Now that we've seen that the first half of the diet-heart hypothesis-- that dietary saturated fat and cholesterol elevate serum cholesterol and low-density lipoprotein (LDL)-- is false, 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 sternly 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.). They also aren't observed on Kitava, where no one seems to have heart attacks or stroke regardless of cholesterol. This suggests that total blood cholesterol as a marker of heart attack risk is not universal. I suspect it would not necessarily apply to someone eating an atypical diet.
Subdividing Cholesterol into Different Lipoprotein Particles Improves its Predictive Value
So far, this probably hasn't shocked anyone. Even entrenched proponents of the lipid hypothesis admit 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 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 up to twice the risk of 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 phenomenon 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). Also from the EPIC-Norfolk study, participants with high triglycerides had twice the risk of heart attack as participants with low triglycerides. Triglycerides and HDL are inversely related to one another, that is, if a person has high HDL, they're likely to have low triglycerides, and vice versa. This has also been consistent between studies.
Together, this suggests that the commonly measured lipoprotein pattern that associates most tightly with heart attack risk in typical Western populations is 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.