A summary up to now
Heart disease is really a disease of the larger arteries in the body. Essentially it is a build-up of atherosclerotic plaques (thickenings and narrowings) in the arteries. This could more accurately defined as cardiovascular disease (CVD), in that it can affect all large arteries, not just the arteries in the heart, or neck.
The final stage of plaque formation is complete blockage of an artery due a large blood clot forming, usually, over an existing plaque. This is the underlying cause of most heart attacks. In the case of an ischaemic stroke, the clot breaks off the main artery in the neck (carotid artery) and gets stuck in a smaller artery in the brain.
Other forms of ‘heart attacks’ and strokes can occur due to different mechanisms e.g. atrial fibrillation causes a clot to form in the atria before breaking of and travelling into the brain. Or, sudden acute stress on the heart can lead to catastrophic ischaemia, causing a ‘heart attack’ – without any underlying plaque. These type of stroke and ‘heart attack’ are not covered in this series of blogs.
When it comes to CVD, the cholesterol hypothesis holds sway over the medical profession i.e. when the cholesterol level is high it is deposited on/in the artery creating the thickenings and narrowings.
I have long argued that this hypothesis makes no sense from any perspective, and that CVD is actually caused by another process that that has little, or nothing, to do with cholesterol (in whatever form cholesterol is described). Instead CVD is a four step process:
Endothelial damage
Clot formation/dysfunctional clot formation
Clot repair/dysfunctional clot repair
The final, fatal, blood clot
In short, plaques are simply blood clots – in various states of repair. The final event (heart attack or stroke) is simply one part of exactly the same process that caused the plaques to form in the first place. Just bigger and more deadly.
In this series, up to now, I have mainly focussed on the process of damaging the endothelium, and explained how this inevitably results in a blood clot forming over the area of damage. Repair of the clot consists of forming a new layer of endothelium over the blood clot, thereby drawing it into the arterial wall. At which point it is attacked and broken down by monocytes and macrophages – amongst other things.
However, if the endothelium is repeatedly and rapidly damaged – at the same spot – the repair systems become overwhelmed and the clot/plaque, rather than being broken down and removed, starts to grow and turn into a dangerous ‘vulnerable’ plaque. I am now going to look at the process of clot formation itself – ‘thrombogenesis’. (Thrombo = clot, genesis = starting)
Clot formation
Clot formation is complicated, very complicated. However, I am going to try and make it as simple as possible by looking at three main players. At least I will to start with.
Tissue factor
Platelets
Fibrinogen/Fibrin
As mentioned earlier, tissue factor (TF) sits within artery walls (and vein walls). It is the key trigger factor for most blood clots. Normally the blood is protected from contact with TF by the endothelium. However, if you damage the endothelium, TF is exposed to blood. This fires the starting gun for a massive and explosive cascade of blood clotting. This is known as the ‘extrinsic pathway.’ By extrinsic I mean basically factors that sit outside the bloodstream. And by this I basically mean TF (at least I do for the purposes of this discussion).
Having said this, it is possible to have blood clots form without TF involvement. This occurs primarily in veins, and is usually due to blood flow stasis i.e. the blood stops flowing in a blood vessel. This happens if you cross your legs, lie in bed, have a plaster cast on, or take a long haul flight, or suchlike. If the stasis lasts too long, the blood can slowly start to form a clot. A big one usually. This is usually referred to as a DVT (deep vein thrombosis).
The other place this can happen is, as described before, in the atria, when you have atrial fibrillation. Rather than the blood being rapidly ejected with each heart beat, when the atria fibrillate, the blood can become trapped in eddies, not moving. Then clotting, then escaping, then stroke.
Blood clots which are created mainly through the action of the intrinsic pathway are, usually, far less strongly bound together – because fibrin is not created to the same extent. Therefore, a DVT that forms in a large vein in your leg can easily break off, travel up the vein and into your heart. It can get stuck there – instant death. Or it can pass straight though the heart and into the lungs, where it gets stuck. Causing a pulmonary embolism. Can be fatal, but not always.
