Arteriosclerosis (4) GAG and sudden death

The process for the development of arteriosclerosis, as put forward by Duguid, is that repetitive stress to the arterial wall produces damage which is patched by a microthrombus. This then covers with epithelium and organises in to what is essentially a scar used to strengthen the arterial wall exactly where this is needed.

Here are a few micropgraphs of Duguid's showing microthrombus on the arterial wall, again taken from his monograph The Dynamics of Arteriosclerosis.





These require frozen sections, formalin fixing and paraffin wax embedding will tend to lose microthrombi or convert them to "gunk" in the lumen of the artery.

Willis used ascorbate deficiency in Guinea Pigs to produce pressure induced trauma (unfortunately without histopathology) and Coulson and Carnes (thanks Stephan) used copper deficiency to produce elastosis lesions, both probably allowing easy intimal damage and subsequent need for repair. In fact the frank adventitial haemorrhage of copper deficiency looks to be a rather extreme model of what actually occurs in apparently normal humans. But the elastosis is there at the start...



Now the processing of thrombus to collagen is just that, a process. It doesn't simply "happen". So the very obvious question is what happens when the process goes wrong?

Unhappily there are a number of mucopolysaccharide storage diseases which result from the inability to degrade proteoglycans. If you cannot degrade proteoglycans but continue to produce the microthrombi, as suggested by Duguid, you might expect some accumulation of mucopolysaccharide in the walls of stressed arteries.

Here is a nice picture (part B) from this paper of the coronary artery of a young child who died of complications of this genetic defect. You might accept that there is some narrowing of the lumen.



There are a number of factors under our control which seem to influence our ability to obstruct our arteries with the sequelae of microthrombi, some of which I'll get to eventually. I happened on this fascinating acount of sudden death in young fit adults.

This condition is usually associated with abnormal cardiac rhythm, particularly sudden onset ventricular fibrillation. Obviously making your salad dressing with sunflower oil is probably your best risk factor for throwing serious cardiac rhythm abnormalities, but developing an ischaemic atrioventricular node seems to be an excellent trigger for local hypoxia to start the fibrillation. Stenosis of the micro artery to the AV node appears to be a feature of sudden death in young males.

I don't have access to the full text so I don't know what the histology pictures look like. I'm a bit suspicious that the changes will turn out to be merely those which any numpty with internet access can down load from Pubmed, in papers going back 60 years.

The terms in the abstract are "dysplasia" and "nonatherosclerotic" and "mucopolysaccharide deposition". Hmmmmmmmmm........

It really brings home the utter ignorance of cardiologists working under the cholesterol paradigm. BTW, does anyone have access to the pictures? It would be nice to have them here... Assuming they look as I think they do!

Peter

EDIT: The pics are here, thanks Anna.

Arteriosclerosis and the breeder rat

Ok, another picture show I composed off line. I'm home next week but there is a lot to do other than use Tinternet. This one is from Wexler's 1964 paper "Spontaneous Coronary Arteriosclerosis in Repeatedly Bred Male and Female Rats". BTW anyone reading it carefully might be tempted to add celibacy to any program of heart health protection. Personally I suspect this is not necessary. Too late now anyway!

Let's look at old rats. If you feed rats a 5% fat diet, with the fat as "heart healthy" corn oil, you can actually make Dean Ornish look like a gourmand.

These rats are old. They are ex breeding rats. They do not have cholesterol poisoning and their diet has been specifically chosen, under a mistaken paradigm, to maximise health, longevity and breeding success.

If you eliminate the impatience of a cardiologist and wait for the rats to age, what do their coronary arteries look like? Bear in mind that rats are supposed to be resistant to arteriosclerosis (But that is probably only at the age a cardiologist can be persuaded to wait until).

First picture is an artery deep in the myocardium. This is where the disease begins in rats:



Notice the contorted internal elastic membrane between the arrows. The elastic lamina is thickened with mucopolysaccharide. There is a neat intimal cushion overlying this area. There is, err, no cholesterol. Oddly enough cholesterol does not seem to rupture elastin fibres! Like Lp(a), the LDL particle would have to carry that flick knife... Which it doesn't.

Next is an epicardial artery. These arteries, especially the left anterior, are particularly interesting because they are not supported by surrounding myocardial muscle so the artery wall is particularly pressure challenged. Apart from the appearance of multiple endothelial cushions overlying shredded elastin there are also dark black areas of "gunk" on the right hand arterial lining area of the artery. These stain positive for calcium.

There is, err, no cholesterol.



Just for fun the authors took another section from the same tissue block as was used for figure 6 and stained it for mucopolysaccharide. The section is nearly identical. This, here in figure 7, clearly shows the extent of the abnormal intima. No cholesterol. Strange that.



Do these rats get ischaemic disease? You bet!



The myocardial necrosis lesions, which are common, do not appear to be directly related to the diseased large arteries. They certainly make me think of Kurt's posts here and here on myocardial damage in marathon runners. The mice don't run, but they do carb load each and every meal. They have no choice. Carbs or starve. To me this suggests that it might actually be the diet used by marathon runners which kills them, rather than the running per se. Though the chronic cardio might well do a great deal of damage to the elastic intima due to the stretching needed to accommodate the high flow generated. But possibly they just eat rather more crap than normal human beings do. Just an idea.

It also begs the question of why cardiologist keep thinking that the cholesterol fed rat (or the equally poisoned Syrian hamster) has anything to do with human arteriosclerosis.

Peter

For the low fat brigade

Still no significant net time and this is not likely to change in the next few weeks, sorry for emails being ignored....

In the mean time folks might enjoy this from Dr Volek. It didn't seem to make headline news, can't imagine why.

Personally I would be loathe to take dietary advice from an AHA cardiologist who stands to benefit from my having a heart attack. They are unlikely to be completely honest.

Peter

Do chylomicrons clog your arteries?

The oral fat tolerance test (OFTT) challenges with a fixed dose of a fixed type of fat. It is very important that the type of fat used and the dose given remains consistent throughout a given study. It tells us completely different things to comparing the chylomicron response to oral loads of differing fat compositions. With a fixed dose of constant fat composition we are then specifically looking at the ability of an individual to use or store fat in general.

The rise in triglycerides after an OFTT is actually chylomicrons (I'll use this term from here on) and gives us an idea of how good we are are putting fat in to use or storage. If we take any standard american chap and make him eat a standardised fat load there will be a surge of chylomicrons in his bloodstream, starting at a couple of hours after eating and going on for a few more hours.

