[Yes, this one took a long time to write]

When I started looking at heart disease, or cardiovascular disease (CVD) it was initially because I was interested to know why the Scots and the French had such different death rates. I had also just finished a book by James le Fanu called ‘Eat your heart out’ in which he made it very clear, or at least he did to me, that fat/saturated fat in the diet had nothing to do with CVD in any way shape of form.

However, at the time le Fanu was very much a voice crying in the wilderness. The experts had a very different song, or dirge. Namely that the Scots diet was terribly unhealthy, and this fully explained why they kept keeling over from heart attacks. Their bad diet raised cholesterol levels and…. thud (sound of Scots person falling over dead).

This is still very much the case. All of our medical authorities still announce the absolute truth of the ‘terrible Scottish diet’ with adamantine confidence. They usually bring out the almost mythical ‘deep fried mars bar’ as the perfect example as to why the Scots die of heart attacks, and strokes, and suchlike. ‘Well, what can you expect of a nation that eats deep fried mars bars… ho, ho.’

The truth is that hardly any Scotsman, or women, has ever eaten such a thing. And if they did it once, they will most certainly never do it again (I was certainly put off for life after one drunken foray on a Saturday night). Of course, there is also a perfect irony here. A mars bar is almost entirely made up sugar (not fat). When you fry it, it will be in vegetable/polyunsaturated fat – as saturated fats have been virtually banned in deep fat fryers. So, in theory, a deep fried mars bar should be somewhat more heart healthy than a ‘virgin’ mars bar. As it now contains a mass of hot sugar plus some heart ‘healthy’ polyunsaturated fat.

I suppose this example, at least to me, highlights the complete lack of any consistent logic or thought in the diet heart world. A fact that I became very painfully aware of, over many years. Indeed, I came to realise that there is no area of human existence where more nonsense is spouted than the ever-changing beliefs about what constitutes a healthy, or unhealthy diet. Frankly, it is almost entirely wall to wall rubbish.

At one point I made an effort to look at the classical ‘risk factors’ for heart disease between France and Scotland. This was done some years ago as part of a paper I wrote called ‘Does Insulin Resistance cause atherosclerosis in the post-prandial period?’ Something which I still think is at least part of the picture of CVD.

Here is the table I put together from a number of different sources – there was no single source for the data I was looking for. [I could not find separate UK and Scottish figures for a number of the factors, so I had to look at the UK as a whole. In addition, at there were no clear cut data on saturated fat, so I used animal fat as a proxy – which is almost the same thing]

As you can see, there was virtually no difference in the classical risk factors for UK men and French men. Despite this, the French had one quarter the risk of death from ischaemic heart disease [what you or I would tend to call heart disease]. Since that time the French rate of heart disease has continued to fall, as it has also done in the UK, whilst the French consumption of saturated fat has risen. Interestingly total cholesterol levels have fallen in both countries.

So, whatever was going on had very little to do with diet. And if it had very little to do with diet, then it also had little to do with cholesterol either. If your hypothesis is that eating saturated fat increases cholesterol, or LDL cholesterol levels, which then causes CVD then how can two countries with exactly the same saturated fat consumption and cholesterol level (and all other risk factors equal) have such a different rate of CVD? And how could France, whilst continuing to eat more saturate fat, have a falling cholesterol levels? And how does the Ukraine, which currently has the lowest saturated fat intake in Europe, end up with the highest rate of CVD etc. etc. etc.

When you start looking at facts like this you must start to question the diet-heart cholesterol hypothesis. Or at least I thought you must. How wrong I was. Virtually the entire medical profession was wedded to the diet-heart cholesterol hypothesis – still is. Facts appear to have no impact whatsoever on this belief system.

Anyway, once I started to look at CVD in more detail, I was confronted with a choice. Accept that I must be wrong. After all, how can all the researchers and experts and Nobel prize winners be wrong. They must surely be seeing things that I cannot. Or, accept that the diet-heart cholesterol hypothesis was wrong. The blue pill, or the red pill.

Dear reader, I chose the red pill, in the sure and certain knowledge that rejecting the conventional thinking was certainly not going to be an easy path to follow. I also knew that if I was going to reject the diet-heart/cholesterol hypothesis, then I had to try and find out what does actually cause CVD. When I looked around at first there, were few alternative voices, or hypotheses out there. If truth be told, there seemed to be none (at least initially). But if not cholesterol, then what?

Over time, as I looked around, some ghosts in the machine began to emerge. I was aware of a doctor (whose name I cannot even remember) who firmly believe that fibrinogen was the main cause of CVD, and I went to a talk that he gave on the subject – not paying it much heed in truth. Then the Scottish Heart Health Study was published, and the single most powerful risk factor that emerged for CVD risk was… fibrinogen. A blood clotting factor. Aha. Could CVD actually be due to blood clotting abnormalities?

This was a time before the internet, before search engines, before finding information was so easy. This was an era when you had to traipse down to the medical library and pull actual books from actual shelves if you wanted to find out stuff. After pulling a lot of books off a lot of shelves I learned of Duguid, a Scottish doctor, who argued that blood clotting was the cause of CVD (I paraphrase).

His work was published shortly after the second world war, and has remained mostly unread. Then I went all the way back to Karl von Rokitansky who, in 1852, felt that atherosclerotic plaques were, in fact, just blood clots – in various stages of repair. An observation which, from time to time, other researchers have noted. Most particularly a doctor called Smith, from Aberdeen. He is no longer active in this area of research.

Here is the abstract from his paper ‘Fibrinogen, fibrin and fibrin degradation products in relation to atherosclerosis’. I have quote the abstract in full, for those who like to see a bit more detail. Others may glaze over, or skip to the last sentence:

‘Many human atherosclerotic lesions, showing no evidence of fissure or ulceration, contain a large amount of fibrin which may be in the form of mural thrombus on the intact surface of the plaque, in layers within the fibrous cap, in the lipid-rich centre, or diffusely distributed throughout the plaque. Small mural thrombi are invaded by SMCs (smooth muscle cells) and collagen is deposited in patterns closely resembling the early proliferative gelatinous lesions. In experimental animals, thrombi are converted into lesions with all the characteristics of fibrous plaques, and in saphenous-vein bypass grafts, fibrin deposition is the main cause of wall thickening and occlusion. There seems little doubt that fibrin deposition can both initiate atherogenesis and contribute to the growth of plaques.

Epidemiological studies indicate that increased levels of fibrinogen and clotting activity are associated with accelerated atherosclerosis, and although blood fibrinolytic activity has given inconsistent results, in arterial intima both fibrinolytic activity and plasminogen concentration are decreased in cardiovascular disease. Fibrin may stimulate cell proliferation by providing a scaffold along which cells migrate, and by binding fibronectin, which stimulates cell migration and adhesion. Fibrin degradation products, which are present in the intima, may stimulate mitogenesis and collagen synthesis, attract leukocytes, and alter endothelial permeability and vascular tone.

In the advanced plaque fibrin may be involved in the tight binding of LDL and accumulation of lipid. Thus there is extensive evidence that enhanced blood coagulation is a risk factor not only for thrombotic occlusion, but also for atherogenesis. Enhanced blood coagulation frequently coexists with hyperlipidaemia and, together, these may have a synergistic effect on atherogenesis.’ ¹

For those whose eyes did glaze over, concentrate only on the last sentence. ‘Enhanced blood coagulation frequently coexists with hyperlipidaemia and, together, these may have a synergistic effect on atherogenesis.’

Here, ladies and gentlemen, lies my little secret. My evil twin brother who I have kept in the attic for the last twenty years, gnawing at the floorboards. The terrible truth that there is an association between LDL levels/familial hypercholesterolemia and CVD. Something which I appear to have argued against for many, many, years.

Does this mean that the experts have been right, all along? High LDL cholesterol levels do cause CVD? Well maybe, maybe not. At this point I need to take you back to the statement again. ‘Enhanced blood coagulation frequently coexists with hyperlipidaemia.’

Does this mean that hyperlipidaemia actually causes enhanced blood coagulation? Or does it mean that something else causes both. Here is the old ‘yellow fingers and lung cancer’ discussion.

‘People with yellow fingers are more likely to die of lung cancer.’

Why… because people with yellow fingers smoke, and smoking causes lung cancer. Ergo yellow fingers are simply a sign of smoking, they do not actually cause lung cancer.

‘People with raised LDL are more likely to die from CVD’

Why… because people with raised LDL are also more likely to have enhanced blood coagulation. Ergo, raised LDL levels are only associated with enhanced blood coagulation, they do not actually cause CVD. It is the blood coagulation factors.

Alternatively, raised LDL may actually enhance blood coagulation, all by itself.

Where does the answer lie? In truth the answer has been very difficult to tease out. Even now, after many years, I do not feel that I can fully disentangle the data. Here for example, is a paper called ‘Maternal familial hypercholesterolaemia (FH) confers altered haemostatic profile in offspring with and without FH.’

‘Children with (n=9) and without (n=7) FH born of mothers with FH, as well as control children (n=16) born of non-FH mothers were included in the study. The concentrations of tissue plasminogen activator, plasminogen activator inhibitor (PAI-1), tissue factor (TF), TF pathway inhibitor (TFPI), thrombomodulin, fibrinogen, prothrombin fragment 1+2 and von Willebrand Factor were measured. Our findings show i) higher levels of PAI-1 and TFPI in children with and without FH born of mothers with FH compared with control children, ii) lower levels of thrombomodulin in children with FH compared with control children, and iii) significant correlations between maternal PAI-1 levels during pregnancy and PAI-1 levels in the offspring.^’2

What this tells us is that, if a mother has Familial Hypercholesterolaemia, she passes on abnormalities of blood coagulation to her children. Both those that have, and those that do not have FH. [Not all children of mothers with FH will end up with the FH gene]. Some of this may be epigenetically modulated. In short, it is not the LDL that is important, it is simply the mother’s genes….

