Friday, 19 September 2014

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.
This is a diagram of a chylomicron or VLDL-c (high TG/C ratio) 'cos I couldn't find one for LDL-c!

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 (see image below), it's advisable to keep cholesterol synthesis to a reasonable level by keeping fat intake to a reasonable level (i.e. not Nutritional Ketosis!) and keeping LDL particle size to a reasonable level by keeping added sugar (e.g. sucrose & fructose) intake and rapidly hydrolysed/overcooked starches (e.g. amylopectin & maltodextrin) intake to a reasonable level (i.e. a level that's oxidised by the body without having a chronic excess). An acute excess of carbohydrate can be stored as liver/muscle glycogen, provided that mean carbohydrate intake is less than mean carbohydrate oxidation.

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


Babs Hogan said...

Nigel, as always, I find your articles useful and sometimes entertaining.

billy the k said...

A. "LDL-P (particle number) ∝ LDL-C (total amount of cholesterol)"
B. "LDL-P (particle number) ∝ 1/LDL size³"

Q (1): Do you think that A  [above] has greater or lesser or equal importance than does B with respect to the initiation of atherosclerosis?

"As it's LDL particle number that determines the infiltration of LDL cholesterol into the media of artery walls..."

Q (2):  Do you think that Chris Masterjohn's alternative view has any merit?—i.e., are you satisfied that the LDL particle number per se determines the infiltration?

[Masterjohn's alternative view]:

"...the depiction in Forks Over Knives is misleading.  It gives the audience the impression that a high concentration of cholesterol is the prime mover in atherosclerotic progression, when in fact the prime mover in the initiation of plaque is the oxidation of lipids and the immune system's effort to protect the blood vessel from these oxidized lipids, and the prime mover in coronary occlusion is the inflammatory process that degrades the plaque, causing it to rupture and re-heal."

Anitschkov considered one of the defining characteristics of his theory of atherosclerosis to be that it considered atherosclerosis infiltrative
instead of degenerative.  He focused on the amount of cholesterol, as did Ahrens and Steinberg after him.

However, our understanding of the molecular mechanisms of atherosclerosis has progressed dramatically since his time, and we have definitive evidence that it is degeneration of lipids rather than their high concentration that drives atherosclerosis.

"I propose a new terminology to distinguish between these two related but fundamentally different hypotheses:

The infiltrative lipid hypothesis
is the hypothesis of Anitschkov, Ahrens, Steinberg, and the medical establishment, focused on the amount of cholesterol in the blood driving its infiltration into the arterial wall, and considering this infiltration to drive any subsequent degeneration.

The degenerative lipid hypothesis
is the hypothesis that considers the amount of cholesterol largely or perhaps entirely irrelevant, and considers the degeneration of lipids in the blood to drive their infiltration into the arterial wall, and this infiltration to actually be partly protective against worse forms of degeneration that would have occurred in its absence."

What do you think about this alternative explanation?

Nigel Kinbrum said...

A1. It's difficult to say. Dr Dayspring said that if LDL-C is extremely high, LDL-P becomes irrelevant.

A2. I subscribe to LDL-P and LDL-C are both relevant to the RR for CHD.

billy the k said...

Nige, it's true that LDL-P and LDL-C are both relevant to the relative risk for CHD, but doesn't the author of your linked article dismiss the importance of this relevance here?:

[p.5]  "High levels of LDL are an important risk factor... however, the statement that high levels of LDL are the main cause of coronary atherosclerosis is inconsistent with established medical concepts."

And here:
[p.6]  "...the fact that lowering LDL levels does not prevent cardiac events in 60-70% of individuals at risk contradicts the causative role of LDL. Unfortunately, it appears that the scientific and medical communities are focusing on and emphasizing biomarkers that can predict risk, without proof that these biomarkers cause the risk."

