Why (LDL particle) size matters.

Having gone through the math(s) with several people, I thought I'd stick it in a blog post for posterity.

I know that this is a diagram of a chylomicron, but bear with me!

Cholesterol synthesised in the liver is exported in LDL particles. The more cholesterol that's synthesised, the more particles there need to be to carry it.

∴ LDL-P (particle number) ∝ LDL-C (total amount of cholesterol)

The particles are roughly spherical with a very thin wall (consisting of a phospholipid mono-layer, the yellow wiggly lines with a green end bit in the above diagram).

Volume of a sphere = 4/3 * π * r³, where r = half the diameter.

If there's a 10% reduction in LDL particle size, the volume reduces to 0.729, relative to the original size. Therefore, to carry the same amount of cholesterol requires 1/0.729 = 1.37 times more particles, which is a 37% increase in the number of LDL particles, relative to the original size.

∴ LDL-P (particle number) ∝ 1/LDLsize³

As it's LDL particle number that determines the infiltration of LDL cholesterol into the media of artery walls, it's advisable to keep cholesterol synthesis to a minimum by keeping fat intake to a reasonable level * (i.e. not Nutritional Ketosis level) and keeping LDL particle size to a maximum by keeping sugars & fast starches intake to a reasonable level*.

Before someone asks, what I mean by a reasonable level is a level that is burned by the body without having a chronic excess. An acute excess can be stored, provided that mean intake is less than mean burning.

How COULD I write a post about LDL-P and forget to include THIS?

Another tasty analogy.

Here's a tasty analogy.

From http://grannychoe.com/recipe3_Soup.php

In Ultra-high-fat (~80%) diets: Fat storage, and a delicious analogy, I analogised the effect of carbohydrate consumption on mean serum glucose level with the effect of fat consumption on mean serum triglyceride level. Here's another one.

Chronic excessive consumption of carbohydrates relative to what are being burned results in excessive fat synthesis in the liver, resulting in excessively-high fasting serum triglyceride level, which is harmful.

Chronic excessive consumption of fats relative to what are being burned results in excessive cholesterol synthesis in the liver, resulting in excessively-high fasting VLDL, LDL & IDL level, which is harmful.

Seems legit.

Lipoproteins & apolipoproteins: E, by 'eck.

In December 2008, I wrote about Cholesterol And Coronary Heart Disease , where I used a limousine metaphor to describe how cholesterol & fat are transported around the body. Here's a diagram of a chylomicron lipoprotein "limousine". Chylomicrons transport dietary fat (triglycerides) & cholesterol from the gut to the liver & other tissues. As there's much more dietary fat than dietary cholesterol, the contents are mostly fat.

A chylomicron. T=Triglyceride C=Cholesterol. From http://en.wikipedia.org/wiki/Lipoprotein

The lipoprotein "limousines" vary a lot in size.

(a) VLDL (b) chylomicrons (c) LDL (d) HDL. 
From http://healthcorrelator.blogspot.co.uk/2011/11/triglycerides-vldl-and-industrial.html

Apolipoproteins are the "chauffeurs" which determine to where lipoproteins transport stuff.
Apo A is found mainly on HDL, which transports fat & cholesterol from tissues to the liver.
Apo B is found mainly on LDL, which transports cholesterol from the liver to tissues.
Apo C is found on HDL when fasted, but moves to chylomicrons & VLDL when fat is eaten.
Apo D is found mainly on HDL and is is associated with an enzyme involved in lipoprotein metabolism.
Apo E is found mainly on chylomicrons & IDL and transports lipoproteins, fat-soluble vitamins, and cholesterol into the lymph system and into the blood. In the CNS, Apo E transports cholesterol to neurons. Defects in Apo E result in hyperlipidaemia , cardiovascular & neurological diseases, and is the E referred to in the title.

There's also Apo H, which is a β-glycoprotein involved in the binding of cardiolipin. It has nothing to do with the above lipoproteins.

Whatever happened to...Torcetrapib?

Peter of Hyperlipid mentioned this stuff back in July 2007 but it didn't get much attention back then, so I am resurrecting it. It's another "Great Idea" that turned out to be absolute cack.

