Dr. Stephan

After a very challenging summer, I've finally turned in my written thesis, so it's official: I have my Ph.D. I'm publishing the abstract below. These findings should all be published in peer-reviewed journals in the next 6 months.


Ataxin-7 Conserved Motifs Determine the Severity of the Neurodegenerative Disorder Spinocerebellar Ataxia Type 7 in Transgenic Mice and Influence Lifespan in Yeast

Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant, progressive neurodegenerative disorder whose characteristic features are cerebellar ataxia, dysarthria, and retinal cone-rod dystrophy culminating in blindness. SCA7 is caused by an abnormally long glutamine-coding CAG repeat in the SCA7 gene, which encodes the protein Ataxin-7.

Ataxin-7 contains several conserved motifs that may influence the toxicity of the glutamine tract. Among these are three conserved regions (conserved block I – III), two caspase-7 cleavage sites, a nuclear export signal and two monopartite nuclear localization signals (NLS). Previous investigations have shown that the caspase-7 cleavage site D266 is required for the full toxicity of the Ataxin-7 protein in cell culture. We generated SCA7 transgenic mice expressing a 92 CAG version of the human SCA7 cDNA, with and without a D266N mutation. Mice carrying the D266N mutation were protected from SCA7-like neurodegeneration, behavioral signs and shortened lifespan.

To further characterize the role of conserved motifs in SCA7 pathology, we generated SCA7 transgenic mice carrying point mutations in both C-terminal NLSs (KKRK -> KAAK). Previous work has shown that nuclear localization is an important step in the pathology of CAG repeat disorders. We observed that mice lacking C-terminal NLS activity were substantially protected from degeneration of the retina and cerebellum, SCA7-like behavioral signs and shortened lifespan.

Age is the primary risk factor for neurodegenerative disease. Even in the absence of overt disease, the aging brain shows histopathological and molecular changes reminiscent of neurodegeneration. To explore the link between neurodegenerative disease and aging, we have examined the replicative lifespan of Saccharomyces cerevisiae missing the SCA7 ortholog, SGF73. This strain exhibits an unusually long lifespan, which is dependent on the function of the NAD+-dependent deacetylase SIR2. We present evidence that the extended lifespan of the SGF73 null strain is due to the influence of Sgf73 on the activity of Sir2 and the histone deubiquitinase Ubp8. Furthermore, we show that the level of ubiquitinated H2B is elevated in an SCA7 transgenic mouse line, indicating that an alteration in Ubp8 activity may play a role in SCA7 pathology and that aging and neurodegeneration may share a common mechanism.

FiveFingers in the Alpine Lakes Wilderness

I recently bought a pair of Vibram FiveFingers Sprint (pictured). They're minimal, lightweight shoes with "toes". They're designed to mimic barefoot walking as closely as possible, while protecting the feet from punctures and abrasion. The soles are thin, flexible and offer no padding whatsoever.

I've always been a barefoot walker, because I enjoy it and our feet evolved to be nude (or close to it). Besides feeling amazing, walking barefoot may allow the body to express better biomechanics. My feet have become tougher over time, but I still can't handle a rough trail barefoot.

When I first put the FiveFingers on, my initial thought was "these don't feel as much like being barefoot as I wish they did". Simply having something between your skin and the ground makes your feet much less sensitive. But I got used to them quickly, eventually using them for my parkour training.

I had a few converstions with my parkour instructor Rafe Kelley, during which I realized I had to re-teach myself how to walk and run correctly. Rafe is well-versed in natural human movement due to his background in MovNat, gymnastics, martial arts, strength training, parkour and anthropology. Modern shoes allow us to walk and run in a way that our bodies did not evolve to tolerate. The padding in shoes allows us to take large steps, in which we overshoot our center of gravity and contact the ground in a jarring manner. It also allows us to strike with our heels when we run, which is not comfortable when you're barefoot.

