Just a quickie. More from the killing fields.
Those poor folks with heterozygous FH are such a playground for cardiologists. My latest accidental find was ACAT inhibition using pactimibe. Medscape describes it this way:
"Pactimibe was in development as an ACAT1 inhibitor, intended to make available more free cholesterol for reverse cholesterol transport, which theoretically could reduce lipid accumulation within atherosclerotic lesions."
Oh, this link works in Safari but not Firefox... Not worth reading, the quote is all you need anyway!
OK, stop foam cell generation and ship out the evil cholesterol (maybe using enhanced LCAT? That'll be next) to HDL for reverse transport. CAPTIVATE-ing idea. I think they were a bit unlucky with this one.
Combined endpoint was deaths, heart attacks and strokes. One out of 438 on placebo, 10 out of 443 on treatment. That's a relative risk of errr, umm... arithmetic fails me.
My biggest worry about drugs being developed based on the lipid hypothesis is that at some time they're going to repeat, again by fluke, the small success of the statins. We'll get a drug which does a little good, a lot of harm and conveniently forget about those who died on pactimibe, torcetrapib or which ever LCAT enhancing drug gets developed. Keeping up the failure rate must be quite difficult, but this continued failure is our best hope for getting some research on heart disease started.
Peter
BTW this drug works really well in genetically hypercholesterolaemic rabbits. No one is suggesting the the WHHL rabbit is a crap model for any sort of arteriosclerosis based on the people injured in this study. OK, I am. It looks like crap model to me.
Saturday, August 29, 2009
Friday, August 28, 2009
Low carbohydrate high protein and ApoE-/- mice (2)
I'm waiting to hear about the mineral content of the high protein low carbohydrate diet used to generate arteriosclerosis in mice. Personally I feel the whole study is totally irrelevant but I'm interested because (a) it is a major achievement in its own right and (b) it is being used politically to specifically warn against low carbohydrate diets. The press release is very cleverly done, anecdote and personal testimony is, I am very well aware, powerful stuff. Just like blogging really!
OK, it's time to talk about renal disease in rats and mice. I'm afraid quite a lot of it involves "models" but, well, that's just how it goes. Much of the information here comes from this paper. I think it took Malcolm Kendrick, to whom I am greatly indebted, about 5 minutes to find it on PubMed.
We're going to talk about CKD-MBD, that is Chronic Kidney Disease-Mineral Bone Disorder. CKD-MBD has three components: 1) abnormal serum biochemistries, 2) abnormal bone remodeling, and 3) vascular calcification.
Especially interesting is the last of these three, vascular calcification.
Using acute models of renal failure, particularly the 5/6ths nephrectomy, it is very very hard to demonstrate arterial calcification within the the lifetime of the animal unless you include a genetic modification, typically apoE-/- or LDLR-/- knockouts. So, if you wish to get calcification of arteries, choose an apoE-/- mouse as it speeds up the process. Adding a high content of phosphorus to the diet is also normal as this accelerates the kidney failure and is a known trigger for the conversion of a smooth muscle cell in to an osteoblast.
The phosphorus in the diet has to be bioavailable. That provided by grains is mostly there as phytic acid and, although rodents do have a phytase (humans don't), the amount of phosphate absorbed from grain based diets is much lower than from casein based diets.
In the face of early renal damage it seems like 0.7% phosphate in a casein diet (0.7g/100g) progresses the renal failure where as 0.2% keeps renal damaged animals similar to controls for many weeks. The control groups being given non bioavailable phosphate from grains.
So the next question you have to ask is whether rats or mice on lab chow have renal damage. Well, I blogged about that here.
Enough to say that nephrocalcinosis was absolutely routine until the NTP-2000 diet was introduced. This improved diet still does this:
"The NTP-2000 diet prevented nephrocalcinosis and decreased the severity of nephropathy and cardiomyopathy, the common lesions of F344 rats in 13-week studies"
Note the time scale for nephropathy. Less than 13 weeks. And this is a grain based diet with its phosphate mostly inaccessible to the rat/mouse. Whether you could get changes in the week between weaning and starting on a specialist diet is an interesting point.
But a casein based diet will allow phosphate uptake far better than a grain based diet. Two question then come to mind. Normal rat/mouse chow usually runs at just under 20% of calories from casein. Does increasing this to 45% increase the phosphate uptake? I don't know.
And perhaps you would still need to add supplementary phosphorus? Again I don't know.
