Medical establishment considers a causal role for cholesterol. There has been a great deal of effort put into lowering cholesterol without significant effect on curing and preventing the disease. How come the failure is so big? Is it really THE cause? I’m especially concerned because my LDL level is >300mg/dL
It turns out that the exact cause is unknown.
The exact cause of atherosclerosis isn’t known. However, studies show that atherosclerosis is a slow, complex disease that may start in childhood. It develops faster as you age.
Atherosclerosis may start when certain factors damage the inner layers of the arteries. These factors include:
– High amounts of certain fats and cholesterol in the blood
– High amounts of sugar in the blood due to insulin resistance or diabetessource: https://www.nhlbi.nih.gov/health/health-topics/topics/atherosclerosis/causes
Despite being unknown, a number of factors are listed that damage the arteries. As you can see it mentions high amounts of certain fats and cholesterol.
What is really at the basis? Is cholesterol a necessary component? Throughout the years I have seen a lot of material to compose a fairly descent picture today. I’ll present it as the step-by-step discovery, the way I did…
Atherosclerosis is recognized by a number of properties so we can start by looking into some of them and deviate as we pick up the breadcrumbs:
- Plaque buildup
- Calcium deposition
Where does the plaque come from? Foam cells that make up the plaque are macrophages that are stuffed with lipids, primarily oxidized LDL. Here we see why LDL cholesterol is claimed to be bad. It is in fact not the LDL cholesterol but the entire LDL particle so why single out only one of the elements that it is carrying?
One of the contributing elements for macrophage uptake of oxidized LDL is hypoxia (low oxygen levels).
“Hypoxia enhances lipid uptake in macrophages: Role of the scavenger receptors Lox1, SRA, and CD36” https://www.sciencedirect.com/science/article/pii/S0021915013002761
In the referenced paper, they say that as the arterial wall thickens, hypoxia establishes at the core.
The core of advanced atherosclerotic plaques turns hypoxic as the arterial wall thickens and oxygen diffusion capacity becomes impaired.source: https://www.sciencedirect.com/science/article/pii/S0021915013002761
But if I were to believe the information on wikipedia, one of the first things in atherosclerosis is macrophage infiltration in conjunction with foam cells. Could hypoxia already be present from the start? And what causes these macrophages to infiltrate in the first place? What attracts them?
Hypoxia before or after, it seems to have a major impact. In a mouse model of atherosclerosis, disabling HIF-1a they were able to reduce atherosclerosis by 72% ! HIF-1a is stabilized under low oxygen levels and sets a whole host of changes in motion to help the cell survive and signal distress through inflammatory markers.
“Hypoxia-Inducible Factor-1α Expression in Macrophages Promotes Development of Atherosclerosis” https://www.ahajournals.org/doi/full/10.1161/atvbaha.116.307830
Interesting to note is that the lack of oxygen can also turn these macrophages in pro-inflammatory M1 macrophages.
One other effect of hypoxia, that we also see in cancer, is angiogenesis. The development of new blood vessels. This is to overcome the lack of oxygen.
“The role of hypoxia in atherosclerosis” https://pubmed.ncbi.nlm.nih.gov/19644366/
And one more effect of low oxygen levels is the stimulation for growth. Again also here we see this happening in cancer. A lack of oxygen leads to glycolysis, the production of ATP from glucose without oxygen, which increases ROS production and this sets a transcription in motion of different genes that are specific for growth. The growth happens in the tunica intima layer mainly although it is also observed in the areas close to it.
The intima is a layer that grows thicker with age.
What we have seen so far are effects that have their origin in hypoxia. But does that mean hypoxia is the cause? Even if hypoxia can be established as a causal factor, what would cause the hypoxia? In order for any of the contributing factors to result in hypoxia we must find a link somehow. Below are 2 factors that we can look into as mentioned at the beginning.
This paper shows how nicotine causes senescence in vascular smooth muscle cells (VSMC), the cells that make up the tunica intima (but not only the tunica intima).
