I have been somewhat silent on this blog for a while. Mainly because I have been putting together ten thousand words on the true cause of heart disease. Of course, by heart disease I mean the thickenings and narrowings in the larger arteries in the body (atherosclerotic plaques). I am also focussing almost entirely on the arteries supplying blood to the heart (coronary arteries), and the main arteries that supply blood to the brain (carotid arteries).
Whilst atherosclerotic plaques can develop in other arteries that supply, for example, the kidneys, or the bowels, problems here are generally less common, and less severe – although not always. In general, however, the main killers in ‘heart disease’ are heart attacks and strokes (not all strokes, only the most common form of stroke, an ischaemic stroke). So, at the risk of becoming over-pedantic, and simultaneously sloppily inaccurate, I am calling heart disease Cardiovascular Disease (CVD), and looking at heart attacks and strokes.
With that out of the way, what causes cardiovascular disease (CVD)? Whilst it took me only a few days of research, many years ago, to realise that the diet-heart/cholesterol hypothesis was clearly nonsense. It has taken over thirty years to work out what is actually going on. In truth I could not truly progress until it suddenly dawned on me that I should not be looking for causes. For that is a mugs game.
Once you start looking for causes, you find that there is almost nothing that a human can ingest, or do, that has not been claimed to be a cause of CVD, or a cure for CVD. In many cases both… simultaneously. In 1981 a paper was published in the journal Atherosclerosis which outlined several hundred possible ‘factors’ involved in causing or preventing CVD. Today, if you hit Google, or Pubmed, I can guarantee that you could find several thousand different factors. If, that is, you could be bothered.
If you could be bothered, what could you possibly make of ten thousand different things involved in CVD in one way or another? Can they all be true risk factors? Some of them are certainly only associations, not causes. A few are simply statistical aberrations, found in one study and contradicted in another. Even removing them, there are so many, so very very many. Pick your favourite and trumpet it to the world. Vitamin K, Vitamin D, coffee, leafy green vegetables, omega 3 fatty acids, intermediate chain monounsaturated fats, HDL raising agents, selenium, lowering homocysteine…. on and on it goes.
Is there any other hypothesis where you have to fit in ten thousand different factors? No, there is not. Yet no one has been put off identifying more and more things. This is why, I believe, we have such a terrible mess. I amuse myself sometimes looking at the knots the cholesterol hypothesis ties itself into to.
Just to give one example. We have had ‘good’ cholesterol and ‘bad’ cholesterol for some time now. More recently we have ‘bad good’ cholesterol (raised HDL increasing CVD risk during the menopause), and ‘good bad’ cholesterol (light and fluffy LDL that protects against CVD). Now, that’s what I call a non-disprovable hypothesis. A risk factor that can be good, or bad. Or ‘Good bad’ and ‘bad good’.
Whilst contemplating such nonsense it came to me, in a moment of the blindingly obvious, that in order to understand CVD I had to move away from trying to fit ten thousand factors into the biggest intellectual jigsaw known to man, and move on. I had to know what the actual process is. What is actually happening in the arteries.
Once you start to look at CVD through this window, you suddenly realise that very little is ever written on this topic. The world famous cardiology bible ‘Braunwald’s Heart Disease’ is virtually silent on the matter. Or at least it was when I looked through it a few years ago.
In a massive book on heart disease, the process of CVD development is covered in less than half a page. The cholesterol hypothesis itself is usually left completely unexplained. Or there are gaping holes, and bits that you just have to take on faith. Raised LDL leaks/travels/gets into the artery wall where it creates inflammation and plaques develop. The end.
Then you start to ask, so why do plaques never develop in veins? Same structure as arteries, same level of LDL. Why do plaques never develop in the blood vessels in the lungs (pulmonary arteries and veins?). What has oxidised LDL got to do with it? Where does oxidation occur? How does LDL leak into coronary arteries, and carotid arteries, but cannot leak into arteries within the brain itself?
Questions, questions, questions and almost no decent answers. There is a kind of collective brouhaha noise with a lot of ‘well it just does’ thrown in when you start to ask. ‘Explain again, how does LDL get into the arterial wall. Each step please?’. You are usually met with perfect anti-Popparin logic. We know that raised cholesterol causes heart disease, so it must get into the arterial wall using some mechanism or other. And look, there is cholesterol in atherosclerotic plaques. So it must get through.
