29th July 2017
When I began this long and winding series on cardiovascular disease (CVD) I already knew a few things that I thought were critically important to the processes underlying CVD.
The first was that, in order to get atherosclerotic plaques started, you needed to damage the endothelium in some way [the endothelium being the layer of cells lining blood vessels]. The second was that blood clot formation was the next key event – thrombogenesis.
Therefore, if you could protect the endothelium and/or stop blood clots from forming, you would most likely see some significant benefits on the risk of CVD. Mainstream medicine is fully in agreement that drugs that reduce the risk of blood clotting will usually have some benefit on CVD risk. Drugs such as aspirin and Clopidogrel – and suchlike.
In addition, most of the acute management of strokes and heart attacks is focussed on getting rid of the blood clot causing the acute event. We have clot busters and stents and other interventions to remove, squash, blow apart and bypass the clot. I often describe interventional cardiologists as ‘blood clot managers’ – obviously not to their faces. They like to think it is all far more cleverer than that.
In short, the importance of blood clotting in CVD is beyond any dispute. Which is why CVD sometimes sits under the umbrella term of ‘atherothrombosis.’
However, the role of the endothelium garners far less attention. If it is ever mentioned, it is towards the end of the process of atherosclerotic plaque development, where it has been noted that in advanced plaques the endothelium is often completely missing. Or if not missing, significantly dysfunctional.
The reason for this, never openly stated, is that to promote the idea that atherosclerotic plaques start with endothelial dysfunction, completely undermines the cholesterol hypothesis. The current hypothesis is that low density lipoprotein (LDL) a.k.a. ‘bad cholesterol’ leaks past/through the endothelium, and into the arterial wall behind.
This in turn triggers the inflammatory processes that creates the plaque (I am paraphrasing madly here). Once the plaque has grown to sufficient size, the overlying endothelium is: weakened, damaged, dysfunctional – choose the word you like best, or add your own. This, in turn makes it more likely that a blood clot will form, as a dysfunctional endothelium no longer represent a powerful anti-coagulant surface, which in my mind I like to think of as a brand new ‘Teflon non-stick frying pan.’
However, if you believe that endothelial dysfunction is the first step, then an entirely different process opens. One that goes like this: The endothelium is damaged/dysfunctional, so a clot forms at that point. The clot is then drawn into the arterial wall and becomes the core of an atherosclerotic plaque which can then grow through repeated blood clots forming at the same point.
This, as I think I have explained many times, fits all the observed phenomena far better than the current cholesterol hypothesis. However, it does knock LDL off its perch as the key factor causing CVD. It can only have a bit part, amongst many other players, in this particular game.
Currently whilst all other conjectures on CVD are allowed to change shape, and swirl around in a massive multifactorial dance, one idea lies beyond challenge, which is that LDL is the conductor, the key player, the factor without which nothing else happens:
Three Rings for the Elven-kings under the sky,
Seven for the Dwarf-lords in their halls of stone,
Nine for Mortal Men doomed to die,
LDL for the Dark Lord on his dark throne
In the Land of Mordor where the Shadows lie.
LDL to rule them all, LDL to find them,
LDL to bring them all and in the darkness bind them
In the Land of Mordor where the Shadows lie.
Or something of the sort.
Currently, it is certainly true that the dark lord rules Mordor, and the ever-seeing eye seeks out all those who criticise the cholesterol hypothesis. Here, for example, is a recent missive from Mordor:
Statin Denial: An Internet-Driven Cult With Deadly Consequences (Editorial JAMA 25th July 2017)
‘We are losing the battle for the hearts and minds of our patients to websites developed by people with little or no scientiﬁc expertise, who often peddle ‘natural’ or ‘drug-free’ remedies for elevated cholesterol levels,” adds Steven Nissen. This “Internet-driven cult” denies statins’ benefits and whips up fears of side effects, then profits from the resulting confusion by peddling snake oil.’1
I think I need to shout ‘House’ at this point. Nissen has manage to get in the full set of insults. ‘Denier’, ‘cult’, ‘deadly’, ‘whips up’, ‘fears’, ‘profit from selling snake oil’. What’s missing. Mass murderers…child killers.