Inhibiting the enzyme that converts A into B results in less of B but more of A. This also applies to something called Cholesterol Ester Transport Protein (CETP) that transports esterified cholesterol (acid + alcohol = ester + water & cholesterol is technically an alcohol) from the tiny HDL discs to the much larger LDL & relatively huge VLDL particles. To see what HDL, LDL, VLDL & chylomicrons look like, see Large LDL and small HDL particles: The best combination.

Inhibiting CETP with Torcetrapib reduces LDL and increases HDL which sounds absolutely wonderful. Unfortunately, what has actually happened is that the cholesterol reverse transport pathway has been interfered with. Not surprisingly, this results in increased mortality. To see how cholesterol transport pathways work, see Figure 3 in Effect of Torcetrapib on the Progression of Coronary Atherosclerosis. See also Effect of Torcetrapib on Carotid Atherosclerosis in Familial Hypercholesterolemia.

If you want to raise your HDL, eat more saturated & monounsaturated fats, also fish oils and/or take high-dose extended-release niacin. Don't bugger about with CETP.

Some more nails for the coffin of the "healthy low-fat" diet.

Every time someone writes "I'm eating a healthy low-fat diet", I cringe. It's presumptuous to assume that, because the fat content is low, the diet is automatically healthy. The media tell us it's healthy. The government tells us it's healthy. "Experts" tell us it's healthy. It must be healthy, right? Um...

See After-eating effects: Carbohydrates vs. fats and Reduced oxidation of dietary fat after a short term high-carbohydrate diet.

The low-fat diet was white bread, potatoes, tuna, chicken, carrots, canned fruit, fruit juices, cola, jam, marmalade, sweets, and sugar cubes.

The higher-fat diet was less of the above, plus a fat spread, which consisted of a mixture of lard, palm oil, olive oil, and corn oil (the ratio of polyunsaturated to saturated fat was 0.5:1).

Please excuse the following "shouting", but some facts need to be shouted from the rooftops:-

1) LDL CHOLESTEROL (LDL-C) DOES NOT CLOG YOUR ARTERIES. LDL-C IS NOT BAD CHOLESTEROL.

2) OXIDISED LDL-C (OX-LDL-C) DOES CLOG YOUR ARTERIES. OX-LDL-C IS BAD CHOLESTEROL.

3) LARGE, FLUFFY (PHENOTYPE A) LDL-C OXIDISES SLOWLY.

4) SMALL, DENSE (PHENOTYPE B) LDL-C OXIDISES RAPIDLY.

5) AS THE PERCENTAGE OF CALORIES FROM FAT DECREASES, YOU GET LESS PHENOTYPE A AND MORE PHENOTYPE B.

If you don't believe me (and why should you?), see A very-low-fat diet is not associated with improved lipoprotein profiles in men with a predominance of large, low-density lipoproteins, with particular reference to the following figure:-

At 50% fat intake, ~15% of the subjects have phenotype B. At 20% fat intake, ~50% of the subjects have phenotype B. At 10% fat intake, over 60% of the subjects have phenotype B. The subjects were all men, but women are no different in this respect.

And now we have Dietary fat intake and subsequent weight change in adults: results from the European Prospective Investigation into Cancer and Nutrition cohorts.

"Results:...The difference in mean annual weight change was 0.90 g/y (95% CI: –0.54, 2.34 g/y) for men and –1.30g/y (95% CI: –3.70, 1.11 g/y) for women per 1 g/d energy-adjusted fat intake (residual method).

Conclusions: We found no significant association between the amount or type of dietary fat and subsequent weight change in this large prospective study. These findings do not support the use of low-fat diets to prevent weight gain."

Note: -1.30g/y means that as dietary fat intake increased, weight decreased.

Cholesterol And Coronary Heart Disease

Cholesterol & coronary heart disease are mentioned a lot in the media. Unfortunately, most of what you see & hear is either completely wrong, or dumbed-down so much that it's inaccurate.

Fat & cholesterol don't stick to the insides of artery walls like grease on the inside of a drainpipe. This article explains what cholesterol is, how arteries get blocked and how to minimise the risk of having a heart attack or ischaemic stroke.


What is cholesterol?

Cholesterol is a large, waxy molecule (C₂₇H₄₅OH) consisting of a hydrocarbon (fat-soluble) tail, a middle section consisting of four carbon rings (the steroid bit) and an alcohol (water-soluble) group on the end. Cholesterol is a powerful anti-oxidant and is what bile acids, mineralcorticoids, glucocorticoids and sex hormones are made from.

