How does too much LDL or ApoB lead to clogged arteries?

LDL particles do not need to 'besiege' the artery wall from the outside: they actively penetrate it. Through a process called transcytosis, LDL particles are transported by the innermost cell layer of the artery (the endothelium) into the space beneath it. There they stick to so-called proteoglycans, a type of adhesive protein structure in the vessel wall. This attachment occurs via specific sites on the apoB protein that every LDL particle carries on its surface. Once a particle is held in place, it can no longer be removed.

Once trapped in the vessel wall, LDL undergoes chemical changes, such as oxidation. The immune system recognises this modified LDL as a threat and dispatches defence cells (macrophages). These engulf the modified LDL, but become overwhelmed in doing so: the normal feedback signal indicating 'enough cholesterol absorbed' does not work here. The macrophages become packed with fat droplets and are then called foam cells. When foam cells eventually die, they leave behind a fat-rich, inflamed mass: the necrotic core of an atherosclerotic plaque. Cholesterol crystals and dead cell debris accumulate there and make the plaque unstable.

The risk depends not only on how much cholesterol is in the blood, but also on how many LDL particles are circulating. Each particle carries exactly one apoB protein, so the total amount of apoB in the blood is a direct measure of the number of atherogenic particles. Two people can have the same LDL cholesterol value but a very different number of particles, and therefore a very different level of risk. The European cardiology association (ESC/EAS) therefore recognised apoB as a more precise risk measure than LDL cholesterol or non-HDL cholesterol.

In addition to ordinary LDL, there are more particles that carry apoB and can cause damage. Triglyceride-rich remnant particles (remnants) and lipoprotein(a) are less numerous in the blood than LDL, but are considerably more harmful to the vessel wall per particle. They partly use the same mechanism as LDL, but can also cause additional damage. In a study of more than 17,000 people without known cardiovascular disease, with a median follow-up of nearly nineteen years, elevated remnant cholesterol was found to increase the risk of a cardiovascular event by 65% (HR 1.65), even when LDL cholesterol and apoB had already been included in the calculation. This suggests that these remnant particles play their own, not yet fully understood role.

Finally, the mechanism deserves attention in certain patient groups. In people with lupus (SLE), LDL, triglycerides and apoB rise sharply: at diagnosis approximately 30% already have elevated values, and after three years this has risen to around 60%. In addition to lipids, inflammatory processes, auto-antibodies and oxidative stress also accelerate plaque formation. Mouse research has revealed that a protein in the liver that regulates apoB production (by breaking down the molecular blueprint for apoB) provides protection against atherosclerosis. This is a potentially promising target for future treatments, but so far it has only been investigated in animal models.