THE TRUTH ABOUT HIGH CHOLESTEROL

THE TRUTH ABOUT HIGH CHOLESTEROL

Today's in-depth study is a translation of this video by Dr. Paul Mason an Australian physician who uses evidence-based medicine with his patients. Here the his site. The texts in black are Dr. Mason's while those in blue are mine.

As a reminder, you can find the other Live Better insights in this page.

This lecture talks about the scientific evidence that contradicts almost everything I learned about LDL from studying medicine.

Until recently, we have almost always pointed to fats and cholesterol in our diet as the cause of atherosclerosis. This is known as the lipid hypothesis: quite simply, eating fat increases our LDL level, which then goes on to block our arteries.

Unfortunately, when President Eisenhower had his heart attack in 1955, this was the reason that was repeated by the most influential scientists of the time. This put the lipid hypothesis on the right path to haunt us from generation to generation.

The question is, what is the evidence that high LDL will kill you?
A systematic review [1] of 19 prospective cohort studies with over 68000 participants answered this question, and the vast majority of the studies-16 out of 19-found that individuals with the highest LDL levels lived longer: the higher the LDL level, the lower the likelihood of dying. No matter how they divided the participants, comparing the group with the highest LDL and the group with the lowest, or even the second lowest, the highest LDL levels always won. Even when subjects with terminal illness, heart disease, diabetes were excluded, the results remained the same. This study found a 50% reduction in the probability of death in the group with the highest LDL compared with the lowest.

Simply put, the findings of this systematic review are robust, and to reject or ignore them is
A scientific fraud.

Let's look more closely at what LDL is.

You have probably learned to associate LDL with cholesterol, perhaps confusing one for the other, and this is a mistake that many doctors make. Very often they talk about cholesterol and LDL as if they were the same thing. The fact is that LDL is much more than just cholesterol. It is in fact a complex structure called lipoprotein A, made up of fat, cholesterol and protein, and the body devotes a large part of its resources to its production. In the image opposite you can see that LDL not only carries cholesterol (the pink particles) bound to fatty acids within it, but also contains some as an integral part of its membrane.

However, both cholesterol and LDL particles are found in atherosclerotic plaques. Does this by any chance imply that they may somehow be the cause? To blame LDL for this is completely nonsensical, tantamount to confusing correlation and causation: just because two things exist together at the same time, that does not mean that one caused the other.

Turning our attention to lipoproteins again, the first thing you need to understand is that LDL is only one of five major classes of lipoproteins, the biggest difference between them being their size.

The lipoprotein in the lower left of the image is called chylomicron, and it forms after eating. When it comes time for a fasting blood test, however, most of it has disappeared, so we need not worry about it. At the top right is HDL, colloquially known as "the good cholesterol"; for now, I would like to focus on the three lipoproteins in the center: the VLDL, IDL and LDL, indicating very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and low density lipoprotein (LDL). The smaller the lipoprotein, the denser it is. And the reason these three are connected by arrows is that they are all essentially the same particle.

Think of VLDL as a balloon with a small leakage: as it shrinks we go on to define it as another type of lipoprotein, eventually coming to be LDL. So in essence LDL is just a shrunken form of VLDL. VLDL shrinks because it is doing its job, which is delivering its lipid load to various tissues throughout the body.

But where exactly does VLDL come from? It is produced by the liver and then released into the bloodstream so that it can deliver its lipid load. As it delivers, it decreases in size, first becoming an intermediate density lipoprotein IDL and then a low density LDL. The LDL is then reabsorbed by the liver for recycling.

Having explained this very important concept, I would like to change the subject for a moment and examine the long-standing myth that the cholesterol and saturated fats we take in through diet raise LDL levels.

The adjacent image shows the production cycle of these lipoproteins. There are two factors that could raise LDL levels:

- An increase in the production of the LDL precursor, VLDL

- A reduction in the reabsorption of LDL by the liver

Cholesterol and the saturated fats we take in through food are not capable of doing either of these things.

If cholesterol intake from food increased LDL then it is assumed that consuming 7,000 milligrams per day would lead to high LDL levels, and that is exactly what this fabulous study did [2]: The researchers had patients eat 35 eggs a day for a month, and their cholesterol levels remained normal. Nor does saturated fat increase LDL : consider this randomized controlled trial [3] which gave subjects 50 grams a day of one of coconut oil, olive oil and butter for four weeks.

The graph below compares LDL levels at the end of the study by fat consumed. Those who consumed coconut oil consumed 94% of saturated fat, while those who ate butter consumed 66%. However, the coconut oil group saw their LDL levels drop, while it increased in the butter group (despite containing less saturated fat than coconut oil).