Cholesterol is "chauffeured" around the body in lipoprotein "limousines". Lipoproteins are lipo (fat-soluble) at one end, protein (water-soluble) at the other end and they form a spherical shell around their contents with the lipo end pointing inwards and the protein end pointing outwards. The shell is like the body of the limousine. In the shell, there are apo(lipo)proteins which are like the chauffeur, as they determine where the particles are taken up. HDL has apo A in its shell which makes it get taken up by receptors in the liver. LDL has apo B in its shell which makes it get taken up by receptors in cells, artery walls etc. The passengers are cholesterol, cholesteryl esters, phospholipids and triglycerides. These limousines have different types, like chylomicrons, VLDL, LDL, IDL & HDL, the difference being the type & amount of apo(lipo)protein and the relative proportions of cholesterol & the other passengers. There are also sub-groups of each type.

The different variants are affected by serum triglycerides. High serum triglycerides (caused by a chronic over-consumption of sugary & starchy carbohydrates for activity level) result in cholesterol-depleted, triglyceride-rich particles and low serum triglycerides result in cholesterol-rich, triglyceride-depleted particles. As cholesterol is a powerful antioxidant, small cholesterol-depleted particles (Type B) oxidise faster than large cholesterol-rich ones (Type A).

Oxidised LDL particles are "bad cholesterol" and are swallowed by scavenger macrophages. These expand into foam cells, which become embedded in the intima of artery walls. Other processes occur which cause cholesterol & calcium to accumulate as a plaque inside the media of artery walls. To see a cross-section through an artery wall, click HERE and scroll down to the bottom of the page. Unoxidised LDL particles are not swallowed by scavenger macrophages, so unoxidised LDL particles are not "bad cholesterol". In young people, plaques of cholesterol with no calcium can accumulate within artery walls, making Coronary Artery Calcium (CAC) scans ineffective. See Stenosis Can Still Exist in Absence of Coronary Calcium.

Plaques force the inner artery wall inwards, making the artery narrower, impeding the flow of blood through it. This can cause angina pectoris (pain in the chest) as the heart is starved of oxygen, or vascular dementia as the brain is starved of blood. The cap covering the plaque may rupture, causing chunks of plaque to circulate and block coronary arteries (causing a heart attack), or cerebral arteries (causing an ischaemic stroke).

It's possible to reduce serum triglycerides significantly by eating lots of long-chain omega-3 fats from oily fish. These inhibit the conversion of glucose into triglycerides. Inhibiting the conversion of glucose into triglycerides can result in increased blood glucose levels (not good - see below) if sugary/starchy carbohydrate intake is too high. Solution? Reduce sugary/starchy carbohydrate intake to suit activity level.


Why do foam cells embed themselves into the intima of artery walls?

Arteries are elastic, muscular tubes which stretch a bit each time the heart pumps and contract again between beats. They also relax & constrict to control the flow of blood through them. When you get cold, they constrict to reduce the flow of blood to the skin to prevent excessive heat loss. When you get hot, they open to increase the flow of blood to the skin to increase heat loss.

Foam cells don't go just anywhere. They embed themselves into damaged areas of artery walls. This is a good thing, otherwise damaged artery walls could rupture, causing a haemorrhage.


What damages artery walls?

Chronically-high blood pressure.
Chronically-high blood glucose.
Chronically-high blood free radicals.
Chronically-high blood homocysteine.
Chronically-low blood antioxidants.
Chronically-high blood pro-oxidants.
Chronically-low blood anti-inflammatories.
Chronically-low Vitamin K2.
Chronically-high LDL due to hypothyroidism or other factors.


How can I reduce damage to my artery walls?

1) Have blood pressure (BP) tested regularly. There's one problem with having your BP taken in a GP's surgery and that is 'white-coat hypertension' where the stress of having your arm squeezed by the cuff sends your BP up! If you buy your own BP monitor (Lloyds pharmacy sell a fully automatic BP monitor with standard cuff for £9.99), you can become accustomed to using it and overcome white-coat hypertension. 5,000iu/day of Vitamin D3 can reduce BP by making artery walls more elastic. 4g/day of Epsom Salts provides 400mg/day of Magnesium, which acts as a smooth muscle relaxant, reducing BP & cardiac arrhythmias.

2) Have blood glucose (BG) tested regularly. If you're lucky, you may be able to get a HbA1c test. This shows accumulated damage to red blood cells by blood glucose.