Of course, it is true you can find cholesterol in atherosclerotic plaques. No-one is going to deny that. But you can also find, for example, red blood cells (RBCs). Now, you might be able to explain how LDL can pass through endothelial cells (the cells that line the arteries) in some fashion. Although I would argue that, if so, why does LDL not pass through endothelial cells in veins. And why cannot it pass through, or between, endothelial cells in the arteries with the brain?
LDL molecules, after all, are minute in comparison to an endothelial cell. However, RBCs and endothelial cells are pretty much the same size. So, please try to explain to me how a RBC finds itself within the artery wall, underneath the endothelium? Try getting one cell, virtually the same size as another, to pass through it. A very clever trick indeed.
Then, if you start exploring further, you find that the cholesterol you find in atherosclerotic plaques almost certainly comes from the cholesterol rich membranes of RBCs.
‘The view that apoptotic macrophages (dead macrophages) are the predominant source of cholesterol in progressive (atherosclerotic) lesions is being challenged as new lines of evidence suggest erythrocyte membranes contribute to a significant amount of free cholesterol in plaques.’1
Oh look, it seems that the cholesterol does not come from LDL. Anyway, I am jumping ahead of myself here, and getting dragged back into explaining why the cholesterol hypothesis is nonsense. Which is playing the game on the opponents’ pitch, under their rules.
The simple fact is that, to replace the Cholesterol hypothesis, there is a need to come up with something better, which actually fits all the facts. That, of course, is rather trickier as – boy – there are a lot of facts. Also, some of them may seem utterly disconnected.
My simple credo is that, if your hypothesis cannot explain everything about CVD you cannot explain anything. Attempting to do otherwise means that you are left suggesting that there are many different causes, and many different processes, all of which end up causing CVD through non-connected mechanisms. Well if that is true, then we just have to give up. Smoking causes CVD like this, LDL causes it like that, diabetes in a completely different way.
This is why I get so frustrated when people simply shrug their shoulders in a debate on CVD, and retreat to the position of inarguable logic when they tell me that CVD is ‘mutifactorial.’ To which I agree that of course it is bleeding mutlfactorial (as are all diseases). But that the statement itself is meaningless, unless you can then tell me how all the ‘multi’ factors fit together within a single, unified process.
In short, with CVD, if you are going to explain it, you need to be able to explain how, for example, the following factors increase risk, and through what single mechanism, or process. [This is not an exhaustive list by any means, but these are all definite, and potent, causes]:
- Rheumatoid arthritis
- Steroid use
- Systemic Lupus Erythematosus
- Kawasaki’s disease
- Use of Non-steroidal anti-inflammatory drugs e.g. ibuprofen, naproxen and suchlike.
- Being a deep coal miner – especially in Russia
- Using cocaine
- Getting older
- Getting up in the morning – especially on Mondays
- Type II diabetes
- Raised fibrinogen level
- Cushing’s disease
- Air pollution
- Acute physical or psychological stress
- Chronic kidney disease
- Avastin – a cancer drug
Looking at one of these risk factors, System Lupus Erythematosus. Young women with this condition have, in some studies, an increased risk of CVD of 5,500%. Compare that with, for example, raised LDL. Even if you believe that it raises the risk of CVD, which is debatable, the increase in risk (as defined by mainstream research) is 66% for a 3mmol/l increase in the LDL level2. Changing the LDL level by this much takes you from low risk, to Familial Hypercholesterolaemia (FH).
If we accept that the 66% figure is, indeed, correct, we can see that SLE increases the risk 83 times more than having a very high LDL level. Or, to frame this differently. SLE increases the risk of CVD 8,300% more. Clearly, therefore, SLE has far more to tell us about what really causes CVD than raised LDL ever could. Deep coal miners in Russia have their final, fatal, heart attack aged 42, on average. Children with Kawasaki’s disease can die of a heart attack aged 3.
Here, therefore, are the real causes of CVD. Super accelerated CVD with death at a young age. No need for statistical games. This is the where the answers truly lie. Now comes the difficult bit. How can you fit them all together within a single disease process, without finding anything contradictory?
Ladies and gentlemen, it took me thirty years.