Coronary arteries are essentially hollow tubes, and the endothelium (lining) of the artery is very thin—only one cell deep. The blood, which carries lipoproteins like LDL, is in constant contact with the endothelial lining. So why does the LDL particle leave the blood, penetrate the endothelium and enter the artery wall? The answer is that it’s a gradient-driven process. Going back to our analogy, the more cars there are on the road at one time, the more likely it is that some of them will “crash” into the fragile lining of the artery. It’s not the number of passengers (cholesterol) the cars are carrying that is the determining factor, but the number of cars on the highway.
The significance of this in terms of determining your risk of heart disease is profound. When you go to the doctor to get your cholesterol tested, chances are he or she will measure your total, LDL and HDL cholesterol. This tells you the concentration of cholesterol (passengers) inside of the lipoproteins (cars), which is not the driving factor behind plaque formation and heart disease. Instead, what should be measured is the number of LDL particles in your blood.
LDL cholesterol levels and LDL particle number are often concordant (i.e. when one is high, the other is high, and vice versa), and this is probably why there is an association between LDL cholesterol and heart disease in observational studies. The elevated LDL cholesterol was more of a proxy marker for elevated LDL particle number in these cases. But here’s the kicker: they can also be discordant. In layperson’s terms, it’s possible to have normal or even low cholesterol, but a high number of LDL particles. (1) If this person only has their cholesterol measured, and not their particle number, they will be falsely led to believe they’re at low risk for heart disease. Even worse, the patients that are the most likely to present with this pattern are among the highest risk patients: those with metabolic syndrome or full-fledged type 2 diabetes. The more components of the metabolic syndrome that are present—such as abdominal obesity, hypertension, insulin resistance, high triglycerides and low HDL—the more likely it is that LDL particle number will be elevated. (2)
On the other hand, patients with high LDL cholesterol (LDL-C) and low LDL particle number (LDL-P) are not at high risk of heart disease. In fact, studies suggest they’re at even lower risk than patients with low LDL-C and low LDL-P. (3) Yet they will often be treated with statin drugs or other cholesterol lowering medications, because the clinician only looked at LDL-C and failed to measure LDL particle number. This is a concern for two reasons. First, statin drugs aren’t harmless. (I’ll go into more detail on this in the third post of the series.) Second, studies suggest that low cholesterol can increase the risk of death, especially in women and the elderly.
In one study of over 52,000 Norwegians, researchers found that women with total cholesterol levels below 195 mg/dL had a higher risk of death than women with cholesterol levels above that cut-off. (4) And a study published in the American Journal of Medicine found that people over 70 years of age with total cholesterol levels below 160 mg/dL had twice the risk of death than those with cholesterol levels between 160-199 mg/dL. (5) Low cholesterol is also associated with increased risk of disease—especially mental health and brain disorders. For example:
- A study in the Journal of Psychiatric Research found that men with low total cholesterol levels were 7 times more likely to die prematurely from unnatural causes such as suicide and accidents than other men in the study. (6)
- A 1993 study published in The Lancet found that depression was 3 times more likely in men over 70 with low cholesterol than in those with normal or high cholesterol. (7)
- A Swedish study found that women with the lowest cholesterol suffered significantly more depressive symptoms than other women in the study. (8)
- A study in the journal Neurology showed that low cholesterol is associated with increased risk of dementia. (9)
- A paper published in the European Journal of Internal Medicine linked low cholesterol levels with Alzheimer’s disease. (10)
It’s important to note that all of these studies were observational, which means that they don’t prove that low cholesterol was the cause of the increased risk of death or disease that was observed. It’s possible, for example, that these patients had another disease that caused both the lower cholesterol and increase in disease or mortality. However, given what we know about the important roles of cholesterol in the body, it’s certainly plausible that low cholesterol is capable of contributing to these problems directly.
Wrapping up: The map is not the territory!
Before concluding, I’d like to point out that although LDL particle number is superior to LDL cholesterol as a marker for heart disease, it’s still just that—a marker. A marker is not a disease. It’s a risk factor for a disease. Having a risk factor for a disease does not guarantee that you will get that disease—it just increases the chance that you will. There are still several gaps in our knowledge about LDL-P and its usefulness in a clinical setting. For example:
- Imagine two people with an LDL-P above 2,000, which puts them in the highest risk group. Person A follows a Paleo diet and lifestyle, gets plenty of sleep, manages stress and has no other significant risk factors for heart disease. Person B eats a Standard American Diet, doesn’t exercise, doesn’t get enough sleep, is stressed out and has several other risk factors for heart disease. Logic would dictate that Person A would be at much lower risk for heart disease than Person B, but there isn’t any comparative data to quantify the difference in risk and it’s unlikely such a study will ever be done. (Who would pay for it?)
- Imagine two people following a healthy Paleo-type diet and lifestyle. Person C has no conventional risk factors for heart disease. Person D has no conventional risk factors either, but does have an LDL-P of 2,000. Logic here would dictate that Person D is at higher risk than Person C, but again, we don’t have actual data to quantify the difference in risk.
Heart disease is a complex, multifactorial process. The likelihood that we’ll have a heart attack depends on numerous factors, including genetics, diet, lifestyle and living environment. The purpose of this article is not to suggest that LDL-P is the only risk factor that matters, or that other risk factors shouldn’t be taken into consideration. It is simply to point out that existing evidence suggests that LDL-P is a much better predictor of heart disease risk than LDL or total cholesterol, and that it appears to be one of the better markers available to us now.
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