Scientific hypotheses are easy. You can make up thirty a day if you want. In the arena of cardiovascular disease, I have watched many a hypothesis spring to life in the middle of a conversation. For example, I was at a meeting where an ‘expert’ was attempting to describe what foods cause CVD. Pizza was held up as a very unhealthy food.
I pointed out that there had only been one study done on pizza consumption and CVD. It showed, very clearly, that the more pizza you ate, the lower your risk of CVD. Quite a strong protective effect as a matter of fact. The study was done in Italy.
The moment the geographical location was mentioned, the expert simply replied. ‘Oh yes, but Italian Pizzas are far healthier than pizzas in the UK.’ Thus, ‘the healthy Italian Pizza hypothesis’, was simply plucked from thin air. It was based on no evidence whatsoever, but it seemed reasonable to the expert at the time I suppose. Who knows, it may even be true. Although I suspect not.
Now, I have nothing against the creation of any scientific hypothesis that anyone cares to put forward. Science progresses, primarily, through the development of new ideas. But if you are going to propose a new hypothesis it is beholden upon you to do something that few people then seem willing to do. You need to try and disprove it. There is no point looking for supporting data, you can find supportive data for almost any idea you decide to come up with.
There is a fairly well-known and humorous explanation for CVD (humorous the first fifty times you are told it anyway) that goes like this:
- Japanese eat very little fat and suffer fewer heart attacks than us
- Mexicans eat a lot of fat and suffer fewer heart attacks than us
- Chinese drink very little red wine and suffer fewer heart attacks than us
- Italians drink excessive amounts of red wine and suffer fewer heart attacks than us
- Germans drink beer and eat lots of sausages and fats and sufferfewer heart attacks than us
- The French eat foie-gras, full fat cheese and drink red wine and suffer fewer heart attacks than us
CONCLUSION: Eat and drink what you like. Speaking English is apparently what kills you
How would I disprove the ‘speaking English’ hypothesis? Assuming, that is, I could be bothered. I would point out that, currently, speaking Ukrainian kills you. Ukrainians have ten times the rate of CVD of the UK, and the US. Ergo, it is not speaking English that kills you. Next.
Moving to slightly more serious things. Disproving is where I started with in my long term search for a hypothesis about CVD. I did not start out with my own hypothesis. I started out trying to disprove other hypotheses.
Which inevitably meant that I started with the diet-heart/cholesterol hypothesis, as this was, and remains, the number one hypothesis in the area. I am not going to go through all the refutations again. Suffice to say that it failed in so many ways that it was clearly bunk.
Of course, this left me thinking, if CVD has nothing to do with saturated fat in diet, or cholesterol levels, it must be something else. What could that something else be? I began by looking at stress (I realise that the term stress is not remotely precise). I started with the thought that stress, whilst eating, could be a cause/the cause. If you are stressed you will be releasing stress hormones, these antagonise insulin, so when you eat blood sugar levels spike and VLDL levels spike etc.
I became interested in the idea that we measure almost all metabolic parameters e.g. blood sugar, VLDL, cortisol, glucagon in the fasting period. Yet, perhaps all the damage was being done within two hours of eating. So it seemed that we may, to use an analogy, be trying to understand football by visiting a football stadium only before and after the match is being played. ‘Blimey, nothing different ever happens here at all.’
I felt I was onto something, but thinking then moved on to a more general stress hypothesis. I felt that I got most of the way to creating a perfect scientific hypothesis. I had causes and pathways and a mass of supportive data. However, I could still find plenty people with an increased risk of CVD who were not in any way stressed. They had such things as antiphospholipid syndrome (Hughes syndrome). Or they were children with Kawasaki’s disease. Or they had type II diabetes, or they were taking drugs, such as non-steroidal anti-inflammatories, or Avastin. Or… the list went on.
Equally, I could find factors that reduced the risk of CVD, that had nothing to do with reducing stress. For example, aspirin (not a massive effect, but it does exist). Von Willibrand disease, omega-3 fatty acids, potassium, vitamin C. As with causal factors, the ‘nothing to do with stress’ list went on.