Also his "hypothesis" statement:
[p.2] "Neovascularization of the normally avascular coronary DIT [diffuse intimal thickening] by permeable vasculature from the adventitial vasa vasorum is the cause of LDL deposition and CA. DIT enlargement, seen in early CA and aging, causes hypoxia of the outer DIT and induces neovascularization. According to this alternative proposal, coronary atherosclerosis is not related to inflammation and can occur in individuals with normal circulating levels of LDL, consistent with research findings."

"...can occur in individuals with normal circulating levels of LDL..."

[i.e., "normal levels"—that is: NOT "high levels of LDL"—isn't this hypothesis saying here  that the LDL particle number per se does not determine the infiltration?]

True, it is the lipoproteins that do invade the coronary intima, but these statements from Subbotin's article do not seem to 
point to the necessity of taking care to reduce one's LDL particle numberin order to avoid coronary atherosclerosis—i.e., via rigorous daily monitoring of one's intake of saturated fats & sugars & fast starches—especially this statement on p. 17:

  " logically follows that since the presence of LDL-C in plasma is a fundamental metabolic requirement for humans,  theoretically there is no “safe LDL-C level” that would be 100% certain to prevent coronary atherosclerosis if intimal neovascularization has already occurred."

billy the k said...

And—unless I'm mistaken—the LDL's themselves do not cause the DIT enlargement that in turn causes the hypoxia that induces neovascularization as an adaptive response.

Nigel Kinbrum said...

I think that infiltration of LDL (also Ca) into the media impedes the diffusion of O2 from the adventitia to the intima, and the resulting hypoxia in the intima induces neovascularisation.

billy the k said...

Q "Why does arterial tunica intima become neovascularized in the first place?"

A  Because "...the cells in the coronary tunica intima possess inherently high proliferative capacity...[so that] these cells respond by proliferating to any stimuli, exogenous or endogenous...Regardless of the nature and magnitude of stimuli/insults, cells that appear in the arterial intima compartment...always proliferate in response."

Now note: those various stimuli and insults that induce the intimal proliferation—that according to his hypothesis initiate the whole atherosclerosis process—do not include LDL's because "...the outer DIT does not have direct contact with the blood, and interaction with LDL-C is PREVENTED by diffusion distance and the properties of this molecule (20nm)."

∴   It is not LDL particle number that determines the infiltration of LDL cholesterol into the media of artery walls.

Oui?  Non???

So while I still don't buy the ubiquitous view [dietary sat fat →↑LDL-C →invasion of arterial wall/atherosclerosis], I do like your other candidate for initiating the "insult"—and which remains compatible with the "neovascularization hypothesis"—b>calcium.

Takuo Fujita has written several papers which have persuaded me that the initiating culprit in atherosclerosis—and a slew of the other diseases of aging—could very well be what he called "the calcium shift phenomenon": i.e., the process that leads to the deposition of calcium into the soft tissues:
"Calcium deficiency is a constant menace to land-abiding animals, including mammals...Low calcium and vitamin D intake, short solar exposure, decreased intestinal absorption, and falling renal function with insufficient 1,25(OH)2 vitamin D biosynthesis all contribute to calcium deficiency, secondary hyperparathyroidism, bone loss and possibly calcium shift from the bone to soft tissue, and from the extracellular to the intracellular compartment, blunting the sharp concentration gap between these compartments. The consequences of calcium deficiency might thus include not only osteoporosis, but also arteriosclerosis and hypertension due to the increase of calcium in the vascular wall, amyotrophic lateral sclerosis and senile dementia due to calcium deposition in the central nervous system, and a decrease in cellular function, because of blunting of the difference in extracellular-intracellular calcium, leading to diabetes mellitus, immune deficiency and others."

Also here:

[it's a big reason why I aim to get some sun & have at least a quart of milk—or it's equivalent— a day]

Nigel Kinbrum said...

There's a link in my post on Cholesterol & Coronary Heart Disease to Eddie Vos' site

At the bottom of the page is

Calcium is in the same place as cholesterol crystals. This suggests that it's both Calcium AND cholesterol that can accumulate and "bung-up the works" in the media.

Nigel Kinbrum said...

Sorry it took so long to approve your first comment, but I mistakenly thought that I'd already white-listed you. I have, now!