So let us summarise: Casein based diets markedly facilitate the toxic action of phosphate on mildly damaged kidneys. Renal failure causes arterial calcification. Arterial calcification will occur in apoE knockout mice with renal failure under circumstances where it is impossible to get it with normal lipid metabolism. With enough tweaks it is possible to get arteriosclerosis in mice by careful manipulation of the model.
Epithelial progenitor cells are produced in the bone marrow under the influence of erythropoietin. Erythropoietin is produced by normal kidneys but only in reduced amounts by nephrotic kidneys. Vascular damage and regeneration appear to be heavily influenced by these cells.
If you wanted to make a diet for a mouse which triggered both arterial calcification and depressed EPC numbers a reasonable stratagem might be to feed a casein based high phosphate diet. To really make things happen choose an apoE knockout mouse. A normal mouse might not oblige.
You really need to know exactly how to manipulate renal function, genetics and EPC numbers in lab mice. This might not happen by accident and would require a great deal of knowledge about renal function and arterial damage.
I think that, for the time being, we will have to await the composition of both the mineral supplement used in the diets and the phosphate content of the calcium salts used as a partial replacement for that supplement in the high protein arm of the study.
But the thought train is interesting.
I was wishing for histopath on the kidneys but, if this hypothesis is correct, all that would have come out would have been that high protein diets damage kidneys.
Peter
OK, it's time to talk about renal disease in rats and mice. I'm afraid quite a lot of it involves "models" but, well, that's just how it goes. Much of the information here comes from this paper. I think it took Malcolm Kendrick, to whom I am greatly indebted, about 5 minutes to find it on PubMed.
We're going to talk about CKD-MBD, that is Chronic Kidney Disease-Mineral Bone Disorder. CKD-MBD has three components: 1) abnormal serum biochemistries, 2) abnormal bone remodeling, and 3) vascular calcification.
Especially interesting is the last of these three, vascular calcification.
Using acute models of renal failure, particularly the 5/6ths nephrectomy, it is very very hard to demonstrate arterial calcification within the the lifetime of the animal unless you include a genetic modification, typically apoE-/- or LDLR-/- knockouts. So, if you wish to get calcification of arteries, choose an apoE-/- mouse as it speeds up the process. Adding a high content of phosphorus to the diet is also normal as this accelerates the kidney failure and is a known trigger for the conversion of a smooth muscle cell in to an osteoblast.
The phosphorus in the diet has to be bioavailable. That provided by grains is mostly there as phytic acid and, although rodents do have a phytase (humans don't), the amount of phosphate absorbed from grain based diets is much lower than from casein based diets.
In the face of early renal damage it seems like 0.7% phosphate in a casein diet (0.7g/100g) progresses the renal failure where as 0.2% keeps renal damaged animals similar to controls for many weeks. The control groups being given non bioavailable phosphate from grains.
So the next question you have to ask is whether rats or mice on lab chow have renal damage. Well, I blogged about that here.
Enough to say that nephrocalcinosis was absolutely routine until the NTP-2000 diet was introduced. This improved diet still does this:
"The NTP-2000 diet prevented nephrocalcinosis and decreased the severity of nephropathy and cardiomyopathy, the common lesions of F344 rats in 13-week studies"
Note the time scale for nephropathy. Less than 13 weeks. And this is a grain based diet with its phosphate mostly inaccessible to the rat/mouse. Whether you could get changes in the week between weaning and starting on a specialist diet is an interesting point.
But a casein based diet will allow phosphate uptake far better than a grain based diet. Two question then come to mind. Normal rat/mouse chow usually runs at just under 20% of calories from casein. Does increasing this to 45% increase the phosphate uptake? I don't know.
And perhaps you would still need to add supplementary phosphorus? Again I don't know.
So let us summarise: Casein based diets markedly facilitate the toxic action of phosphate on mildly damaged kidneys. Renal failure causes arterial calcification. Arterial calcification will occur in apoE knockout mice with renal failure under circumstances where it is impossible to get it with normal lipid metabolism. With enough tweaks it is possible to get arteriosclerosis in mice by careful manipulation of the model.
Epithelial progenitor cells are produced in the bone marrow under the influence of erythropoietin. Erythropoietin is produced by normal kidneys but only in reduced amounts by nephrotic kidneys. Vascular damage and regeneration appear to be heavily influenced by these cells.
If you wanted to make a diet for a mouse which triggered both arterial calcification and depressed EPC numbers a reasonable stratagem might be to feed a casein based high phosphate diet. To really make things happen choose an apoE knockout mouse. A normal mouse might not oblige.
You really need to know exactly how to manipulate renal function, genetics and EPC numbers in lab mice. This might not happen by accident and would require a great deal of knowledge about renal function and arterial damage.