Or is it? Here is a paper suggesting that the LDL itself, independently of anything else, makes platelets more likely to stick together (a key step in blood clotting).

‘The interaction of platelets with lipoproteins has been under intense investigation. Particularly the initiation of platelet signaling pathways by low density lipoprotein (LDL) has been studied thoroughly, since platelets of hypercholesterolemic patients, whose plasma contains elevated LDL levels due to absent or defective LDL receptors, show hyperaggregability in vitro and enhanced activity in vivo. These observations suggest that LDL enhances platelet responsiveness….’ ³

However, maybe these researches misinterpreted what they were seeing. For example, another paper found that the level of LDL in those with FH was not related to their risk CVD. It was purely the level of clotting factors that was related to CVD. This paper entitled: ‘Coronary artery disease and haemostatic variables in heterozygous familial hypercholesterolaemia.’

‘Haemostatic variables were measured in 61 patients with heterozygous familial hypercholesterolaemia, 32 of whom had evidence of coronary heart disease. Age adjusted mean concentrations of plasma fibrinogen and factor VIII were significantly higher in these patients than in the 29 patients without coronary heart disease, but there were no significant differences in serum lipid concentrations between the two groups. Comparisons in 30 patients taking and not taking lipid lowering drugs showed lower values for low density lipoprotein cholesterol, high density lipoprotein cholesterol and antithrombin III, and a higher high density lipoprotein ratio while receiving treatment. The results suggest that hypercoagulability may play a role in the pathogenesis of coronary heart disease in patients with familial hypercholesterolaemia.’⁴

So it is not the high LDL? It is the raised blood clotting factors that are found in some, but not all of those with FH. As you can see, it is not straightforward at all.

Just to complicate the picture further, here is a paper strongly suggesting that HDL is directly anti-coagulant.

‘Native HDL prevents platelet hyperreactivity by limiting intraplatelet cholesterol overload, as well as by modulating platelet signalling pathways after binding platelet HDL receptors such as scavenger receptor class B type I (SR-BI) and apoER2′. The antithrombotic properties of native HDL are also related to the suppression of the coagulation cascade and stimulation of clot fibrinolysis. Furthermore, HDL stimulates the endothelial production of nitric oxide and prostacyclin, which are potent inhibitors of platelet activation. Thus, HDL’s antithrombotic actions are multiple and therefore, raising HDL may be an important therapeutic strategy to reduce the risk of arterial and venous thrombosis.’ ⁵

And what about VLDL?

‘There is a considerable body of evidence supporting an association between hypertriglyceridaemia (high level of VLDL), a hypercoagulable state and atherothrombosis. A disorder of triglyceride metabolism is a key feature of the metabolic syndrome that increases risk of both ischaemic heart disease and type 2 diabetes approximately 3-fold. An increasing prevalence of obesity and metabolic syndrome is likely to contribute markedly to the prevalent ischaemic heart in the foreseeable future, and therefore it is crucial to understand mechanisms linking hypertriglyceridaemia and a hypercoagulable state. Activation of platelets and the coagulation cascade are intertwined. VLDL and remnant lipoprotein concentrations are often increased with the metabolic syndrome. These lipoproteins have the capacity to activate platelets and the coagulation pathway, and to support the assembly of the prothrombinase complex. VLDL also upregulates expression of the plasminogen activator inhibitor-1 gene and plasminogen activator inhibitor-1 antigen…’ ⁶ etc.

You can go back and forward in this area, finding research that contradicts itself upside down and inside out again. What I think I know for certain is the following:

• High LDL levels/familial hypercholesterolemia is closely associated with increased blood coagulation (in a high percentage of those with FH, though not all) – through many different interrelated mechanisms. Some genetic, some possibly directly due to LDL itself.
• VLDL (triglyceride) seems to increase blood coagulation – and this seems a very consistent finding
• HDL has anticoagulant effects

I don’t know how powerful these different pro and anti-coagulant effects are, but they certainly exist. To an extent I could just say what does it matter if LDL does, or does not increase blood coagulation directly – but is simply associated with blood clotting abnormalities. It all fits within the processes that I have outlined in this series of blogs. Namely, anything that increases the risk of blood clotting increases the risk of CVD. And LDL (directly, or through genetic association) does increase the risk.

However, I thought it would be dishonest of me not to highlight the fact that there could well be a causal association between LDL (and VLDL) and CVD. Also there does seem to be a causal protective mechanism provided by HDL.

Or, to put this another way, perhaps all the experts were (a bit) right all along. Even if they have consistently promoted a process that does not make any sense at all i.e. LDL leaks into artery walls causing inflammation and plaque growth etc.

A further proviso is that I cannot see that the LDL/VLDL/HDL effects are very strong. After all I just co-authored a paper showing that higher LDL levels in the elderly are associated with increased life expectancy and a slight reduction in CVD risk. [There are many other factors clouding the issue here – too many to discuss in one go]. Confused yet… welcome to my world.

So where did I get to. I think I got to the point where I accept that:

• LDL is pro-coagulant and – at very high levels e.g. in FH – increases the risk of CVD [though it is difficult to disentangle this from intertwined genetic pro-coagulant factors]
• VLDL is pro-coagulant, and increases the risk of CVD
• HDL is anticoagulant and protects against CVD

Which then brings onto statins, and how they work. First to re-iterate that statins do reduce the risk of CVD [Something, I have never disputed]. However, they do it not by lowering LDL, but because they have anticoagulant effects. Not that potent, about the same as aspirin, but the effect does exist.

Here from a paper entitled ‘statins and blood coagulation’:

‘The 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase inhibitors (statins) have been shown to exhibit several vascular protective effects, including antithrombotic properties, that are not related to changes in lipid profile. There is growing evidence that treatment with statins can lead to a significant downregulation of the blood coagulation cascade, most probably as a result of decreased tissue factor expression, which leads to reduced thrombin generation…. Treatment with statins can lead to a significant downregulation of the blood coagulation cascade….’ ⁷ An effect confirmed by their protection against DVT.

‘Venous thromboembolism (VTE) includes both deep vein thrombosis (DVT) and pulmonary embolism. The 2009 JUPITER trial showed a significant decrease in DVT in non-hyperlipidemic patients, with elevated C-reactive protein (CRP) levels, treated with rosuvastatin.’ ⁸ Yet, the experts continue to tell us that statins work, purely, by lowering LDL levels. Ho hum.

Whilst I could have written this series and simply pushed LDL, VLDL and HDL to one side. I thought I needed to bring them into the discussion. Not to dismiss them but, I hope, to explain what their role within CVD may actually be – pro and anti-coagulant agents. Here is where they fit, and make sense. Looking at lipoproteins in the light also helps to explain how statins actually work.

References:
1: http://www.ncbi.nlm.nih.gov/pubmed/3524931
2: http://europepmc.org/abstract/med/23199546
3: http://www.ncbi.nlm.nih.gov/pubmed/16877876
4: Br Heart j 1985; 53: 265-8
5: http://www.ncbi.nlm.nih.gov/pubmed/24891399
6: https://www.karger.com/Article/Pdf/93221
7: http://www.ncbi.nlm.nih.gov/pubmed/15569822
8: http://www.ncbi.nlm.nih.gov/pubmed/22278047

When you start thinking about things in a new way it is funny where it takes you. You end up seeing connections, where you may previously only have seen confusion. You see links where they could not, or should not, seemingly exist before. In this blog, I am going to take you from migraine to sickle cell disease, and explain how they both cause CVD – and how they both do it through exactly the same underlying mechanisms.

Before reading on, perhaps you might like to think about how this can possibly work … It is always much more satisfying to work things out for yourself. Or maybe that’s just me.

To begin. As you will have picked up from this blog, I believe that cardiovascular disease (CVD) is, essentially, a disease created by endothelial damage and/or dysfunctional blood clotting. With a bit of impaired clot repair thrown in. I spend too much of my life tracking down anything, and everything, that may cause CVD to see if this hypothesis fits – or does not.

Which is why I was interested to see a headline that appeared very recently on Doctors Net (A website for doctors in the UK). It was entitled ‘Migraine cardiovascular link examined’. Up to this point, I had not realised that migraine and CVD were related. So it was something new to me:

As the article, in the BMJ, went on to say:

Young women who suffer from regular migraine attacks appear to have an increased risk of cardiovascular disease, researchers warn today.

Women are three to four times more likely to experience regular migraines. The condition has previously been linked to an increased risk of stroke, but although the physiology of migraine has close links to the vascular system, the way in which migraine increases risk of stroke is unclear.

A team led by Professor Tobias Kurth of the Institute of Public Health in Berlin, Germany, looked at this association, and the link with cardiovascular disease in general.

They used details on 115,541 women aged 25 to 42 years at baseline, taking part in the US Nurses’ Health Study II, which began in 1989. Over the 20 years of follow-up, 15% of the women were diagnosed with migraine.

Cardiovascular disease was 50% more likely among the women with migraine. Heart attack was 39% more likely, stroke 62% more likely, and these women were 73% more likely to have a revascularization procedure.

In addition, women with migraine were 37% more likely to die from cardiovascular disease than women without migraine, and the risk was not significantly altered by age, smoking, high blood pressure, or use of hormone medications.¹

So here is, yet another possible cause of CVD. There was no explanation put forward in this study, it was simply an observation. However, I find that unexplained observations are where the answers lie. These are the ghosts in the machine. Truths that occasionally emerge from the dark depths of the ocean, like oarfish, or giant squid, before slipping back into the abyss.

