Thursday, July 23, 2009

The Diet-Heart Hypothesis: A Little Perspective

Now that we've discussed the first half of the diet-heart hypothesis, that saturated fat elevated total and LDL cholesterol, let's take a look at the second half. This is the idea that elevated serum cholesterol causes cardiovascular disease, also called the "lipid hypothesis".

Heart Attack Mortality vs. Total Mortality

We've been warned that high serum cholesterol leads to heart attacks and that it should be reduced by any means necessary, including powerful cholesterol-lowering drugs. We've been assailed by scientific articles and media reports showing associations between cholesterol and heart disease. What I'm going to show you is a single graph that puts this whole issue into perspective.

The following is drawn from the Framingham Heart study (via the book Prevention of Coronary Heart Disease, by Dr. Harumi Okuyama et al.), which is one of the longest-running observational studies ever conducted. The study subjects are fairly representative of the general population, although less racially diverse (largely Caucasian). The graph is of total mortality (vertical axis) by total cholesterol level (horizontal axis), for different age groups: If you're 80 or older, and you have low cholesterol, it's time to get your affairs in order. Between the age of 50 and 80, when most heart attacks occur, there's no association between cholesterol level and total mortality. At age 50 and below, men with higher cholesterol die more often. In the youngest age group, the percent increase in mortality between low and high cholesterol is fairly large, but the absolute risk of death at that age is still low. There is no positive association between total cholesterol and mortality in women at any age, only a negative association in the oldest age group.

Here's more data from the Framingham study, this time heart attack deaths rather than total mortality
(from the book Prevention of Coronary Heart Disease, by Dr. Harumi Okuyama et al.): Up to age 47, men with higher cholesterol have more heart attacks. At ages above 47, cholesterol does not associate with heart attacks or total mortality. Since the frequency of heart attacks and total mortality are low before the age of 47, it follows that total cholesterol isn't a great predictor of heart attacks in the general population.

These findings are consistent with other studies that looked at the relationship between total cholesterol and heart attacks in Western populations. For example, the observational arm of the massive MRFIT study found that higher cholesterol predicted a higher risk of heart attack in men age 35-57, but total mortality was highest both at low and high cholesterol levels. The "ideal" cholesterol range for total mortality was between 140 and 260 mg/dL (reference). Quite a range. That encompasses the large majority of the American public.

The Association Between Blood Cholesterol and Heart Attacks is Not Universal
The association between total cholesterol and heart attacks has generally not been observed in Japanese studies that did not pre-select for participants with cardiovascular risk factors (
Prevention of Coronary Heart Disease, by Dr. Harumi Okuyama et al.). This suggests that total blood cholesterol as a marker of heart attack risk is not universal. It would not necessarily apply to someone eating a non-Western diet.

Subdividing Cholesterol into Different Lipoprotein Particles Improves its Predictive Value

So far, this probably hasn't shocked anyone. Most people agree that total cholesterol isn't a great marker. Researchers long ago sliced up total cholesterol into several more specific categories, the most discussed being low-density lipoprotein (LDL) and high-density lipoprotein (HDL). These are tiny fatty droplets (lipoproteins) containing fats, cholesterol and proteins. They transport cholesterol, fats, and fat-soluble vitamins between tissues via the blood.

The LDL and HDL numbers you get back from the doctor's office typically refer to the amount of cholesterol contained in LDL or HDL per unit blood serum, but you can get the actual particle number measured as well.
One can also measure the level of triglyceride (a type of fat) in the blood. Triglycerides are absorbed from the digestive tract and manufactured by the liver in response to carbohydrate, then sent to other organs via lipoproteins.

The level of LDL in the blood gives a better approximation of heart attack risk than total cholesterol. If you're living the average Western lifestyle and you have high LDL, your risk of heart attack is substantially higher than someone who has low LDL. LDL particle number has more predictive value than LDL cholesterol concentration. The latter is what's typically measured at the doctor's office. For example, in the EPIC-Norfolk study (free full text)
, patients with high LDL cholesterol concentration had a 73% higher risk of heart attack than patients with low LDL. Participants with high LDL particle number had exactly twice the risk of those with low LDL number. We'll get back to this observation in a future post.