I think that, for the time being, we will have to await the composition of both the mineral supplement used in the diets and the phosphate content of the calcium salts used as a partial replacement for that supplement in the high protein arm of the study.
But the thought train is interesting.
I was wishing for histopath on the kidneys but, if this hypothesis is correct, all that would have come out would have been that high protein diets damage kidneys.
Peter
Tuesday, August 25, 2009
Low carbohydrate, high protein and ApoE-/- mice
OK, here's the hot abstract from back in 2007.
And here's the press release from 2009, I've put the text up on my odds and sods blog as press releases don't last for ever on the net. The paragraphs are a bit chewed up but you can get the gist OK.
Cardiologists are impatient people. If they want to study aortic aneurisms they tend to do things like placing a balloon in the aorta via the femoral artery, inflating it and then pulling. Down the aorta, with the balloon inflated. Or they might go in there surgically, cross clamp the aorta in two places, perfuse the isolated section of aorta with some unpleasant chemical, then set all back to normal and try out the latest drug for aneurism treatment on the preparation. The prime requirement is the suspension of disbelief that the "model" has anything to do with human senile dissecting aortic aneurisms. It doesn't.
Obviously the cholesterol fed Syrian hamster is a great model for arteriosclerosis, but it's boring. There's nothing sexy about feeding a herbivore cholesterol. Sexy needs genetically modified mammals to make it happen.
So you want a mouse to get atheroma? Well, they don't. Feed them mouse chow and they get arterial damage and fibrosis all right, but not nice big juicy cholesterol filled plaque. What to do? Delete a gene.
One offspring from the impatience of cardiologists is the apoE-/- mouse. This mouse is a genetic cripple who's ability to process fat has been severely damaged. There are a very, very, very small number of people in the world who are homozygous for defective apoE. They are functionally apoE-/-. Nature does not allow this commonly. Contrast it with FH where there are hundreds of different types of FH, ie breaking your LDL receptor gene is easily done and evolution has not attempted to conserve it particularly highly.
Feeding a high fat diet to apoE-/- mice is bad news for the mice. Until anyone gives us the full text of the paper we'll have no idea of exactly what they fed to the mice but, ultimately, they broke the mice first. Actually, if Dr Murray is anything to go by, even the full text won't tell us much about what they fed the mice!
If you are apoE -/- I wish you luck. Statistically, you're not. Neither is the cardiologist, Dr Rosenzweig, who gave up his LC diet on the basis of this study. But then, he thinks the transgenic apoE-/- mouse is a model for human arteriosclerosis.
Peter
EDIT: OK, I now have the full text (thanks H) and here is the total information supplied in the methods section about the diets:
"Male pups were placed on one of the three study diets 1 week after weaning: standard chow diet (Harlan Teklad #2018 rodent chow), high-fat ‘Western’ diet (Harlan Teklad # 88137) and a custom-ordered low-carbohydrate diet manufactured to our specifications (Harlan Teklad)."
That's it. It is traditional to give enough information in the methods section to allow another group to repeat your protocol. If the problems in these mice are NOT from being apoE-/- then Foo et all are to be congratulated on developing a diet to produce more problems than the Western or Cafeteria diet, but they ain't telling anyone how to do it! No answer from Murray on the same query.
Prompt reply from Dr Rosenzweig with the table of diet compostion, just asking now about the Ca modification and if it involves PO4 changes
And here's the press release from 2009, I've put the text up on my odds and sods blog as press releases don't last for ever on the net. The paragraphs are a bit chewed up but you can get the gist OK.
Cardiologists are impatient people. If they want to study aortic aneurisms they tend to do things like placing a balloon in the aorta via the femoral artery, inflating it and then pulling. Down the aorta, with the balloon inflated. Or they might go in there surgically, cross clamp the aorta in two places, perfuse the isolated section of aorta with some unpleasant chemical, then set all back to normal and try out the latest drug for aneurism treatment on the preparation. The prime requirement is the suspension of disbelief that the "model" has anything to do with human senile dissecting aortic aneurisms. It doesn't.
Obviously the cholesterol fed Syrian hamster is a great model for arteriosclerosis, but it's boring. There's nothing sexy about feeding a herbivore cholesterol. Sexy needs genetically modified mammals to make it happen.
So you want a mouse to get atheroma? Well, they don't. Feed them mouse chow and they get arterial damage and fibrosis all right, but not nice big juicy cholesterol filled plaque. What to do? Delete a gene.
