Cholesterol and Vascular Disease Part 3: How Tiny LDL Particles Can Cause Such Harm

Last week we discussed the relevance of LDL particles, emphasizing their role as the main drivers of vascular disease. We did not, however, discuss how they wreak such havoc upon our blood vessels. Today we will do so.

LDL particles do wonderful things. They transport cholesterol and triglycerides to various parts of our body for fuel, storage, or even to serve as building blocks for other important molecules. They even transport vitamin E to our brains in order to enhance growth and development in infants, and proper brain function in adults. So how can something so good, be so bad? The answer lies in numbers. The aphorism “too much of a good thing can be bad” applies perfectly to LDL particles; they are necessary for a healthy body, but only in small quantities. The numbers most of us possess are so far out of range, they are literally killing us. But how? What happens when these tiny particles make their way beneath the delicate yet vital single cell layer (called the endothelium) that lines our blood vessels?

When LDL particles penetrate the boundary that separates blood from the blood vessel wall, they often cause a chain reaction that leads to plaque accumulation.

First they become oxidized. Oxidation leads to activation of an enzyme called LpPLA2 (lipoprotein associated phospholipase A2). Enzymes are biological molecules that initiate chemical reactions. In this case, LpPLA2 destroys a type of fat (a phospholipid) that sits within the surface membrane of LDL particles. The fat is broken in two, creating two independent but highly inflammatory elements – an oxidized fatty acid and Lyso-phosphatidylcholine (Lyso-PC). These “freed” fats summon other agents of atherogenesis (plaque formation) – adhesion molecules and cytokines are released bringing in specialized white blood cells called macrophages which then consume the oxidized LDL particles. As more oxidized particles are consumed, the macrophage weakens and ultimately dies, releasing its atherogenic contents and essentially pouring fuel on the fire beneath the endothelium. Other “bad” substances are also produced – MMPs (matrix metalloproteinases) for example chew away at the cap that has formed over the budding plaque in an attempt to contain the fire below. As MMPs thin the cap it becomes more likely to tear. (Dr. Abela, Professor and Chief of Cardiology at MSU produced spectacular images of cholesterol crystals helping MMPs tear through the thinning cap. Remember, cholesterol that floats freely will crystallize. Once the cap tears, the fire rages into the vessel lumen (where our blood is freely flowing in order to bring nourishment to the tissues it feeds – in this case the heart muscle). The blood in turn attempts to quench the fire, but by doing so produces a blood clot, which in turn can entirely block the bloods passage. The end result – a heart attack and death of heart muscle. And it all started with the excessive LDL particles! Next week we will discuss methods to lower LDL particles to diminish our risk of heart attacks.

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One Comment

  1. Martin September 28, 2013 at 9:02 am #

    Thanks so much for the post, Dr Baum. Fascinating.

    Why is it that some plaque ruptures and other plaque does not? I recently read in an opinion piece by Michael Rothberg in Circulation “most cardiac events occur at lesions that appeared mild on previous angiography”

    We all develop plaque throughout our lives, but why does some plaque rupture? and is there a correlation between how much plaque is built up vs. risk?

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