In the same study, participants with low HDL had twice the heart attack risk of participants with high HDL. That's why HDL is called "good cholesterol". This finding is fairly consistent throughout the medical literature. HDL is probably the main reason why total cholesterol doesn't associate very tightly with heart attack risk. High total cholesterol doesn't tell you if you have high LDL, high HDL or both (LDL and HDL are the predominant cholesterol-carrying lipoproteins).

Together, this suggests that the commonly measured lipoprotein pattern that associates most tightly with heart attack risk in typical Western populations is some combination of high LDL (particularly LDL particle number), low HDL, and high triglycerides.
In the next post, I'll slice up the lipoproteins even further and comment on their association with cardiovascular disease. I'll also begin to delve into how diet affects the lipoproteins.

21 comments:

Brock Cusick said...

Stephan,

I think Dr. William Davis, who administers the Track Your Plaque program and blogs at HeartScan Blog (http://heartscanblog.blogspot.com) would disagree with your closing statements.

First, you have to understand that LDL is rarely directly measured by these tests. It is calculated using a formula that accepts HDL and your triglycerides as inputs. This formula can be wrong by as much as 2x or 1/2 (depending on the direction of the error) compared to actually measured results.

Secondly, there are two types of LDL (as I suspect you will go into in your next post), but your second-to-last paragraph further develops widely held misunderstanding. The two types of LDL are "large and fluffy" (LDL-a) and "small and dense" (LDL-b, and there is no clinical evidence that high LDL is dangerous if your LDL particle count is primarily LDL-a (the large and fluffy). In fact a higher LDL count (as long as it's LDL-a) is probably healthier.

Lastly, as useful as LDL-b is as a predictor of CVD heart disease risk, it's not the most direct measure. Even better tests are lipoprotein(a) particle counts and Vitamin D deficiency. Cholesterol is largely a red herring.

Nick said...

Stephan,

Thank you for a great post, again. I know it will be particularly useful as a resource in discussions I have with friends who haven't been exposed to how to think about cholesterol and may be encouraged to take a statin.

Outlining the risk factors and liklihood of CVD as you have is a simple and straight forward way to introduce someone to challenge the conventional wisdom about TC. I have had people actually get mad at me for stating that organ meat and eggs are healthy foods that should not be avoided, so I love it that you have provided a series of such rich and informative information that can be shared.

homertobias said...

stephan
How useful is Okuyama's book? I've looked at it on amazon several times but the price always stops me from buying. I have read, liked and respected Artemous Simopolous (second author) for years.

Nancy LC said...

Brock,

I suspect Stephan already knows what you're saying, since he wrote this: http://wholehealthsource.blogspot.com/2009/06/when-friedewald-attacks.html

Just keep reading, he'll probably get into that stuff later.

Brock Cusick said...

Nancy LC,

I suspect he does too. That's why I pointed out that the second-to-last paragraph could be misleading to the reader who only reads this post. It's not a "reasonable simplification" but actually (IMO) misleading.

Stephan Guyenet said...

Brock,

Here's another way of putting what I wrote: If you were given nothing but the cholesterol fractions that doctors typically measure (TC, LDL, HDL, trigs), how would you extract the maximum amount of information from it? You would look at your LDL value (higher associates with risk), your HDL value (lower associates with risk), and your trigs (higher associates with risk). I doubt Dr. Davis would disagree with that.

I'll get into the fancy stuff in later posts.

Homertobias,

I really enjoyed Dr. Okuyama's book. Dr. Bill Lands is also an author. I actually have a limited tolerance for Dr. Simopoulos myself, because he buys into the saturated fat thing fairly uncritically. But he was just the editor. Okuyama and Lands think saturated fat is probably a red herring, as do I.