One offspring from the impatience of cardiologists is the apoE-/- mouse. This mouse is a genetic cripple who's ability to process fat has been severely damaged. There are a very, very, very small number of people in the world who are homozygous for defective apoE. They are functionally apoE-/-. Nature does not allow this commonly. Contrast it with FH where there are hundreds of different types of FH, ie breaking your LDL receptor gene is easily done and evolution has not attempted to conserve it particularly highly.
Feeding a high fat diet to apoE-/- mice is bad news for the mice. Until anyone gives us the full text of the paper we'll have no idea of exactly what they fed to the mice but, ultimately, they broke the mice first. Actually, if Dr Murray is anything to go by, even the full text won't tell us much about what they fed the mice!
If you are apoE -/- I wish you luck. Statistically, you're not. Neither is the cardiologist, Dr Rosenzweig, who gave up his LC diet on the basis of this study. But then, he thinks the transgenic apoE-/- mouse is a model for human arteriosclerosis.
Peter
EDIT: OK, I now have the full text (thanks H) and here is the total information supplied in the methods section about the diets:
"Male pups were placed on one of the three study diets 1 week after weaning: standard chow diet (Harlan Teklad #2018 rodent chow), high-fat ‘Western’ diet (Harlan Teklad # 88137) and a custom-ordered low-carbohydrate diet manufactured to our specifications (Harlan Teklad)."
That's it. It is traditional to give enough information in the methods section to allow another group to repeat your protocol. If the problems in these mice are NOT from being apoE-/- then Foo et all are to be congratulated on developing a diet to produce more problems than the Western or Cafeteria diet, but they ain't telling anyone how to do it! No answer from Murray on the same query.
Prompt reply from Dr Rosenzweig with the table of diet compostion, just asking now about the Ca modification and if it involves PO4 changes
Monday, August 24, 2009
High fat diets make you fat and stupid (2)
While trying to understand what was going on in the "Deterioration of physical performance and cognitive function in rats with short-term high-fat feeding" paper by Andrew Murray I came across a similar paper by PubMed-ing "fructose insulin memory" or the like.
This paper provides more information and is very up front about added fructose! Here is what they did:
"In the present study we fed rats a diet high in saturated fats and simple sugars, and supplemented their water with high-fructose corn syrup. This diet increased fasting blood glucose levels and serum cholesterol and triglycerides. Additionally, we found that the diet impairs hippocampus-dependent learning, synaptic plasticity, and dendritic spine density. These adverse effects on brain function were associated with reduced levels of BDNF in the hippocampus and suggest that “Western” diets impair synaptic function and cognition by a mechanism involving reductions in BDNF and atrophy of dendritic spines"
The control diet was good old "standard NIH chow".
The high calorie diet was high in both saturated fat and glucose but was also supplemented with high fructose corn syrup as 20% of the drinking water.
This means that it was impossible for a rat to take a mouthful, any mouthful of food without a glucose load. It was also impossible to drink any water without a fructose load. Rats have to drink.
The most notable thing to me was the fructose in the water. If it was possible to do this with a fat/glucose combo, why add fructose to the drinking water? Answer: It's probably not possible to do this without the fructose. Is there any other possible answer? I guess you could suggest it's the equivalent of the Fanta with the big mac and extra fries... So would the big mac and fries be OK without the Fanta? That we'll not find out from this study because including a fat/glucose combo without fructose was not on the agenda.
I would guess that the fat stupid rats in Andrew Murray's study will have had a fair dose of fructose (as sucrose) in the 16% of calories they derived from carbohydrate. The control diet contained zero fructose.
There are many other points in the paper which are interesting when you take the Taubes view of obesity but they're not core to what is going on. Ultimately there is a lot of insulin sloshing around in the rats on their high fat diet.
Peter
This paper provides more information and is very up front about added fructose! Here is what they did:
"In the present study we fed rats a diet high in saturated fats and simple sugars, and supplemented their water with high-fructose corn syrup. This diet increased fasting blood glucose levels and serum cholesterol and triglycerides. Additionally, we found that the diet impairs hippocampus-dependent learning, synaptic plasticity, and dendritic spine density. These adverse effects on brain function were associated with reduced levels of BDNF in the hippocampus and suggest that “Western” diets impair synaptic function and cognition by a mechanism involving reductions in BDNF and atrophy of dendritic spines"
The control diet was good old "standard NIH chow".
The high calorie diet was high in both saturated fat and glucose but was also supplemented with high fructose corn syrup as 20% of the drinking water.
This means that it was impossible for a rat to take a mouthful, any mouthful of food without a glucose load. It was also impossible to drink any water without a fructose load. Rats have to drink.