When I see a study like this, the first thing that I do is to look for an association with blood clotting, or endothelial damage, or both. If there is no association, then my hypothesis has suffered a serious blow. On the other hand…

So, taking a deep breath, I looked around the research done in this area. There has not been a great deal, but to my relief. [Yes, I know, a true scientist should never get too attached their own ideas. But, you know what, it’s hard not to….] To my relief I found that migraine is associated with, or causes, blood clotting abnormalities – and also damage to the endothelium.

Just to quote one short section from the Stroke Association:

‘Migraine-Related Stroke – There is evidence that patients with migraine, particularly migraine with aura, have an increased risk of stroke. The mechanism for this is unclear, although migraine is associated with abnormalities of platelet, coagulation and blood vessel inner lining function, and that may contribute to an increased risk of stroke.’ ²

Just to add further to the connections that potentially open up, I was interested to stumble across a case study where a patient’s migraines were ‘cured’ by using warfarin.

An unusual case report on the possible role of warfarin in migraine prophylaxis

Abstract

Background: Migraine is a complex disease whose physiopathological mechanisms are still not completely revealed.

Findings: We describe an unusual case, not yet described in literature, of a patient who reported migraine remission, but still presented aura attacks, since starting a therapy with Warfarin.

Conclusions: This case report brings out new questions on the role of the coagulation, especially the blood coagulation pathway, in migraine with aura pathogenesis, and on the possibility to use vitamin K inhibitors, Warfarin or new generation drugs, as possible therapy to use in migraine prophylaxis.³

I must admit I never saw that one coming. Migraines can be treated with warfarin? Though, I suppose, had I thought things through, I might have worked it out. Or maybe not.

Anyway, pulling this information together, we now know that migraines increase the risk of CVD, – more often strokes than heart disease. When you look deeper, you find that migraines are also associated with endothelial dysfunction, and blood clotting abnormalities.

As should be pretty obvious, this all fits perfectly with the ‘CVD is all caused by blood clotting’ hypothesis. On the other hand, if you would like to try to explain how migraines cause CVD through any another process, please let me know. Of course, it could be that another deeper process causes both blood clotting abnormalities, and migraines, but that is for another day.

Of greater interest to me is that, whilst I was studying migraine and CVD, another condition kept popping up on the search criteria. Something that was, again, completely new to me. Which is that there is a very strong association between sickle cell disease (SCD), and CVD. I had never previously thought to link these conditions. However, a number of the migraine articles pointed me towards sickle cell disease (SCD).

Sickle cell disease is a genetic condition whereby red blood cells are malformed and have a sickle shape. This accounts for the name. It is a genetic mutation that, in milder forms, is thought to to protect against malaria, because mildly sickle shaped red blood cells are more difficult for the malaria parasite to enter. However, in its more severe forms, sickle cell disease is quite damaging. Sickle cells can burst, get stuck in smaller blood vessels, form clots in blood vessels in the eyes – leading to blindness, lung and kidney problems etc.

To cut a long story short, in sickle cell disease there are all sorts of ‘clotting’ problems. There is also the potential for significant endothelial damage due to the abnormal shape and function of the red blood cells. Given this, you might expect increased risk of CVD. Which there is, as covered in the paper ‘Atherosclerosis in sickle cell disease – a review:’

‘Ischemic (lack of oxygen) complications are the major causes of morbidity and mortality in patients with sickle cell disease (SCD). The pathogenesis (what causes these problems) of these complications is poorly understood. Ischemic events in these patients have been attributed to the effects of hemoglobin polymerization, resulting in rigid, dense and sickled cells trapped in the microcirculation. Therefore, vascular occlusion is often considered to be synonymous with occlusion of microvasculature by sickled red blood cells. Several observations suggest that other factors may also play a pathogenic role. Atherosclerosis is one of these factors and may affect many arteries all over the body.’

It is fascinating what you find, when you decide to look at things from a different perspective. You start looking at the connection between migraine, CVD, and blood clotting, and end up studying sickle cell disease. I must admit that I get a great sense of satisfaction when I come across facts like this. Somewhat like completing a jigsaw puzzle. ‘Yes, hoorah, it all fits. In fact, it all fits perfectly.’

Indeed, the article on Atherosclerosis in sickle cell disease goes on to bring in Nitric Oxide and L-arginine. I have covered both of these factors in some in detail earlier on in this series. [Sorry this section a bit jargon filled]:

‘The sickling process leads to vascular occlusion, tissue hypoxia and subsequent reperfusion injury, thus inducing inflammation and endothelial injury. This causes a blunted response to nitric oxide (NO) synthase inhibition. In recent years, investigators’ attention has been attracted by the effects of chronic hemolysis on vascular bed integrity and function in patients with congenital hemolytic anemias. Hemolysis results in the release of free hemoglobin.

On one hand, it scavenges NO by oxidizing it to nitrate and releasing red blood cell arginase. On the other hand, it hydrolyzes L-arginine, the substrate of NO synthase. Because of these effects, NO bioavailability and its action is limited. All the previous mechanisms cause impairment of NO production. NO is an important vascular relaxing factor and its deficiency would lead to large artery stiffness. In addition, NO promotes general vascular homeostasis by decreasing endothelial expression of adhesion molecules, decreasing platelet activation, and inhibiting fibroblast, smooth muscle cell and endothelial cell mitogenesis and proliferation.’

In one short section on SCD we have virtually everything I have been writing about in this series so far. There is:

• Reduced NO synthesis
• Damage to the endothelium
• Increased risk of blood clotting in general
• Increased platelet activation and adhesion
• Inhibition of endothelial cell repair and proliferation
• Increased risk of CVD and accelerated atherosclerotic plaque development

Another highly important point here is, as follows. You may recall that I said atherosclerosis almost never forms in the blood vessels in the lungs (pulmonary blood vessels). The only time it does is if you have pulmonary hypertension (high blood pressure in the blood vessels in the lungs).

Well, I just found out that if you have sickle cells disease, you are at high risk of developing atherosclerosis in the lungs:

‘The pulmonary artery is one of the common sites of atherosclerosis in sickle cell disease (SCD). Autopsy of the pulmonary artery in patients with SCD showed that approximately one-third of the patients had histological evidence of medial hypertrophy, intimal proliferation, and subintimal proliferation and fibrosis.’

Now you may not think this is particularly important, but to me it is a killer fact. Atherosclerosis in the pulmonary arteries is something so unusual that when you find it, you are looking at the mother lode. If you can cause atherosclerosis here, then you are gazing at a true underlying cause, with all other risk factors stripped out.

Here is the process (or processes) revealed. Deep joy. It is not often that I come across a fact that I had no idea existed before. Certainly not one that confirms so perfectly everything that I have been saying.

I realise that I have repeatedly stated that the primary purpose of science should be to contradict hypotheses. Here, all I have ended up doing, is providing more facts that support my own hypothesis. I would ask you to believe that I started out looking for a contradiction. I ended up with greater confirmation. Confirmation from places where I had never previously even thought to look.

References:

1: BMJ 1 June 2016; doi: 10.1136/bmj.i2610

2: http://www.strokeassociation.org/STROKEORG/StrokeConnectionMagazine/ReadSCNow/Uncommon-Causes-of-Stroke_UCM_461424_Article.jsp#.V1aXV5EgthE

3: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2780857/

4: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2780857/

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:

• Smoking
• Cocaine use
• Cortisol
• Kawasaki’s disease
• Diabetes
• Rheumatoid Arthritis
• Kidney failure
• Non-steroidal anti-inflammatories e.g. brufen, naproxen
• Biomechanical stress (within arteries)
• Dehydration
• Systemic Lupus Erythematosus
• Antiphospholipid syndrome (Hughes syndrome)
• Vitamin C deficiency
• Raised fibrinogen levels (key clotting factor)
• Homocysteine
• 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
• Aspirin
• Clopidogrel (expensive aspirin)
• ACE- inhibitors (a blood pressure lowering agent)
• Yoga
• Haemophilia
• Statins
• 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.

I have been much cheered by all the discussion on my series about what caused heart disease a.k.a. cardiovascular disease. Because of various comments, my series has gone off in a few different directions. I realise that not everyone agrees with everything (or anything?) I have to say, and that several issues I thought were clear, clearly are not. This is fine. Science should progress by discussion and debate and contradictions.

In this blog, in order to answer some of what people have written (albeit indirectly), I am going to look at two of the conventional risk factors for CVD in a bit more detail, and try to explain why they represent a major problem for conventional thinking.

As many of you may have discovered, if you go to see your GP – almost anywhere in the world – they will use a list of ‘standard’ risk factors to calculate your risk of a cardiovascular ‘event’ over the next five or ten years.

There are a few of these calculators, but two of most commonly used are probably QRISK2 and the ASCVD, created by the American College of Cardiology and American Heart Association. [ASCVD = atherosclerotic cardiovascular disease]. I cannot find out where the term QRISK comes from – perhaps someone can help me.

The ASCVD is a bit shorter than QRISK. It looks at:

• Age
• Gender
• Race
• Total Cholesterol
• HDL
• Systolic blood pressure
• Diastolic blood pressure
• Treatment for blood pressure
• Diabetes
• Smoker

The QRISK is a UK developed risk calculator. It is a bit bigger and more complicated than ASCVD. It looks at:

• Age
• Sex
• Systolic blood pressure
• Diastolic blood pressure
• Total Cholesterol
• Total Cholesterol/HDL ratio
• Serum triglyceride
• Smoking
• Glucose Impaired glucose tolerance/diabetes
• Left Ventricular hypertrophy
• Central obesity
• South Asian (South Asians, in the UK, have a far higher risk of CVD)
• Family history of CVD

Now, there is no doubt that all of the factors on both lists are associated with CVD – to a greater or lesser degree. At least they are for the US and UK population currently living. It has to be pointed out thought, that if you use QRISK in France, you have to divide the risk by 4… ahem, slight problem.