I took the FiveFingers on a 13-mile hike in the Alpine Lakes wilderness with a few friends last weekend. The Pacific Northwest has to be one of the most beautiful places in the world. I was expecting to use the shoes for a few miles and then swap them for my lightweight hiking shoes (Inov8 Flyroc trail runners). The beginning of the trail was really rocky and I thought I was going to have to take them off in the first few hundred yards. Surprisingly, my feet adapted, and although the trail stayed rocky, it became fairly comfortable by the time we had walked a mile.

I found myself thinking about Rafe's advice, and taking smaller steps that strike closer to my center of gravity. Although my strides were shorter, I had no trouble keeping up, and in fact going up the hills was remarkably easy. We gained 3,000 feet of elevation but I never got winded. I had to pay close attention to foot placement, which kept me from looking around much but was actually kind of fun.

After a few miles, I switched to my hiking shoes, with the idea that I should switch before my feet really started to hurt, rather than after. I immediately noticed that going up hills was harder, especially on my calves. My feet felt more cumbersome as well.

Here's me foraging for mushrooms on the trail. This is Laetiporus sulphureus, also known as "chicken of the woods". It's widely eaten in this area. However, my mushroom guide All That the Rain Primises, and More, had this to say about it:

"If you eat and enjoy this moushroom, always cook it thoroughly and do not serve it to lawyers, landlords, employers, policemen, pit bull owners, or others whose good will you cherish!"

I didn't take my chances. If you're going to pick wild mushrooms, make sure you know what you're doing and carry a regional identification guide. "I recognize them from China/Russia/Europe" kills several people a year in the Pacific Northwest. If you're experienced, this area is a mushroom bonanza. I can't set foot outside without stepping on a king bolete (porcini, cep) in the fall.

I ended up switching back to the FiveFingers for the majority of the hike, about 9 miles of it. The soles of my feet were a bit sore by the end (due to stepping on sharp rocks for miles), but my joints and muscles felt remarkably good! I had no joint pain or muscle tightness. I also felt pretty energetic. This was a big surprise, since I haven't done much hiking this year. The next day, my calves were sore, but that was it.

All in all, I really like the FiveFingers. I can wear them in places that require shoes, yet remain nearly barefoot. One potential drawback is the price-to-durability ratio. They cost me $80 and I don't expect them to last a year [Update 2013-- they are surprisingly durable]. That being said, I'm putting a beating on them. Parkour training destroys shoes. The rubber seems to be excellent quality (which you'd expect from Vibram), but it's thin and it has cuts in it for flexibility and grip, which will lower its lifespan. The upper is simply a piece of stretchy fabric that tears easily. I'm willing to deal with the durability issues because the advantages outweigh them [update- several FiveFingers wearers have commented that they actually last a surprisingly long time. See comments].

Ischemic Heart Attacks: Disease of Civilization

Or, more precisely, disease of industrial civilization.

The scientific literature contains examples of cultures that don't suffer from the chronic non-communicable diseases that are so common in modern societies. Much of what I've read indicates that heart attacks are practically unique to cultures that have adopted industrial foodways and a modern lifestyle, being infrequent or entirely absent in those that have not.

I recently came across an incredible paper from 1964 in the American Journal of Cardiology, titled "Geographic Pathology of Myocardial Infarction", by lead author Dr. Kyu Taik Lee (Am. J. Cardiol. 13:30. 1964). This was published during a period of intense research into the cardiovascular health of non-industrial cultures, including Dr. George V. Mann's famous study of the Masai.

The first thing Lee and his colleagues did was collect autopsy statistics from San Francisco and Los Angeles hospitals. They analyzed the data by race, including categories for Caucasian-Americans (white), Japanese-Americans, Chinese-Americans, and Filipino-Americans. All races had a similar incidence of autopsy-proven myocardial infarction (MI = heart attack), including both silent (healed) and fatal MI. For comparison, they included a table with autopsy data from hospitals in Tokyo, South Japan and North Japan. I'm including the data from Tokyo in the graph because it's also an urban environment, but the finding was the same in all three regions. Here's what they found, by age group: The Japanese had a very low rate of MI compared to both Caucasian-Americans and Japanese-Americans. The rate of MI in Caucasian-Americans and Japanese-Americans did not differ significantly. Thus, location but not race determined the susceptibility to MI.