The most notable thing to me was the fructose in the water. If it was possible to do this with a fat/glucose combo, why add fructose to the drinking water? Answer: It's probably not possible to do this without the fructose. Is there any other possible answer? I guess you could suggest it's the equivalent of the Fanta with the big mac and extra fries... So would the big mac and fries be OK without the Fanta? That we'll not find out from this study because including a fat/glucose combo without fructose was not on the agenda.
I would guess that the fat stupid rats in Andrew Murray's study will have had a fair dose of fructose (as sucrose) in the 16% of calories they derived from carbohydrate. The control diet contained zero fructose.
There are many other points in the paper which are interesting when you take the Taubes view of obesity but they're not core to what is going on. Ultimately there is a lot of insulin sloshing around in the rats on their high fat diet.
Peter
High fat diets make you fat and stupid (1)
Dear Dr Murray,
I have read with great interest your recent publication
Deterioration of physical performance and cognitive function in rats with short-term high-fat feeding
in FASEB.
I have been unable to determine the carbohydrate composition of the diets used from the materials and methods section.
I note that Rat and Mouse No. 1 Maintenance (Special Diet Services, Witham, UK) is composed of wheat, barley, wheat middlings, soyabean meal, dried whey, soya oil and vits/minerals and, as such, is a standard lab rodent maintenance diet.
The composition of the custom diet (diet code 829197; Special Diet Services) is not given in the methods section of your paper. Is it a simple replacement of a proportion of the cereals with a lipid mixture to produce the fat composition detailed, or has the nature of the carbohydrate source used been altered in addition to the reduction in quantity? This seems to be quite an important aspects to the study.
I would very much appreciate a breakdown of the diets.
Thanks in advance.
Beyond that, fascinating paper.
Best wishes
Petro
I have read with great interest your recent publication
Deterioration of physical performance and cognitive function in rats with short-term high-fat feeding
in FASEB.
I have been unable to determine the carbohydrate composition of the diets used from the materials and methods section.
I note that Rat and Mouse No. 1 Maintenance (Special Diet Services, Witham, UK) is composed of wheat, barley, wheat middlings, soyabean meal, dried whey, soya oil and vits/minerals and, as such, is a standard lab rodent maintenance diet.
The composition of the custom diet (diet code 829197; Special Diet Services) is not given in the methods section of your paper. Is it a simple replacement of a proportion of the cereals with a lipid mixture to produce the fat composition detailed, or has the nature of the carbohydrate source used been altered in addition to the reduction in quantity? This seems to be quite an important aspects to the study.
I would very much appreciate a breakdown of the diets.
Thanks in advance.
Beyond that, fascinating paper.
Best wishes
Petro
Friday, August 21, 2009
Cholesterol: LCAT and rabbits
Just a brief word about LCAT and rabbits before getting to the "high fat food makes you lazy and stupid" paper. The full text of this is quite interesting but it will take some time to go through and it's the weekend with houses to view and stuff to do...
Back to LCAT. I was checking the spelling of the non abbreviated text of LCAT and this grant proposal from 1995 was the first hit. I just had to read in in the aftermath of Franceschini's findings.
This is the logic to what they want to do, it's straightforward, hard core lipid hypothesis:
"SUMMARY: In humans, the development of atherosclerosis is positively and inversely correlated with the plasma levels of low density lipoproteins (LDL) and high density lipoproteins (HDL) respectively. LCAT, the major enzyme involved in the esterification of free cholesterol present in circulating plasma lipoproteins, is a major determinant of plasma HDL concentrations. Recent studies have established that transgenic rabbits overexpressing human LCAT have 6-7 fold higher plasma HDL levels than control, non-transgenic siblings. In addition, LCAT transgenic rabbits have reduced plasma concentrations of the atherogenic LDL and apoB-containing lipoproteins. This lipoprotein phenotype characterized by elevated plasma HDL and reduced LDL levels leads to marked protection against the development of diet-induced atherosclerosis in LCAT transgenic rabbits compared to control animals."
This is what they actually want to do:
"1) Evaluate the feasibility of gene therapy utilizing the LCAT gene and suitable vectors as a treatment approach for the prevention of atherosclerosis in animal models as well as patients with premature cardiovascular disease; and,
2) Evaluate the use of gene therapy to correct LCAT deficiency in LCAT knockout mice models systems and patients with LCAT deficiency; and,
3) Develop and evaluate the anti-atherogenic properties of pharmacological agents that raise plasma concentrations of LCAT."
