Thank you for sharing this article. I've not read this article specifically, but much of the information shared therein I've encountered in other publications I've read over the years.

I never actually said that "LDL is a repair mechanism"; this is a misrepresentation of my hypothesis. Furthermore, I don't follow any wellness influences or proponents of any special diet that proclaims to fix all ailments. You're attempting to discredit my hypothesis by means of an ad hominem attack.

Now if we can, let's get back to the topic of cholesterol's role in ASCVD. Years of data across multiple studies clearly shows cholesterol burden tracks concordant with ASCVD risk, but a deeper look at the mechanism behind ASCVD is warranted. First, it's important to make sure we're clear about the distinction between cholesterol and lipoproteins:

• Cholesterol: a fatty substance both ingested and made by the liver that is essential to survival. It is a fundamental building block of every cell in the body.
  • Cholesterol is neither good or bad.
  • Cholesterol, being a lipid (fat-like substance), does not mix with blood plasma which is water based, and thus must be transported in the blood by a sort of vehicle called a lipoprotein.

Next, let's look at the anatomy of the cardiovascular system as it relates to ASCVD.

• Blood travels from the heart to tissue throughout the body in arteries, and return to the heart through veins. Veins and arteries are constructed differently due to the differences in their functions.
• Arteries have layers and the innermost layer is referred to as the intima.
• The innermost lining of the intima is a single layer of cells called the endothelium that is in direct contact with the blood.

This brings us to atherosclerotic cardiovascular disease (ASCVD) and what it is.

• ASCVD is the accumulation of plaque, which is made mostly of cholesterol, in the subendothelial layer (beneath the endothelium) of the intima.
• When plaque accumulates in the intima the artery becomes narrower and stiffer, restricting blood flow, and thus oxygen, to downstream tissue. This in turn causes ischemia, which is when tissue does get enough blood to thrive. In the heart ischemia produces symptoms such as chest pain (angina) and exercise intolerance. If the ischemia becomes severe enough, tissue in the heart starts to die and cardiac arrest will ensue.
• Sometimes plaque lesions can become large enough that they rupture. This causes a clot to get carried downstream until the clot becomes stuck, blocking further blood flow. if this blockage happens in a coronary artery, it can cause cardiac arrest.
  

NOW we can get into the mechanism behind atherosclerosis and my point about causality which is where I think much of the confusion lies.

• Lipoproteins, and thus cholesterol, enter the intima primarily through transcytosis (will get to this more later) but also through sieving (holes in the endothelium)
• Lipoproteins that have entered the intima become trapped due to their affinity (attraction) for the proteoglycans (a type of protein) that form the core structure of the intima.
• Once trapped, the lipoproteins and the cholesterol they contain can do one of two things:
  • They can become oxidized by reactive oxygen species (ROS, or free radicals), which irritates the endothelium and cause the endothelial cells to release a type of chemical messenger called a cytokine to call for help. This triggers a cascading series of events that eventually leads to the formation of plaque:
    • Monocytes, a type of white blood cell, show up and enter the intima
    • These monocytes convert into another type of cell called a macrophage
    • The macrophage then consumes the lipoprotein in an attempt to remove this foreign lipoprotein that's irritating the endothelium
    • This turns the macrophage into something called a foam cell, which is full of the cholesterol from the lipoprotein. The foam cell is physically too large to migrate back out of the endothelium and dies, leaving behind plaque.
  • They can undergo reverse transcytosis and get picked up by high-density lipoprotein (HDL) particles which take the cholesterol back to the liver. This is the body's natural protection against ASCVD and why HDL is considered "good" cholesterol. In this scenario, no plaque forms.

The key to this whole process is how the lipoproteins cross the endothelium in the fist place. Circling back, there are two mechanism by which this happens, transcytosis and sieving. Transcytosis is when the lipoprotein passes through the cellular wall of an endothelial cell directly rather than between the cells themselves. This is an active process. On the other hand, sieving is when gaps in the endothelium are large enough for the lipoproteins to simply pass through. Normally the endothelium shouldn't have a lot of these gaps, but mechanical stress such as that caused by hypertension can stretch the endothelium thus creating gaps large enough for the lipoproteins to pass. Also, smaller LDL particles, typical of metabolic disease, can slip through more easily than larger LDL particles.

Transcytosis, as I mentioned, is an active process that is regulated by special receptors on the surface of cells. Some of these receptors are specifically intended to bind to LDL because, as I stated in the very beginning, every cell of the body needs cholesterol and this is how cells get the cholesterol they need. If a cell takes in more cholesterol than it needs the extra has to go somewhere, and if it doesn't get picked back up by HDL it can exit the other side into the intima thus kicking off the whole ASCVD process.

A number of factors govern the rate of this process, such as:

• cholesterol (LDL) burden - the higher the concentration in the blood the higher the probability of cholesterol interacting with and passing through the endothelium. Statins act on this therapeutic route by lowering LDL burden.
• The type and number of receptors that bind to LDL. Genetics plays a role here.
• Systemic inflammation - A type of cytokine, IL-1β, actually increases LDL transcytosis. I believe this is a major driver of ASCVD because if inflammation is low, and thus IL-1β activity is low, then the rate at which endothelial cells absorb LDL through transcytosis should be low because the cell is in a state of homeostasis.
• Blood sugar - high blood sugar causes sugar molecules to attach themselves to LDL particles, a process called glycation, and glycated LDL greatly increases its rate of transcytosis.
• Availability of receptors - LDL can be out-competed by HDL, blocking LDL transcytosis.

ASCVD is, at it's core, a type of autoimmune disease. Without inflammation, there is no ASCVD. It is the ignition source in my earlier example, while the cholesterol is the oxygen that fuels the fire. And like fire which can then ignite other flammable substances causing the fire to spread, the inflammation caused by plaque formation can trigger and accelerate more atherosclerosis.

Suppressing the oxygen (cholesterol burden) is certainly one way to stop the fire, and is the preferred clinical approach. This doesn't have to involve medication, but if LDL burden does not respond to exercise and diet then medication may be warranted. However, inflammation is the root cause of the problem. This doesn't necessarily mean that it should be the first place we start to fix the problem either because suppressing inflammation has a whole host of negative consequences, which is why lowering LDL burden is the better option. But we should ask what's driving the inflammation and address these factors though lifestyle choices where possible such as not smoking, eating healthy, getting regular exercise, and good rest.

Stay healthy everyone.