So what determines the size of the rise in chylomicrons? As Dr Volek has pointed out, a ketogenic diet for six weeks markedly reduces your chylomicron concentration after an OFTT, ie you clear the chylomicrons from your blood stream more rapidly. This should hardly be surprising. If you have been in ketosis for 6 weeks you are hardly going to be running your metabolism on sugar. Fat comes in, fat gets used. But it still has to be transported.

How do we transport bulk fat from our gut to our butt? Dietary fat (medium chain triglycerides excepted) is ALWAYS transported in bulk as chylomicrons. "Regulated" fat, for metabolic needs, is ALWAYS transported as free fatty acids. These FFAs can be attached to albumin as their transport molecule in the plasma or can be accessed directly from chylomicrons via lipoprotein lipase, at the sites on the vascular wall where FFAs are needed by the tissues. But we can never transport all of a bulk fat meal as free fatty acids. Even when we are in ketosis. In ketosis we clear our chylomicrons faster because we are using a lot of fat. But we can never get rid of them altogether.

So if apoB48 containing chylomicrons kill, then fat kills. Post prandial chylomicrons kill. Even ketogenic diets kill. Eat anything to generate chylomicronaemia above 100mg/dl and you can kiss your coronary arteries goodbye. Gulp.


But how do we actually know that chylomicrons kill? From Denmark of course. Land of the Danish Pastry.

Denmark hosts The Copenhagen Heart Study. Just take 13,981 people, measure their non-fasting chylomicrons (described as "remnants"), record the results and watch who dies of heart disease and all cause mortality (bit risky that last one, but cardiologists were so naive back in the 70s) over the next 30 odd years. If chylomicrons kill, the higher the chylomicron count after a random meal, the more people should die, especially of heart disease.

Here are the "event" and death Hazard Ratios for men. Women are similar if not worse:





Random chylomicrons after a routine Danish breakfast or lunch are going to kill you. Heart disease. ApoB48. Simple. QED. Convincing enough to a cardiologist!

Woooooaaaaah, just a minute. This is observational. What are we observing? We are observing a group of people and they looked like this when they entered the study:





Look at hypertension incidence, diabetes incidence, physical inactivity prevalence and BMI splurge. All increase across rising chylomicron quartiles! Chylomicrons even make you smoke! They don't seem to make you alcoholic, a little disappointing that last one.

And you just thought apoB48 just caused heart disease!

Does anyone recognise the metabolic syndrome in these patient characteristics? Well I think that the size of your chylomicron surge after an average Danish pastry is determined by how far in to metabolic syndrome you are. However, the authors corrected for all of these factors and STILL chylomicrons kill.

The baseline characteristics recorded were crude in the extreme. Heavy drinking is defined as more than one drink a week (drinking two or more times a week is heavy)! But the fascinating one is diabetes. The definition of diabetes is anyone self reporting themselves as such, anyone who mainlines insulin (perhaps some body-builders got accidentally included here?), sulpha drug usage or having a random post prandial glucose above 11mmol/l.

Quick repeat: Anyone randomly detected with a blood glucose over

200mg/dl

(actually, over 198.2mg/dl) was classed as diabetic. Perhaps they missed a few diabetics in their multifactorial adjustments! But perhaps they don't think hyperglycaemia has anything to do with heart disease.

We know from Volek that if you eat a ketogenic diet your OFTT "improves". I'll just say that again. Elevated chylomicrons levels after a fat challenge reduce if you have been eating a VERY high fat diet. I think it is a reasonable extrapolation to say that a high carbohydrate diet might worsen OFTT results.

So in Denmark a high post prandial chylomicron count, which can be viewed as a surrogate marker for the metabolic syndrome, correlates positively with your risk of heart disease. The hallmark of metabolic syndrome is hyperinsulinaemia. If that hyperinsulinaemia is inadequate to maintain normoglycaemia in the face of carbohydrate consumption then HbA1c rises and other nasty hyperglycaemic stuff happens. And the bulk fat transport gets the blame. Certainly in Copenhagen and perhaps other places too!

Let's stop bashing those poor apoB48 molecules.

Peter

As on a number of other occasions, thanks to Dr Davis for pointing to both of these studies even if I completely disagree with his interpretation of what is happening in Copenhagen. Lipophobes have such strange yet fascinating ideas. But then I love Goth stuff too.