A further problem is that it has been discovered that they both vastly over-estimate risk in US and UK population.

‘A widely recommended risk calculator for predicting a person’s chance of experiencing a cardiovascular disease event — such as heart attack, ischemic stroke or dying from coronary artery disease — has been found to substantially overestimate the actual five-year risk in adults overall and across all sociodemographic subgroups. The study by Kaiser Permanente was published today in the Journal of the American College of Cardiology.

The actual incidence of atherosclerotic cardiovascular disease events over five years was substantially lower than the predicted risk in each category of the ACC/AHA Pooled Cohort equation:

• For predicted risk less than 2.5 percent, actual incidence was 0.2 percent
• For predicted risk between 2.5 and 3.74 percent, actual incidence was 0.65 percent
• For predicted risk between 3.75 and 4.99 percent, actual incidence was 0.9 percent
• For predicted risk equal to or greater than 5 percent, actual incidence was 1.85 percent

“From a relative standpoint, the overestimation is approximately five- to six-fold,” explained Dr. Go. “Translating this, it would mean that we would be over-treating a good many people based on the risk calculator.”’¹

So, you feed your risk factors in a risk calculator that took many years to create, using data carefully gathered by experts from the world of cardiology, and your true risk is overestimated five to six fold. Excellent. That mean millions upon millions of people have been told to take a statin based on a calculation that is so inaccurate as to be virtually meaningless. [This was always going to happen, because risk was established using clinical data from decades ago, since when, CVD rates have fallen dramatically]

Anyway, leaving the horrible inaccuracy of these risk factor calculators aside for the moment. What of the risk factors themselves? I am not going to look at all of them here, just two. Firstly, age. There is no doubt that age is the single most important risk for CVD. Your risk at 65 is around ten times as high as at age 35 – no matter what the overall risk may be in your particular country.

In fact, if you have no other factors at all, in the US, your future CVD risk at the age of 67 is so high (according to the calculator) it means that you are advised to go on a statin immediately, for the rest of your life. Ho hum. For women it is a few years later. ‘Here’s your first pension payment – with built in statin prescription.’

I find it fascinating that almost everyone seems to accept age as a risk factor for CVD, without really questioning why this should be so. Age does not necessarily increase the risk of diseases. There are many which are more common when you are younger, and the risk diminishes as you age.

The argument seems to be that CVD slowly progresses. Thus, as you get older, the risk increases. Yes, perhaps. However, if you have no conventional risk factors for CVD, why should it progress at all? At the risk of repeating myself, I shall repeat myself. You have no risk factors for CVD. Yet, as you grow older, your risk of CVD reaches the point where you are statinated. Because your future risk is so high.

But what is causing the atherosclerosis in your arteries to develop. Age? Through what process can age created atherosclerotic plaques, assuming no other risk factors? Raised cholesterol… well you don’t have raised cholesterol. Raised BP? Well, you don’t have raised BP. Smoking, well, you don’t smoke… etc.

The other major risk factor where we have an acceptance of a fact – without even an attempt at explanation is gender. In most populations younger men have a far higher risk of CVD than women. The different in risk varies greatly, but averages at about three to one. By which I mean, a women aged 55 women will have around one third the risk of a man aged 55 (living in the same country). Even if they have exactly the same risk factors.

For years it was stated, with great confidence, that this difference was due to female sex hormones. These hormones in some – never fully stated fashion – protected women against CVD. It has now been proven, beyond a molecule of doubt, that this is not true. Female sex hormones do not protect against CVD. Indeed, they probably accelerate it.

So, what does protect women against CVD. There is no explanation. It just is. Feed gender into the calculator and a different risk pops out for men and women. Why, because men and women, have a different risk of CVD. Why? Because they do. [BTW, the South Asian issue is much the same. Multiply the risk by 1.4. Why, because you do].

The reality is that age, and gender, are two of the most powerful risk factors for CVD. In that, if you use the ASCVD or QRISK calculator and change only age, and gender, the risk will go from close to zero, in a young woman to dark red – danger, danger, in an older man. Even if you set all other risk factors to zero.

It has always baffled me that experts in cardiology seem utterly unconcerned about this. They do not even consider that this is an issue. However, if the two most powerful risk factors you have for CVD, cannot be explained, are not explained, then you really have a major problem. Even if you cannot even comprehend that you do.

If you cannot explain why age, and gender, cause CVD… you cannot explain CVD.

1: http://www.eurekalert.org/pub_releases/2016-05/kp-crt042916.php

Twelve parts and not finished yet. Oh well.

At this point I have an admission to make – having recently been thinking about things in a different way. Up to now I have been using a model which I have called the ‘four step’ process of cardiovascular disease.

• Endothelial damage
• Clot formation/dysfunctional clot formation
• Clot repair/dysfunctional clot repair
• The final, fatal, blood clot

I still think that all the parts of the model are correct. However, it is probably best to look at this more as overlapping sets, rather than steps. Whilst it is true that, until the endothelium is damaged, nothing else can happen in the process of atherosclerotic plaque development. Once endothelial damage has occurred we are not looking at step 2, step 3, step 4 – as a linear process. After the first episode of endothelial damage, all the processes can be going on, virtually simultaneously (apart from the final, fatal clot obviously).

So, the thought I wish to make at this point, is that we are looking at a dynamic process, where all processes overlap and interconnect. Endothelial damage can be going on, whilst dysfunctional clot repair is also happening, in addition to further clot formation.

I was trying to think of a good analogy. The best I could come up with was rust on paintwork on a car. Before you can get rust, you need some damage to the paintwork. After that other factors can come into play. Water, salt…. Um, water and a bit more salt…um. Well, I am sure that other things can make cars rust more quickly, but hope you get the general idea.

Thus, I have decided not to call this the four step process anymore. I shall call it the four process process. No, that is rather clumsy. I shall call it the…not sure. The quadrilateral process. The ‘four process clotting’ hypothesis of heart disease. Anyway. I hope you know what I am going on about (those that have read the previous eleven blogs may do).

The role of lipoproteins

Now I am going to take this discussion in a direction those who have followed my writing thus far, may not quite expect. I want to look at the role of lipoproteins in blood clotting. Mea Culpa. I have spent a great deal of time telling people that lipoproteins have nothing to do with CVD. This is not entirely true. They can, and do, play a role.

The reality is that virtually every substance that can be found in the blood has some influence on blood clotting – and there are an enormous number of substances in the blood. So, it should come as no real surprise to find that high density lipoprotein (HDL), low density lipoproteins (LDL) and very low density lipoproteins (VLDL) are also involved.

Just to recap on one lipoprotein, namely lipoprotein (a) (Lp(a). As I have discussed earlier Lp(a), is produced by the body to plug areas of damage to artery wall. It is found in animals that cannot synthesize vitamin C – and are therefore at high risk of scurvy. Scurvy is, primarily, a disease of connective tissue e.g. collagen (which needs vitamin C for its synthesis).

Breakdown of collagen leads to cracks in blood vessels, and Lp(a) plugs the gaps. Thus, here is one lipoprotein, the entire function of which, is to help form very strongly bound blood clots. What I wish to highlight here is that Lp(a) could also be called LDL(a). Because Lp(a) is LDL which has one different protein attached to it.

With LDL and Lp(a) being virtually identical, it should come as no surprise that LDL itself also has an impact on blood clotting, through a number of different mechanisms. Indeed, the interaction between LDL and blood clotting is mind-boggling in its complexity. I am not going into things here in too much detail, and I will just highlight one study. It has the catchy title: ‘LDL receptor cooperates with LDL receptor–related protein in regulating plasma levels of coagulation factor VIII in vivo.’ Here we go:

‘High levels of FVIII in plasma (greater than 1.5 U/mL) constitute a major risk factor for arterial and venous thrombosis in humans. Our observation that the up-regulation of hepatic LDLR protein expression in mice by gene transfer accelerated FVIII clearance from the circulation may be of therapeutic interest for patients who have elevated plasma FVIII levels. In humans, the up-regulation of LDLR protein is achieved by treatment with 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase inhibitors, also called statins. Statins are widely recognized in the treatment of hypercholesterolemia in humans.’ ¹

What is all this about? Basically if you have fewer LDL receptors (LDLR) there will be slower clearance of factor VIII (a key blood clotting factor) and the level in the blood rises. If you increase LDL receptors, by using statins, more factor VIII will be removed, and the risk of blood clotting will fall. So, here we have statins reducing the risk of cardiovascular disease by increasing the number of LDL receptors on the liver, which causes factor VIII (a blood clotting factor) to be removed from the blood.

In addition to this LDL interacts with platelets (the key blood cells involved in blood clotting) and the more LDL you have, the greater the tendency of platelets to clump together:

‘Platelets and lipoproteins are intimately involved in the pathogenesis of a wide variety of disease including atherosclerosis, thrombosis, and coronary heart disease. Evidence accumulated over the years suggests the possibility of a direct relationship between plasma lipoproteins and the hemostatic function of platelets. A number of studies demonstrated that native LDL enhanced the platelet sensitivity to stimulation and induced platelet activation.’²

In short, LDL activates platelets, and activate platelets are the starting point for blood clot formation.