“Nicotine in Senescence and Atherosclerosis” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226537/
What is important is then to look at what senescent cells trigger. They send out scenecent-cell-specific signals that will attract macrophages. This will lead to the destruction of the cells by the macrophages. Interesting, because now we see at least that there are causal factors for attracting macrophages before they infiltrate and accumulate LDL particles.
Depending on whether MOs are in the classically-activated M1 or alternatively-activated M2 states, MOs can promote cell death through either cytotoxicity or phagocytosis, respectively. MOs in the M1 state secrete TNFα, IL-1β, and IL-6, potentially amplifying effects of the SASP [140,141].
“Senescent cell clearance by the immune system: Emerging therapeutic opportunities” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7061456/
But does this cause hypoxia? And VSMCs are responsible for the contraction and relaxation of the artery but then again they are lining up throughout all the arteries so do we have atheriosclerosis all over the place?
Atherosclerosis is not found all over the place. It is primarily seen at specific areas in the arteries. Namely at the bifurcations.
“Atherosclerosis at arterial bifurcations: evidence for the role of haemodynamics and geometry” https://pubmed.ncbi.nlm.nih.gov/26740210/
This has been investigated and the reason why it occurs there has to do with the shear stress. Measured in subjects with CVD in the carotid intima we see a lower level of shear stress compared to healthy individuals.
The bifurcation areas are specifically prone to low endothelial shear stress. That is to say – under certain conditions –
“Flow and atherosclerosis in coronary bifurcations” https://pubmed.ncbi.nlm.nih.gov/21930484/
These areas of low shear stress at the bifurcations causes lower oxygen delivery to the arterial wall so we get to understand why hypoxia could be involved.
Arterial Wall stiffness
OK so far we understand why it happens where it happens but we haven’t differentiated on why it happens in some people and not in others. But first, the shear stress is something that is negatively correlated with the elasticity of the arterial wall.
“Study of correlation between wall shear stress and elasticity in atherosclerotic carotid arteries” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5771221/
Not surprisingly, the VSMCs are responsible for the elasticity.
“Smooth muscle cell and arterial aging: basic and clinical aspects” https://academic.oup.com/cardiovascres/article/114/4/513/4919538
There are other effects at play with VSMC than senescence as we saw under smoking. They can change their phenotype from contractile towards proliferation depending on signaling that takes place. A loss of function sort of.
“Regulation of Vascular Smooth Muscle Cell Dysfunction Under Diabetic Conditions by miR-504” https://www.ahajournals.org/doi/full/10.1161/ATVBAHA.115.306770
What do we have so far? Most of the noted effects such as plaque buildup, hyperplasia, angiogenesis are all factors due to hypoxia. The hypoxia result from regions in the artery that are prone to result in low shear stress regions. But before we get such regions there must be factors that cause the reduction in elasticity, which means factors that affect the functioning of VSMCs.
We’ve seen smoking causes scenescence of VSCM so that they reduce their elasticity. But are there other damaging effects that can cause VSCM to become inflammatory and start to function badly?
I mentioned smoking and sugar earlier on but haven’t touched on sugar yet so here we go…
Knowing what we know so far, we could ask the question why insulin resistance (caused by sugar) is a contributing factor. Does it affect the VSCM? Does it lead to wall stiffness? Does it lower oxygen in the blood?
What is specific about the effect of insulin is that it lowers the ability to survive for the VSMC so any negative effect on VSMC and insulin may reduce their recovery.
“Insulin resistance aggravates atherosclerosis by reducing vascular smooth muscle cell survival and increasing CX3CL1/CX3CR1 axis” https://academic.oup.com/cardiovascres/article/103/2/324/300501
I’ve already referred to the following article but wanted to quote on the factors that lead to VSMC dysfunction (loss of contractile function):
Key pathological factors associated with diabetes mellitus including high glucose (HG), advanced glycation end products, growth factors, and oxidized lipids promote VSMCs dysfunction by enhancing inflammatory gene expression, migration, and proliferation via activation of multiple signal transduction pathways and downstream transcription factors.source: https://www.ahajournals.org/doi/full/10.1161/ATVBAHA.115.306770
High glucose is the result of high carb and sugar intake and is both cause and result of insulin resistance.
