In previous blogs I have written about how LDL is very beneficial to the body, how low levels of it can be dangerous, and how it is not causative in the atherosclerotic process. One argument I often hear is that while the LDL particle itself is not causative in atherosclerosis, when it becomes damaged it does become causative. The thinking here is that a normal undamaged LDL is very healthy and just does its job of delivering cholesterol and other nutrients to the body tissues. However, when those particles become damaged through oxidative stress, all of the sudden the LDL molecules become causative in atherosclerosis. Let’s investigate that a bit.
One way of measuring damage to LDL particles is by measuring their size. There are various lipoproteins that all have different sizes. In order from largest to smallest they are the chylomicron, the VLDL, the IDL, the LDL, and the HDL. Since the LDL is so focused on when it comes to atherosclerosis, we have developed ways to measure the various sizes of the LDL particles. When LDL particles get damaged, they seem to get smaller and this is often said to be a risk factor for atherosclerosis. (1) It is thought that as they get smaller, from this damage, their smaller size allows them to squeeze in between the endothelial lining and make their way into the arterial wall. Below are images of test results of an LDL particle size test. One shows what it would look like if the LDL particles were undamaged and normal size and the other shows what it would look like with damaged LDL particles getting smaller.
You can see that the smaller the LDL particle size the more red shows up on the chart.
Now, I don’t necessarily buy the idea that a smaller LDL particle is able to infiltrate the endothelium and take up residence in the arterial wall. First off, if the fact that it was smaller is what allows it to do this, then why is it that HDL, the smallest of all the lipoproteins, doesn’t do this as well? That is just a logical question that places doubt in the idea, but there is one scientific phenomenon that draws into question the idea that smaller LDL particles can penetrate the arterial lining better.
This is the phenomenon of what is called 4th phase water. I discuss this in my previous post on why we don’t see atherosclerosis in veins, but I will review it briefly here. Water has properties unlike other liquids. When placed next to a hydrophilic surface, like the inner lining of the artery, water structures itself into what is called 4th phase water, or exclusion zone (EZ) water. (2) Since the blood is nearly half water, this happens on the inner lining of the artery. This exclusion zone water has the consistency of a gel. It is called EZ water because it does just that, it excludes almost everything that isn’t it, it acts as a barrier. (3)
Because of this, if we have healthy EZ water in our arteries they protect the arteries and preserve the function of the endothelium. Radiant energy, of which one form is infrared light, has been shown to help build and maintain EZ water on hydrophilic surfaces. (4) This is why studies using infrared sauna have been shown to boost endothelial function. (5,6,7,8)
In his book on 4th phase water, Dr. Gerald Pollack notes that even the smallest protein found in the blood stream, albumin, cannot penetrate the EZ water. The protein albumin is 3.8 nanometers in diameter. EZ water is created in such a way, the planer sheets are slightly offset, that this small molecule cannot penetrate the barrier it creates if it is intact and healthy EZ water.
Looking at the size of other things found in the blood can give us some insight. Red blood cells come in at around 6000-8000 nm in size and bacteria range from 1000-2000 nm in width and 10000-20000 nm in length. If albumin, at 3.8 nm in size, can’t get through, those definitely aren’t getting through the exclusion zone. An LDL molecule comes in at around 24-28 nm in diameter, and an HDL molecule, the smallest lipoprotein, is around 7-12 nm in diameter. All of those are still bigger than albumin, those aren’t getting through either.
The only things that have been shown to get through are ionic forms of minerals. To give you an idea, ionic sodium is 0.25 nm in diameter and potassium ion is 0.273 nm in diameter. However, it is not their ionic size that matters, it is their hydrated ionic size. This is measured in what is called the Hofmeister series. This arranges ionic forms of common solutes in order from biggest to smallest according to their hydrated diameters. The order is Mg2+ > Ca2+ > Na+ > K+ > Cl- > NO3-. It seems that anything the size of sodium (Na+) or larger is excluded by EZ water, and anything the size of potassium (K+) or smaller can pass through the EZ water.
The point is that even if LDL particles become damaged and therefore get smaller in size, no matter how much damage they incur they never get as small or smaller than a hydrated ion of potassium and therefore the idea that the size of the particle, because of oxidative damage to it, is what allows these particles to trigger atherosclerosis independently, it not a valid idea, if we have healthy intact EZ water in our arteries.
However, a test of LDL particle size that comes back showing lots of small LDL particles is not completely worthless. What it does tell us is that there is a lot of oxidative stress and inflammation in the body. Oxidative stress and inflammation are the true cause of atherosclerosis. Though there are many blood tests that will help us assess this, one way to assess if oxidative stress and inflammation is present is through an LDL particle size test. The smaller the LDL particles the more oxidative stress and inflammation.