Would this be the same Steven Nissen who stated the following, when the new cholesterol guidelines came out in 2013:
“The science was never there for the LDL targets.’ He said. ‘Past committees made them up out of thin air.’ He added.”2 Make your mind up Steven. Either there should be LDL targets or not.
Where was I. Oh yes, just explaining that anyone who dares criticize the cholesterol hypothesis – which is basically interchangeable with statin worship – can find themselves under significant attack. As you can imagine, those working in mainstream research are going to make sure they never do such a silly thing. Grants have a nasty habit of drying up. Tenure can be whipped from under your feet at any time. Do not attract the interest of the ever-seeing eye, my precious.
However, facts have this nasty habit of coming along that cannot be fitted within the LDL hypothesis, and are completely supportive of the ‘endothelial damage/clotting’ hypothesis. A few blogs ago I wrote of a study demonstrating that men with diabetes, who used Viagra, or other PDE5 inhibitors e.g. Cialis, were far less likely to die from CVD.
We know that Viagra/sildenafil has, as a primary mode of action, increasing nitric oxide synthesis in endothelial cells. This is how it maintains erections in erectile dysfunction. It also reduces blood pressure, particularly reducing blood pressure in the lungs. Nitric oxide is also the most powerful anti-coagulant agent known to man. Furthermore, it protects the endothelium from damage, and stimulates the production of endothelial progenitor cells in the bone marrow.
What effect does it have on LDL? None.
What effect does it have on cardiovascular and overall mortality? Well, very recently I was sent this paper: ‘Association between treatment for erectile dysfunction and death or cardiovascular outcomes after myocardial infarction.’
This was a study on over forty-three thousand men over a six-year period, who had previously had a myocardial infarction (MI). Just over forty thousand did not have medication dispensed for erectile dysfunction (ED) (40,077), three thousand did (3,068). They were split into three groups: lowest number of ED scripts, medium and highest number.3
For the sake of brevity here I am just looking at the highest script group.
Well, well, well. Perhaps a couple of other well, wells for luck.
Yes, this study was observational. Yes, this means that other factors that may be at play. For example, those men requesting Viagra and other PDE5 inhibitors, may have been healthier than those who did not. But it is hard to believe they were over five times as healthy. The simple fact is that, when you see an effect as massive as this, it can generally be considered that you are looking at a causal relationship.
To put it another way, this is 81% relative risk reduction in overall mortality. Compare this with statins, in secondary prevention (using best figures possible), statins achieved a 15% relative risk reduction in overall mortality. But statins lower cholesterol levels…right? That is how they work…right? So, LDL does have an impact?
Well, it is of course true that statins lower the LDL level. However, they also do some other things as well. Now, in general I am not a great fan of animal studies. However, I am just presenting one study, done on atorvastatin, looking at the impact on many factors (including NO synthesis) that have nothing whatsoever to do with LDL lowering.
The study was called:
‘Atorvastatin enhanced nitric oxide release and reduced blood pressure, nitroxidative stress and RANTES levels in hypertensive rats with diabetes.’
A quick summary:
- Atorvastatin had no effect on blood glucose or cholesterol levels
- Blood pressure was reduced by 21% (in diabetic rats)
- RANTES levels were reduced by 50% (RANTES is a ‘chemokine’ associated with endothelial damage)
- Nitric Oxide (NO) was increased
- ONOO (peroxynitrate) was decreased. (ONOO is a potent inhibitor of NO).
Summary: ‘These findings provide insights into mechanisms of restoration of endothelial function and vascular protection by atorvastatin in diabetes and hypertension.’ 4
When statins first emerged, they swept all before them. Included the discussion on what causes CVD. Cholesterol skeptics, such as, Professor Michael Oliver, were completely bowled over, and admitted they had been wrong, when statins were shown to lower CVD risk (the true magnitude of the benefits was massively over-hyped, but that is a discussion for another day).
Statins were designed to lower LDL/cholesterol and lower CVD risk and they did. End of argument.
Well, perhaps not quite.
If you decide to look more closely at the process of CVD, and more closely as the actions of statins, a different picture emerges. One which fully supports endothelial damage as the first step in plaque formation. Because statins do many more things than LDL lowering. It could be said that statins are simply the poor man’s Viagra (other PDE5 inhibitors are available).