Butter, insulin and Dr Davis

Sigh. Okay, here we go. It's the weekend and I'll correct the typos when I get chance! Better read Dr Davis' post here here to get the lie of the ground before reading this post. Now, before we get to the Spanish study, let's look at the insulogenic effect of cream (the closest I can find to butter in a study which, unlike the Spanish study, controlled its variables). Please bear in mind that cream contains small amounts of both casein and lactose. So does butter. BTW look what casein does to insulin. But it doesn't budge glucose levels (they should drop!) so there has to be a counter regulatory system here, glucagon was not measured. It's not relevant to the role of palmitic acid in the Spanish study, but it's interesting never the less. Taken from Dandona's paper here. This is the effect of 300kcal of cream (equivalent to about 30g of butter) or the equivalent in casein calories: Okay, on 300kcal of cream alone insulin "spikes" from 39.6pmol/l to 49.2pmol/l at 1h (remember the casein and lactose?) and then insulin drops below baseline at 2h and 3h. During this period there will be palmitic acid in to the blood stream and muscles. Palmitic acid is the primary metabolic signal to switch from glucose burning to fat burning. Because essentially zero carbohydrate is supplied with cream there is neither a rise in blood glucose or in insulin. The Spanish study uses about 40g of carbohydrate (22% of about 800kcal) with their fat load. It gets eaten along side just under 60 grams of fat or oil. The rise in glucose is trivial for all groups. It is neither statistically nor biologically significant. We can ignore it. Now, let's look at insulin. The full figure and caption is here Butter is the black squares. Obviously, the best meal for minimising insulin response is the control meal. That's the one with round dots. That's the one we should eat to maximise weight loss, if it is a simple matter of minimising insulin! Ah, but the control meal is 40g of carbohydrate and no fat at all! Eating just 40g of carbs before an eight hour fast drops your insulin levels all right, this is starvation! But does it allow weight loss? Calories in, calories out, 40g of carbohydrate is only roughly 170kcal. To answer this we have to look at the free fatty Acids (FFAs): The study started with FFAs around 500micromol/l in all groups. The carb-only 40g snack DROPPED FFAs from fasting levels of 500micomol/l down to 150micomol/l at 2hours and it took until 5 hours for FFAs to get back up even close to the fasting levels seen at the start of the experiment. After a 40g fat-free carbohydrate "snack" the only source of FFAs is lipolysis and we can say that the small 40g carb snack blunts lipolysis, and so weight loss (rather I should say fat loss), for 5 hours! And you're hungry too. Now the butter group produced the least fall in FFAs while the insulin was elevated from the carbohydrate and also allowed the most sustained rise in levels of FFAs once the carbs were dealt with. The FFAs were still significantly elevated at the end of the study. The area under the curve for chylomicrons (no VLDLS involved in this study) is also bigger and peak chylomicron-triglyceride level is higher in the butter group than after any other fat meal. Butter provides palmitic acid which is the physiological signal to switch from using glucose to using fat. It also provides medium chain triglycerides which will produce ketone bodies for a few hours, which also produce physiological insulin resistance and a rise in insulin in their own right. So in the presence of 40 grams of carbohydrate extra insulin is need to maintain normoglycaemia. The insulin should inhibit lipolysis. It certainly does in the 40g carbohydrate snack group! What about the butter group? The butter provides plenty of FFAs to run metabolism on and storing some calories is no big deal. But does this insulin effectively store calories? What if the adipocytes become physiologically insulin resistant with palmitc acid in exactly the same way as muscle cells do? You know, my mantra: The function of insulin is the inhibition of lipolysis. This study makes it look as if it is not quite that simple. In fact, you have to ask some interesting questions about exactly where all of these FFAs come from and where the chylomicrons go to. ALL of the fat meals provided the SAME number of fat calories, but the FFA levels in the butter group where ALWAYS higher than other fat meal groups, even before chylomicrons levels became different between groups. Now, FFAs do not pop in to existence merely to prove that butter is going to kills us through obesity. They come from SOMEWHERE. And chylomicrons. These are lower in the oil meal groups than in the butter meal group. Where are the chylomicrons going to? Because all fat based meals provide the same number of fat calories then either: a) the butter group has to be allowing more lipolysis from adipocytes or from chylomicrons to get those extra FFAs. Lipolysis means fat loss. or b) the non-butter groups are allowing more fatty acid storage and less FFA release. Insulin sensitive fat cells store fat! Low FFAs means less fat release. You CANNOT burn fat without lipolysis! As I see it butter produces sustained chylomicronaemia. The chylomicrons are used to provide FFAs to run metabolism on rather than going in to storage. There is no hyperglycaemia to glycate apoB48s, so who cares if they hang around. Either they (or possibly adipocytes) are supplying energy. Oil based meals can only produce lower levels of chylomicrons if they are storing the chylomicron fat ON YOUR BUTT and lowered FFAs means the INHIBITION of lipolysis from chylomicrons or from YOUR BUTT. There is no other explanation that I can see, whatever the insulin levels are. Take you pick. More fat gain and/or less fat loss: The gift of olive oil! To summarise: Insulin controls bodyweight. Physiological insulin resistance modifies this. Of course if you think apoB48 was evolved to kill you, run from the butter and knock back the vegetable oil/fish oil combination. Maybe cut a few calories too! Me, I'll stick to FFAs and butter as my energy source. Peter BTW 40g is close to the total daily carb intake for a reasonable LC diet. After that it's fat on its own and, as we all well know, fat on it's own causes ZERO insulin spike and allows FFA run metabolism where fat can be both stored and accessed freely. Okay, add a little protein somewhere along the line.

Statin plus fibrate sucks

Haven't read the full paper yet but the abstract says it all: Extra lipid lowering does nothing to alter the trivial benefits seen with statin therapy.

"Conclusions The combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events, nonfatal myocardial infarction, or nonfatal stroke, as compared with simvastatin alone. These results do not support the routine use of combination therapy with fenofibrate and simvastatin to reduce cardiovascular risk in the majority of high-risk patients with type 2 diabetes."

IT'S NOT THE CHOLESTEROL

EDIT from the full text, it's not the triglycerides either. Why not just eat less sugar as per Nigel's comment? Simple but scary! To me this is pretty convincing that trigs are harmless, they are a surrogate for carbohydrate/fructose...

Peter

Paradox: Obesity and heart failure

Just taking a break from the busy stuff going on away from the blog. This paper deserves a brief comment. Here is a mainstream discussion, thanks Elizabeth. [And here is the text for when the blog link goes down].

To begin:

"Being skinny confers no advantage when it comes to the risk of dying suddenly from cardiac causes"

That lead statement about being skinny is somewhat misleading. A 99% increase in risk is not quite neutral....

So how does a lipophile see this paradox?

Well, the first thing is that the population is pre-selected. They have (a) had a heart attack and (b) have cardiac muscle wastage.

It's a little pointless going through the detail of the studies linking hyperglycaemia to heart disease when Jenny Ruhl has very neatly collated the studies that matter. I have mentioned the role of hyperglycaemia in cardiac muscle apoptosis before. Ischaemia and apoptosis is a great recipe for heart failure.


So we can reasonably describe this population as a set of people who have been routinely achieving post prandial blood glucose levels in excess of 8.0mmol/l, ie about 140mg/dl, almost certainly for years.

How they have achieved this seems unimportant, what matters to me is that by definition this is a group of recurrently hyperglycaemic people. Their LDL cholesterol level is of no interest and, thankfully, does not get mentioned here.

Why do the skinny people do so badly?

These people are skinny. They don't eat huge amounts of calories, but what they do eat spikes their blood sugar. They may well not be hyperinsulinaemic. After all, they are not squirreling away fat and they are allowing their blood sugar to rise... Those suggest, if anything, a blunted insulin response. Is someone with a BMI of 21, who has just had a heart attack, going to set out to lose a serious amount of weight? No, I doubt it. Cutting the fat would probably be the standard advice, obviously cutting saturated fat specifically. But backing off on fat (that scary stuff which Ancel Keys told us causes heart attacks, and cardiologists still believe him!) will invariably lead to increased carbohydrate intake. We know these people already develop post prandial hyperglycaemia. Low fat means more hyperglycaemia. Hyperglycaemia = death.

What about the healthier fatties?

Obviously these people are recurrently hyperglycaemic too, again because they are in the same cardiovascular situation as the skinnies. But they must have been eating a bit more of everything in the past than the thin people. They have to have eaten more to (a) eat enough calories to move themselves around, (b) eat enough calories to provide enough for their basal metabolic rate and (c) eat enough fat to go in to storage in their adipocytes.