The enormous complexity of the clotting system is further revealed when we look at High Density Lipoproteins (HDL) a.k.a. ‘good’ cholesterol. It is widely accepted that HDL is protective against death from CVD. It is generally believed that this protection comes through the process of reverse cholesterol transport i.e. HDL sucks cholesterol out of plaques. [Which I do not believe]

However, this is almost certainly not how HDL works. It has other important and potent effects on blood coagulation:

‘….Furthermore, HDL stimulates the endothelial production of nitric oxide and prostacyclin, which are potent inhibitors of platelet activation. Thus, HDL’s antithrombotic actions are multiple and therefore, raising HDL may be an important therapeutic strategy to reduce the risk of arterial and venous thrombosis.’³

VLDL (triglyceride)

Finally, for now, what to triglycerides do – with regard to blood clotting? More jargon here, but a very powerful statement linking VLDL/triglyceride levels to blood clotting.

‘Activation of platelets and the coagulation cascade are intertwined. VLDL and remnant lipoprotein concentrations are often increased with the metabolic syndrome. These lipoproteins have the capacity to activate platelets and the coagulation pathway, and to support the assembly of the prothrombinase complex. VLDL also upregulates expression of the plasminogen activator inhibitor-1 gene and plasminogen activator inhibitor-1 antigen and activity, a process accompanied by platelet aggregation and clot formation. The surface membrane of activated platelets also supports the assembly and activity of the prothrombinase complex, resulting in further thrombin generation and amplification of the coagulation cascade.’⁴

If you don’t like the jargon, I will simplify:

• High levels of LDL increase the risk of blood clots forming
• High levels of HDL reduce the risk of blood clots forming
• VLDL/triglycerides increase the risk of blood clots forming

To this, I will just add that ‘oxidised’ LDL is particularly pro-coagulant. It reduces Nitric Oxide synthesis in the endothelium, triggers platelet activation and damages the endothelium. Thus the condition known as ‘dyslipidaemia’ is particularly dangerous. Dyslipidaemia consists of low HDL, high VLDL and more ‘oxidised’ LDL. It is usually caused by insulin resistance a.k.a. the metabolic syndrome a.k.a. pre-diabetes.

So, ahem yes, blood borne lipoproteins do have a role to play in CVD. The role is not key, but it is there. I thought I should get that off my chest.

References:

1: http://www.bloodjournal.org/content/106/3/906?ijkey=7bc28d479d9564c9b2e6b769303bb28dd05de91b&keytype2=tf_ipsecsha

2: Yashika Gupta, V. Mallika* and D.K. Srivastava: ‘INTERACTION OF LDL AND PLATELETS IN ISCHAEMIC AND ISCHAEMIC RISK SUBJECTS’ Indian Journal of Clinical Biochemistry, 2005, 20 (1) 97 – 92

3: http://www.ncbi.nlm.nih.gov/pubmed/24891399

4: http://www.ncbi.nlm.nih.gov/pubmed/16877877

This blog was going to be all about bringing together all of the strands about what causes heart disease. However, as often seems to happen, I was sent an article about a study that will be presented at the American College of Cardiology conference in Chicago. It led me down a slight detour, which is actually highly relevant to what I have been discussing.

At present I have no more details of this study than can be found in this press release.

Depressed CAD Patients May be at Higher Risk For MI, Death

Patients with coronary artery disease (CAD) who are depressed may have a much higher risk of myocardial infarction (MI) or death compared to those who are not depressed, according to research published March 23 which will be presented at ACC.16 in Chicago.

The study, conducted by Natalie Szpakowski, MD, and colleagues, included 22,917 patients who had been diagnosed with stable CAD following a coronary angiogram for chest pain. Results showed that the incidence of depression following a diagnosis of stable CAD was 18.8 percent. Patients who were female or who had more severe angina were more likely to be diagnosed with depression.

Further, depressed CAD patients were 83 percent more likely to die from any cause compared to those who were not depressed. They were also 36 percent more likely to present at a hospital for MI. Those who were diagnosed with depression 90 to 180 days following the diagnosis of CAD were at greatest risk.

According to the authors, these findings suggest that these patients may need to be screened for mood disorders, either by their family physician or their cardiologist.

“Based on these findings, there may be an opportunity to improve outcomes in people with coronary heart disease by screening for and treating mood disorders, but this needs to be further studied,” says Szpakowski. “Stable chronic angina due to narrowing of the coronary arteries is common, and our findings show that many of these patients struggle with depression. Our follow-up was at most five years, so many more might be affected.”¹

Here, I thought, was an opportunity look at the process(es) by which depression can lead to heart disease. Up to now, the ‘experts’ in cardiology have stated that have heart disease causes depression…yawn. In this way they have dismissed the need to explain how, or why, depression could cause heart disease. Primarily, because this association cannot be explained using the currently accepted risk factors.

I thought this study represented a perfect opportunity to demonstrate exactly how, and why, depression will increase the risk of CVD, using the four step model for CVD (cardiovascular disease) which I have outlined in this series:

• Endothelial damage
• Clot formation/dysfunctional clot formation
• Clot repair/dysfunctional clot repair
• The final, fatal, blood clot

Your first thought may well be. How does depression damage the endothelium, or increase clot formation… or anything else in the four step process?

Well, clearly depression cannot directly damage the endothelium, or increase dysfunctional clot formation. However, the pathways that lead from depression to the four step process are easily defined, pretty straightforward, and supported by a mass of evidence, and they go like this.

Depression, from whatever cause, creates a dysfunction of the hypothalamic-pituitary-adrenal axis (HPA-axis). Sorry to bring in the jargon straight away. However, in an attempt to keep this is simple as possible, think of the HPA-axis as the ‘unconscious’ system of hormones, and nerves, that control how we react to stress. We are talking about hormones such as adrenaline, cortisol, glucagon and suchlike.

We are also talking about the sympathetic and parasympathetic nervous systems which control heart rate, pupil dilation, blood flow to muscles, contraction of the bladder – so just about involved in everything we do. The HPA-axis can also be thought of as the central management system for the ‘flight or fight’ response.

When I use the term, ‘dysfunctional HPA-axis’, what I mean that the HPA-axis has been knocked out of whack. Usually this means it is overproducing stress hormones (particularly cortisol), and is overdriving the sympathetic nervous system. [Yes, I know it is actually all far more complex than this – for those who will undoubtedly write in to tell me so].

The type of things that damage the HPA-axis are: episodes of extreme stress, leading to PTSD, anxiety, depression, schizophrenia. In fact, most mental disorders will be reflected in a dysfunctional HPA-axis – to one degree or another.

If you want more information on this, I suggest going to Google and typing in depression and HPA-axis and/or stress. Or PTSD and HPA-axis dysfunction etc. You will find that much information springs to life before your very eyes. Essentially, you will begin to see how stress, mental illness, depression, anxiety etc. can all be linked through the HPA-axis, to one degree or another.

In short, if you suffer from stress/anxiety/depression… etc, your HPA-axis will go wrong. It will go wrong in many, many, different ways. The complexities and interactions of HPA-axis dysfunction stretch as far as the eye can see – and further. Believe me, I have disappeared over the horizon in many different directions over the years.

However, for the sake of brevity, and understanding, I will look at focus on one hormone, Cortisol. Cortisol is quite easy to measure, and it usually the hormone used to diagnose HPA-axis dysfunction. If the levels of cortisol are high, or low, or do not go up and down in a flexible fashion during the day, you have HPA-axis dysfunction.

Yes, unfortunately, measuring cortisol levels can result in much confusion. I can guarantee that if you look into this area you will end up mind-boggled and mired in apparent contradictions. Just to give one example. Finding a low cortisol level in the morning does not mean that do not have a ‘stress’ related problems, which would normally lead to high cortisol levels.

It simply means that your neuro-hormonal system has ‘burnt-out,’ leading to low cortisol levels in the morning (but overall higher levels over 24 hours). Somewhat similar as to what happens in diabetes where the pancreas eventually gives up the effort of producing insulin to overcome insulin resistance, and ‘burns-out.’ At which point you may well be diagnosed with type II diabetes.

Is that a good analogy… yes, I think so. Because I have seen papers stating that raised cortisol/stress/anxiety/depression cannot be causes of CVD, because many people with CVD have low cortisol levels in the morning. Bong! Wrong answer. A low cortisol level in the morning is probably the single most powerful indication of HPA-axis dysfunction. [Look up Bjorntorp on Google]

Anyhoo. Getting back to depression. If you are depressed, your HPA-axis will become dysfunctional. You will have abnormal cortisol levels, and you will become insulin resistant (because cortisol is a direct antagonist to insulin at many sites). In fact, severe depression can actually cause type II diabetes. Yes, you can look that up too.

Even if you don’t develop frank diabetes, you will end up with a whole serious of metabolic abnormalities. For the sake of keeping this short, you will also end up with blood clotting abnormalities too. Just to give one example, depression increases fibrinogen level in the blood.

‘In cross-sectional analyses, a stepwise increase in fibrinogen percentile categories was associated with a stepwise increase in risk of psychological distress, use of antidepressant medication, and hospitalization with depression.’ ²

Another important clotting factor is Plasminogen Activator Inhibitor-1 (PAI-1). This stops blood clots getting broken down/repaired after they form. Another quick quote here from a paper called ‘Mental disorders and thrombotic risk.’

‘Patients with psychosis, severe depression, or chronic stress are at increased risk for thromboembolism. Evidence suggests that tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) imbalance may play an important role in pathophysiology of mental and thromboembolic disorders. tPA facilitates clot dissolution and participates in several brain functions, including response to stress, learning, and memory. Depression is characterized by high PAI-1 level.’ ³

Linking it together

I hope that, at this point, it has become very clear how depression can, should, and in fact does link directly to an increase in the risk of CVD. Depression causes creates HPA-axis dysfunction and abnormal cortisol secretion, leading to insulin resistance and even diabetes (in severe cases).