3) Don't smoke! Apart from lung cancer, chronic obstructive pulmonary disease & emphysema, smoking speeds the oxidation of LDL.

4) Take a B-complex containing B6, B12 & folic acid, which lowers serum homocysteine levels.

5) Eat a diet rich in anti-oxidants from coloured veggies (beta-carotene), fruits (Vitamin C + bioflavonoids), tomatoes (lycopene), nuts & seeds (gamma-tocopherol & copper), Brazil nuts (selenium), beer/wine in moderation (muscle relaxant), green tea (polyphenols), cocoa/dark chocolate (polyphenols & copper), onions/garlic (quercetin) etc. See Antioxidant state and mortality from coronary heart disease in Lithuanian and Swedish men: concomitant cross sectional study of men aged 50.

6) In men and non-menstruating women, too much iron in the blood relative to copper is pro-oxidant, so don't supplement with iron. Menstruating women have the opposite problem.

7) Take about 2g/day of long-chain omega-3 fats from oily fish, or about 20g/day of flaxseed oil if male, or about 10g/day of flaxseed oil if female. Please note that tinned tuna contains virtually zero omega-3 fats. See Clinical nutrition: 4. Omega-3 fatty acids in cardiovascular care.

8) Eat a diet rich in Vitamin K2, to make calcium go into bones & teeth, instead of into artery walls, kidneys & brain. For good sources of Vitamin K2, see HERE. Note: Warfarin/Coumadin works by depleting Vitamin K, so lots of Vitamin K2 makes Warfarin/Coumadin ineffective.

9) If you're feeling tired and are gaining weight for no obvious reason, get serum thyroid hormone levels tested (TSH, FT4 & FT3 preferably), as low thyroid hormones down-regulate LDL receptors, resulting in LDL particles lingering in the blood for longer than usual. This increases LDL-C, LDL-P (particle count) and the oxidation of the particles. See Neovascularization of coronary tunica intima (DIT) is the cause of coronary atherosclerosis. Lipoproteins invade coronary intima via neovascularization from adventitial vasa vasorum, but not from the arterial lumen: a hypothesis.


What about Benecol & Flora Pro-Activ?

These yoghurts & spreads contain plant sterols/stanols, which reduce total serum cholesterol by up to 15%. However, LDL quality is more important than LDL quantity (up to a point) and there is no evidence that these foods save lives.


What about statins?

Statins (HydroxyMethylGlutarate Coenzyme-A Reductase inhibitors) reduce serum cholesterol. They also have anti-inflammatory & anti-clotting effects by reducing levels of the non-sterol derivative mevalonate and subsequent products. Click HERE to see the cholesterol synthesis pathway. Statins save lives in people who have had a heart attack and in men between the ages of 30 and 60. However, younger & older men and women do not get a significant reduction in deaths, (though heart-attack deaths may be reduced) and there can be undesirable side-effects (muscle pains, memory loss etc). I strongly recommend that anyone taking statins, supplements with at least 100mg/day of Co-Q10, as the synthesis of this vital substance is reduced. Note that fish oils have anti-inflammatory, anti-clotting and anti-arrhythmia actions, but don't suppress the production of Co-Q10.


What about dietary cholesterol?

When cholesterol is eaten, the liver produces less cholesterol. An average egg contains about 250mg of cholesterol. The vast majority of people (who don't have genes for familial hypercholesterolaemia) can eat two eggs a day without significantly affecting their serum cholesterol & triglyceride levels. See Effect of dietary egg on human serum cholesterol and triglycerides, and Eat Whole Eggs All Day and Throw Your Statins Away? 375x Increased Dietary Cholesterol Intake From Eggs Reduces Visceral Fat & Promotes Healthy Cholesterol Metabolism. People with the ApoE4/E4 polymorphism are more sensitive to dietary fat & cholesterol raising serum LDL, and cannot eat fat & cholesterol willy-nilly.

There are a couple of sites that have CVD risk calculators, JBS2 and QRISK®2-2013. The National Institute for Clinical Excellence (NICE) no longer recommends the use of JBS2, as it's overly-pessimistic. Note that CVD mortality isn't the same thing as overall mortality. Slightly higher-than-"normal" total cholesterol level is associated with lower overall mortality, according to Research finds ‘raised’ cholesterol to be associated with a reduced risk of death.