Franceschini thinks they will kill people doing this. OK, he's a bit more polite than that:
"This finding challenges the notion that LCAT is required for effective atheroprotection and suggests that elevating LCAT expression or activity is not a promising therapeutic strategy to reduce cardiovascular risk."
He has probably read about torcetrapib!
Anyway the bit which really absolutely grabbed me and had me rolling around giggling is this bit, selected from the above:
"This lipoprotein phenotype characterized by elevated plasma HDL and reduced LDL levels leads to marked protection against the development of diet-induced atherosclerosis in LCAT transgenic rabbits compared to control animals."
Okaaaaaay. Genetically engineered rabbits which make too much LCAT are protected against DIET INDUCED atherosclerosis. These people are talking about the cholesterol fed rabbit. Excess LCAT protects against cholesterol poisoning in rabbits.
Franceschini found DEFICIENCY of LCAT, in real humans, eating real human food (such as is eaten in Italy in 2009), is apparently protective against arteriosclerosis.
I find it very difficult to make a better case for the irrelevance of the cholesterol fed rabbit to anything other than the study of cholesterol poisoning in rabbits. This is rare in clinical practice. Ok, it's non existent outside of cardiology institutes!
Personally I'm not a rabbit.
Peter
Back to LCAT. I was checking the spelling of the non abbreviated text of LCAT and this grant proposal from 1995 was the first hit. I just had to read in in the aftermath of Franceschini's findings.
This is the logic to what they want to do, it's straightforward, hard core lipid hypothesis:
"SUMMARY: In humans, the development of atherosclerosis is positively and inversely correlated with the plasma levels of low density lipoproteins (LDL) and high density lipoproteins (HDL) respectively. LCAT, the major enzyme involved in the esterification of free cholesterol present in circulating plasma lipoproteins, is a major determinant of plasma HDL concentrations. Recent studies have established that transgenic rabbits overexpressing human LCAT have 6-7 fold higher plasma HDL levels than control, non-transgenic siblings. In addition, LCAT transgenic rabbits have reduced plasma concentrations of the atherogenic LDL and apoB-containing lipoproteins. This lipoprotein phenotype characterized by elevated plasma HDL and reduced LDL levels leads to marked protection against the development of diet-induced atherosclerosis in LCAT transgenic rabbits compared to control animals."
This is what they actually want to do:
"1) Evaluate the feasibility of gene therapy utilizing the LCAT gene and suitable vectors as a treatment approach for the prevention of atherosclerosis in animal models as well as patients with premature cardiovascular disease; and,
2) Evaluate the use of gene therapy to correct LCAT deficiency in LCAT knockout mice models systems and patients with LCAT deficiency; and,
3) Develop and evaluate the anti-atherogenic properties of pharmacological agents that raise plasma concentrations of LCAT."
Franceschini thinks they will kill people doing this. OK, he's a bit more polite than that:
"This finding challenges the notion that LCAT is required for effective atheroprotection and suggests that elevating LCAT expression or activity is not a promising therapeutic strategy to reduce cardiovascular risk."
He has probably read about torcetrapib!
Anyway the bit which really absolutely grabbed me and had me rolling around giggling is this bit, selected from the above:
"This lipoprotein phenotype characterized by elevated plasma HDL and reduced LDL levels leads to marked protection against the development of diet-induced atherosclerosis in LCAT transgenic rabbits compared to control animals."
Okaaaaaay. Genetically engineered rabbits which make too much LCAT are protected against DIET INDUCED atherosclerosis. These people are talking about the cholesterol fed rabbit. Excess LCAT protects against cholesterol poisoning in rabbits.
Franceschini found DEFICIENCY of LCAT, in real humans, eating real human food (such as is eaten in Italy in 2009), is apparently protective against arteriosclerosis.
I find it very difficult to make a better case for the irrelevance of the cholesterol fed rabbit to anything other than the study of cholesterol poisoning in rabbits. This is rare in clinical practice. Ok, it's non existent outside of cardiology institutes!
Personally I'm not a rabbit.
Peter
Wednesday, August 19, 2009
Cholesterol Milano style
This is my car, Milano. He's oldish, high milage, quite stylish and is somewhat ambivalent about whether he is a boy car or a girl car. He's also some sort of Italian derivative which means that spares can be an issue. I like him a lot and am dreading what the Glasgow winters will to to his incipient rust...
Anyway, this post is really about another Milano, the magical apoA1 Milano.