So, what did this mean? That stress did not cause CVD, or that it caused only one type of CVD. Or it caused CVD through a completely different process than other causes of CVD? It was at this point that I began to realise I was looking at things the wrong way round. There was no point in saying what things may, or may not, cause CVD – and compiling an ever-lengthening list of ‘risk’ factors.
I had to work out the process through which any factor may operate, both causal and protected. As some of you will know, in this series, I have pointed this out before… many times. But I think that it cannot be said often enough.
So I turned the entire thinking process inside out, and started again. I began by asking the question, what are atherosclerotic plaques? What do they consist of? What do they contain? It became very clear that they are primarily blood clots – in various stages of development and repair.
Having recognised this, I went further back, or forward, to look at the final event in CVD. This is, basically, the formation of a blood clot. Heart attacks occur when a blood clot blocks an artery supplying blood to the heart (there are caveats here, but I am not going into them at this point). Stokes occur when a blood clot blocks an artery in the brain (further caveats).
There is little disagreement that the blood clot is the final event in CVD. Most acute treatments for heart attacks and strokes are, essentially, ways of removing any clot that has formed. You can use aspirin, or more potent clot busters, or you can stick in a catheter to remove the clot/open it up/stick in a stent. You can do a bypass, diverting the blood round the clot… etc. Interventional cardiology could, pretty, accurately be described as ‘blood clot management.’
Many of the drugs used to prevent heart attacks and/or strokes are also anti-coagulants e.g. aspirin, Clopidogrel, warfarin, apixiban etc. [Statins are also potent anticoagulants]. Yet, and yet, no-one seemed willing even to countenance the possibility that blood clots also cause atherosclerotic plaque development. ‘Yes, blood clots kill you, but they have nothing to do with plaque formation.’
‘What, even when plaque contain such things as red blood cells, cholesterol crystals, fibrin, fibrinogen and Lp(a) and….’ the list of things found in both blood clots and plaques is very long.
But of course no expert can agree to this ‘blood clot’ hypothesis. To do so means that you have to discard the cholesterol hypothesis. Which ain’t going to happen anytime soon. So we currently have the dual hypothesis. Cholesterol causes plaques to form, then blood clots kill you. The ‘atherothrombosis’ hypothesis. Which can look as though the mainstream is agreeing about the importance of thrombosis, but is actually a way of keeping the cholesterol hypothesis alive.
For a while I half agreed with this atherothrombosis hypothesis, but the more I thought about it, the more it started to fall apart. I began to focus down on one thought. Can you explain CVD though the ‘abnormal’ development of blood clots alone? Can you link any and all factors, known to cause CVD by their impact on one of two things:
- Endothelial damage (which triggers blood clot formation)
- Increasing blood coagulability (making clots more like to form, become bigger and/or less easy to break down)
Then I started writing out a list of things that I knew did one, or both, of these things. There was no particular order to this:
- Cocaine use
- Kawasaki’s disease
- Rheumatoid Arthritis
- Kidney failure
- Non-steroidal anti-inflammatories e.g. brufen, naproxen
- Biomechanical stress (within arteries)
- Systemic Lupus Erythematosus
- Antiphospholipid syndrome (Hughes syndrome)
- Vitamin C deficiency
- Raised fibrinogen levels (key clotting factor)
- Bacterial infections inc. gingivitis
- Increased plasminogen activator inhibitor – (1 PAI-1) levels (critical factor in blood clot repair/breakdown)
I could have kept going, but that is enough for now. What do all of these things have in common. They increase the risk of atherosclerotic plaque formation, death from CVD. Most importantly, of course, they cause endothelial damage and/or increased blood coagulability. And I could not, and cannot, think of anything else that links them all together.
Then I started to think about factors that reduce the risk of CVD.
- Exercise (overall, not whilst doing it)
- Moderate alcohol consumption
- Clopidogrel (expensive aspirin)
- ACE- inhibitors (a blood pressure lowering agent)
- Von Willibrand disease (lack of a specific clotting factor in platelets)
- B vitamins (enough to reduce homocysteine)
- Adequate Vit C (no idea what the correct intake should be)
- Potassium (higher consumption reduces platelets sticking together)
- Vitamin D
- Nitric Oxide (through sunlight – and other nutrients e.g. l-arginine)
- Magnesium (and other micronutrients)
Again, I could keep going. What do all of these things have in common. Well, once again, they either protect the endothelium, or they reduce blood clotting. And they all reduce the risk of CVD.
