This post first appeared on Second Nature - nutrition. READ ORIGINAL ARTICLE HERE

In our guide on saturated fat and heart disease we introduced the three steps that lead to the cholesterol theory of heart disease:

1) Saturated fat in the diet increases the amount of ‘bad’ cholesterol (also known as LDL cholesterol) in the blood
2) Higher levels of ‘bad’ cholesterol clog the arteries and lead to heart disease.

Therefore:

3) Saturated fat increases the risk of heart disease.

We discussed how the evidence supporting this third claim seemed very weak. In this guide we’ll be looking at the second claim: Do higher blood cholesterol levels cause heart disease?

Why does it matter?

You might be asking yourself, why does it matter what causes heart disease? Is it that important to know whether it’s ‘bad’ LDL cholesterol or something else?

The reason we believe this is so important is because understanding the cause of a disease is the first step to preventing it. If you know the risk factors, you’re likely to change the actions you do every day to lower your risk. However, if we get these risk factors wrong, we might actually be doing more harm than good.

So, what’s the answer? Should we be worried about eating foods with saturated fat? Should everyone be taking drugs to reduce cholesterol levels?

Or is there a better way?

Our current view is that high levels of ‘bad’ LDL cholesterol in the blood are not the main cause of heart disease. Instead, we believe there’s another hypothesis that provides a good explanation for all the known risk factors for heart disease.

But before we get into this, let’s understand a bit more about heart disease and the current widely held hypotheses.

Key points:

  • It’s important to know whether LDL cholesterol causes heart disease because understanding the cause of a disease is the first step to preventing it.
  • Currently, the evidence suggesting LDL cholesterol is to blame for heart disease seems weak.

What is heart disease?

The formation of heart disease is an extremely complicated process. In the medical world, heart disease is often referred to as cardiovascular disease (CVD), but for simplicity, we’ll call it ‘heart disease’. Usually, heart disease develops over time and the final ‘event’ is a heart attack or stroke.

Arteries and veins are the two types of large blood vessels in your body that transport blood. Arteries carry blood with oxygen from your heart to other organs, whereas veins take the blood back to the heart.

Heart attacks are normally a result of blood clots forming in the main artery that supplies the heart with blood (coronary artery). Strokes, on the other hand, tend to result from a blood clot forming in an artery in the neck (carotid artery) and breaking off, blocking the blood supply to the brain.

The main process that contributes to the final heart attack or stroke is called atherosclerosis. This is just a scientific word to describe the build-up of plaques in the inner wall of arteries. Atherosclerosis results in the thickening and narrowing of these arteries:

Key points:

  • Heart disease develops over a long period of time and results in a heart attack or stroke.
  • Atherosclerosis contributes to heart disease by thickening and narrowing the arteries. 

The Cholesterol Hypothesis

The mainstream hypothesis for the development of heart disease is best known as ‘the Cholesterol Hypothesis’. It suggests that atherosclerosis is a result of ‘bad’ cholesterol in your blood getting into the artery walls, subsequently causing inflammation and thickening of the arteries.

Before explaining the different stages of the Cholesterol Hypothesis, let’s return to the idea of ‘bad’ cholesterol and introduce lipoproteins.

It is widely accepted that there is ‘good’ and ‘bad’ cholesterol floating around our bodies. Low-density lipoproteins (LDL) are the ‘bad’ guys and high-density lipoproteins (HDL) are the ‘good’ guys.

The reason LDL is seen as bad is that it’s thought to build up in the arteries, and contribute to atherosclerosis (remember, the thickening and narrowing of the arteries). Contrastingly, HDL is seen as ‘good’ as it’s thought to carry LDL away from the arteries and back to the liver to be broken down.

With this in mind, the Cholesterol Hypothesis for the development of heart disease is as follows:

  1. You have high levels of LDL in your blood
  2. LDL leaks into the lining of the artery walls (endothelium layer)
  3. There is an inflammatory response
  4. Plaques start to form and grow

The above steps happen over a very long time (roughly 30-60 years), resulting in the gradual build-up of plaques. These plaques can rupture and create a major blood clot in your arteries which, if the clot breaks off, can cause a heart attack or stroke.

