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.

Back in the US

Hello everyone,
Sorry for the lack of new posts. I've been out of the country for work and vacation the last couple months but I'm back and ready to finish the series. In good news while onsite for two months I did run across a number of new OWA log format that I wrote some new parsers for that I will be posting soon.

Hindari Usilnya Batu Ginjal

By Republika Newsroom
Selasa, 21 Juli 2009 pukul 12:11:00

Pastikan air minum yang Anda konsumsi telah sterill dari virus dan bakteri. Rebus selama delapan jam atau jemur dibawah sinar matahari.

Benda padat yang terbentuk menyerupai batu pada ginjal bisa mengakibatkan rasa sakit serta infeksi yang membahayakan jika berada di saluran buang air kecil.

Tidak seimbangnya pola makan, kurang aktivitas fisik serta penyakit kronis yang menahun merupakan beberapa faktor yang mempertinggi risiko pembentukan batu ginjal.

Ada beberapa tips yang dapat Anda lakukan untuk menghindari terbentuknya batu ginjal tersebut, antara lain :

Minum banyak air setiap hari. Batu ginjal terbentuk dari garam dan mineral dalam urin yang bercampur. Cairan yang cukup dapat membantu urin kelancaran dan kejernihannya. Urin yang sehat berwarna kuning cerah. Jika urin berwarna kuning gelap, artinya Anda kuring minum. Usahakan untuk minum setiap beberapa jam, jangan hanya waktu-waktu tertentu.

Turunkan berat badan berlebih. Penelitian menunjukkan orang yang kelebihan berat badan secara signifikan lebih cenderung mengalami batu ginjal.

Kontrol diabetes yang Anda alami. Penyakit kronis biasanya mempengaruhi fungsi ginjal. Sebagai catatan, batu ginjal juga bisa menjadi tanda dari diabetes, juga tekanan darah tinggi dan osteoporosis. Jika Anda terbukti memiliki batu ginjal, konsultasikan lebih lanjut dengan dokter.

Variasikan konsumsi makanan. Pembentuk batu ginjal bisa berbagai macam, tergantung pola makan setiap orang. Sebaiknya, Anda mengganti pola makan yang bervariasi setiap hari. Konsultasi dengan dokter mengenai jenis makanan yang bisa Anda makan. Misalnya, sebagian orang sangat cocok dengan memfokuskan makanan yang mengandung cukup kalsium dan serat sekaligus mengurangi asupan protein dan menghindari garam.

Hindari jus grapefruit atau jeruk besar yang asam. Secara umum, buah sitrus membantu mengurangi asam pada urin. Pengecualian pada grapefruit yang menurut penelitian, justru dapat meningkatkan risiko batu ginjal. Waspada juga jangan sampai melebihi dosis rekomendasi asupan vitamin C dan D tambahan.

Berolahraga secara teratur. Orang yagn tidak aktif memiliki risiko lebih tinggi terhadap batu ginjal. Langkahkan kaki ke luar ruangan dan mulailah berjalan, meskipun sangat singkat setiap hari.

Jangan ragu bertanya mengenai obat-obatan yang diberikan kepada Anda. Tergantung dari zat apa batu ginjal yang Anda miliki, obat justru bisa mendorong pertumbuhannya. Hindari asupan obat tersebut untuk menghindarinya. (newsday/rin)http://republika.co.id/berita/63701/Hindari_Usilnya_Batu_Ginjal

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