This, in turn, stimulates the over-production of various clotting factors, such as fibrinogen. In addition, there is an increase in PAI-1, which prevents the breakdown/repair of the blood clot. [It causes other things too, but I am trying to keep this as concise as possible]

Clearly all this links directly to the four step model. Diabetes/raised blood sugar levels are directly damaging to the endothelium. Raised fibrinogen and PAI-1 are very powerful risk factors for CVD, primarily because they make the blood more likely to clot, and the clot more difficult to clear up.

In short, it is extremely straightforward to link depression to CVD, through the four step process:

• Endothelial damage
• Clot formation/dysfunctional clot formation
• Clot repair/dysfunctional clot repair
• The final, fatal, blood clot

Next, I will try to demonstrate how a number of other apparently unrelated conditions link to CVD through the ‘four-step’ process. Finally, I will put together, what I believe, are the ten (or so) best things you can do to protect yourself from CVD. I suspect you will already have worked out a number of them for yourself.

Then, anyone who cares to, can attack the four step hypothesis of heart disease and, I trust, do their best to pull it apart. I welcome the debate.

REFERENCES:

1: http://www.acc.org/latest-in-cardiology/articles/2016/03/23/15/41/depressed-cad-patients-may-be-at-higher-risk-for-mi-death?w_nav=LC

2: http://www.ncbi.nlm.nih.gov/pubmed/22981529

3: http://www.ncbi.nlm.nih.gov/pubmed/24114008

P.S. For those who like this sort of thing. Here is a paper by Bjrontorp which outlines how the HPA-axis dysfunction actually happens, and how it can be measured. http://onlinelibrary.wiley.com/doi/10.1046/j.1365-2796.2000.00603.x/epdf

P.P.S. Bjorntorp worked out the main cause of CVD many years ago

(Calcification)

Yes, part X, and not at the end… yet. Before trying to sum up I thought I should discuss calcification of the arteries. This is an area I have tended to shy away from in the past, because I am not sure exactly where to place it. Association, end-result, cause… Ignore.

Firstly, what is calcification? It is generally accepted, and I think it is true, that calcification represents the final stage of atherosclerotic plaque development, or growth – or whatever word fits most accurately. The best way of looking at calcification, within the spectrum of CVD, would be to define it as the end stage of plaque development.

Having said that, this is not always the case. Not all plaques calcify. Some do, some don’t, and there are many other factors that have a key role in calcification. Various vitamins, such as Vitamin K(K2) and vitamin D are important. Warfarin, which blocks the effects of vitamin K, increases plaque calcification. The picture is complex.

You may have heard of a condition called fibrordysplasia ossificans progressiva, where muscle turns to bone. Not nice, but it does demonstrate that, in certain circumstances, various other tissues can also calcify – to one extent or another.

The main reason for mentioning calcification is that the Calcium artery score (CAC) has become the latest way of frightening people about CVD. You do a CT scan, count of the amount of calcium you can see, and score it. The more the calcium, the worse things are.

In truth, despite my slightly sceptical tone, measuring calcification seems to be one of the most accurate ways of assessing overall plaque burden, and your true risk of dying of CVD. Like everything else in this area, the CAC score is far from perfect. However, even with many provisos in place, if you have a high CAC then you are definitely at a higher risk of dying of CVD. Equally, if you have a zero calcium score, you can pretty much relax. So it is important.

I suppose you may be wondering, at this point, why would plaques calcify? What is the body doing here? Well, you might find these quotes interesting:

“Atherosclerotic calcification is an organized, regulated process similar to bone formation that occurs only when other aspects of atherosclerosis are present.” L Wexler, et al., American Heart Association Writing Group

In short – and, by the way, I fully agree with the above quote, calcification is not an accident, or an unwanted effect. It seems to be an organised, and regulated process. But organised, and regulated, for what purpose…

‘This chapter will show that vascular calcification is a physiologic defense against active, progressive atherosclerotic disease, that it is produced by physiologic mechanisms similar to those required for normal bone formation and that it is potentially reversible.’ ¹

You might well then ask the following. If calcification is a physiologic defense mechanism… why would you want to reverse it? You might just be making things worse. It is certainly true that plaques pass through several different phases. The most dangerous of which seems to be the ‘unstable’ plaque. This is when the central core of the plaque is a kind of liquid goo which, if it ruptures, stimulates a massive – and potentially fatal – blood clot. Plaques in this state are sometimes called ‘vulnerable.’

On the other hand, once a plaque calcifies, it appears to become more stable, and less likely to rupture… and kill you. Which means that reversal of calcification may look good on a scan, and your doctor may smile with pleasure at your reduced CAC. But… it is all good? I have seen an argument used (by the pro-statin camp) that statins accelerate calcification – but this might be a good thing, because the plaque is less likely to rupture. Is this true? [It would by a nice irony].

Perhaps, here, you can see why I struggle a bit with the whole calcification thing. Is it a natural progression of the plaque? It is a way that the body closes down further damage, and stops further plaque progression. Does calcification help to strengthen the artery wall to prevent it rupturing? Should we be trying to reverse calcification… would we simple be turning a calcified plaque back into a vulnerable plaque?

Calcification is certainly not a new thing. CT scans of mummies – from a number of different cultures – have demonstrated that many/most mummified bodies have large areas of arterial calcification. Ergo, CVD is most certainly not a disease of modern humanity. The mummies from Egypt are well over two thousand years old.

As you can probably tell I am not sure exactly what to make of calcification. However, I think you can probably make the following statements:

• If you do a CT scan and have no demonstrable calcification – after the age of about forty to fifty – you are at very low risk of dying of CVD
• If you have a high CAC score this means that you have been developing plaques for quite a while, and therefore (unless you change something) you are at high risk of dying of CVD. [However, bear in mind that CAC represents your history, not necessarily your future].
• Calcification can reverse. Vitamin K2s (Menaquinones) seem to be more protective/able to reverse calcification than Vitamin K1. Menaquinones are primarily found in meat and dairy-based foods and fermented soybeans (known as natto, commonly consumed in Japan)
• Calcification is not a cause of CVD, it is (or seems to be) the final stage of plaque development. It may be a protective mechanism to stabilise plaques.
• There is no evidence, that I am aware of, that if you reverse calcification you improve CVD risk. But it seems likely there would be benefit.

Sorry, I am not sure if that is very helpful, but I thought I had to discuss calcification in this series.

1: http://www.ncbi.nlm.nih.gov/books/NBK2015/

Heart disease part IX? I think my little series is getting a bit like the Superbowl, with the ever increasing roman numerals. Oh well, it just started that way, now I’m stuck with it. Never mind.

I know people have been reading this series with different purposes in mind. Still, a number of people seem to be asking ‘OK, what’s the cause?’ In which case, I have failed rather miserably in my quest. My main theme is that there is no cause. I shall repeat. There is no cause. Or, perhaps to be more accurate – there is no single cause. There cannot be.

There is a process.

To reiterated what I have been trying to say up to now, you cannot identify real causes, unless you understand what is actually going on with CVD. Indeed, I firmly believe that the search for causes has been the main reason why we are in the current situation – a multifactorial mess. In 1981 the Journal Atherosclerosis searched for all the factors that had been identified as either causing CVD, or protecting against CVD. There were nearly three hundred. Some, such as copper in the diet, were simultaneously causal and protective.

If anyone were to try to scour all medical papers to carry out such a study today, there would be thousands more factors – this I can guarantee. Cholesterol alone itself has split and multiplied into good and bad, light and fluffy, small and dense LLD-C, LDL-P, eight subtractions of HDL (good cholesterol), dyslipidaemia, Lp(a)… Each one has somebody waving a flag furiously in support of it. New and expensive tests developed each and every day.

How could anyone possibly try to make sense of such a thing? Three thousand eight hundred and fifty causal factors, four thousand two hundred and eighty-six protective factors. Go figure. Get a super-computer and run it for the entire life-span of the rest of the Universe. You may be a trillionth of the way through working out how they all add and subtract, multiply, or divide risk.

I spent twenty-five years looking for a cause, or causes, and gave up. It was a fool’s errand. It was the transmutation of lead into the gold, the search for the missing chord, the creating of a perpetual motion machine, a discussion of how many angels can dance on the head of a pin – an attempt to fit planetary motion into a Geocentric model of the Universe (Everything rotates around the Earth). In short, impossible.

The first step to understanding CVD (and this happened for me, many years ago) was to strip cholesterol/LDL cholesterol out of the model. For so many people, then as now, Cholesterol was/is the Earth at the centre of the Geocentric model. It still represents the key jigsaw piece placed triumphantly in the middle of the puzzle. Hammered in, and decreed immovable by the likes of Ancel Keys, before anyone really knew what the picture looks like.

I have read paper after paper where people seem to be going in the right direction about heart disease, then they find they have to shoehorn cholesterol into the centre of their research. At which point everything distorts into a mess of twisted logic. A truth may be jumping up and down in front of them shouting ‘Me, me, me. Here. Look.’ But the truth is invisible. There are no so blind as those who will not see.

There is a process

The conclusion that I came to, eventually, is that we have to define the underlying process. As we should do with all diseases I suppose. However, the ‘disease’ model that medicine has become fixated with, as a way of thinking, was in major part started by a famous microbiologist Robert Koch in the late nineteenth century. His thinking was mainly directed microorganisms e.g. bacteria, viruses and suchlike. He decreed that for any microorganisms to be identified as a true cause of a disease, the following postulates must be fulfilled.