We all know that low HDL is associated with an increased risk of CHD. We know this from an enormous amount of observational evidence. In general, people with low HDL are much more likely to suffer a heart attack. Totally convincing association. This has lead to the hypothesis that HDL protects against heart attacks. To the point where researchers are now developing HDL-like particles as drugs. Pour 'em in and suck out that arteriosclerosis. Sooooo cool.
I suppose the first spanner in the works was apoA1 Milano. Even before torcetrapib.
The original study was published back in 1985 and is available as a pdf download here.
The original authors, Franceschini's group, concluded:
"The AIM [apoA1 Milano] variant originated in a community with a low prevalence of cardiovascular disease, which is certainly not attributable to the modest number of AIM carriers. We put forward the hypothesis that this may be the consequence of a general environmental condition in which the small community lived and which did not allow, up to now, the expression of the selective effect of the mutation."
It's worth emphasising that apoA1 Milano was found in a community which had a low prevalence of heart disease and, within that community, it was not considered to be the explanation for that low incidence of CVD. Everyone in the community was protected. An hypothesis I might suggest, derived from the lipid hypothesis patch of "HDL is good", is that under high CVD risk conditions that apoA1 Milano might be bad news. There was no selection effect to eliminate the gene in Limone sul Gardo because the population here was already doing something very right. Probably living on Lardo.
The impression I get from Franceschini is that he is proposing the opposite hypothesis. Because apoA1 Milano results in low HDL, people with it should have been sick, so there is magic in the single amino acid change which stops people with low HDL getting heart disease, so long as it's the Milano type HDL they have. Magic. Cranks up their trigs too, but still no problems. Super magic. This was back in 1985 and I don't see that Franceschini would be knocking the "HDL is good" hypothesis at that stage. The fact that Milano is different to normal apoA1 allowed this hypothesis to float briefly.
There's another genetic error resulting in low HDL, a problem with the gene for LCAT (Lecithin Cholesterol Acyltransferase). LCAT takes free cholesterol from tissues/lipoproteins and esterifies it ready for placing in to HDL particles. The mutation leads to cholesterol build up in some tissues and very low HDL levels in the blood. If you can't put cholesterol in to HDL, there won't be much HDL cholesterol. And what little HDL is present will have a normal apoA1 on it's surface. Nothing Milanesque about it. It's a dribble of that same HDL that keeps anyone with high HDL free of CVD, if you believe that. You would have thought this was an absolute cert of a recipe for atherosclerosis. It's not.
Franceschini's group did the work and were again good enough to publish in a journal with free access. The abstract is here. Just click on the PubMed link for full text.
It turns out that if you have a double dose of the defective LCAT gene you will be walking around with an HDL of around 9mg/dl. The standard deviation around this mean is almost 5mg/dl. Go figure how low some of these people must be on the HDL front. People with the LCAT mutation are rare, but are not clumped in anywhere particularly pleasant like Limone sul Gardo. They live in a nasty world of pasta and sugar based ice cream.
So what about arteriosclerosis?
The study used carotid intima-media thickness as a surrogate for arteriosclerosis. This seems reasonable to me. This is what was found:
"The average and maximum IMT values in the carriers were 0.07 [average] and 0.21 mm [maximum] smaller than in controls (P=0.0003 and P=0.0027), respectively. Moreover, the inheritance of a mutated LCAT genotype had a remarkable gene-dose-dependent effect in reducing carotid IMT (P=0.0003 for average IMT; P=0.001 for maximum IMT)."
I'll translate that. The lower the HDL the less the arteriosclerosis, p<0.0003. Count the zeros.
I think it's also worth mentioning that HDL transfers both apoprotein C2 and apoprotein E to VLDLs. No HDL means poor processing of VLDLs, exactly as for the Milano carriers. Do these victims also have high trigs, as well as low HDL? You bet they do. The lower the HDL and the higher the trigs, the less arteriosclerosis. Even though their HDL:trig ratio is appalling. Go figure. And you thought trigs were sticky and caused...
That's really all I wanted to say about papers. Having a high HDL might or might not be good or bad. If you are a sort of average person with sort of average genes the level of HDL in you bloodstream reflects the amount of fat, particularly saturated fat, in your diet. It's a surrogate. It seems a perfectly reasonable point of view that it is the saturated fat that is good and the HDL merely reflects this, an epiphenomenon. Get a gene for low HDL but do what, in anyone else, should raise HDL and perhaps you will still get the benefits, without the "marker" of high HDL. This seems to be a perfectly reasonable hypothesis to me.
Other than eating saturated fat, accessing saturated fat by weight loss or mimicking ketones by taking niacin, you don't have many levers left to raise HDL anyway. Torcetrapib excepted, and we all know about poor old torcetrapib.