How this inflammation and oxidative stress can initiate atherosclerosis sheds more light on how an LDL particle can end up in the arterial wall. There are a whole host of things that have been shown to cause endothelial damage and associate with higher rates of atherosclerosis. Things like fluctuating blood sugar, (9) advanced glycation end-products, (10) BPA, (11) heavy metals, (12) endotoxemia, (13) and vegetable oils (14) have all been shown to contribute to this. These things create oxidative stress and when that comes in contact with the EZ water layer in the arteries it can actually break down the layer, it then damages the glycocalyx. If this happens to enough of an extent it can leave the lining of the artery without its protective layer and then the same things that damaged the EZ can now start to damage the artery wall.
At this point, some would say that this is where the LDL starts to get stuck in the artery wall. Once we have the damage and the protective mechanisms of the artery wall are broken down, then the LDL can infiltrate the artery. This idea is depicted in the images below (which you can see I stole from a presentation by Ivor Cummins). In the intact EZ picture, you can see that the LDL is depicted as being in the EZ layer, we know this is inaccurate as they cannot penetrate due to their size.
If this is indeed what happens when the EZ is damaged and then the endothelia are damaged, it is important to note that it is still not the LDL, or the size of the LDL, that initiates any sort of atherosclerosis. It is the oxidative stress that starts the whole process and the LDL being oxidized and smaller is just another consequence of the body being in a state of oxidative stress and inflammation that is also damaging the artery and it’s protective layers.
Great, we could stop there and have a reasonable explanation for the events in atherosclerosis. However, atherosclerosis develops in the layer of the artery closest to the bloodstream, the intima layer, so it has always been thought that the process that starts atherosclerosis comes from molecules within the bloodstream of the artery that is damaged. Some curious observations have been made when it comes to atherosclerosis and these layers. The first is that the arteries that supply the arteries, vasa vasorum, are much more numerous and developed in arteries that have developed atherosclerosis. (15) The second is that researchers have shown that when atherosclerosis develops, the first signs of it appear in the outer most area of the intima layer with no sign that the molecules of which atherosclerosis is composed having traveled from the bloodstream through the intima to the outer most layer of it. (16) This suggests that they come from the outer layers of the arteries.
This observation could possibly be explained by the work of Dr. Vladimir Subbotin. He explains that when the inner layer of the artery is damaged (which we have learned is due to breakdown of EZ water) then it starts to create more cells (proliferation) in the intimal layer. This causes the arteries of the vasa vasorum to grow new arteries from the adventitia into the deeper layers of the artery. (17) Since these new arteries are going through stages of development, they are fenestrated, they have holes in them. This causes some molecules, like LDL, to leak into the tissue it comes in contact with. Since these arteries are coming from the outer layer to the inner layers it makes sense that researchers have observed that the deposition of LDL in the arterial wall starts in the outer most area of the intima layer. It also explains why the vasa vasorum are more numerous and developed in atherosclerotic arteries, they have to be to penetrate deeper into the artery wall.
In this situation, LDL size could be more relevant. You could say that a smaller LDL particle could slip through the fenestrations easier and find their way into the arterial wall, but this still doesn’t mean they are causative in the process. It’s still the oxidative stress and inflammation that starts it all off. So while I think the cause of atherosclerosis, insult to the inner lining, is pretty well established, the exact mechanisms of it’s development of atherosclerosis is up for debate.
So, does LDL particle size matter. Yes and no. If there are lots of smaller, damaged LDL particles, this suggests the person has an issue with oxidative stress and inflammation that could be creating a situation where atherosclerosis develops. But I do not believe that small, damaged LDL particles can initiate atherosclerosis on their own. The thing that has made this all so tricky is that when we are in a state of oxidative stress and inflammation, lots of things happen at the same time. When the many things that cause oxidative stress and inflammation are present, the LDL’s get damaged and smaller, the EZ breaks down, the artery lining gets damaged, and atherosclerosis starts to occur. When researchers see any of these things happening at the same time the natural thought is that one or more of them is causing the others. This combined with the obsession over cholesterol and LDL, is how the idea that smaller denser LDL particles were causing atherosclerosis started. In reality, they are all cause by the same thing regardless of how the actual mechanism plays out in the end.
So how do you protect yourself from the oxidative stress and inflammation. Eat whole foods and avoid processed grains, processed sugars, and vegetable oils. Also, limit the toxins you are exposed to in your food, water, air, cosmetics, and cleaning products. Eat connective tissue parts of animal foods like collagen protein, bone broth, or the connective tissue parts of steak, these are rich in glycine and boost your bodies ability to make its own antioxidants. (18)
Stay healthy out there!
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