Next, the investigators collected autopsy data from hospitals in New Orleans, again divided by race. This time they exained Caucasian-Americans and African-Americans. Both groups had a very high rate of MI, as expected, although the African-Americans had a lower rate than Caucasian-Americans. They also collected data from autopsies in Nigeria and Uganda for comparison. Here are the data for men: And for women: Again, location but not race largely determined the incidence of MI. MI was extremely rare in the African autopsies. Here's what they had to say:

There was only 1 case of healed myocardial infarction among over 4,000 adult autopsies in the Uganda series, and only 2 cases of healed myocardial infarction among over 500 adult autopsies in the Nigerian series. In the New Orleans Negro series the occurrence rate was far greater in every sex and age group than in either one of the Negro series in East and West Africa.

Over 4,500 autopsies and not a single fatal MI. If this isn't worth studying, what is? These data should be part of first-year training in medicine and health programs.

To satisfy the skeptics, Lee and colleagues imported hundreds of hearts from consecutive autopsies in Albany (USA), Africa, Korea and Japan. They had an American pathologist analyze them side-by side to eliminate any diagnostic bias. Here's what they found:

In the African Negro series no infarct was found in any age group [out of 244 hearts, 39 over 60 years old]. In the Korean series there were only 2 cases of myocardial infarction [out of 106 hearts] and they were both women... In the Japanese series there were 8 cases of myocardial infarction in 259 hearts. All were men...

In the American sample, nearly 40% of the hearts of men and women over 60 showed signs of MI. The findings of the American pathologist confirmed the international autopsy data, showing that diagnostic bias did not contribute to the results significantly. They also took measurements of the thickness of the coronary artery wall, an index of atherosclerosis. They found that the Americans had the most atherosclerosis, but all cultures had some degree of it and there was overlap in the amount of atherosclerosis between samples. This led the investigators to state:

Myocardial infarction and coronary thrombosis are almost nonexistent in Uganda and Nigeria, and the amount of coronary arteriosclerosis is significantly less in Africans than in whites. However, in the two groups there was some overlapping in the degree of arteriosclerosis. No Africans had infarcts, but some had the same or a greater degree of coronary arteriosclerosis as a few whites who had myocardial infarctions. One explanation for this may be that some difference in clotting or clot-lysis mechanisms is present in the two groups. In a previous study, we showed that the incidence of thromboembolic phenomena in the pulmonary circulation [blood clots in the lungs] was low in East Africans as compared with Americans.

Now, the authors' conclusions:

These data strongly suggest that among the Orientals the environmental factor is playing a major role in the etiology of myocardial infarction and coronary thrombosis. If the genetic factor is an important one, those Orientals who moved to this country many years ago or who were born in this country should still maintain their low occurrence rate of myocardial infarction at least to some extent, and one would not expect to see similar occurrence rates of myocardial infarction in Orientals and whites as old as 50 to 59 years... As with the Orientals, this suggests that for Negroes in the United States environmental factors are more important than genetic factors in the etiology of myocardial infarction.

Africans in Africa and Japanese in Japan = low incidence of MI. Africans, Japanese and Caucasians in the US = high and similar incidence of MI. Genes only influence a person's susceptibility to MI when they live in an environment that promotes MI. Otherwise, genes are basically irrelevant.

What do the traditional diets and lifestyles of Japan and Africa have in common? Not much. Even within Nigeria, the diet varies from heavily starch-based (root vegetables, soaked/fermented non-gluten grains, beans, plantains) to mostly reliant on high-fat dairy and meat, though the former is much more common and I'm not sure how much the latter is represented in the data. In fact, I believe it's the wrong question to ask. A better question is "what do we eat/do in the US that traditional Japanese, Koreans, Chinese, Polynesians, Melanesians and Africans don't"? For starters, none of them rely on industrially processed foods. Their food is generally prepared at home using wholesome ingredients and traditional methods.

