High Cholesterol and the Risk of Cardiovascular Disease

Cholesterol is a essential structural component of all the cell membranes in the body and is used in the making of steroid hormones such as cortisol and aldosterone by the adrenal glands, sex hormones such as estrogen, testosterone and progesterone by the gonads, and is also used in the making of bile acid. Approximately 80% of cholesterol made daily by the body occurs in the liver and  intestines, with the remainder being made in the adrenal glands and reproductive organs.

Different Types of Cholesterol

Triglyceride isn’t actually a type of cholesterol, but is measured on lipid panels along with cholesterol.

Triglyceride is made up of three fatty acids (hence “tri-“) attached to a glycerol molecule (also known as glycerine), which is a sugar alcohol. Some triglyceride is taken in through the diet and the rest is manufactured by the body during lipogenesis (literally meaning the ‘making of fat’). Lipogenesis is how the body stores the excess carbohydrate we eat in our diet that isn’t immediately needed for energy.  Yes, excess dietary carbohydrate is stored in the body as glycogen and when glycogen stores are full, it is stored as fat.

As for cholesterol itself, there are several different types found in the blood;

• high density lipoprotein (HDL)
• low density lipoprotein (LDL)
• very low density lipoprotein (VLDL)

Most people think of high density lipoprotein (HDL) as ”good cholesterol” and low density lipoprotein (LDL) as ”bad cholesterol” but there are actually two sub-fractions of LDL; the small, dense LDL sub-fraction which is associated with atherosclerotic plaque, and the large, fluffy LDL sub-fraction which is considered protective against cardiovascular disease[1].

This is important, because when people are told they have “high cholesterol“, this is usually implies that they have high LDL. This is often presented to them as them having a high level of “bad” cholesterol.

High Cholesterol

A couple of things need to be clarified about “high cholesterol”;

Firstly, “high LDL” cholesterol means high total LDL cholesterol. When blood tests are said to indicate “high LDL” a good question to ask is “which LDL cholesterol is high; the small dense ones or the large fluffy ones?”. More on this below.

Secondly, it is important to note that lab tests don’t actually measure total LDL but calculate it from the Friedewald formula; which (in mg/dl) is calculated by total cholesterol (TC) – HDL lipoprotein (HDL)-cholesterol – triglycerides (TGs) / 5. 

When people are told that they have “high LDL” results on a blood test, they are often presented with a recommendation to begin statin medication, but does high total LDL provide sufficient information about cardiovascular risk? More on this below. The use of statin medication will be covered in the subsequent article.

Very low density lipoprotein (VLDL) is produced in the liver and the best way to understand its role is to think of it as a “taxi” which the liver makes and then release into the bloodstream to shuttle triglycerides around to the various tissues.  VLDL cholesterol on blood test results isn’t actually measured either, but estimated as a percentage of the triglyceride value. High VLDL is said to be a risk for cardiovascular disease but as elaborated on below, a more accurate measure is the ratio of Apopoprotein B (the lipoprotein in VLDL) compared to the Apoprotein A (the lipoprotein in HDL). 

Where does LDL come from?

Once a large amount of triglyceride has been unloaded in the tissues by the VLDL “taxi”, it becomes a new, smaller lipoprotein called low density lipoprotein, or LDL which contains mostly cholesterol and some protein.

Some LDLs are removed from the circulation by cells around the body that need the cholesterol contained in them and the rest is taken out of the circulation by the liver.

A key point here is that the only source of LDL is VLDL. This is important.

LDL is what is left once the VLDL which is made by the body has offloaded its triglyceride ‘passenger’ to the tissues.

LDL and Heart Disease

Research has often reported that elevated LDL-cholesterol is a risk factor for cardiovascular disease, including heart disease and stroke and it has been assumed that lowering LDL-cholesterol in the blood would decrease cardiovascular deaths and illness. It is this premise that lead to recommendation of treatment of high LDL with statin drugs.