Let us now return to our VLDL, IDL and LDL lipoproteins. Since each of these particles are essentially identical, they all have the same identifying protein on their membrane, which is called APO B100. APO B100 has the basic function of acting as an identification badge, allowing the lipoproteins to be recognized by receptors on the liver and on cells throughout the body.

In the side image, you can see the consequences of damage to APO B100: lipoproteins can reach the receptors, but they are not allowed to enter and thus accumulate in the blood. This situation is the cause of the increased "LDL particle count" in the blood.

Because they are small, the overall volume of these particles is not huge compared to their actual amounts, so you basically get to have a lot of particles, but not that much volume. That volume, however, is what we call the LDL cholesterol level, which is what we normally measure, which explains why the number of particles is a much more accurate indicator of cardiovascular disease risk than the total volume of LDL.

This study [4] conducted in 2018 based on 15 years of follow-up on more than 28,000 women supports this hypothesis. The study found that LDL cholesterol volume was not minimally predictive of the onset of cardiovascular disease, while particle count was: those with high particle counts had an almost two and a half times higher risk of developing cardiovascular disease.

So the question now becomes: given damaged LDL lipoproteins increase the risk of cardiovascular disease, can we tell whether we have normal or damaged LDL? The answer is yes. [5,6,7] When an LDL lipoprotein is damaged it shrinks. The more damage it sustains, the smaller it shrinks.

Evidence of the importance of LDL status in considering heart disease risk comes from this study [8] with more than 11,000 subjects: in this graph you can see 4 lines, each representing various levels of undamaged LDL (which are often called large, fluffy LDL), and these were included in the graph in correlation with cardiovascular risk as years increased. You can see that the lines are almost completely overlapping; higher levels of undamaged LDL do not increase cardiac risk.

In contrast, analysis of small and dense LDL (the damaged version of LDL) clearly shows that high levels of small and dense LDL are associated with a much higher risk of cardiovascular disease; even when overall LDL levels were low, the presence of small and dense LDL is predictive of cardiovascular risk.

And this is not an isolated finding: this eight-year study [9] done in Japan found that those who had more small, dense LDL were five times more at risk of suffering from heart disease.

Small, dense LDL can be tested by using a centrifuge to separate LDL particles: LDL samples are placed in a gel and then spun at high speeds so that the lipoproteins move within the gel according to their size and density.

The image on the left is an example of a healthy LDL sample: in the yellow box we see a single vertical dark line. The results of the vertical dark lines are presented with a graph in which the peaks correspond to the dark lines in the gel. The height of the peaks corresponds to the total volume of each lipoprotein. In the LDL section (the one in yellow) there is only one well-defined peak, evidence of a single, healthy LDL population.

The image on the right, on the other hand, represents a sample of harmful LDL. Inside the yellow box now are two distinct vertical lines, which appear as two distinct LDL peaks on the graph.

Further damage to LDL can lead to the presence of a third, or even a fourth peak, as in the image on the left, where you can see that the population of damaged LDL is much larger than the healthy population, and you can also see a large amount of lipoprotein in the fourth and fifth bands. And the fourth band is where things start to get complicated.

This study [10] from 2021 predictably found that there was no difference in overall LDL levels between those who were healthy and those who had coronary heart disease. But looking at LDL subfractions, they found that the presence of LDL from band 4 onward was almost always associated with coronary heart disease.

This means that a double-peaked LDL trend extending to band 3 as in the left image could safely have no problems, while the triple peak extending to band 4 in the right image almost certainly indicates a problem.

However, as informative as it is, this test is expensive. Fortunately, we can get an idea of the likelihood of the presence of damaged LDL based on a normal lipid profile. The main indicator is triglycerides: an analysis [11] of more than 5000 patients with heart disease found a clear correlation between triglyceride levels and the amount of small, dense LDL particles.

In the graph below, the group on the left represents those patients with high small and dense LDL, and the group on the right, the one that looks L-shaped, represents the patients with large and fluffy LDL, while the vertical axis is the level of triglycerides. You can see that in the group on the left, the group of damaged LDL, patients had much higher triglyceride levels on average; what's more, as you move to the right, where the LDL was larger and fluffier, the levels are lower.

In fact, a triglyceride level below 0.8 millimoles per liter or 70 milligrams per deciliter is indicative of a low risk of having small, dense LDL, and conversely, a triglyceride level above 2.8 millimoles per liter or 250 milligrams per deciliter is a bearer of bad news.