However, they do have considerable scope for weight loss and ANY reduction in calorie intake is likely to reduce carbohydrate calories somewhat, as well as fat calories. The two tend to go together. Any decrease in carbohydrate calories will reduce hyperglycaemia in a person who is proven to develop post prandial hyperglycaemia.

Even cutting fat can be good. Less omega 6 PUFA and less trans fats from the diet, both of which, during weight loss, get replaced by an excellent mix of saturated fat with some mono unsaturated fat from butt fat. Butt fat, once again, is an excellent and healthy source of calories.

I have no idea whether surviving a heart attack and having a pacemaker implanted in your chest might make you think about losing a little weight if you are officially obese. Perhaps it concentrates the mind a little. Or maybe overhearing what the doctor's skinny receptionist called you when she thought you were out of earshot might help!

Obesity should become protective when someone starts to use their stored fat, because human adipose tissue is a health resource which can usefully replace anything with a heart-healthy logo on its plastic wrapping. It doesn't spike glucose! The more weight you have to start with, the longer it takes before the corrosive effect of a low fat diet kicks in. This kicks in when you stop losing weight!

If someone is losing weight on a low fat diet there will obviously come a time when weight loss stops and, at that time, they then simply join the ranks of the initially skinny low-fat eaters but, of course, a fair few of those will be dead by then....

Leaves some space in the queue I guess.

Peter

Getting fat is good: Official

This paper (thanks Elizabeth):

"Gluttony, sloth and the metabolic syndrome: a roadmap to lipotoxicity"
Roger H. Unger and Philipp E. Scherer

doesn't seem to be published yet, so I'm not sure if this will actually be the abstract:

"Once considered divine retribution for sins, comorbidities of obesity (metabolic syndrome) are today attributed to obesity-induced metabolic defects. Here, we propose that obesity and hyperleptinemia protect lipid-intolerant nonadipose organs against lipotoxic lipid spillover during sustained caloric surplus. Metabolic syndrome is ascribed to lipotoxicity caused by age-related resistance to antilipotoxic protection by leptin.

"The wrath of God came upon them, and slew the
fattest of them. . ." 78th Psalm, Verse 31."



Great start, even I have to admit. It gets better.

I got as far as the this diagram before having to stop. Head banging is fine for rock concerts, not so good on a hard desk.

Why are Texans so fat? According to Messrs Unger and Scherer:




Woo hoo! It's gluttony and sloth. With the number of guns that there are supposed to be in Texas (I wouldn't really know) I'd be careful about throwing such generalised insults around! Though I guess insulting people in a scientific journal is a lot safer than doing the same thing in a bar in down town Dallas.

They are also, being diabetologist and/or obesity experts, utter lipophobes (see the bottom line and text of their illustration) and struggle manfully with trying to show lipids (and even, OMG, cholesterol) are directly toxic. As I say, these folks are not too bright. I doubt they would understand glucotoxicity if it kicked them in the pancreas. But then, they are probably both on a statin.

I briefly re drew their illustration for them:



I had to split the slide in two to fit in the basic cause at the top of slide 1!




The ability to confuse symptoms with causes is hysterical. They really should read Good Calories Bad Calories, but it might be a little technical (and dispiriting!) for them.


However the reason for this post is that we have, on page 3 under "Protective role of obesity", this AMAZING quote:

"Thus, we propose that adipogenesis delays, rather than causes, the metabolic syndrome induced by chronic caloric surplus."

This is ABSOLUTELY crucial. These people have finally gotten the message! And they are idiots! When a concept is so clear cut that even morons can see it, there really is hope for the world.

GOOD.





Then (thanks, Hege) there is George Bray. Bray is one of the architects of the current obesity epidemic. Probably believes in gluttony and sloth as Unger and Scherer do. Anyway, have a read at Michael Eades' post to find a little more about what Bray is like. If you haven't already got him on the list (come the revolution).

Bray is now blaming fructose for the obesity epidemic.

When dinosaurs move, well, there will be progress!

It's a good year so far!

Peter

Lipoprotein(a) and the Fairies at the bottom of my garden

Just a brief giggle. You recall that a reduced fat diet, packed with plant antioxidants raises Lp(a). Without the plant toxins it works even better to raise Lp(a). This paradox is explained by the immense power of the low fat diet to physically tear Lp(a) out of atheromatous plaque and place it in to the circulation in antigenically recognisable form. It's healing. Snigger.

This is powerful medicine. I don't know how many covalent bonds the lysines and glutamines in apo(a) have made to the lysines and glutamines in fibronectin. Let's say quite a few. But the low fat diet appears to be able to tear several hundred of these covalent bonds apart and then it reassembles the apo(a) molecule in to its original shape in the plasma. Gasp in awe. Well that's incredible.

So incredible that anyone who believes it does not realise what incredible means.

Incredible means unbelievable. Better not to believe unbelievable things. These are the believers who published (just a little name and shame here):

Silaste ML, Rantala M, Alfthan G, Aro A, Witztum JL, Kesäniemi YA, Hörkkö S.

and the believers who editorialised:

Mohamad Navab; Srinivasa T. Reddy; Brian J. Van Lenten; Alan M. Fogelman


Even the Fairies at the bottom of my garden tell me not to believe stuff this stupid!

Peter

Lipoprotein(a) and tissue transglutaminase

"Lp(a) levels are low at birth and rise significantly between 0 and 7 days post partum; in this newborn population, a continuous rise of the mean Lp(a) levels was observed until 180 days"

Well, that's it. The smoking gun of arteriosclerosis. As we know, arteriosclerosis is essentially non existent for humans in-utero and it starts soon after birth (in the 1950s anyway, we may do better at damaging unborn children nowadays). Lp(a) starts low at birth and rises soon after. You only need to be a cardiologist to see the obvious cause and effect here.

OMG it must be so embarrassing to realise that LDL-C has nothing to do with the process, it's been that nasty Lp(a) all the time!

So the obvious explanation must be that Lp(a) worms its way through the arterial endothelium and rips and tears the elastin fibres of the intima to shreds. Simple and utterly plausible. Probably carries a flick-knife.

Except for the tissue transglutaminase (TTG) issue.

We have all heard of this enzyme as an antibody-ligand when testing for coeliac disease, but what does TTG actually do?

Well there is an awful lot of information in this paper. This is what they looked at:

"Because of its intimate interaction with fibrin and/or cell surface oriented structures, we asked whether Lp(a) could be a substrate for transglutaminases (e.g. Factor XIII, tissue transglutaminase). These enzymes catalyze cross-linking between endo-gamma-glutaminyl and endo-epsilon-lysyl residues of proteins (16) resulting in irreversible homo or heteropolymerization of susceptible proteins."