There are different proposed factors that all contribute to arterial stiffness in the following paper but all resulting from insulin resistance.
“Vascular stiffness in insulin resistance and obesity” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4536384/
Fructose metabolism itself also contributes to a change in VSMC phenotype and reduction in relaxation capacity through eNOS inhibition resulting in arterial stiffness.
“Aortic smooth muscle cell proliferation and endothelial nitric oxide synthase activity in fructose-fed rats” https://academic.oup.com/ajh/article/14/11/1135/186286
Although not related to the stiffness there is more in the way fructose contributes to atherosclerosis. I also mentioned the oxidized LDL at the beginning which macrophages take up with higher affinity. Fructose causes an increase in oxidized LDL and in small dense LDL which oxidizes more easily.
In addition to increases of postprandial TG and fasting and postprandial apoB, we show for what we believe is the first time that fructose consumption increases plasma concentrations of fasting sdLDL, oxidized LDL, and postprandial RLP-C and RLP-TG in older, overweight/obese men and women, whereas glucose consumption does not.source: https://www.jci.org/articles/view/37385?ref=binfind.com/web
“Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans” https://www.jci.org/articles/view/37385?ref=binfind.com/web
LDL particles are more prone to oxidize depending on the type of fat it is carrying and lack of anti-oxidants it is carrying. The more unsaturated content the more oxidized it gets. That is in stark contradiction with the recommendation to reduce our intake of saturated fat.
The LDL oxidative state is elevated by increased ratio of poly/mono unsaturated fatty acids, and it is reduced by elevation of LDL-associated antioxidants such as vitamin E, beta-carotene, lycopene, and polyphenolic flavonoids.source: https://pubmed.ncbi.nlm.nih.gov/9823020/
“LDL oxidation by arterial wall macrophages depends on the oxidative status in the lipoprotein and in the cells: role of prooxidants vs. antioxidants” https://pubmed.ncbi.nlm.nih.gov/9823020/
Since about a year I focus on animal-based food and eat a high amount of butter. My vitamin E level pre-high fat diet was 11.3mg/L. The first 2 years into the diet it was 19.9 and 17.8mg/L and now since the more focused approach it is 25.3mg/L (reference values of 5 and 20).
A severe increase in saturated fat and a doubling of my vitamin E intake. I can only wonder how that has affected the level of oxidation of my LDL particles.
As you can see the overall picture is complex. As for the question “Do we know what causes atherosclerosis?”.
I think the answer is yes but science is in trouble. From what I could find, cholesterol is not the cause and that is also in line with how bad the results are in prevention. Not until research comes out that shows high levels of circulating LDL causes malfunction in VSMCs.
How can science keep up its multi-billion industry of cholesterol-lowering drugs while at the same time admitting that they were wrong about cholesterol?
We were able to ban cigarettes. We are unable to ban sugar. As long as we are not able to reduce the impact of sugar and high glucose, we’ll not be able to prevent atherosclerosis.
There are other causes than smoking and sugar but in order to be a cause, it seems first there must be a deleterious effect on the functioning of the VSMCs.
Update: In the comments there was a reference to Subottin’s work. After watching it again I realized why the thickening of the intima is taking place.
The reason why thickening of the intima takes place is to maintain blood pressure! Although people with high blood pressure are at higher risk, the problem is with localized low pressure.
The mechanism works in such a way that by increasing the thickness of the intima, pressure can be restored. So it is by design that the intima is supposed to increase in thickness but… The problem of low pressure isn’t fixed due to how we affect the flexibility of the arteries with our lifestyle so that a low pressure area persists and the thickening has to persist as well.
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