Intrinsic pathway clots are stimulated by all the clotting factors you may have heard of. Factor X, factor IX, factor VIII, prothrombin, and suchlike. If you want to stop these clots forming you can use various anticoagulants such as warfarin, or heparin, or the new oral anticoagulants (NOACs). These block various intrinsic factors making the blood ‘thinner’ and less likely to clot.
Warfarin, for example, interferes the action of vitamin K, which is needed by the liver to synthesize several clotting factors. Indeed, warfarin is often referred to as a vitamin K antagonist. Practically, this means that you can rapidly reverse the actions of warfarin by giving a massive dose of vitamin K.
Sorry, I said I was only going to talk about tissue factor, platelets and fibrinogen. But I think the fact that blood clotting has different pathways can help to explain why, for example, warfarin is very poor at preventing CVD, but very good at preventing stokes caused by atrial fibrillation, and can prevent dearth from DVT.
At times I am just staggered by the amazing ingenuity of human physiology. How the hell, I think to myself, did all of this evolve? Blood clotting is just one physiological system, one small part of how the body works, and just this one part is frighteningly complex.
Anyway, moving on. In the arteries, if you want to get a blood clot to form, you need expose the blood to TF and the clotting system then fires into action. The first part of the process is that platelets are attracted to the site of damage. Platelets are small blood cells which, when ‘activated’ become very sticky and start to clump together. They then release a massive family of different factors, including clotting factors, that stimulate the rest of the clotting cascade. [Platelets also contain quite a lot of TF, which is transferred to them by circulating monocytes – a tale for another day].
The final step of the clotting cascade is to join lots of small fibrinogen stands together. Fibrinogen consists of short thin strands of protein. If you stick hundreds of strands together, end to end, you get fibrin. This is a bit like fishing line. Long, tangly, sticky and extremely strong. It binds platelets together into a furiously strong clot.
At the same time, fibrin drags in almost everything else into the blood stream, and binds it into the clot. White blood cells, red blood cells, lipoproteins etc. Some of these may, or may not, be innocent bystanders in the clotting process. Although, the closer you look, the more you will find that almost all blood elements are actually players in the process.
Just to look at one example here, very low density lipoproteins (VLDLs), also known as ‘triglycerides’. These lipoproteins have significant effects on clotting. To understand how this happens I need to move sideways for a moment, and bring in something that most of you will never have heard of. Plasminogen activation inhibitor 1 (PAI-1).
To explain. Blood clots, when they form, incorporate within them an enzyme called plasminogen. This enzyme, when activated, can slice strands of fibrin apart and, thus, break down blood clots into tiny bits. After a heart attack, or stroke, you can be given tissue plasminogen activator (tPa) – or something very similar. This activates plasminogen within the blood clot, and causes the clot to disintegrate. Thus, a blocked artery will be reopened.
Now, as with everything else to do with blood clots, we have yin and yang. On one side we have plasminogen; on the other side we have plasminogen activator inhibitor – 1 (PAI-1). This does exactly what you would expect. It inhibits the action of plasminogen. This is not surprising. In all parts of the clotting system, for every factor that reduces blood clotting tendency, there is an equal and opposite factor increasing blood clotting. All is in balance.
Plasminogen slices clots apart, PAI-1 prevent this from happening. Clearly, therefore, the more PAI-1 you have, the more difficult it is for a clot to be broken apart. So any factor that increases PAI-1, will make any blood clot that forms bigger and more difficult to shift. Which brings us back to VLDL – a.k.a. triglycerides.
‘In vitro data have shown that triglyceride-rich very low density lipoprotein (VLDL) particles enhance PAI-1 secretion from endothelial cells and liver cells Furthermore, it has been shown that VLDL stimulation of PAI-1 expression in endothelial cells is mediated through transcriptional activation of the PAI-1 gene, and a VLDL response element has been identified in the promoter region.’ 1
Or, to put this more simply. If you have lots of VLDL in your blood, you will stimulate the production of PAI-1. So, you will have impaired breakdown of blood clots (impaired fibrinolytic activity). Which means that (from the same paper):
‘Hypertriglyceridemia is associated with an increased risk of coronary heart disease (CHD). Impaired endogenous fibrinolytic function is a frequent finding in subjects with hypertriglyceridemia.’
