetes and the risks will fall. I can’t argue with any of these actions, but they only get you so far.
In the end, you cannot just bring a whole bunch of wildly different factors together, declare that cardiovascular disease is ‘multifactorial’, and everything is now, officially, sorted. No need to look further. Move on, nothing to see here.
Many years ago, the French mathematician and science philosopher Henri Poincaré stated the following, which I find describes the situation almost perfectly. ‘Science is built of facts, as a house is with stone. But a collection of facts is no more a science than a heap of stones is a house.’
In the same way, calling cardiovascular disease “multifactorial” is just a clever sounding way of describing a pile of stones. There is no structure, no understanding, no hypothesis.
Below, for example, is a list of factors that are closely associated with an increased risk of cardiovascular disease. It comes from the latest UK cardiovascular risk factor calculator, called Qrisk3, which you can see here https://qrisk.org/three/
You input your personal data e.g., age, sex, diabetes, blood pressure and suchlike, it then purports to calculate your risk of a cardiovascular event in the next ten years. In truth, not that accurately.
I deconstructed the Qrisk3 factors and put them into a list:
- Total cholesterol/HDL ratio
- Raised blood pressure.
- Variation in two blood pressure readings
- 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
Fine…ish. It is true that all these things are associated with an increased risk of cardiovascular disease, in the UK, at present. However, to create a coherent hypothesis, you have to explain how they fit together. Where’s the house?
For example, you need to link a ‘history of migraines’ together with smoking. Then explain how they both lead to exactly the same disease. Or diabetes and severe mental illness. Or ethnicity and chronic kidney disease. Someone, anyone. Good luck.
As a quick aside, you may notice that the low-density lipoprotein level plays no part in this list of ‘most important’ risk factors in Qrisk3. None. Instead, we have the total cholesterol/HDL ratio – which is a very different thing indeed. It is only very indirectly related to the low-density lipoprotein level, if at all.
Moving on, the more I studied cardiovascular disease, the more I became aware of an inescapable fact. Which was that, in order to claim that I understood it, I had to establish how such very disparate factors can all lead to exactly the same disease.
This, in turn, meant giving up on the causal model. Because all that the causal model had produced was an ever-growing pile of ‘stones.’ Beneath which, the structure of an underlying house was becoming increasingly difficult to discern.
The process model
What I had to do, as pointed out to me by the late, great, Paul Rosch, was to turn my attention to the disease process. As in, what is actually going on? What is cardiovascular disease? What are we looking at?
What became very clear to me, very early on, is that what we cannot be looking at LDL molecules leaking through artery walls – or to be more exact, the endothelial cells that line all artery walls – then gradually building up into cholesterol plaques/thickenings.
This blog is not long enough to describe in any great detail why this ‘LDL leaking through’ process makes no sense. There is a great deal of information to be covered. Most of which is described, in some detail, in the book.
However, just to give you a couple of thoughts to consider. All blood vessels are lined by cells called endothelial cells. These cells, and indeed all cells in the body, have enormously complex mechanisms in place to regulate what gets into them, and what can then escape from them.
This regulation can control the movement of the largest molecule, down to the very smallest. Including tight control of the entrance, and exit, of single atoms e.g., sodium, or potassium, or calcium (in truth, in the body, these atoms exist as ions – which is just the name for a charged atom).
In short, nothing can gain entry to a cell unless the cell grants entry. Nothing [Unless you are a virus e.g., COVID19, whereby you hijack a receptor to sneak in – the cunning little devils]. For anything to gain entry, the cell must open a channel of some sort i.e., an ion channel. Or it has to manufacture a receptor. The receptor will then lock onto the substance floating in the bloodstream and drag it through the cell membrane and into the cell.
Just to pluck an example from the air. In order to get low-density lipoprotein into a cell, the cell must first synthesize a low-density lipoprotein (LDL) receptor. It then transports the receptor to the cell membrane. Once in place, it locks on to a passing LDL molecule, and then drags the entire LDL/receptor complex back inside – before breaking it down. Without this machinery getting to work, there is no way to get LDL into a cell. None.
Just to repeat this, from a slightly different direction. Cells can control the movement of single ions/atoms through their cell membranes. An LDL molecule is massive in comparison to an ion. Think rowing boat vs. super tanker.
Yet, if we are to accept the LDL hypothesis, we are supposed to believe that cell membranes simply step aside, or part like the red sea, to wave through a super-tanker sized molecule.
