Cholesterol and Vascular Disease: Part 2: LDL-Cholesterol is Important, but LDL-Particle Number is Far More Revealing

We left off with part 1 of the Cholesterol and Vascular Disease blog concluding that the two key assumptions made by cholesterol scientists in the 1940s and ‘50s were wrong. These assumptions were: 1. All LDL particles are the same size and 2.  All similarly-sized LDL particles have the same cholesterol content. Had these assumptions been correct there would have been no need to evaluate any other LDL parameter beyond LDL cholesterol. Given the fact that they are wrong however, means that looking simply at LDL cholesterol allows for the persistence of significant and dangerous “hidden risk”.  And risk that is hidden is risk that will not be corrected. Therefore we must dig deeper into this issue and how it can translate into a higher risk for developing arterial plaque.

First, let’s deal with the size issue. We now know that many individuals have very small LDL particles, while others have large, normally-sized particles. The larger the LDL particles, the more cholesterol they can fit within them. Smaller particles on the other hand cannot carry nearly as much cholesterol as their larger brethren. (That is simple enough. A large bucket holds far more water than a tiny cup.) Therefore, if you have very tiny LDL particles, you need many more of them to generate an LDL cholesterol content (LDL-C) than someone with very large particles. (Back to the water analogy –  If you need to carry a quart of water and you have one quart-sized bottle, you can carry all the water in one bottle. If you have only cups available, you will need four of them to carry the same amount of water.) The result of this disparity in LDL size is that two people with the same LDL-C (130 mg/dL for example) will have very different LDL particle numbers when their LDL particles are very different sizes.

The second erroneous assumption was that similarly-sized LDL particles always carry the same amount of cholesterol within them.  This too has turned out to be false.  Under certain metabolic conditions – diabetes, obesity, overweight, high triglycerides, low HDL– LDL particles tend to be under-filled. Once again in these patients in order to generate a particular LDL-C level, more particles are required.  (Back to the water analogy – if you have only cups available to fill, but are permitted to fill them only half way, it will take twice as many cups to carry the same amount of water as your friend who is allowed to fill the cups to the very brim.) Therefore, two individuals with precisely the same LDL-C can have vastly different LDL-Ps. So the bottom line is that LDL-C is NOT a good surrogate for LDL-P after all. OK, you buy that, but you might now be asking yourself,” Does it really matter if I have a lot of LDL particles?” A common and excellent question with a simple answer – YES! This is because more particles translate into a higher risk for developing plaque.  And the reason this is so, is actually quite intuitive. The more LDL particles a person has bouncing around in the blood stream, the more likely the particles are to encounter and penetrate the walls of his/her arteries. (The shotgun vs. the pistol is another helpful analogy. Even if you are an expert marksman, you are much more likely to hit your target with a shotgun than a single-shot pistol.) This is important because the penetration of our arteries by LDL particles initiates the process of atherosclerotic plaque formation. Yes, it all begins with a single particle. Next week we will discuss how such simple LDL particles can initiate a process that still kills more Americans than any other disease.

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Cholesterol and Vascular Disease: Part One – The History of Cholesterol

For over twenty years I have practiced and taught Cardiology. Starting in the invasive and hospital-based world (performing angioplasties, stents, atherctomies, lasers, and electrophysiologic procedures) and then segueing into prevention, cholesterol abnormalities, and cutting-edge non-invasive imaging of the carotid and coronary arteries, I have had the unique and great fortune to participate in exceptionally diverse aspects of cardiovascular health and illness. I have learned a great deal along the way and some of these experiences have been shared in articles and books I’ve written. Now I’d like to clarify one of the murkiest issues I’ve encountered in all my years of practice – the cholesterol conundrum. This post is the first of a series that will hopefully clarify the cholesterol debates that currently perplex numerous patients and physicians.

In the early 1900s a young medical student named Anitschkow made the initial association between cholesterol and vascular disease. He fed unsuspecting rabbits a high cholesterol diet. After they had enjoyed a number of tasty meals he sacrificed them in order to examine their aortas (the very large blood vessel that runs from our heart to our legs). What he found was revolutionary. The rabbits that consumed their normal low fat diets were just fine, but the cholesterol-fed rabbits had all developed severe plaques in their aortas. Of course none of the rabbits was lucky (they were all killed) but had they been allowed to live, the ones with normal diets would have done great, while those who had consumed large quantities of cholesterol would have suffered from heart attacks, strokes and premature death. Years went on and more and more scientists studied cholesterol and its effect on our bodies. In the 1940s, a technique called analytic ultracentrifugation was developed to study the fat within our blood. Scientists learned a great deal from this technology but one discovery stands out most for me. They learned that cholesterol does not float freely in our blood. It circulates instead securely contained within a variety of tiny particles called lipoproteins. These particles are used to shuttle cholesterol from one part of our body to another. Their job is to prohibit cholesterol from being exposed to contents in our blood stream – by protecting the cholesterol these particles prevent its crystallization, a phenomenon that if it occurred, would have devastating consequences.

The major lipoproteins – remember, these are the carriers of cholesterol – are called LDL, HDL, VLDL and Chylomicrons. Our livers make VLDL particles while our intestines make chylomicrons. LDL is the most atherogenic particle (causing plaque build-up), while HDL is an athero-protective particle (decreases plaque). The scientists and physicians of that time understood this and therefore wanted to establish a way to test patients and ultimately treat them for cholesterol disorders. They knew that counting the number of LDL lipoprotein particles would have been optimal, but the ultracentrifugation machines were too large and costly to place throughout the nation. They made a couple of assumptions and concluded that testing for the amount of cholesterol contained within all of our LDL particles could serve as an accurate surrogate marker for the number of LDL particles (LDL-P). They believed LDL-C (the amount of cholesterol within our LDL particles) would track beautifully with LDL-P. And so, LDL-C was dubbed the gold standard for cholesterol measurement and therapeutic interventions. Unfortunately the assumptions they made to dub LDL-C the gold standard by default were dead wrong.

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Salmon with Arugula, Tomato, and Caper Sauce

6 plum tomatoes, seeded and chopped
1 cup lightly packed chopped fresh Arugula
¼ cup olive oil
1 small shallot, chopped
1 Tablespoon fresh lemon juice
1 Tablespoon drained capers
4 6-ounce salmon fillets

Combine first 6 ingredients in a medium bowl. Season with salt and pepper; set aside. Preheat broiler. Brush both sides of salmon with a small amount of additional olive oil; season with salt and pepper. Broil without turning until just cooked through, about 4-5 minutes. Transfer salmon to plates. Spoon tomato mixture over. Garnish with lemon wedges.

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