The most common condition where you are most likely to find high VLDL levels is type II diabetes. In type II diabetes there is, always, a high PAI-1 level. I am not sure if this needs a reference, but you are getting one anyway, with regard to type II diabetes:
‘The combination of hypertriglyceridemia, glucose intolerance and inflammation is linked with increased production of the primary inhibitor of endogenous thrombolysis, plasminogen activator inhibitor-1 (PAI-1). Recent data suggest that PAI-1 contributes directly to the complications of obesity, including type 2 diabetes, coronary arterial thrombi, and may even influence the accumulation of visceral fat.’2
The bigger picture – other factors
I think, as always, I have become in danger of heading off down a narrow channel here. Time to drag the discussion back to the main process. The point I want to make clear, in this part of the argument, is that after you have damaged the endothelium a clot will form. This is quite natural.
However, if you have factors in the blood that make any clot that forms bigger, or more difficult to break down, the chances are that any clot that forms will end up within the artery wall as a bigger plaque. Or the clot may simply block the artery altogether, first time.
Some of the other factors that make blood clots likely to be bigger, and/or more difficult to clear up, in addition to type II diabetes and high VLDL levels, are:
Raised fibrinogen levels
Raised Lp(a) levels
Antiphospholipid syndrome (Hughes syndrome)
Smoking
Raised homocysteine levels
Not an exhaustive list by any manner of means, and I am only going to look at two of these in this blog. Fibrinogen and Lp(a) levels.
Fibrinogen
It would seem common sense that raised fibrinogen levels would make blood clots bigger when they form, and thus more difficult to clear up, as they are a key component of any blood clot.
The importance of a high fibrinogen level was something I first saw in the Scottish Heart Health Study. This was a major study that lasted ten years and included thousands of people. The researchers looked at many different factors which were thought to be involved with causing heart disease (and death from all causes). Raised cholesterol was found to have no effect. Instead they found that:
‘Fibrinogen is a strong predictor of coronary heart disease, fatal or non-fatal, new or recurrent, and of death from an unspecified cause, for both men and women. Its effect is only partially attributable to other coronary risk factors, the most important of which is smoking.’
The increase in (relative risk) between the highest and lowest fibrinogen levels was:
301% for men and 342% for women (CVD death)
259% for men and 220% for women (Death from any cause)
In fact, a high fibrinogen level was the single most important risk factor they found – just beneath already suffering a previous heart attack. A raised fibrinogen was an even more powerful risk factor than smoking (although smoking can raise fibrinogen levels, which complicates this picture somewhat).
This finding was reinforced by the Prospective Cardiovascular Münster (PROCAM) study.
‘The incidence of coronary events in the upper tertile (top third) of the plasma fibrinogen distribution was 2.4-fold higher than in the lower tertile (bottom third)… plasma fibrinogen was found to be an independent risk indicator for CHD (P < .05). Individuals in the high serum low-density lipoprotein (LDL) cholesterol tertile who also showed high plasma fibrinogen concentrations had a 6.1-fold increase in coronary risk. Unexpectedly, individuals with low plasma fibrinogen had a low incidence of coronary events even when serum LDL cholesterol was high.’ 3
[Ah yes, the old ‘high cholesterol low rate of heart disease conundrum.’ It must be, let me see, a paradox. I do love the word unexpectedly. Mainly, because, here is where scientific truths hide]
I feel the need to add that a 2.4-fold increase in coronary events = relative risk increase of 240%, which is in the same ball park as the Scottish Heart Health study. Some of the things that can raise your fibrinogen levels are:
Smoking
Stress (physical or psychological)
Type II diabetes
Depression
Cushing’s disease
Post-traumatic stress disorder (PTSD)
Obstructive sleep apnoea
Of course, all of these things are also associated with a greatly increased risk of CVD. You can have hours of fun by typing CVD raised fibrinogen and… (insert favourite risk factor for CVD of your choice here).