Note the heteropolymerization. Hetero means mixed. If TTG really acts on Lp(a), it doesn't just bind it to more Lp(a), it will bind it to other TTG substrate proteins too. Many of the other TTG substrates are physically part of the cement between cells. Molecules like fibronectin.

"First, substrate specificity was compared with known transglutaminase substrates including fibronectin (17) and alpha 2-plasmin inhibitor (30) and substrates of poor or unknown transglutaminase susceptibility including IgG, alpha 1-proteinase inhibitor, and albumin. This showed that Lp(a) had amine acceptor qualities comparable to that of fibronectin and alpha 2-plasmin inhibitor where as IgG, alpha 1-proteinase inhibitor and albumin failed to incorporate significant amounts of DSC."

So Lp(a) will heteropolymerise with fibronectin:

"FXIII or tissue transglutaminase may catalyze cross-linking and deposition of Lp(a) to surface oriented structures (e.g. connective tissue matrix proteins) and/or cell surfaces."

If you are wondering what fibronectin really does, from wiki:

"fibronectin also binds extracellular matrix components such as collagen, fibrin and heparan sulfate proteoglycans" (as well as intergins). Oh, look, proteoglycans...

And integrins, from wiki:

"Integrins are receptors that mediate attachment between a cell and the tissues surrounding it, which may be other cells or the extracellular matrix (ECM). They also play a role in cell signaling and thereby define cellular shape, mobility, and regulate the cell cycle."

So TTG binds Lp(a), almost certainly to fibronectin, one the main proteins which glue our tissues together. Lp(a) is not randomly sticky. It is enzymatically and specifically integrated in to the matrix of exposed extracellular material in the wall of a damaged artery.

If we reject the hypothesis that Lp(a) circulates with an elastin-targeted flick-knife in its pocket, we can look at the specific and deliberate incorporation of Lp(a) in to a cross-linked network of tissue proteins. This looks like an emergency repair kit to me. Elastin is broken by mechanical stress. Birth, growth, pulsation of arteries, hypertension, relative movement of the supply artery against fixed arteries like the intercostals, branch points in arteries etc are all mechanical stressors. Broken elastin implies stretching of the artery beyond what the elastin will tolerate. Damage to the elastin comes with damage to the endothelium. Disrupted endothelium exposes extracellular matrix and needs a clot to patch it and the clot needs strengthening. An area of damage intrinsically means that the location was too weak. Adding some fibrous tissue and a stronger muscle around damage is an adaptive stratagem in an injury-disrupted provenly-weak arterial area.

Looking at Lp(a) as a repair kit you can make certain predictions, especially if the repair kit is rather helpful.

First is that not having any Lp(a) is bad. Well, we know that's the case.

Next is that having some Lp(a) is good, we know that too from the same graph.

If you are genetically well endowed (with repair kits) they will not show up as repair patches on your arterial wall unless you are actively damaging that arterial wall. ie High Lp(a), (genetic low kringle IV repeat numbers) means nothing if you are not damaging your arteries. Thanks to Kurt for that anecdote!

If you do lots of damage, you will need lots of repair kits. Lp(a) goes up with carb intake and down with saturated fat intake. Check DELTA.

EDIT: Also from DELTA, your body anticipates damage, or detects actual damage, if you replace the saturated fat of the SAD with monounsaturated fat. So it makes more Lp(a). That's it. You liver is worried by MUFA. Extra virgin olive oil is heart healthy? Dump it for lard or, better still, beef dripping! Less plant antioxidants for your liver to eliminate too.

If you do some thing stupid, like pushing your carb intake beyond what is acceptable (even as a non industrialised form of carbs), your liver will make extra repair kits and they will be both needed and used on your arteries. Remember the vegetarian Bantu farmers getting nearly 90% of their calories from complex carbohydrate? Blood pressure rises with age. Not so at 70% from carbs in the Bantu fishermen.

The more damage, the more repair kits get made, the more repair kits get used. The more damage, the more blood pressure rises with age.

Lp(a) rises soon after birth because birth is when pressure induced damage starts. Life, especially being born, is a damaging process. Some lives are more damaging than others.

Are you going to blame the rising blood pressure on the repair kits? Have you forgotten to take your statin today? You may also have forgotten where you left your blood pressure tablets.

Peter

BTW, obviously these stable fibrous arteriosclerotic lesions have nothing to do with heart attacks. Heart attacks happen in the elderly, not in infants!

Intellectual honesty vs obfuscation

This papragraph is taken from Eric Westman's paper on LC for managing diabetes. Thanks to Valtsu for the heads up. Concise, accurate, comprehensive, numerical:

"Prior to the study intervention, the mean ± SD dietary intake for both groups was 2128 ± 993 kcal, 245 ± 136 g of carbohydrate (46% of daily energy intake), 86 ± 33 g of protein (18% of daily energy intake), 88 ± 57 g of fat (36% of daily energy intake). Over the 24-week duration of the intervention, the LCKD group consumed 1550 ± 440 kcal per day, 49 ± 33 g of carbohydrate (13% of daily energy intake), 108 ± 33 g of protein (28% of daily energy intake), 101 ± 35 g of fat (59% of daily energy intake). In comparison, the LGID group consumed 1335 ± 372 kcal per day, 149 ± 46 g of carbohydrate (44% of daily energy intake), 67 ± 20 g of protein (20% of daily energy intake), 55 ± 23 g of fat (36% of daily energy intake). There was no difference in self-reported exercise between the groups: the mean number of exercise sessions per week increased from 2.0 ± 2.0 to 3.0 ± 2.0 for the LCKD group and from 2.2 ± 2.2 to 3.8 ± 2.9 for the LGID group (p = 0.39 for comparison)."

For anyone who has slogged through the Ben-Gurion study, including the full text, looking for exactly this information, it simply is not there. You can stop hunting now. In a weight loss study there is NO REPORT of the absolute calories consumed! Either the DIRECT group does not include anyone who can present data or they are too scared of their own data to actually present it! But for people with a LC bias and honest data, there is no need for fear. Just generate the data, let the truth speak and and expect to be ignored! But not for ever....

A few IMT changes in a LCKD group over 6m would be nice too! I guess they are on their way if Dr Westman has anything to do with it.

Peter

Intimal wall volume reductions with weight loss

Thanks to Chris for the heads up on this one.