Key points:

  • The mainstream hypothesis for the development of heart disease is best known as ‘the Cholesterol Hypothesis’.
  • The Cholesterol Hypothesis suggests that LDL cholesterol in our blood leaks into our artery walls and starts forming atherosclerotic plaques. 

Where do the cracks begin to show?

You would think, given the widespread acceptance of the Cholesterol Hypothesis, that science would back it up nicely to explain cause and effect. In other words, the factors or conditions that increase your risk of heart disease would also show an increase in blood cholesterol, and factors decreasing your risk would lower blood cholesterol.

However, this is not always the case. When we look at a list of some of the most well-established risk factors for increasing and decreasing the risk of heart disease, there’s a very poor correlation between risk and blood cholesterol levels. Simply put, if someone is at high risk of heart disease, we would expect to also see high cholesterol levels, but this isn’t the case:

Key
Decrease
Increase
No change
Risk factor Effect on heart disease risk Effect on LDL cholesterol
Rheumatoid arthritis
Steroid use
Systemic Lupus Erythematosus
Smoking
Kawasaki’s disease
Use of NSAIDs (e.g. Ibuprofen)
Using cocaine
Getting older
Type II diabetes
Cushing’s disease
Air pollution
Chronic kidney disease
Avastin – a cancer drug
Dehydration
Acute physical stress
Acute psychological stress
High blood pressure
Vitamin C deficiency
Vitamin D deficiency
Sickle cell disease
Malaria
Bacterial infections
Acute psychological stress
Acute psychological stress
Haemophilia
Von Willebrand Disease
Aspirin
Moderate alcohol consumption
Clopidogrel (Blood thinner)
Yoga
Regular exercise
Statins (only for certain groups of people, e.g. men who have previously had a heart attack)
Tocopherol (Vitamin E)

A key argument of those who support the Cholesterol Hypothesis is that cholesterol has actually been found to be present in atherosclerotic plaques.

However, there are also lots of other things in these plaques, like red blood cells. Interestingly, cholesterol is actually used in the formation of red blood cell membranes. Therefore, a different theory suggests that the cholesterol found in these plaques is from the membranes of red blood cells, rather than harmful free deposits.

This illustrates how many unanswered questions and possible hypotheses when it comes to cholesterol. Because there’s so much we still don’t know, it’s probably not that helpful to delve into the specifics in this guide.

Instead, it might be more helpful to go through what we do know and explore some facts that contradict the Cholesterol hypothesis.

Key points:

  • When we look at a list of some of the most well-established factors for increasing and decreasing the risk of heart disease, there’s a very weak relationship between risk and blood cholesterol levels.
  • The Cholesterol Hypothesis blames cholesterol partly because cholesterol is found inside plaques, but many other things are present in the plaques, e.g. red blood cells. 

The Japanese paradox

Japan is renowned for having some of the lowest rates of heart disease in the world. However, it wasn’t always quite as low.

One recent study analysed how Japan’s consumption of fat has changed over the last fifty years, and how this has affected their rates of heart disease.

They found that fat consumption in Japan has increased by 400% in the last fifty years. Alongside this, average blood cholesterol levels have risen from 3.9 mmol/l to 5.1 mmol/l.

If fat consumption and average blood cholesterol levels were the cause of heart disease, then you would expect rates of heart disease to have increased.

In fact, the rates of heart disease have dropped by 60%, and the rate of stroke has fallen by 7 times.

If you went along to your GP today and had a check-up to evaluate your risk for heart disease, some of the key factors your GP would check would be: blood pressure, whether you smoke, your saturated fat intake, and your blood cholesterol levels.

If we then compare these risk factors between Japan and Russia for men under the age of 65, there is an interesting contradiction. If these are indeed the main risk factors, then given that Japan and Russia have very similar values, you would expect the rates of heart disease to be approximately the same. However, Russia has a much higher rate of heart disease than Japan. We’re talking almost 18 times higher (1680% higher).

Japan Russia
Average systolic blood pressure 135 125
Smoking 45.5% 47%
Saturated fat intake 7.5% 8.3%
Cholesterol levels 5.1 mmol/l 5.1 mmol/l
Rate of heart disease per 100,000 people per year 15 267

Which raises the question: are these the correct risk factors for heart disease?