There are a number of lifestyle factors that probably play a role here.  They probably get more exercise than Americans, even if it's only walking in Tokyo or domestic tasks for women in parts of Africa. Traditional Africans surely get more sunlight and thus more vitamin D. I can't imagine life is less stressful in Tokyo than in San Francisco or Los Angeles.  Cigarettes are probably much less prevalent in parts of Africa than in the modern US.

I really like this study, and I think these graphs should be disseminated as much as possible. I've prepared high-resolution versions in JPEG, Powerpoint and PDF formats. E-mail me (click on my profile for the link) if you would like a copy. Let me know which format(s) you want.

The Diet-Heart Hypothesis: Oxidized LDL, Part I

In my reading about lipoprotein particles (LDL, HDL, etc.) and how they associate with cardiac risk, I've come across three LDL-related markers that associate with risk: LDL cholesterol, LDL particle number, and LDL size/density. Is this a coincidence, or is there a reason for it?

The first marker, LDL cholesterol, is probably nothing more than a crude approximation of particle number. But LDL particle number and size/density are related to something else, that probably actually causes atherosclerosis rather than simply being associated with it: oxidized LDL (oxLDL).

oxLDL is formed when the lipids in LDL particles react with oxygen and break down. This happens specifically to the unsaturated fats in LDL, because saturated fats, by their chemical nature, are very resistant to oxidative damage. Polyunsaturated fats are much more susceptible to oxidative damage than saturated or monounsaturated fats. Linoleic acid (the omega-6 fatty acid found abundantly in industrial seed oils) is the main polyunsaturated fatty acid in LDL.

LDL is packaged with antioxidants in the liver, primarily vitamin E and coenzyme Q10 (CoQ10), to prevent its oxidation. However, the more time it spends in the blood, the more likely it is to exhaust its antioxidant store and become oxidized. Also, the smaller the LDL particle, the more likely it is to become trapped in the vessel wall and become oxidized there.

Oxidized LDL Correlates Tightly with Cardiac Risk

oxLDL has turned out to be a very sensitive marker of cardiac risk, surpassing traditional markers like LDL, HDL, and triglycerides in most studies to date. Since the discovery of sensitive assays that detect oxidized LDL drawn directly from patient blood, a number of studies have been published supporting its ability to detect atherosclerosis (plaque buildup in the arteries), heart attack risk and even the metabolic syndrome.

Holovet and colleagues published a study comparing the ability of oxLDL and a traditional risk factor assessment to detect coronary artery disease. The traditional method is called the Global Risk Factor Assessment Score (GRAS), and includes age, total cholesterol, HDL, blood pressure, diabetes and smoking status. It's similar to the commonly used Framingham risk score (which, interestingly enough, doesn't include LDL).

GRAS was able to correctly differentiate a healthy person from a person with coronary artery disease 49% of the time, while oxLDL was correct 82% of the time. Thus, oxLDL by itself was far more accurate than a whole battery of traditional cholesterol and cardiac markers. Coronary patients had more than twice the level of circulating oxLDL than the healthy comparison group.

In a large prospective study by Meisinger and colleagues, participants with high oxLDL had a 4.25 higher risk of heart attack than patients with lower oxLDL. oxLDL blew away all other blood lipid markers by nearly a factor of two. From the abstract:

Plasma oxLDL was the strongest predictor of CHD events compared with a conventional lipoprotein profile and other traditional risk factors for CHD.

Oxidized LDL Makes Sense

 Regular, non-oxidized LDL has few properties that would make it a suspect in atherosclerosis. It's just a little particle carrying cholesterol and fats from the liver to other organs. As soon as it oxidizes, however, it becomes pro-inflammatory, immunogenic, damaging to the vessel wall, and most importantly, capable of transforming immune cells called macrophages into foam cells, a major constituent of arterial plaque.