These data correspond well with previous research: this study [12] from 1990 found that only about 5% of the subjects had small LDL and dense their triglycerides were less than 0.8 millimoles per liter or 70 milligrams per deciliter, and I would also point out that at less than 0.5 millimoles per liter or 40 milligrams per deciliter the incidence of small, dense LDL is very close to zero.

And now we come to HDL, for which what we are looking for is a high level. Here it is clear that the level of small, dense LDL increases substantially with HDL levels below 1.3 millimoles per liter or 52 milligrams per deciliter (image 1).

Even better than looking at triglycerides or HDL on their own is to look at their ratio, as this study [13] proves: it can be seen here that a ratio of more than 0.9 considering the two measurements in millimoles per liter or above 2.0 measuring in milligrams per deciliter is associated with a higher likelihood of having small, dense LDL (image 2).

Consequently, I believe this is a reliable calculation for determining the likelihood that a lipid profile is atherogenic or nonatherogenic, i.e., capable or not capable of clogging arteries.

→ Possible trend B (consider further evaluation)

→ Probable pattern A

Elena's note: so if it is very likely that the LDL is healthy, then large and fluffy if

HDL is greater than 52 mg/dL
Triglycerides are less than 70 mg/dL
The "triglyceride : HDL" ratio is less than 2.0 mg/dL

If, on the other hand, the numbers are different, there is a high possibility that the LDL is small and damaged, and thus there is cardiovascular risk.

Now I'm going to muddy the waters a little bit. I have shown that higher levels of LDL are on average associated with longevity, however, that does not mean that every case of increased LDL is a good thing. Taking this graph [14] correlating LDL and mortality, you can clearly see, on the sinis

among, that the highest risk of death is associated with the lowest LDL level; it can also be seen that, toward the right, the risk increases, though less, as LDL increases.

This is not surprising, because numerous factors can increase VLDL production, thereby increasing the number of LDL particles. The most obvious of these is insulin resistance [15], and something that might surprise you is that this can increase in low-carb diets, often associated with increased LDL and usual

mind in the context of high dairy consumption.

In fact, dairy products may contribute to insulin resistance: this study [16] found that high dairy consumption was indicative of insulin resistance in middle-aged women. A finding supported by this other experimental study [17] that compared diets high in dairy and diets high in red meat, over the course of four weeks. Subjects on the diet with lots of dairy products experienced an increase in their fasting insulin, consistent with insulin resistance, despite having normal glucose tolerance at the beginning of the study.

It should be pointed out that although dairy products may worsen insulin resistance, they are still not as harmful as most foods in the typical Western diet. This is why studies done on populations may indicate that dairy products are associated with improvement in insulin resistance: because dairy products ultimately replace foods that are far worse.

It is also easy to overdo the consumption of dairy products, and I think one reason is that these naturally contain a version of morphine [18]. For so many who struggle to get away from the warm embrace that sugary foods give you with their dopamine rush, dairy products may simply become an afterthought, and considering that the constipating effects of morphine are very well known, this would also explain why dairy products can cause constipation.

There is also good evidence that vitamin B12 deficiency can result in increased LDL. One study [19] saw a significant increase in cholesterol synthesis caused by low vitamin B12, and if you are trying to figure out whether or not you are deficient, don't think for a second that standard references for vitamin B12 levels accurately identify a B12 deficiency. The standard references are extrapolated from the average levels within a population, but because the population is B12 deficient even the standard levels do not represent the optimal level.

Another possible cause of increased LDL is related to inflammation, specifically a signal protein that often circulates in the blood during inflammatory states. This is called tumor necrosis factor alpha, and this study [20] done on golden hamsters, whose lipid system is very similar to ours, showed that tumor necrosis factor caused VLDL (the precursor to LDL) to be overproduced by more than eight times the normal amount. Therefore, whenever I see high LDL levels, I am always looking for possible sources of inflammation.

Similarly, I want to point out that there are numerous causes that can lead to high triglyceride levels outside of sugary carbohydrates and alcohol. Some of the most common ones I encounter include hypothyroidism, kidney disease, diabetes, hemochromatosis, and numerous medications, including beta blockers and corticosteroids. So, as with LDL, if you see an unexpected high triglyceride level remember to consider other factors besides diet.

Summing up:

the story we've been told about how LDL is the leading cause of heart disease is clearly nonsense.
When LDL is oxidized, however, it can become a problem
the "triglyceride : HDL" ratio is a reliable method to check the oxidation status of LDL.
A high LDL level (even if not oxidized) could be symptomatic of another problem and therefore should definitely not be overlooked

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