Key points:

  • Fat consumption in Japan has increased by 400% in the last 50 years and cholesterol has also increased, yet the rates of heart disease and stroke have severely decreased.
  • Japan and Russia have nearly identical amounts of saturated fat intake and cholesterol levels, yet the rate of heart disease in Russia is almost 18 times higher. 

Heart disease in the USA

The second interesting contradiction comes from a study done in the USA in 2006. During this time, the authors analysed 231,986 hospitalisations from heart attacks across 541 hospitals. Of all of these hospitalisations, cholesterol levels were recorded in 136,905 of the patients (59%) when they arrived at the hospital.

As you can see, this is a vast amount of data and not a small study with 50 to 100 people.

From the 136,905 people who had their cholesterol levels taken, their average LDL levels were 105 mg/dL.

What is interesting is when this number is compared to the average LDL levels across the whole population in the USA at the time, which was 126 mg/DL.

The data showed that 78% of people who were admitted to hospital after having a heart attack had an LDL level lower than the average in the USA.

If you were looking at this study in isolation, the conclusion would quite clearly be that people who have had a heart attack are more likely to have a low LDL cholesterol level.

Key points:

  • A vast study demonstrated that 78% of people who were admitted to hospital after having a heart attack had an LDL level lower than the average in the USA.
  • This contradicts the Cholesterol Hypothesis.

Alternative hypotheses

For such a complex process where we still don’t have all the facts, the best we can do is find a theory that answers as much as possible through explained processes, rather than a theory that leaves many points unanswered. Now let’s explore 2 different theories to see if they can better explain heart disease.

1. The Inflammation Hypothesis

This theory suggests that heart disease occurs as a result of inflammation in the body. At first glance, this seems logical. Many people who have heart disease tend to have raised indicators of inflammation.

On top of this, some other chronic conditions are caused by abnormal inflammation (e.g. Crohn’s disease). So it seems simple, right? Those with heart disease have a high level of inflammation, so inflammation could be the cause? Unfortunately, it’s not so simple.

By this theory, you would expect low levels of inflammation to decrease your risk of heart disease. However, individuals with Cushing’s disease provide a gap in this theory.

Cushing’s is a disease where too much cortisol is produced. Cortisol is anti-inflammatory. So, individuals with Cushing’s disease constantly have a very low level of inflammation in their body. Yet, this group of people have 4 times the level of risk of developing heart disease.

This contradicts the theory that heart disease is primarily a result of inflammation. It’s more likely that the development of heart disease triggers the bodies’ natural immune response to any injury, resulting in a higher level of inflammation.

Key points:

  • The theory that heart disease is a result of inflammation  seems logical as some other chronic disease are caused by abnormal inflammation (e.g. Crohn’s disease).
  • However, those with the lowest amounts of inflammation (individuals with Cushing’s disease) appear to have a much higher risk of heart disease. 

2. The Blood Clotting Hypothesis

Many diseases are simply the result of normal healthy processes going wrong. Blood clotting is a normal healthy process. If our bodies weren’t able to form blood clots then we would bleed to death anytime we cut ourselves. This theory proposes that heart disease is a disease where the normal, healthy process of blood clotting goes wrong.

A small amount of damage to the blood vessel endothelium (the inner lining) isn’t a big problem. When this happens, a blood clot will form, be shaved down in size, and then a new layer of endothelium grows on top. This means the blood clot gets incorporated into the artery wall.

Interestingly, when you look at atherosclerotic plaques, they contain many similar components to a blood clot. By this theory, they’re the same thing.

When the blood clot is being shaved down in size, it triggers ‘repair’ systems that increase inflammation. As we said earlier, inflammation is the bodies’ natural immune response to any injury. This explains why individuals with heart disease seem to have higher levels of inflammation in the body.

So up until this point, everything is a normal healthy process. Where does it go wrong? The blood clotting theory suggests that problems occur when the rate of endothelium damage is higher than the rate of repair.

By this theory, heart disease does not have one specific cause but rather develops by an ongoing process of:

  • An increased rate of endothelium layer damage occurs
  • Larger, harder to remove blood clots form
  • The body has a reduced ability to repair/remove these blood clots
  • Atherosclerosis develops over time (if the rate of blood clotting exceeds the rate of repair)

Another gap explained by this theory is why atherosclerosis does not occur in veins. A very simplified answer is that blood in the arteries travels at a much higher pressure than blood in veins, which increases the chances of endothelium damage. Particularly at parts where the arteries branch, the blood is travelling with a lot of force. Interestingly, these areas are the most common areas in arteries to see atherosclerosis. So, this doesn’t happen in veins as the blood is not travelling with such force.

