Atherosclerosis

This isn't a perfect analogy, but I think of atherosclerosis as kind of like the scene of a crime—breaking and entering, more or less. Let's say we have a street, which represents the blood vessel, and the street is lined with houses, representing the arterial wall. The fence in front of each house is analogous to something called the endothelium, a delicate but critical layer of tissue that lines all our arteries and veins, as well as certain other tissues, such as the kidneys.

Composed of just a single layer of cells, the endothelium acts as a semipermeable barrier between the vessel lumen (i.e., the street, where the blood flows) and the arterial wall proper, controlling the passage of materials and nutrients and white blood cells into and out of the bloodstream. It also helps maintain our electrolyte and fluid balance; endothelial problems can lead to edema and swelling. Another very important job it does is to dilate and contract to allow increased or decreased blood flow, a process modulated by nitric oxide. Last, the endothelium regulates blood-clotting mechanisms, which can be important if you accidentally cut yourself. It's a pretty important little structure.

The Process Begins

The street is very busy, with a constant flow of blood cells and lipoproteins and plasma and everything else that our circulation carries, all brushing past the endothelium. Inevitably, some of these cholesterol-bearing lipoprotein particles will penetrate the barrier, into an area called the subendothelial space—or in our analogy, the front porch. Normally, this is fine, like guests stopping by for a visit. They enter, and then they leave.

This is what HDL particles generally do: particles tagged with apoA (HDL) can cross the endothelial barrier easily in both directions, in and out. LDL particles and other particles with the apoB protein are far more prone to getting stuck inside.

This is what actually makes HDL particles potentially "good" and LDL particles potentially "bad"—not the cholesterol, but the particles that carry it.

The Trouble Starts

The trouble starts when LDL particles stick in the arterial wall and subsequently become oxidized, meaning the cholesterol (and phospholipid) molecules they contain come into contact with a highly reactive molecule known as reactive oxygen species, or ROS, the cause of oxidative stress. It's the oxidation of the lipids on the LDL that kicks off the entire atherosclerotic cascade.

Now that it is lodged in the subendothelial space and oxidized, rendering it somewhat toxic, the LDL/apoB particle stops behaving like a polite guest, refusing to leave—and inviting its friends, other LDLs, to join the party. Many of these also are retained and oxidized.

It is not an accident that the two biggest risk factors for heart disease, smoking and high blood pressure, cause damage to the endothelium. Smoking damages it chemically, while high blood pressure does so mechanically, but the end result is endothelial harm that, in turn, leads to greater retention of LDL. As oxidized LDL accumulates, it causes still more damage to the endothelium.

The Key Factor: apoB Particles

I've been saying LDL, but the key factor here is actually exposure to apoB-tagged particles, over time. The more of these particles that you have in your circulation, not only LDL but VLDL and some others, the greater the risk that some of them will penetrate the endothelium and get stuck.

Going back to our street analogy, imagine that we have, say, one ton of cholesterol moving down the street, divided among four pickup trucks. The chance of an accident is fairly small. But if that same total amount of cholesterol is being carried on five hundred of those little rental scooters that swarm around cities like Austin, where I live, we are going to have absolute mayhem on our hands.

[Note: switching from pick up trucks to scooters is innacurate usage of analogy to illustrate the point, TODO: find out range of cholesterol difference per apoB]

So to gauge the true extent of your risk, we have to know how many of these apoB particles are circulating in your bloodstream. That number is much more relevant than the total quantity of cholesterol that these particles are carrying.

The Immune Response

If you take a healthy coronary artery and expose it to high enough concentrations of apoB particles, over a long enough time, a certain amount of LDL (and VLDL) will get stuck in that subendothelial space and become oxidized, which then leads to it sticking together in clumps or aggregates.

In response to this incursion, the endothelium dials up the biochemical equivalent of 911, summoning specialized immune cells called monocytes to the scene to confront the intruders. Monocytes are large white blood cells that enter the subendothelial space and transform into macrophages, larger and hungrier immune cells that are sometimes compared to Pac-Man.

The macrophage, whose name means "big eater," swallows up the aggregated or oxidized LDL, trying to remove it from the artery wall. But if it consumes too much cholesterol, then it blows up into a foam cell... - Outlive

Initial testing

What to start with

Start with testing of:

• Apolipoprotein-B (apoB)
• Lp(a)

Quote

When I look at a patient’s blood panel for the first time, my eyes immediately dart to two numbers: Apolipoprotein-B (apoB) and Lp(a). I look at the other numbers, too, but these two tell me the most when it comes to predicting their risk of ASCVD [atherosclerotic cardiovascular disease]. ApoB not only tells me the concentration of LDL particles (which, you’ll recall, is more predictive of disease than the concentration of cholesterol found within LDL particles, LDL-C), but it also captures the concentration of VLDL particles, which as members of the apoB family can also contribute to atherosclerosis. Furthermore, even someone whose apoB is low can still have a dangerously elevated Lp(a). - Outlive

For Searchability

For Searchability

Key test for risk of cardiovascular, heart attack. Heart health testing. Blood test/analysis.