To my mind there was, and is, an almost perfect correlation. But, as I said earlier. Looking for supportive data is all very well. Can you find the black swan? Or black swans. Are there facts that completely contradict the ‘it’s all to do with blood clots’ hypothesis of CVD?
Warfarin could be one such black swan. Warfarin reduces the risk of stroke (in atrial fibrillation), but it does not really reduce the risk of heart attacks. It is a very powerful anti-coagulant, so surely it should do both. Yet it does not. Why not? Is this a black swan, or can it be explained?
My conjecture is, as follows.
Warfarin is a vitamin K antagonist. It is active in the liver, and interferes with the production of a number of clotting factors (mainly prothrombin and factor VII). This tends to inhibit clots forming, spontaneously, within the blood itself. Which is why warfarin is very effective in Atrial Fibrillation.
In Atrial Fibrillation, the upper chambers of the heart fibrillate (twitch rapidly) so some of the blood tends to get stuck in the upper chambers (the atria). Blood in stasis tends to start clotting. A clot forms, it is then ejected into the lower chamber (the ventricles) where it is then immediately pumped out into the rest of the body. These clots can get stuck anywhere the blood vessel narrows sufficiently – often in the brain, causing a stroke.
Warfarin also works well when you have blood stasis in the veins. For instance, if you break your leg, you will be put in a cast. At which point, due to physical immobility, the blood tends to stop flowing freely, if at all. At which point clots can form, a deep venous thrombosis – DVT. This can then break off and travel through your heart into your lungs causing a pulmonary embolus (PE), which can kill you. Warfarin tends to stop this ‘stasis’ blood clot formation. [Long distance flight and sitting anywhere for a long time can have the same effect]
So why does warfarin have little effect on the clots that cause myocardial infarction. This is probably because damage to the endothelium – the trigger for all the other downstream problems – exposes tissue factor (TF) to the blood. Tissue factor sits within the artery wall itself, and it is the big daddy of clotting.
As you can imagine, the body views damage to an arterial wall as a potential emergency situation that requires immediate and powerful clotting. A damaged artery wall exposes TF Once TF is in play, it will ride straight over such things as a lack of factor VII and prothrombin. TF will directly drive platelets to stick together, and form a plug over the area of damage. It can also directly activate thrombin etc.
Thus, whilst warfarin will prevent the slower ‘stasis’ clots from forming, it will have little effect on the emergency ‘damage to the artery wall’ clotting caused by exposure to TF. I am not going into any more detail on this, but it could be said that warfarin is a good ‘intrinsic’ anticoagulant. But has far less impact on the ‘extrinsic’ clotting system.
On the other hand aspirin, which prevents platelets sticking together, will have a more significant effect on reducing clot formation after activation of TF, as will Clopidogrel, as will a lack of von Willibrand factor (as found in Von Willibrand disease). This, to my mind at least, fits with the fact that ‘less potent’ anticoagulant factors can reduce risk of heart attacks (albeit by differing amounts), whereas warfarin does not.
So, the lack of effect of warfarin on heart attacks can be understood, in relation to where it actually acts in the coagulation system. In addition, because warfarin is a vitamin K antagonist, and vitamin K appears to protect against the build of calcium in various tissues, warfarin accelerates calcification in artery wall. Which could be a further problem in itself – leading to a higher rate of CVD.
Now, you could think this is all rather convoluted. An attempt to explain why an apparent contradiction is not a contradiction all. You could, of course, be right to think this. But firmly believe that the lack of effect on warfarin, on heart attacks, can be explained. Through a deeper understanding of the clotting system. In fact, the different effects of different anticoagulants on CVD risk supports rather than undermines the hypothesis.
Perhaps, now, you may gain an inkling as to why it has taken me so many, many, years to try and establish the true underlying cause of CVD. It did not take too long, at least once I got my thinking the right way round, to work out that blood clotting may be the underlying process that underpins CVD. What has really taken the time is looking for contradictions.
And, in the spirit of true scientific endeavour, I welcome as many attacks/contradictions as people can think of. What does not kill a scientific hypothesis can only make it stronger.