It all gets more unlikely. The cell must then allow the LDL molecule to propel itself from one cell membrane to the other. A very clever trick for an inanimate molecule, with no means of propulsion. Looked at from a human scale, if I were an LDL molecule, a cell would be about half a mile across.
Even if the LDL managed this, once it reached the other side of the cell, the LDL would need to pop back out of the cell and into the artery wall behind – using an inside-out LDL receptor perhaps?
Some people have therefore suggested the LDL molecules simply sneak between endothelial cells. But this, too, is impossible. Endothelial cells are tightly bound to each other, with a whole series of protein bridges a.k.a. ‘tight junctions.’ These too, can prevent the passage of single ions. Which means that nothing can get from the blood and into the artery wall though a side entrance either:
‘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.’1
If this were not the case, if the ‘endothelium’ did not represent a perfect barrier, we would all die immediately. To quote from a paper in the journal ‘Tissue Barriers’ yes indeed, there is such a journal:
‘Physiological barriers provide the framework for a boundary between circulating blood and interstitial fluid, a pre-requisite for mammalian life.’2
So, yes, there is simply no way for LDL to sneak between cells either.
Just to give you one example of what happens if you loosen the tight junctions between cells, we can look at the Ebola virus. This virus opens up the tight junctions between endothelial cells. At which point the endothelial barrier function is critically compromised, and blood can now escape into the tissues, and organs.
This leakage is the reason why Ebola is also known as a form of haemorrhagic fever. Blood appears in the cornea, so your eyes become bloodshot. You cough up the blood that that has escaped into your lungs. Your tongue falls off. Your urine is filled with blood from your kidneys, your bowel motions turn black, and then…. Bang, dead, from massive fluid loss and vascular collapse.
Ebola demonstrates very clearly the critical importance of tight junctions between cells. Open them up… and you die. How did you think Ebola actually kills you? I imagine that you, like me, before I started looking at this area in detail, probably never really thought much about it. You just vowed never to catch it:
‘Ebola patients experience a breakdown in endothelial barrier integrity that leads to massive fluid losses and vascular collapse.’3
That would be where the ‘pre-requisite for mammalian life’ comes in.
Anyway, forgetting about that for the moment. Let me take you back to think about an alternative process model. To ask, so what is the disease process that allows you link smoking to, say, systemic lupus erythematosus? Because both things are most certainly causal. ‘A’ cause, rather than ‘the’ cause, of course.
And what of the many, many, other factors, not mentioned in Qrisk3? This is a very long list indeed. For example: cocaine use, antiphospholipid syndrome, Avastin, use of steroids, periodontitis, Sjogren’s syndrome, sickle cell disease, high fibrinogen levels. I could go on… for a few pages.
The harder you look, the more stones you unearth. In the end I had this massive pile of stones which became my two-thousand-piece jigsaw puzzle – just to change metaphors abruptly. A puzzle that didn’t even have a box to go with it, so I didn’t know what the picture was supposed to look like once I fitted all the pieces together. Was it a cow, or a lake, or a mountain scene?
At this point, you may get some insight as to why I called the book ‘the enduring mystery of heart disease’. Admit defeat …me? Well, usually, I am quite good at chucking in the towel. If at first you don’t succeed, give up, why make an idiot of yourself. But for some reason I did not, could not.
This bloody thing kept nagging away. I would lie awake at night considering the morphology (structure) of plaques. I contemplated the blood clotting system in all of its massively complex detail. I read papers outlining the thirty-two different types of HDL (good cholesterol). I discussed plaques with cardiologists and pathologists. I stumbled across entirely new entire worlds of research that I didn’t know existed. There were few rabbit holes down which I did not disappear.
The answer, when it finally lodged in my brain, was surprisingly simple. Not only was it simple, but it has also been kicking around for very nearly one hundred and seventy years. In 1852 Karl von Rokitansky published his ‘encrustation hypothesis.’ Describing what he saw when he closely examined atherosclerotic plaques.
‘Rokitansky proposed that the disease is the result of an excessive intimal deposition of blood components (blood clots) including fibrin. He maintained that localized thickening, atheromatous changes and calcification of the arterial wall are due to the repeated deposition of blood elements and their subsequent metamorphosis and degeneration on the lining membrane of the vascular wall.
There you go, that’s it. Blood clots, blood clots… and more blood clots.