Just briefly: Low fat, Mediterranean and low carbohydrate: Statistically significant reductions in carotid vessel wall volume for all of them, with no significant differences between groups, so long as you lose weight:

"with no differences in the low-fat, Mediterranean, or low-carbohydrate groups (-60.69 mm(3), -37.69 mm(3), -84.33 mm(3), respectively; P=0.28"

But the LC group lost more intimal vessel wall volume than the other two groups, even if this wasn't statistically significant. I've also not got access the information about what they mean by low carbohydrate. As we know this could be anything up to 150g/d in some people's book!

2010 could be a good year for LC and honesty!

Peter

A tale of two abstracts

I've kindly re written the abstract for the high fat, low carbohydrate vs semi starvation paper by Eckel's group of clowns in Colorado. I've not attempted to re-title it as the current title needs to be discarded rather than corrected. Especially describing a non significant rise in LDL cholesterol as "hypercholesterolaemia" is not simply incorrect, it is completely dishonest. These people are, like Black's group in Belfast, not stupid. They're just bent.

The original:

Background: Little is known about the comparative effect of weight-loss diets on metabolic profiles during dieting. Objective: The purpose of this study was to compare the effect of a low-carbohydrate diet (<20 g/d) with a high-carbohydrate diet (55% of total energy intake) on fasting and hourly metabolic variables during active weight loss. Design: Healthy, obese adults (n = 32; 22 women, 10 men) were randomly assigned to receive either a carbohydrate-restricted diet [High Fat; mean +/- SD body mass index (BMI; in kg/m2): 35.8 +/- 2.9] or a calorie-restricted, low-fat diet (High Carb; BMI: 36.7 +/- 4.6) for 6 wk. A 24-h in-patient feeding study was performed at baseline and after 6 wk. Glucose, insulin, free fatty acids (FFAs), and triglycerides were measured hourly during meals, at regimented times. Remnant lipoprotein cholesterol was measured every 4 h. Results: Patients lost a similar amount of weight in both groups (P = 0.57). There was an absence of any diet treatment effect between groups on fasting triglycerides or on remnant lipoprotein cholesterol, which was the main outcome. Fasting insulin decreased (P = 0.03), and both fasting (P = 0.040) and 24-h FFAs (P < 0.0001) increased within the High Fat group. Twenty-four-hour insulin decreased (P < 0.05 for both groups). Fasting LDL cholesterol decreased in the High Carb group only (P = 0.003). In both groups, the differences in fasting and 24-h FFAs at 6 wk were significantly correlated with the change in LDL cholesterol (fasting FFA: r = 0.41, P = 0.02; 24-h FFA: r = 0.52, P = 0.002). Conclusions: Weight loss was similar between diets, but only the high-fat diet increased LDL-cholesterol concentrations. This effect was related to the lack of suppression of both fasting and 24-h FFAs.

Corrected version:

Background: Much is known about the comparative effect of weight-loss diets on metabolic profiles during dieting, though our research group seem peculiarly ignorant of the literature. Objective: The purpose of this study was to compare the effect of a low-carbohydrate diet (<20 g/d) with a high-carbohydrate diet (55% of total energy intake) on fasting and hourly metabolic variables during active weight loss. Design: Healthy, obese adults (n = 32; 22 women, 10 men) were randomly assigned to receive either a carbohydrate-restricted diet which was unrestricted in calories or fat and was consumed to satiation [High Fat; mean +/- SD body mass index (BMI; in kg/m2): 35.8 +/- 2.9] or a severely calorie-restricted, low-fat diet (High Carb; BMI: 36.7 +/- 4.6) for 6 wk. A 24-h in-patient feeding study was performed at baseline and after 6 wk. Glucose, insulin, free fatty acids (FFAs), and triglycerides were measured hourly during meals, at regimented times. Remnant lipoprotein cholesterol was measured every 4 h. Results: Patients lost a similar amount of weight in both groups (P = 0.57), the excess weight loss in the calorie and fat unrestricted High Fat diet not reaching statistical significance. There was an absence of any diet treatment effect between groups on fasting triglycerides or on remnant lipoprotein cholesterol, which was the main outcome. Fasting insulin decreased (P = 0.03) only in the High Fat diet, and both fasting (P = 0.040) and 24-h FFAs (P < 0.0001) increased within the High Fat group, as is appropriate for a fatty acid based metabolic profile. Twenty-four-hour insulin decreased (P < 0.05 for both groups), the decrease within the High Fat group being twice that seen in the High Carb group. Fasting LDL cholesterol decreased in the High Carb group only (P = 0.003), representing an increase in the atherogenic sdLDL particle subgroup. In both groups, the differences in fasting and 24-h FFAs at 6 wk were significantly correlated with the change in LDL cholesterol (fasting FFA: r = 0.41, P = 0.02; 24-h FFA: r = 0.52, P = 0.002). Conclusions: Weight loss was similar between diets despite unrestricted calories and fat intake in the High Fat group. The high-fat diet did not significantly increase LDL-cholesterol concentrations (P = 0.13). High Fat diets increase LDL lipoprotein size non significantly, potentially decreasing atherogenicity, which is possibly related to the increase in both fasting and 24h FFAs.


Peter

Arteriosclerosis images (2): Models

All of these images are taken from Dr John Duguid's monograph The Dynamics of Arterisclerosis. I'm not sure they are available elsewhere, so here come some horrible copyright infringements.

Duguid never uses the term mucopolysaccharide or GAGs, but it is pretty clear from the pictures that this is what the hyaline substance in Duguid's rabbit images represents. The body replaces the fibrin of blood clots with GAG, as it does in the healing process of fractures. Oddly enough the parallel goes on to calcification too but I think I might be stretching a point there...

Please bear in mind that the pulmonary emboli are a model. They are not arteriosclerosis, but just look at the vascular wall changes over the months after embolisation. Obviously they are in the pulmonary artery as this is where all emboli from peripheral veins end up!

Duguid has a whole series of picture of microthrombi in human arterial sections which produce similar changes to the model but in minute amounts. Hence in the previous post the clot over the frayed elastic membrane does not look like the large fibrin particle in the rabbit artery here.

Just for a giggle I've also included two of his images of the cholesterol fed rabbit. Classic.

The titles are self explanatory. The fibrin clot is huge and it's the lump on the lower left side in the lumen of the artery. The paler granular stuff is just blood in the artery. All of the stains are H and E and don't show elastin (not needed as the model does not use intimal trauma to produce the clots).