Researchers have been interested in the plaque-generating properties of oxLDL for over three decades, and quite a bit of data have accumulated. They've identified cellular receptors that allow macrophages to ingest oxLDL (CD36 and SR-A). These receptors are specific for oxLDL and do not recognize normal LDL to a significant degree. Mice whose macrophages lack either of these two receptors have the same amount of circulating LDL as normal mice, yet have 60 to 70 percent less atherosclerosis when fed a plaque-forming diet (1, 2). Shorter-term studies have not always been consistent however, suggesting that there are alternative mechanisms. I'll expand on this more later.

Another line of evidence comes from the ability of LDL-borne antioxidants to prevent atherosclerosis in animal models. The powerful synthetic antioxidant probucol greatly reduces atherosclerosis in a number of animal models. It also reduces the extremely high cholesterol rodents and herbivorous animals get when they eat a high-cholesterol "atherogenic diet", but several studies have concluded that the majority of probucol's effect is due to its antioxidant ability rather than its ability to reduce cholesterol (ref).

Vitamin E and CoQ10 are two other LDL-borne antioxidants that can reduce atherosclerosis in animal models, particularly in combination with one another. Vitamin E alone is not as effective, and in some studies totally ineffective, which is one possible explanation for the equivocal results of vitamin E cardiovascular trials in humans. The most effective combination of antioxidants is probably the one provided by a nutrient-dense diet.

In Summary

Multiple lines of evidence suggest that oxidized LDL plays a dominant role in atherosclerosis. Not only is it associated with cardiovascular risk, there's also a large body of evidence suggesting it actually directly contributes to it. 

The Diet-Heart Hypothesis: Subdividing Lipoproteins

Two posts ago, we made the rounds of the commonly measured blood lipids (total cholesterol, LDL, HDL, triglycerides) and how they associate with cardiac risk.

Lipoproteins Can be Subdivided into Several Subcategories

In the continual search for better measures of cardiac risk, researchers in the 1980s decided to break down lipoprotein particles into sub-categories. One of these researchers is Dr. Ronald M. Krauss. Krauss published extensively on the association between lipoprotein size and cardiac risk, eventually concluding (source):

The plasma lipoprotein profile accompanying a preponderance of small, dense LDL particles (specifically LDL-III) is associated with up to a threefold increase in the susceptibility of developing [coronary artery disease]. This has been demonstrated in case-control studies of myocardial infarction and angiographically documented coronary disease.

Krauss found that small, dense LDL (sdLDL) doesn't travel alone: it typically comes along with low HDL and high triglycerides*. He called this combination of factors "lipoprotein pattern B"; its opposite is "lipoprotein pattern A": large, buoyant LDL, high HDL and low triglycerides. Incidentally, low HDL and high triglycerides are hallmarks of the metabolic syndrome, the quintessential modern metabolic disorder.

Krauss and his colleagues went on to hypothesize that sdLDL promotes atherosclerosis because of its ability to penetrate the artery wall more easily than large LDL. He and others subsequently showed that sdLDL are also more prone to oxidation than large LDL (1, 2).

Diet Affects LDL Subcategories

The next step in Krauss's research was to see how diet affects lipoprotein patterns. In 1994, he published a study comparing the effects of a low-fat (24%), high-carbohydrate (56%) diet to a "high-fat" (46%), "low-carbohydrate" (34%) diet on lipoprotein patterns. The high-fat diet also happened to be high in saturated fat-- 18% of calories. He found that (quote source):

Out of the 87 men with pattern A on the high-fat diet, 36 converted to pattern B on the low-fat diet... Taken together, these results indicate that in the majority of men, the reduction in LDL cholesterol seen on a low-fat, high-carbohydrate diet is mainly because of a shift from larger, more cholesterol-enriched LDL to smaller, cholesterol-depleted LDL [sdLDL].

In other words, in the majority of people, high-carbohydrate diets lower LDL cholesterol not by decreasing LDL particle count (which might be good), but by decreasing LDL size and increasing sdLDL (probably not good). This has been shown repeatedly, including with a 10% fat diet and in children. However, in people who already exhibit pattern B, reducing fat does reduce LDL particle number. Keep in mind that the majority of carbohydrate in modern America comes from refined wheat and sugar; a diet of unrefined carbohydrate may not have these effects.