In fact, I am being slightly disingenuous here. I had been thinking about blood clots for many years, but in a rather uninformed and directionless way. Many moons ago, when I was a medical student at Aberdeen, I was briefly taught cardiology by Dr Elspeth Smith. In a small group tutorial, she mentioned to us fresh faced students that LDL cannot penetrate the endothelium. Bing!
This was almost an off the cuff remark. Almost… but the way she said it… I knew that there was something critical here. A secret never to be told. Or, it was like a good murder mystery, where a chance remark represents the most important clue. My antennae pricked up at that moment and have not stopped twitching since.
She also wrote this over forty years ago:
‘After many years of neglect, the role of thrombosis (blood clots) 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.’
Yes, she knew what causes cardiovascular disease. I now know, for sure, that she knew. She never knew that I knew she knew. I was daft and did not take the opportunity to discuss things with her. Too much ego, I suppose. I also went off in other daft directions for many years. Looking for ‘the’ cause: the lost chord, the Ark of the Covenant, the Holy Grail. Of course, I never found ‘the’ cause, because it does not exist. Oh, well.
It was only when I was directed to return to process, that I came to fully recognise her genius – and the genius of others. I only hope that this book will help to raise her status up to where it belongs. Along with Rokitansky, Duguid, Ross and all those who pursued the blood clotting route over the decades, nay, centuries now.
Yes, I know this probably sounds very simple, and possibly completely wrong. There is no way you are going to believe straightaway that atherosclerotic plaques are just blood clots, ‘in various stages of metamorphosis and degeneration’. How can this possibly be true?
The reason why it can be true, is because it fits all the known facts about cardiovascular disease, and atherosclerotic plaques, and heart attacks, and strokes, and suchlike. Yes, everything.
For example. It is widely known, and accepted, that the single most common ‘final’ event in cardiovascular disease is the formation of a large blood clot – almost inevitably on top of an existing plaque. This can fully block an artery, leading to downstream mayhem.
It is also widely accepted that thrombus formation, on top of an already existing plaque, can make plaques suddenly jump in size. Here, for example, is a passage from a paper in the journal Atherosclerosis. This is about as mainstream a publication as you can get in cardiovascular disease research. The paper was called: ‘The role of plaque rupture and thrombosis in coronary artery disease.’
‘In addition, plaque rupture and subsequent healing is recognized to be a major cause of further rapid plaque progression.’ 4
I could find a million quotes confirming this mechanism, without even breaking sweat.
In short, it is not remotely controversial to say that blood clots represent the final event, the thing that kills you. Nor is it controversial to say that plaques grow through the deposition of a new clot on top of an existing plaque. I would get very little argument from any cardiologist about this sequence of events. I know, I have had many such discussions.
But what is not accepted, will simply not be accepted, is that the arrival of a blood clot on the ‘healthy’ arterial wall is what initiates atherosclerotic plaque formation. Instead, it is almost universally accepted that it is LDL that does this, and LDL alone. Therefore, current conventional wisdom is that we have a three-step process:
- The plaque starts – due to LDL leaking through the artery wall
- The plaque grows – due to deposition of new blood clots on top of the existing plaque (which has become a point of clotting vulnerability)
- A ‘final’ obstructive blood clot forms on the already grown plaque, causing a heart attack, or stroke – due to a blood clot
In one way, all I have done in this book is to make it clear that, yes, we do have a three-stage process. However, low-density lipoprotein plays no part in it. It is entirely driven by blood clots, from start to finish. Which means that the first step is not:
- The plaque starts – due to LDL leaking through the artery wall
The first step is that:
- The plaque starts, due to endothelial damage, and resultant clot formation (creating the ‘focus’ for further plaque growth)
Then, everything else follows, as described earlier by Elspeth Smith:
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.
Yes indeed, the Clot Thickens.
In truth, this is not a major leap in thinking? All I actually needed to do was remove low density lipoprotein from the picture. Once I did that, the jigsaw actually fitted together. Leave it in, and you cannot create a coherent hypothesis. Everything is distorted, nothing works, the picture is a mess. Take it out and it all makes sense.
I hope this brief foray into the process of cardiovascular disease has left you suitably enthused to buy the book, read it, and find out in much greater detail what is really going on here. And also, what you can do to prevent heart disease. It has been my life’s work. I hope I am right. I hope you can learn from it and enjoy it.
The Clot Thickens is available in paperback and eBook.
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