• The microorganism must be found in abundance in all organisms suffering from the disease, but should not be found in healthy organisms.
• The microorganism must be isolated from a diseased organism and grown in pure culture.
• The cultured microorganism should cause disease when introduced into a healthy organism.
• The microorganism must be reisolated from the inoculated, diseased experimental host and identified as being identical to the original specific causative agent.

Now, these are pretty tough criteria. If not just from an ethical perspective. You try putting a cultured microorganism into a healthily organism nowadays and see how far you get. ‘We are not sure that Ebola virus causes Ebola in humans. Let me isolate if from a patient and introduce into a healthy human.’ Good luck with that.

However, the main point I want to make here is the ‘single causal agent’ concept of medicine has become the meme. You start by looking for the cause of a disease. Once you believe you have it, all research, and all thinking starts to crystallize around that cause. It becomes the centre of all thinking, and dominates the landscape.

I see this in CVD researchers all the time. There are those who are still convinced that cholesterol causes heart disease. All facts are twisted and bent around to fit this central fact. Contradictions are ‘immunised’ against in various ways.

Me:                           ‘People with low cholesterol levels can still have plaques and an MI. So a raised cholesterol level is neither necessary, nor sufficient, to cause CVD.’ {See under Koch’s postulates}.

A.N. Expert:         ‘Actually the normal level of cholesterol in modern humans is far higher than the ‘healthy level.’ So, everyone actually has does have a high cholesterol level. Look at hunter gatherer’s, neonates and other animal species. Where cholesterol levels are much lower.’

The argument here is almost perfect. Everyone has a high cholesterol, so you cannot rule out a high cholesterol level as a cause of CVD- in anyone. [Total nonsense of course].

Me:                           ‘In the Framingham study, those whose cholesterol levels fell, in the first fourteen years of the study, had a greatly increased risk of CVD over the next eighteen years.’

A.N. Expert:         ‘The is reverse causality. A falling cholesterol is caused by an underlying disease, and it is the underlying disease causing the problem, not the low cholesterol.’

Me;                           ‘The French have higher cholesterol levels than the Russians and one tenth the rate of CVD

A.N. Expert:         ‘The French are protected by drinking red wine and eating lightly cooked vegetables and eating garlic.’

Me:                           ‘Asian Indians do not have high cholesterol levels, yet their rate of CVD is far higher than the surrounding population

A.N. Expert:         ‘The Asians are genetically susceptible to CVD.’

‘Ad-Hoc hypotheses – that is, at the time untestable auxiliary hypotheses – can save almost any theory from any particular refutation. But this does not mean that we can go on with an ad hoc hypothesis as long as we like. It may become testable; and a negative test may force us either to give it up or to introduce a new secondary ad hoc hypothesis, and on and on, ad infinitum.’ Karl Popper.

One of my favourite ad-hoc hypothesis, which covers the entire diet-heart/cholesterol hypothesis, rather than just the cholesterol hypothesis, was the use of teleoanlysis. Here, the authors looked at all the studies on using a low fat died and found they had no effect on CVD. However, they knew (and claimed as fact) that eating saturated fat raised cholesterol levels, and they knew (and claimed as fact) that raised cholesterol causes CVD. Ergo, eating saturated fat must cause CVD, so the trials must be wrong.

At which point, rather than relying on the published evidence, they decided that you simply make up studies in your head, and use them to prove that saturated fat does, actually, cause CVD. If you think I am making this up, here is the quote from the study, published in the BMJ

‘….teleoanalysis combines different categories of study to quantify the relation between a causative factor and the risk of disease. This is helpful in determining medical practice and public health policy. Put simply, meta-analysis is the analysis of many studies that have already been done; teleoanalysis provides the answer to questions that would be obtained from studies that have not been done and often, for ethical and financial reasons, could never be done.’ http://www.bmj.com/content/327/7415/616?sso=

Yes, this was published in the BMJ, no less. I always enjoy this paper. It is so ludicrous that it goes well beyond despair and into surrealism. ‘Ceci n’est pas une Pipe.’ Ignore the evidence and, instead, rely on what you know to be true. This, of course, is the way high quality science should be done… not.

More recently we have equally mad studies on mendelian randomisation. Which may not immediately look like teleoanalysis, but at heart it is are exactly the same thing.

It has been found that older people with high cholesterol levels live longer than those with low cholesterol levels, and get less CVD. This does not fit well into a world where billions can be made lowering cholesterol levels – particularly in the elderly. The first attempt to refute this finding was to say that other diseases lead to low cholesterol levels (as mentioned earlier), and it is the other diseases causing the problem, not the low cholesterol. It was Iribarren who came up with this one.

This, so called ‘reverse causality hypothesis’, has been proven to be wrong in several major studies. So, a new attempt was made using ‘mendelian randomisation’ [Yes, genetics, after Gregor Mendel who proved the concept of genetic inheritance]. By using mendelian randomisation, you can identify people who would have had high cholesterol during most of their lifespan (they have genes associated with high cholesterol levels). So, their cholesterol may be low when you measured it, but it would have been high for most of their lifetime.

Ergo, people with low cholesterol levels, and higher mortality rates, actually had higher cholesterol levels when they were younger, and the lifetime effect of these high cholesterol levels will have caused them to die of CVD. Not, I repeat not, the low cholesterol levels they now have. Yes, this stuff gets published too, and rolled out to confuse the hell out of everyone. [Luckily, I have contact with people within the pharma industry who set up and run genetic studies. They tell me this stuff is simply smoke and mirrors].

I shall paraphrase mendelian randomisation studies. ‘Your cholesterol level is not your cholesterol level…. So there. It is whatever we decide it is.’

Believe me, attempts to refute contradictions to the cholesterol hypothesis get more complex than this. As you can see, in the world of CVD you can play the game of ad-hoc hypothesis, ad-infinitum. In the end there are so many ad-hoc hypothesis created that A.N. Expert can slip from one the other and back again without ever having to accept that any single fact represents a contradiction to the hypothesis. The final trick, when you are getting close to nailing them they just say ‘Oh well, CVD is multifactorial.’ This is not an answer. It is just a polite way of saying ‘shut up and do as I say.’

I ended up with a further realisation. There is no point attacking the cholesterol hypothesis. Those who believe in it have created a majestic Byzantine world of mind-numbing complexity where you can wonder the corridors of ad-hoc hypotheses forever, and never escape.

So, I made a decision, which I have just gone back on. Do not bother attacking the diet-heart/cholesterol (whatever you want to call it) hypothesis. You just get dragged onto a playing field that is not your own, chasing round and round in circles, trying to refute the latest made up ad-hoc hypothesis. It is like discussing the existence, or non-existence, of God with a Professor in theology. They can call on two thousand years of well-rehearsed arguments to confuse you with. You don’t stand a chance.

Instead I have spent, what I hope to be more productive, years and years, working out a hypothesis that actually fits the facts. There is no need for ad-hoc hypothesis, no need for teleoanalysis, or mendalian randomisation. No need for planets doing little circles in the sky, to support the Geocentric model of the Universe.

I could only do this by moving away from looking at causes, and trying to establish the underlying processes at work in CVD. I am not the first to attempt this. Rokitansky was first, Duguid had a good go, Ross also attempted to demonstrate the ‘response to injury hypothesis.’ Up to now, those who believe that CVD is, essentially, a disease of dysfunctional blood clotting have simply bounced off the well-guarded walls of the cholesterol citadel.

In the end, though, someone is going to break through. It is just a matter of time. You can stomp on the truth for many years. You can concrete it over. But the truth has a major advantage over sophistry. It is immortal. No matter how deep you try to bury it, It lies there, waiting to be discovered, pushing little green shoots up into the sunlight waiting to be discovered.

The healing process

Most people, when they think about atherosclerotic plaques, think of them as starting very small – as fatty streaks and suchlike. Then they inevitably get bigger and bigger over many years. However, this is not correct:

‘Atherosclerosis was originally considered to be an ongoing process that was inevitably associated with age. However, plaques are highly dynamic, and are able to progress, stabilize or regress depending on their surrounding milieu. A great deal of research attention has been focused on understanding the involvement of high-density lipoprotein in atherosclerotic plaque regression. However, atherosclerotic plaque regression encompasses a variety of processes that can be grouped into three main areas: removal of lipids and necrotic material; restoration of endothelial function and repair of denuded areas; and cessation of vascular smooth muscle cell proliferation and phenotype reversal.’ ¹

In short, progression is not inevitable. Plaques can shrink down in size, the smooth muscle proliferation (often considered and irreversible components of plaques) reversed, and endothelial function restored. In truth, you will most likely not end up with a perfectly healed plaque with no signs it was ever there. You will be left with a bit of a ‘scar’ or some sort. However, the important point is that we are not looking at a one-way street. The body can heal plaques. (Probably not once calcified, but that is another issue).

This leads me onto the third part of the process of CVD. As I have been discussing in this series, the process of CVD has four basic components:

• Endothelial damage
• Clot formation/dysfunctional clot formation
• Clot repair/dysfunctional clot repair
• The final, fatal, blood clot

Up to now I have mainly talked about endothelial damage, and clot formation, which are plaque ‘growth’ factors. However, repair is also very important. Anything that can interfere with the repair process is going to make plaques grow, rather than regress.

The key players in repair are: monocytes, macrophages and Endothelial Progenitor Cells (EPCs). As mentioned several times before, once the endothelium is damaged, and a clot formed, EPCs are attracted to the area to form a new layer of endothelium. So, clearly EPCS are critical players. Just to quote one paper:

‘BACKGROUND: Cardiovascular risk factors contribute to atherogenesis by inducing endothelial-cell injury and dysfunction. We hypothesized that endothelial progenitor cells derived from bone marrow have a role in ongoing endothelial repair and that impaired mobilization or depletion of these cells contributes to endothelial dysfunction and cardiovascular disease progression.