When you take a closer look at all the factors that affect your risk of developing heart disease, you can see that they will either affect:

1) Endothelium damage

OR

2) Blood clot formation

Key
Decrease
Increase
No change
Risk factor Effect on heart disease risk Effect on blood clotting OR endothelium damage Effect on LDL cholesterol
Rheumatoid arthritis
Steroid use
Systemic Lupus Erythematosus
Smoking
Kawasaki’s disease
Use of NSAIDs (e.g. Ibuprofen)
Using cocaine
Getting older
Type II diabetes
Cushing’s disease
Air pollution
Chronic kidney disease
Avastin – a cancer drug
Dehydration
Acute physical stress
Acute psychological stress
High blood pressure
Vitamin C deficiency
Vitamin D deficiency
Sickle cell disease
Malaria
Bacterial infections
Acute psychological stress
Acute psychological stress
Haemophilia
Von Willebrand Disease
Aspirin
Moderate alcohol consumption
Clopidogrel (Blood thinner)
Yoga
Regular exercise
Statins (only for certain groups of people, e.g. men who have previously had a heart attack)
Tocopherol (Vitamin E)

Overall, the Blood Clotting Hypothesis seems to leave the least amount of unanswered questions, compared to other theories of the development of heart disease.

Key points:

  • The Blood Clotting Hypothesis proposes that heart disease is a result of endothelium damage and larger, harder to remove blood clots forming. 
  • This would explain why atherosclerosis is not seen in veins (blood in the arteries travels at a much higher pressure than blood in veins, which increases the chances of endothelium damage).
  • Looking at all the factors that affect your risk of developing heart disease, there isn’t a consistent link with cholesterol but there does seem to be a link with endothelium damage and/or blood clotting. 

The bigger picture

To conclude this guide, we should be clear about what we are saying, and what we’re not saying.

We’re not saying that high levels of cholesterol are irrelevant in the heart disease process, as high levels of anything are often not good.

That being said, the evidence supporting the notion that ‘bad’ LDL cholesterol is the primary driving force of heart disease is weak.

It’s very difficult to make firm conclusions in the scientific world, partly because human biology is so complicated. Scientists often use ‘observational studies’ to try and come to conclusions on what is good and bad. These studies observe people over long periods of time and try to understand how different lifestyle factors affect things like heart disease and cancer.

The challenge is that there are so many unknown factors in people’s lives, such as whether they smoke or exercise, that ultimately it’s almost impossible to conclude anything from these observational studies.

Different observational studies that don’t focus on heart disease actually suggest that the higher our blood cholesterol, the lower our risk of death in general as we get older.

Only when large volumes of observational studies repeatedly show the same effect, can you start to consider causality of a particular factor.

To date, the only health-related conclusions that we have confidently drawn from observational studies are:

  • Exercise is good for you
  • Smoking is bad for you (causing lung cancer and other damaging effects, interestingly, such as increased endothelium damage)

So, you can choose to accept the conclusions of observational studies, with their inherent weaknesses, or you can be more cautious with their conclusions. This means searching for physiological explanations that explain the associations we’re seeing, rather than relying on broad assumptions.

At Second Nature, we believe that finding compelling physiological explanations of disease systems is a stronger approach than relying largely on observational studies.

In our guide on risk factors for heart disease, we’ll explore some of the lifestyle choices thought to affect heart disease.

Key points:

  • We aren’t claiming that high levels of cholesterol are irrelevant in the heart disease process (high levels of anything are usually not good). 
  • However, the evidence supporting the notion that ‘bad’ LDL cholesterol is the primary driving force of heart disease is observational, and different observational evidence suggests the exact opposite.

Take home message

  • ‘Bad’ LDL cholesterol doesn’t seem to be the main driving force behind atherosclerosis.
  • The Inflammation Hypothesis has a logical appeal but doesn’t actually fit with the evidence.
  • The Blood Clotting Hypothesis seems to leave the fewest unanswered questions.

This post first appeared on Second Nature - nutrition. READ ORIGINAL ARTICLE HERE

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