Okuyama would argue that the association between TC and infarction risk in Western populations probably comes exclusively from the confounding variable of familial hypercholesterolemia. He cites examples of populations that have a low prevalence of FH, and a weak or nonexistent association between TC and infarction risk.

I honestly think FH is unlikely to explain the association, because it exists even at TC levels below what you see in FH individuals. I think TC is just a crude measure of LDL, which is probably just a crude measure of oxidized LDL.

Nevertheless, it was a great book. They handily put the lipid hypothesis in its place, then develop the idea of n-6:3 balance as a better marker and causative agent. I was able to get the book from the library so I didn't have to pay for it. You can get excerpts on Google books.

Robert McLeod said...

Stephan wrote:
For example, in the EPIC-Norfolk study (free full text), patients with high LDL cholesterol concentration had a 73% higher risk of heart attack than patients with low LDL.


Just a little aside, but this is stated as an odds ratio of 1:1.73, not a relative risk.

When the underlying probability of an event in the odds ratio is high (i.e. having a heart attack) then the odds ratio overstates the relative risk, often greatly. Unfortunately, they don't tell us how many infarctions they actually observed... It was probably somewhere around 1.5 % of the control population based on UK trends for six years of observation, so the correction would be small.

Personally I find odds ratios a completely useless statistic. I know why it's used, but it's not really necessary to display it in public.

Stephan Guyenet said...

Hi Robert,

I'm not understanding the difference. Are they not both calculated by making a ratio between the frequency of events in one group to the frequency of events in another?

Robert McLeod said...

Stephan:

Take two probabilities, P1 and P2. We'll say P2 is the probability of a high LDL patient having a heart attack and P2 is the probability of low LDL patient having a heart attack.

Then the relative risk (RR) and odds ratios (OR) are:

RR = P1 / P2

OR = (P1/(1-P1)) / (P2/(1-P2))

So they differ by a factor of (1-P2)/(1-P1). If either P1 or P2 are not much less than 1.0 then the relative risk and odds ratio diverge.

Since the annual probability of having a heart attack in the UK is around 0.3 %, they're probably ok in this case and I'm being overly fastidious. The point I would make is that they should remain "under the hood" since they are not intuitive, especially when provided without the constituent probabilities. I have run into this problem in other papers where OR ~ 10, which is why I'm complaining. I have no idea what the OR represents in such a case because I don't have enough information to draw an inference from it.

Stephan Guyenet said...

Robert,

Thanks. I'll keep that in mind as I interpret papers in the future.

Melchior Meijer said...

Stephan, trivial remark, but Dr Artemis Simopoulos is a lady ;-). A very nice and friendly lady, but indeed, she seems to be a bit afraid of saturated fat.

Stephan Guyenet said...

Oops! My apologies to Dr. Simopoulos.

Bris said...

Dr Simopolous seems to be be a quite obsessed by the Mediterranean Diet. This is probably due to her being born on Crete

Thackray said...

Steven,

I agree with you about Artemis P. Simopoulos M.D. While I give her credit for being an early proponent of Omega 3 ( I read her book the Omega Diet when it came out in 1999), she is mostly wrong (in my opinion) about everything else. She is anti-saturated fat, as you point out, she is also pro-carb, pro-canola and walnut oils, pro-grains and high fiber. The recipes from that book didn’t even get the Omega 3 thing right as they were mostly based on flax products and canola oil. An omelet made with egg whites??

Perhaps she has changed her beliefs but as of 1999 she was way off.

I’m enjoying the blog!!

Regards,

Philip Thackray

Bris said...

I always look at the photos of various diet gurus. They tell an interesting story.

Artemis Simopoulos - fat

Barry Sears - flabby

Rosemary Stanton (ultra low fat diet) - anorexic

Barry Groves - fit

Loren Cordain - fit

randy said...

The graph you provided starts at a TC level of 200. According to the Framington Data 30% of all CAD events happen between 160 and 200.
The rise in events follow the rise from 160- 200 in linear scale.