CONCLUSIONS: In healthy men, levels of endothelial progenitor cells may be a surrogate biologic marker for vascular function and cumulative cardiovascular risk. These findings suggest that endothelial injury in the absence of sufficient circulating progenitor cells may affect the progression of cardiovascular disease.’² Which means that with fewer EPCS, plaques grow faster.

The critical part that EPCs have to play is also seen in patients who have angioplasty, or stents. Immediately following the procedure, the bone marrow starts making more EPCs.

‘In conclusion, endothelial injury from angioplasty can lead to time-dependent mobilization or homing of EPCs; mature EPC subpopulations are actively mobilized, and may contribute more to endothelial reparation; and the mobilization amplitude of the main EPC subpopulations is significantly influenced by the degree of endothelial injury and certain clinical factors.’³

It follows that, if you have fewer EPCs the risk of CVD will be much higher. This is clearly seen in Systemic Lupus Erythematosus (mentioned a few times before). The paper quoted from below looked at SLE, and the number of EPCs, and also haematopoietic stem Cells (HSCs) – which are the precursor to EPCs – found in the bone marrow:

‘SLE patients have lower levels of circulating HSC and EPC, even during clinical remission. Our data suggest that increased HSC apoptosis (cell death) is the underlying cause for this depletion. These observations indicate that progenitor cell mediated endogenous vascular repair is impaired in SLE, which may contribute to the accelerated development of atherosclerosis.’⁴

Other conditions, or factors, that reduce EPC numbers include:

• Type II diabetes
• Avastin
• Rheumatoid arthritis
• Smoking

To name but four.

Of course there tends to be a tight association between factors that damage the endothelial cells, and factors that reduce EPC number. This appears to be primarily modulated by nitric oxide levels. Anything that increases NO levels in endothelial cells and also helps to protect them from damage appears to increase EPC production in the bone marrow.

A non-exhaustive list of things can do this this are:

• Exercise
• L-arginine/L-citrulline
• ACE-inhibitors (used for BP reduction)
• Statins

Yes, the dreaded statins… Boooo! In truth, for many years I have accepted (albeit with great reluctance), that statins do have some benefits in CVD. Not enough, in my opinion, to overcome the damage that they can do. However, the benefit is there, it is real.

I knew it could be nothing to do with the impact of statins on lowering LDL, as LDL has nothing to do with CVD (well, almost nothing). So there had to be another effect. And that effect is, in my opinion, almost entirely to do with the ability of statins to increase nitric oxide (NO) production:

‘Endothelial nitric oxide (eNO) bioavailability is severely reduced after myocardial infarction (MI) and in heart failure. Statins enhance eNO availability by both increasing eNO production and reducing NO inactivation. We therefore studied the effect of statin treatment on eNO availability after MI and tested its role for endothelial progenitor cell mobilization, myocardial neovascularization, left ventricular (LV) dysfunction, remodeling, and survival after MI….. These findings suggest that increased eNO availability is required for statin-induced improvement of endothelial progenitor cell mobilization, myocardial neovascularization, LV dysfunction, interstitial fibrosis, and survival after MI. eNO bioavailability after MI likely represents an important therapeutic target in heart failure after MI and mediates beneficial effects of statin treatment after MI.⁵’

Yes, when you decide to look through a different prism, you can find that things you thought were one thing, turn out to be another thing entirely. Professor Michael Oliver – a trenchant critic of the cholesterol hypothesis before statins came along – changed his mind, once he saw that statins lowered LDL and lowered CVD risk. Case proven – he said.

No, case not proven. Instead, if you look at EPCs and nitric oxide (NO) and take the view of CVD that it is all due to endothelial dysfunction, blood clotting and impaired repair, you can see exactly where statins may fit into the picture.

Next: The final event.

References:

1: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3209544/

2: http://www.ncbi.nlm.nih.gov/pubmed/12584367?dopt=Abstract

3: http://www.spandidos-publications.com/etm/10/2/809

4: http://ard.bmj.com/content/early/2007/02/28/ard.2006.065631.abstract

5: http://www.ncbi.nlm.nih.gov/pubmed/15466656

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/

The first stage of cardiovascular disease is damage to the endothelium. The single layer of cells lining the arteries. After this, we need to look at what then happens? Before looking at this more closely, I would like to take you back in time around one hundred and sixty years. This was when the first scientific debates about plaque development were taking place.

Rudolf Virchow and Karl von Rokitansky were the proponents of different hypotheses at this time. I am grateful to Professor Paul Rosch for providing the information on Virchow’s ideas. He provided this description in one of his newsletter.

‘Rudolph Virchow was the first to demonstrate the presence of cholesterol in atheroma in 1856. He described atherosclerosis as “endarteritis deformans” The suffix “itis” emphasized that it resulted from an inflammatory process that injured the inner lining of the arteries, and that the cholesterol deposits started to appear subsequently

Virchow was very specific about this when he wrote. ‘We cannot help regarding the process as one which has arisen out of irritation of the parts, stimulating them to new, formative actions; so far therefore it comes under our ideas of inflammation, or at least of those processes which are extremely nearly allied to inflammation.

We can distinguish a stage of irritation preceding the fatty metamorphosis, comparable to the stage of swelling, cloudiness, and enlargement which we see in other inflamed parts. I have therefore felt no hesitation in siding with the old view in this matter, and in admitting an inflammation of the inner arterial coat to be the starting point of the so-called atheromatous degeneration and the cholesterol deposits came later.’

So, even one hundred and sixty years ago, eminent professors recognised that atherosclerotic plaques started with ‘inflammation of the inner arterial coat’ a.k.a…the endothelium. The cholesterol deposits came later. Quite so. Or to put this another way, the cholesterol was not the cause of the plaque, the appearance of cholesterol in a plaque was part of the second stage of plaque development.

However, whilst agreeing on this observation, Karl Von Rokitansky had a further hypothesis.

‘Rokitansky proposed that the deposits observed in the inner layer of the arterial wall were derived primarily from fibrin and other blood elements rather than being the result of a purulent process. Subsequently, the atheroma resulted from the degeneration of the fibrin and other blood proteins and finally these deposits were modified toward a pulpy mass containing cholesterol crystals and fatty globules.’

Or, to put it another way. He believed that plaques were, in fact, blood clots, in various stages of repair. He believed this because plaques looked exactly like blood clots, and contained everything that you can see in a blood clot. Perhaps most critically, a great deal of fibrin, which is the key component of all blood clots.

However, Virchow objected to this idea on the simple basis. ‘How can a blood clot form within the arterial wall?’ Or, how can a blood clot form under the endothelium. A good point, and Rokitansky had no effective response. So he lost.

However, there is a very simple explanation as to exactly how a blood clot can be found beneath the endothelium. And this is, because the endothelium wasn’t there when the clot formed. It grew over the top of the clot afterwards. Which takes us to Endothelial Progenitor Cells (EPCs).

After my last blog, a poster made the following comment.

‘And then… the clot, now trapped under the new endothelium, becomes plaque? If true, seems a stupidly “designed” 🙂 healing process.’

Well, superficially, this is a good point. Simply incorporating clot into arterial wall, where is forms a plaque and then kills you, does not seem a great idea. However, I would ask you to consider what would happen to a blood clot, lying on an artery wall, that simply broke off and travelled down the artery. What would happen?

The answer is simple; it would jam up as the artery narrowed. This could cause a stroke, or a heart attack, or suchlike. Exactly as happens with atrial fibrillation. Where small clots that break off from the atria travel into the brain and get jammed. The body does not like blood clots floating about in the arterial system.

So this does not happen/is not allowed to happen. When the endothelium is damaged, a clot forms on top of it. It is true that a certain amount/a great deal of this clot will be shaved away into very small (not stroke creating sized) pieces, but a ‘core’ will be left. This has to be got rid of in some way.

How are you going to do this? There is only one possible way. Firstly, you cover it over with another layer of endothelium, then you attack it, break it down, and destroy it. And this is exactly and precisely what the body does.

Once a blood clot has stabilized, Endothelial Progenitor Cells (EPCs), that are manufactured in the bone marrow, and float around in the bloodstream, are attracted to the clot. They stick to it, then they grow into fully mature endothelial cells, forming a new layer of endothelium, effectively drawing the clot inside the arterial wall. Then the clot is attacked and got rid of. How?

Well, a critical fact to add in here is that. EPCs do not always become endothelial cells, they can go down another developmental pathway as well. They can become monocytes, which in turn become macrophages. Macrophages are the ‘clear up’ cells of the immune system. They attack alien material and then engulf/ingest it. After this they either exit back into the blood stream or travel directly into the lymphatic system. Whereupon they are transported to lymph glands where they are broken down and all the ‘alien material’ is disposed of.

The body is amazingly clever is it not? After endothelium is damaged, and a clot forms, EPCs not only cover over the area of damage, they can also turn into the very cells that can clear up the clot/plaque and get rid of it. So, not a stupidly designed healing process at all. One of absolute brilliance. In fact, this is probably happening inside your artery walls right now.

The problems start to occur when the process of endothelial damage is occurring too rapidly for the healing system to clear up the mess. Repeated endothelial damage and clot formation over the same spot, time and time again. At which point, instead of having clot/plaque healing we end up with clot/plaque growth and development. Or as Rokitansky put it so eloquently

‘Subsequently, the atheroma resulted from the degeneration of the fibrin and other blood proteins and finally these deposits were modified toward a pulpy mass containing cholesterol crystals and fatty globules.’

Next, clot formation and associated problems.