One major problem is that these studies looked at total LDL which doesn’t distinguish between the small, dense sub-fractions of LDL that are atherosclerotic, and the large, fluffy ones that are not [1].

Total LDL (LDL-C) calculates (not measures!) the total content or concentration of cholesterol within all the LDL particles.

LDL particle number (LDL-P) measures the particle concentration.

Since the amount of cholesterol in each particle varies, measuring LDL-C does not necessarily reflect the actual number of particles  — but an increased number of LDL particles occurs in patients with lots of small, dense particles.

Therefore, LDL-particle number (LDL-P) is a more accurate predictor of cardiovascular events than total LDL (LDL-C).

An NMR lipid profile test directly measures the number of LDL particles (as well as HDL particles). For LDL particles, a value of less  than 1.000 in nmol/L is considered ideal, a value of 1000-1299 is considered moderate,  a value of 1300-1599 is considered borderline high, and a value >1600 is considered high.

Apolipoprotein B:Apolipoprotein A1

Apolipoprotein B (apo B) is the main lipoprotein in VLDL, and subsequently in LDL after the VLDL has offloaded its triglyceride to the tissues. Apolipoprotein B is correlated with the actual number of LDL-particles, which makes it a very good assessor of the risk of cardiovascular disease, 

Apolipoprotein A1 (apo A1) is the main lipoprotein in HDL (commonly called “good” cholesterol).

An Apo B / Apo A1 ratio of > 0.9 is considered at risk for CVD.

Measuring Apo B to Apo A1 requires special blood tests, but a proxy can be calculated by dividing triglycerides (TG) by HDL-cholesterol (HDL-C) from a standard lipid panel. Studies have found this to be a very good assessor of cardiovascular risk.

Triglyceride:HDL Ratio

In Canada (as well as Europe), values are expressed as mmol/L and the ratios are interpreted as follows [2];

TG:HDL-C < 0.87 is ideal

TG:HDL-C > 1.74 is too high

TG:HDL-C > 2.62 is much too high

In the US, values are expressed in mg/dl and the ratios are interpreted as follows [2];

TG:HDL-C < 2 is ideal

TG:HDL-C > 4 is too high

TG:HDL-C > 6 is much too high

Several studies have found that TG:HDL-C ratio also reflects particle size;

One study from 2004 reported that almost 80% of people with a TG:HDL-C ratio of greater than 3.8 (when values are expressed in mg/dl) had mostly small, dense LDL particles, indicating cardiovascular risk. This same study found that more than 80% with a TG:HDL-C ratio of less than 3.8 (when values are expressed in mg/dl) had mostly large, fluffy LDL particles, indicating lower cardiovascular risk[3].

A 2005 study [4] reported that a TG:HDL-C ratio of 3.5 or greater was highly correlated with atherosclerosis in men, as well as insulin resistance and metabolic syndrome.

A recent 2014 [5] study found that a high TG:HDL-C ratio was a strong independent predictor of cardiovascular disease, coronary heart disease and all-cause mortality both before- and after adjustment for age, smoking, BMI and blood pressure.

Based on this metric, lower cardiovascular risk would be associated with lower triglycerides, raising HDL or both.

But how?

Lowering TG:HDL-C ratio

Losing weight will lower triglycerides, however low-fat diets are not usually helpful in this regard because they are often also high in carbohydrate[2].

Decreasing intake of carbohydrates — especially fructose which is found in fruit, as well as processed products made with high fructose corn syrup has been anecdotally reported to decrease hunger, making weight loss easier. Most importantly, clinical studies using well-designed low carbohydrate diets (already covered in several previous articles) are associated with both a lowering of triglycerides and a increase in HDL.

Lowering the risk of cardiovascular disease through weight loss, along with a lowering of triglycerides and an increase in HDL is where I can help.

UPDATE (June 23, 2019): Part 2 of this article titled Lowering LDL and Saturated Fat to Lower the Risk of Cardiovascular Disease is available by clicking here.

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To your good health!

Joy

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