Lipoprotein (a) (Lp(a))
There has been much discussion of Lp(a) of late. What it is, what does it do, why does it matter? The first thing to point out about Lp(a) is that it is, essentially, LDL a.k.a. LDL-cholesterol a.k.a. ‘bad cholesterol.’ However, it differs in one way. It has a special strand of protein attached to it, known as apolipoprotein A.
This protein is very interesting, from a blood clotting perspective, in that it is chemically identical to plasminogen. Yes, the one and only clot busting enzyme, switched on by tissue plasminogen activator.
But, big but. Apolipoprotein A is folded into a slightly different structure than plasminogen. Let us say it has a right handed thread, instead of left handed thread. (This is not fully accurate, but it is close enough).
This is important because almost of the receptors in the body have a symmetry to them, as do most of the molecules that nature provides, and most of them are left handed (levo-rotated). If you aim a right handed molecule at a left handed receptor very little happens – or strange and unpleasant things can happen. Thalidomide for example The L handed version causes no problems, but the R handed version causes serious birth defects – or was it the other way round. Remove one, or the other, version and you could give thalidomide perfectly safely in pregnancy. I would dare you to try.
As it is, thalidomide has been relegated to a cancer treatment, under the brand name Immunoporin. How does it work? It works by stopping angiogenesis (formation of new blood vessels) which cancer cells need to grow into a larger tumour mass.
The way that Thalidomide does this is that it damages endothelial cells, and endothelial progenitor cells (EPCs), as discovered in this study: ‘Thalidomide attenuates nitric oxide mediated angiogenesis by blocking migration of endothelial cells.’
‘….thalidomide interferes with nitric oxide-induced migration of endothelial cells at the initial phase of angiogenesis before cells co-ordinate themselves to form organized tubes in endothelial cells and thereby inhibits angiogenesis.’4
Okay, maybe that means nothing to you. What it means is that thalidomide stops new blood vessels forming, by blocking the action of NO on both endothelial cells and endothelial progenitor cells (EPCs). Whilst this is a good thing in cancer treatment, it is not so great in the developing fetus.
A pregnant women taking thalidomide will find that new blood vessels do not form properly in her baby. This means that arms and legs cannot get blood supply, so they don’t develop, so you are left with a severely deformed baby, often with missing limbs.
It would be interesting to know what impact thalidomide has on CVD risk? We already know what impact Avastin has on CVD risk. It increases it massively. Avastin, like thalidomide, works primarily by inhibiting endothelial cell growth and EPC production. Whilst this stops tumours growing, it also greatly accelerates CVD. Oooh, I do love the way everything is connected.
Anyway. To return to apolipoprotein A again. If you incorporate Lp(a), and thus apolipoprotein A, into a blood clot, it cannot be broken down. This is because tissue plasminogen activator cannot activate it, because it is right handed. Effectively, therefore, apoliporotein A blocks the enzymatic destruction of fibrin, thus protecting the clot from destruction. Why, you may ask, would the body create such a stupid thing?
Well, as with everything the body does, it is not stupid. It is very, very, clever. Lp(a) is only made in animals that cannot synthesize vitamin C. Guinea pigs, fruit bats, great apes and…humans. The reason for this is that, if you are vitamin C deficient, the body cannot manufacture certain important support materials/connective tissue, the most important of which is collagen.
Without collagen, your blood vessels start to crack apart. When this happens, blood escapes, so you start bleeding from the gums, and suchlike. This condition is known as scurvy. In scurvy you start bleeding all over the place and, in the end, you die from blood loss. It is what killed many sailors of in the olden days.