We now know that circulating endothelial progenitor cells rapidly coat thrombi, or other nasties (like foam cells), so finding a covering by six days is not surprising.



By two months the lesion is looking more like a typical childhood arteriosclerosis lesion:



By six months the lesions do look quite like the mature lesions seen in young children:



I would suggest that there is still a lump of what is probably GAG, but the bulk of the lesion (bottom of the section) is mostly just fibrous thickened intima.

It would have been lovely to have Prussian Blue stained sections and Sudan Red sections to confirm the presence of GAG and the near absence of cholesterol, but you don't get what's not in the book.

Don't forget this is a model!

Now, for the current prefered model in cardiovasciular research, fanfare please for the Cholesterol Fed (poisoned?) Rabbit:



All of the bubbly stuff is cholesterol. There is no GAG, there is no fibrin. EPCs coat these foam cells as well as they do fibrin clots, hence the layers of epithelial cells between the foam cells.

And, if your rabbit survives long enough, what does its aorta look like? Here's one (on the left) I prepared earlier:



Duguid does say quite explicitly that this particular rabbit was an exceptional example. Perhaps it has FH as well as cholesterol poisoning!

Now, did this rabbit die of a heart attack?

Hahahahahahaahahahahahahahahahahahahahaha

Peter

Arteriosclerosis in 1957

I was born in 1956, so I was an infant at the time these photographs were being taken. Each one records a personal tragedy. We should learn from them.

All illustrations are taken from Henry Moon's classic 1957 paper.

This is a normal coronary artery. It has been stained to emphasise elastic tissue. Note the continuous folded band of elastin with nothing visible between the elastic layer and the artery lumen (there is actually a single layer of epithelial cells here).



The thicker layer outside the thin black elastic layer is media and is made of muscle. The more granular layer outside the muscle layer is the adventitia. The slide comes from a 5 months gestation human foetus who died, without being born, in a tragic accident. Accidental death autopsies are where all of the pictures in this post come from. Non are cardiac patients.

Next is this picture of the coronary artery of an infant who was 4 days old. Note that most of the intima (dark red wavy layer) is normal and that all of the media is normal. But look at the lower right, there is an abnormal area of the elastic layer. It is shredded and there is fuzziness over the surface. This is the earliest stage of arteriosclerosis noted in this series.



If we next go on to look (slide below) at the coronary arteries from an infant of four months of age we can see a small section of normal intima, with intact elastic layer, on the upper left of the section of artery with normal muscle in the media outside it. Over the rest of the artery the elastic layer is grossly disrupted or absent, the intima is grossly thickened and the muscular media is still relatively normal, though it is a bit thickened at the lower area of the section:



And then we have this superb section actually through a branch of the coronary artery of a child of three years of age. There are some areas of elastic tissue intact but much of it is damaged and the intima has generally thickened wherever the elastic tissue is disrupted. The effect is most marked by the mouth of the branch. The smooth muscle layer (media) is still quite normal but somewhat thickened at the mouth of the branch too.



These last two high magnification images in one picture are stained to show the material of which the thickened intima is composed. In the lower image the changes extend in to the muscular media too.



Do you think it might be cholesterol?

You know, LDL-C, the stick-and-die stuff? Oddly enough if you do frozen sections and stain them with sudan red there are very occasional macrophages with a little lipid in their cytoplasm scattered thinly through this gunk.

But no, the wall to wall stuff stained with Prussian Blue is mucopolysaccharide, I think nowadays it's called glycosaminoglycans or GAG.

To me it's really weird how a cardiologist can think that LDL causes this, and that statins might stop it.

But then the world is a weird place!

Peter

It's Friday and we're heading south for the weekend so the blog will be quiet for a few days.

Saturated fat and sdLDL?

The post itself and the exchange of comments on Dr Davis' blog about genetic causes of sdLDL piqued the interest of many of us. You need to have read the post and comments to make sense of this particular post here. I'm not keen on decrying the concept of genetic sdLDL out of hand but, obviously, there is a great deal that can be thought about around the non genetic concept. My thoughts are down here as I don't want to go cluttering Dr D's post up with comments that are clearly mine, from my biased viewpoint, and very probably not congruent with those of Dr D. The situation is too interesting not to expand a little though...

I roughed out Stan and Ollie on Fitday, very crudely and making big guestimates.

Here they are:

Very crudely for Stan



I gave them both half a kilo of cabbage each, nuts as almonds, (slightly more for Stan as he is weight stable) and chicken, again slightly more for Stan to keep him weight stable. I also allowed Stan some cannola oil to make his total calories up to 2000kcal/d.


And here is a guess for Ollie


I assumed Ollie was burning 0.34lb/d of his own fat and entered this as lard. I allowed him a total (including the lard from his butt/belly) of 2,300kcal/d as he was carting a fair bit more weight around than Stan. Probably an underestimate.

Saturated fat "consumption" for Ollie (who near eliminated sdLDL) worked out as 67g/d, total fat was 83% of 2300kcal, MUFA 105g and PUFA 31g. Most of this fat was from belly-fat plus almonds.

Fat for Stan (who retained sdLDL) was from his diet only as he, quite correctly, lost very little weight over 6m. Results were saturated fat 17g/d, total fat 70% of 2000 calories eaten, MUFA 84g/d and PUFA 53g/d.

I find it hard to see that Stan's saturated fat is the reason for his sdLDL, unless one posits that 17g/d of saturated fat as chylomicrons (apoB48 labelled, gut produced) causes sdLDL in some way (sdLDL is apoB100 labelled and produced by the liver). While at the same time Ollie's 67g/d of saturated fat, available as FFAs after release by hormone sensitive lipase from his adipocytes, behaves differently to Stan's 17g/d saturated fat released from chylomicrons by lipoprotein lipase....

It's possible, but it seems implausible to me.

Dr Davis mentioned the tendency of this sub group of his patients to be borderline diabetic. This to me is far more interesting and makes my ears prick up. Both apoB100 and apoB48 have glycation-predisposed sites which, once glycated, inhibit their uptake by the LDL receptor (certainly for the apoB100 particles, probably something similar works for the apoB48 particle, I've not chased this).

If apoB100s are not taken up because they are glycated due to a borderline diabetes tendency we have a very plausible mechanism for "atherogenic" remnant particles both being formed and "remaining". It just needs a little sugar to get them there. And of course, some of us think sugar and arteriosclerosis might be linked anyway...