Its only when you TC levels fall below 150 that CAD disappears, no heart attachs, no CAD deaths. And only TC matters at this level. TG and HDL level are irrelavent. Get your TC close to 150 or below and your heart attack proof.

Here's what Castelli, the director of Framington when this data was collected said:

"We’ve never had a heart attack in Framingham in 35 years in anyone who had a cholesterol level under 150…Three-quarters of the people who live on the face of this Earth never have a heart attack. They live in Asia, Africa, and South America, and their cholesterols are all around 150"

This is consistent with the results of other very low fat low TC levels that been reported earlier.

Regards
Randy

Refs:

1.
Atherosclerotic risk factors : are there ten, or is there only one ?
ROBERTS W. C. ;


2.
The new pathophysiology of coronary artery disease.
Castelli WP.
Framingham Cardiovascular Institute, Massachusetts, USA.

3.
Serum cholesterol concentration and coronary heart disease in population with low cholesterol concentrations.
Z Chen, R Peto, R Collins, S MacMahon, J Lu, W Li

Stephan Guyenet said...

I believe you read the graph wrong. It's of total mortality, not heart attack mortality. And there's a group called "<200", so it doesn't start at 200 as you said.

Barkeater said...

I think randy is way off base in claiming that TC less than 150 makes one “bullet proof” for heart disease. That is nonsense.

A Jan. 2009 article (reporting on a study by Dr. Gregg Fonarow, UCLA) contained intriguing tables regarding HDL and LDL levels of heart disease victims at hospital admission, including one for 48,093 persons with no previous heart disease (coronary artery disease or CAD) or diabetes. 12.5% had LDL below 70 mg/dl, and 29% had LDL between 70 and 99. So, 41.5% had LDL less than 100, with most of those having pretty low HDL (more than half had less than 40 mg/dl of HDL. We know that under the Friedewald calculation (deeply flawed as it is), the other component of TC is triglycerides divided by 5; the study referred to average triglycerides for heart disease victims of around 160 (for a larger cohort including those with previous heart disease). 160 on the trigs would add 32 to the TC. It is obvious that plenty of people who go to the hospital with heart disease for the first time have TC at the “bullet proof” level of 150 or less.

http://www.ahjonline.com/article/S0002-8703(08)00717-5/fulltext

randy said...

Barkeater said:

I think randy is way off base in claiming that TC less than 150 makes one “bullet proof” for heart disease. That is nonsense.

Reply:
It may be nonsense to your beleif systems,but the idea is based on the references I provided. These directly look at the issue.

The paper you quoted didn't even mention total TC.

Regards
Randy

Stephan Guyenet said...

This question is easy to settle. Just look at the MRFIT graph I posted in the next post. It has a line for CHD. It's low below 150 TC, but heart attacks at that TC level are not unheard of. The risk was roughly 1/2 to 1/3 of the average. Keep in mind this study was much bigger then Framingham.

randy said...

Stephan Wrote:
It's low below 150 TC, but heart attacks at that TC level are not unheard of. The risk was roughly 1/2 to 1/3 of the average. Keep in mind this study was much bigger then Framingham.

Reply:
No, its much much lower than that and the graph is not accurate or they are including people that had previous heart attacks at high TC levels that were reduced by drugs.

Here's what Castelli, the former director of Framington when this data was collected said:

"We’ve never had a heart attack in Framingham in 35 years in anyone who had a cholesterol level under 150…Three-quarters of the people who live on the face of this Earth never have a heart attack. They live in Asia, Africa, and South America, and their cholesterols are all around 150"

This phenomena (next to 0 MI at TC <150 is also discussed in these refs.

1.
Atherosclerotic risk factors : are there ten, or is there only one ?
ROBERTS W. C. ;


2.
The new pathophysiology of coronary artery disease.
Castelli WP.
Framingham Cardiovascular Institute, Massachusetts, USA.

3.
Serum cholesterol concentration and coronary heart disease in population with low cholesterol concentrations.
Z Chen, R Peto, R Collins, S MacMahon, J Lu, W Li