Along to the rescue comes Lp(a).. well, it can rescue you for a bit. Lp(a) sticks to cracks in blood vessel walls and forms, impossible to break up blood clots that ‘plug’ the gaps created by collagen deficiency. So you can see that Lp(a) is actually evolution’s way of protecting animals, that cannot synthesize vitamin C, from the early stages of scurvy.
All of which means that if you don’t eat enough vitamin C, and you have a high level of Lp(a), you will end up with a multitude of very difficult to break up blood clots scattered all over your arterial walls, and inside your arterial walls too. Thus, you are going to develop CVD at a rapid rate.
This, the ‘vitamin C deficiency’ theory of CVD was proposed by Linus Pauling (double Nobel prize winner) and Matthias Rath (and you can look him up too – but be prepared for some interesting information). Here is a short section from their modestly entitled paper ‘A Unified Theory of Human Cardiovascular Disease Leading the Way to the Abolition of This Disease as a Cause for Human Mortality.’
‘We have recently presented ascorbate (Vitamin C) deficiency as the primary cause of human CVD. We proposed that the most frequent patho-mechanism (think of this term as the ‘process) leading to the development of atherosclerotic plaques is the deposition of Lp(a) and fibrinogen/fibrin in the ascorbate-deficient vascular wall. In the course of this work we discovered that virtually every patho-mechanism for human CVD known today can be induced by ascorbate deficiency.’
So there you go, vitamin C deficiency is the answer to CVD? No, it is not THE answer, but it is an answer, or a part of an answer. There is no doubt that a low level vitamin C is a bad thing. There is equally no doubt that a low vitamin C level, associated with a high Lp(a) is a double bad thing. Furthermore, there is absolutely and completely no doubt that taking extra vitamin C would be a good thing for everyone – just in case.
However, Pauling and Rath, brilliant though their thinking was, made the number one error in medicine. They looked for the single cause, and the single cure of a disease. They became so certain they were right, that they stopped looking elsewhere.
Having said this, their ideas about the process of CVD were, in my opinion, absolutely right. They realised that the essential underlying process was: arterial wall damage, followed by blood clots, followed by the development of atherosclerotic plaques. But they thought it could all be explained by a single factor, Vitamin C deficiency. In this they were wrong. It is a great shame they did not look at the wider picture.
However, I hope you can now see what Lp(a) is, what it does, and why it is important in the whole CVD argument. It is not a clotting factor per se, but it has a huge impact on the clots that do form. Unfortunately, it seems that Lp(a) levels are genetically determined and there seems little you can do to alter them. I would suggest that, if you decided to get your Lp(a) level tested, and it is high, you should make sure you get plenty of vitamin C in your diet.
Summary
I realise that you may think I have taken you off on a couple of wide detours in this blog. More than a couple actually. However, my cunning plan was to give a sense of how everything in the physiology of endothelial health and blood clotting can be fitted together. Also, how it can be seen that any factor which has an impact on the development of blood clots (following endothelial damage), will have an impact on CVD through mechanisms that can be easily understood.
Looking at an even wider picture I hope that you can now see, why drugs such as thalidomide – which may seem a million miles away from CVD – are actuallly closely related. How Lp(a), which at first glance may appear to have nothing to do with the four step process of CVD, can be brought into the picture. In addition, where, and how, such things as VLDL and PAI-1 fit in…. to name only a few. Over the years I have followed the story down a million different pathways. Each fascinating, but there are far too many to discuss them all here.
Yes, it is a complex story. Did you really think it would be easy? Did you really think there would be ONE factor that caused everything, and ONE factor that cured everything? CVD is not binary, it is about propensity, chaos theory. It is about changing the odds here and there. It is about the weighting of the dice. You can improve the odds in your favour, but you will never make them zero.
Next….the repair process.
References
1: http://www.jlr.org/content/40/5/913.full.pdf
2: http://www.ncbi.nlm.nih.gov/pubmed/15780823
3: http://www.ncbi.nlm.nih.gov/pubmed/8274478
4: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1456963/