Peter

Physiological insulin resistance: Dolphins

This article was sent to me by Stan, and it's interesting on many levels. At the most basic is the gross error in the description of the management of diabetes. This is what the article says:

"In diabetic people, chronic insulin resistance means having to carefully control blood glucose, usually with a diet low in sugar, to avoid a variety of medical complications."

NO NO NO NO NO!

Human diabetes is managed by a diet low in FAT. Ask any diabetologist.

The experience of Dr Dahlqvist encapsulates the monstrous medical approach to the use of low carbohydrate diets in diabetes.

I'm feeling a bit polite tonight for some reason so I won't mention what I think about low fat diets and diabetets. Perhaps I need a glass of wine.



This marine mammal researcher can see physiological insulin resistance in dolphins and see that it is PHYSIOLOGICAL. The difference between a healthy dolphin and a healthy human is minimal (can she see that too?). We humans "do" physiological insulin resistance. But she and her collaborators cannot see that there is a difference between physiological insulin resistance and breaking your liver by living on soda and bagels to get pathological insulin resistance... As she says:

"If we started feeding dolphins Twinkies, they would have diabetes."

Not true. Their insulin resistance would go as they switched on carbohydrate metabolism in their muscles. It would take several years of Twinkies to cause diabetes. Like humans. We're fine for the first few hundred/thousand Twinkies. Then we break.

EDIT: Being in the UK I hadn't realised how small Twinkies are. Let's say 100,000 or so to break your liver...

But ultimately we humans need Twinkies to survive. We must eat them to remain happy and feel part of normal society. Imagine a teenager saying no to a Twinkie, just because they are diabetic! No, we must help people to eat Twinkies while diabetic, so we MUST research the "fasting gene" which is abnormally activated in human diabetes. And develop a drug to turn it off, of course.

BTW the activator of the fasting gene will turn out to be palmitic acid. What other messenger would you use to suggest that there is a fasting state? So we're back to using Palmitofake and a continuous supply of Twinkies.


The title says "Dolphins have diabetes off switch"

No, they do not. There is no off switch for a broken liver. Unbroken dolphins are just behaving like unbroken humans. They turn off physiological insulin resistance when carbohydrate becomes available, even if that carbohydrate come from fish via gluconeogenesis. It's simple and it's NOT diabetes.

Sigh.

Peter

There is potentially a whole load more posts from this link, follow up depends on all sorts of things...

John Hawks on Paleo in NY

I was looking for this report by scrolling back through John Hawks' weblog (it wasn't there, it was in Thinking Meat).

It had come to mind because I had made a bolognaise sauce for tonight's supper and had seared the mince and onions, quite deliberately, because I like the taste of seared meat. I guess like sweetness because it was rare before sucrose became widely available. But burned meat? AGEs and ALEs? Why? And is it bad for me? With quite well defined hearth use at 750,000 years ago I think I'm OK to eat seared meat. I'm not sure why I like it. It's not quite the same as feeding gamma irradiated "food" to cats (their brains fall to pieces) and I suspect it's something humans have been doing for a long time. A lot longer than the 10,000 years of growing grains, which Hawks rightly suggests some of us may be better adapted to than others, even on this brief time scale.

So AGEs and ALEs, yes. Unless, of course, those out-of-Africa-a long-time-ago people had stainless steel cooking pots for boiling meat in, which we've just not found yet...

Scrolling back through Arrested Adaptation, in a vain effort to find what wasn't there, I stumbled on his take about the Paleo in NY article which was discussed in "our" zone of the bloggosphere when it came out. I enjoyed it a lot. Though he has some gripes and beefs about "modern paleo" (with a particular BIG down on Crossfit), his article was generally enjoyable and informed. Being one of those weirdo's with strange dietary habits, even if not paleo, it's a good to get a bit of fun poked at me occasionally, provided it's not malicious...

You do tend to forget how strange you are.

Well, I do anyway.

Peter

Cholesterol: Near miss in Edinburgh

Just another brief post. This group were very, very, very lucky. Crucifiction is supposed to be unpleasant.

What did they do? Well it was more of the usual stuff but, back in the early years of this century, it was still considered ethical to include a placebo group in a statin trial! Gasp, horror, call the ethics committee.

Anyway, 54 people, all with known heart disesae, were allowed to go for 24 months without the benefit of atrovastatin. You wouldn't do this in the states! But here in Scotland, well, a few more heart attacks and no one will notice.

So what does a greater than 50% reduction of LDL-C and a near 50% reduction in C reactive protein do for CAC score progression?

Diddley squat, as you would expect. It's all the usual quotes:

"statin treatment does not have a major effect on the rate of progression of coronary artery calcification"

and

"Serum low density lipoprotein concentrations were not correlated with the rate of progression of coronary calcification (r = 0.05, p = 0.62)"

All utterly tedious.

What grabbed me was the near miss. The CAC score progression in the atrovastatin group was not significantly different to the placebo group.

The p value was 0.18

What would have happened if the p had cracked the mystical p<0.05, say with bigger groups or longer follow up?

In this study atrovastatin "allowed" or "facilitated" progesssion by 26% per year, placebo by only 18% per year.

As I say, p=0.18

A near miss for the careers of all involved.

Peter

Oh, and in the full text you can find that there were actually 2 diabetic patients and 10 current smokers in the placebo group vs no diabetics and only 5 current smokers in the statin group. Equalising these might have given catastrophe.

Cholesterol: Peto seeing some light?

Even Sir Richard Peto (second author) is seeing the light. Sir P is famous for stating (loosely remembered by me) that no individual study of the role of cholesterol in CVD is particularly convincing, but the overall weight of evidence was. I'm stuck with reading study after study and realising they are crap. A big heap of crap is no more convincing than a small heap, to me. But then I'll never get a knighthood.

Back to the Oxford abstract:

"Given usual apoB, lower LDL-C (consistent with smaller LDL particles) was associated with higher risk (P < 0.0001)."

Translation: at a given number of apoB100 particles, the lower the measured LDL the HIGHER the risk.

"The ratio apoB/apoA(1) was substantially more informative about risk (chi(1)(2) = 550) than were commonly used measures such as LDL-C/HDL-C, total/HDL cholesterol, non-HDL cholesterol, and total cholesterol"

Translation: Most of what we have measured in the past is bollocks. Our new ratio is slightly less bollocks.

Notice they didn't mention HDL/trigs. And they still believe sdLDL is out to get you. And no one has pointed out to them that sugar is a great generator of sdLDL.

I've not bothered down loading the free full text. The abstract says exactly what you would expect a real view of the world to say. That's enough to take notice of without working too hard.

Peter