Krauss then specifically explored the effect of saturated fat on LDL size (free full text). He re-analyzed the data from the study above, and found that:

In summary, the present study showed that changes in dietary saturated fat are associated with changes in LDL subclasses in healthy men. An increase in saturated fat, and in particular, myristic acid [as well as palmitic acid], was associated with increases in larger LDL particles (and decreases in smaller LDL particles). LDL particle diameter and peak flotation rate [density] were also positively associated with saturated fat, indicating shifts in LDL-particle distribution toward larger, cholesterol-enriched LDL.

Participants who ate the most saturated fat had the largest LDL, and vice versa. Kudos to Dr. Krauss for publishing these provocative data. It's not an isolated finding. He noted in 1994 that:

Cross-sectional population analyses have suggested an association between reduced LDL particle size and relatively reduced dietary animal-fat intake, and increased consumption of carbohydrates.

Diet Affects HDL Subcategories

Krauss also tested the effect of his dietary intervention on HDL. Several studies have found that the largest HDL particles, HDL2b, associate most strongly with HDL's protective effects (more HDL2b = fewer heart attacks). Compared to the diet high in total fat and saturated fat, the low-fat diet decreased HDL2b significantly. A separate study found that the effect persists at one year. Berglund et al. independently confirmed the finding using the low-fat American Heart Association diet in men and women of diverse racial backgrounds. Here's what they had to say about it:

The results indicate that dietary changes suggested to be prudent for a large segment of the population will primarily affect [i.e., reduce] the concentrations of the most prominent antiatherogenic [anti-heart attack] HDL subpopulation.

Saturated and omega-3 fats selectively increase large HDL. Dr. B. G. of Animal Pharm has written about this a number of times.

Wrapping it Up

Contrary to the simplistic idea that saturated fat increases LDL and thus cardiac risk, total fat and saturated fat have a complex influence on blood lipids, the net effect of which is unclear. These blood lipid changes persist for at least one year, so they may represent a long-term effect. It's important to remember that the primary sources of carbohydrate in the modern Western diet are refined wheat and sugar.  Healthier sources of carbohydrate have different effects on blood lipids.
* This is why you may read that small, dense LDL is not an "independent predictor" of heart attack risk. Since it travels along with a particular pattern of HDL and triglycerides, in most studies it does not give information on cardiac risk beyond what you can get by measuring other lipoproteins.

MRFIT Mortality

The Multiple Risk Factor Intervention trial was a very large controlled diet trial conducted in the 1980s. It involved an initial phase in which investigators screened over 350,000 men age 35-57 for cardiovascular risk factors including total blood cholesterol. 12,866 participants with major cardiovascular risk factors were selected for the diet intervention trial, while the rest were followed for six years. I discussed the intervention trial here.

During the six years of the observational arm of MRFIT, investigators kept track of deaths in the patients they had screened. They compared the occurrence of deaths from multiple causes to the blood cholesterol values they had measured at the beginning of the study. Here's a graph of the results (source):


Click on the graph for a larger image. Coronary heart disease does indeed rise with increasing total cholesterol in American men of this age group. But total mortality is nearly as high at low cholesterol levels as at high cholesterol levels. What accounts for the increase in mortality at low cholesterol levels, if not coronary heart disease? Stroke is part of the explanation. It was twice as prevalent in the lowest-cholesterol group as it was in other participants. But that hardly explains the large increase in mortality.

Possible explanations from other studies include higher infection rates and higher rates of accidents and suicide. But the study didn't provide those statistics so I'm only guessing.

The MRFIT study cannot be replicated, because it was conducted at a time when fewer people were taking cholesterol-lowering drugs. In 2009, a 50-year old whose doctor discovers he has high cholesterol will likely be prescribed a statin, after which he will probably no longer have high cholesterol. This will confound studies examining the association between blood cholesterol and disease outcomes.

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.