This was all floating around the desktop but the post was triggered by Lynn's comments on the previous post. She has an elevated sdLDL number, the evil incarnate sort of LDL, despite a very sensible eating pattern. So you have to ask whether what matters is the eating pattern or the lipoprotein pattern. Does it matter what your lipids are, if you are eating real food such as eaten by Lynn or even the Kitavans?
Personally I'm a little envious of Lynn's calcium score of zero despite the sdLDL. Only an n=1 anecdote, but I like it. I feel this calcium score might matter more than a sdLDL number. After all, people try and lower their sdLDL to achieve what she already possesses...
Never forget that originally total cholesterol was evil incarnate, then LDL was bad, now sdLDL is bad, what will be the next bodge? I tend to favour purple spotted sdLDL as the problem. Anyone with the pink tinged sdLDL will be fine. Until the next ad hoc is floated.
Oh, and just an addendum on apoA1 Milano and my favourite cardiologist Dr Nissen:
Nissen is using apoA1 Milano as "Drano" [©Kendrick] to unblock coronary arteries. His logic, as far as logic goes, appears to have been that the low HDL in a few members of a generally heart disease free population must have been due to some magic in its structure to produce protection using just this miniscule amount of special HDL. The fact that the whole population was particularly heart healthy seems to have escaped him. And of course, if he'd been interested enough to find out why that population was healthy he might have succeeded in preventing heart disease. But that's not a lot of use when you can make money from a cure. Nissen can get atherosclerosis regression with intravenous apoA1 Milano, a cure!
So how does apoA1 Milano Drano work? You could say it doesn't, and Nissen is a crook, but I would never say anything like that. Obviously apoA1 Milano really does hoover cholesterol out of atheroma and transport it back to the liver. Err, like yeah.
What have people other than Nissen found out about apoA1 Milano? How about this:
"In fact, in some systems, acceptors containing the Milano variant of apoA-I promoted significantly less efflux than the acceptors containing wild-type apoA-I (apoA-I(wt)). Additionally, intracellular cholesteryl ester hydrolysis in macrophage foam cells was not different in the presence of either apoA-I(Milano) or apoA-I(wt). CONCLUSION: Collectively these studies suggest that if the Milano variant of apoA-I offers greater atheroprotection than wild-type apoA-I, it is not attributable to greater cellular lipid mobilization."
Translation: However the Drano works (oops, I mean IF the Drano works... sceptics, these folks), it's not by reverse cholesterol transport. Poof, what's that I hear, another patch on the lipid hypothesis bursting?
So how does apoA1 Milano work to alter the thickness of abnormal arteries on ultrasound scan?
These people seem to have some sort of an idea:
"In in vitro studies, incubation of platelets with apoA1 Milano reduced ADP-induced platelet aggregation by about 50%, but apoA1 Milano had no direct effect on vasoreactivity. This study provides further evidence for critical role of platelets in thrombosis. Use of apoA1 Milano offers a novel approach to inhibit arterial thrombosis."
Translation: apoA1 Milano is an antithrombotic agent. A bit like statins really. Or, dare I mention anything this cheap, aspirin. The thrombosis theory of arteriosclerosis got a bit sidelined by the cholesterol fed rabbit. Amazing what people believe.
Peter
Anyway, this post is really about another Milano, the magical apoA1 Milano.
We all know that low HDL is associated with an increased risk of CHD. We know this from an enormous amount of observational evidence. In general, people with low HDL are much more likely to suffer a heart attack. Totally convincing association. This has lead to the hypothesis that HDL protects against heart attacks. To the point where researchers are now developing HDL-like particles as drugs. Pour 'em in and suck out that arteriosclerosis. Sooooo cool.
I suppose the first spanner in the works was apoA1 Milano. Even before torcetrapib.
The original study was published back in 1985 and is available as a pdf download here.
The original authors, Franceschini's group, concluded:
"The AIM [apoA1 Milano] variant originated in a community with a low prevalence of cardiovascular disease, which is certainly not attributable to the modest number of AIM carriers. We put forward the hypothesis that this may be the consequence of a general environmental condition in which the small community lived and which did not allow, up to now, the expression of the selective effect of the mutation."
It's worth emphasising that apoA1 Milano was found in a community which had a low prevalence of heart disease and, within that community, it was not considered to be the explanation for that low incidence of CVD. Everyone in the community was protected. An hypothesis I might suggest, derived from the lipid hypothesis patch of "HDL is good", is that under high CVD risk conditions that apoA1 Milano might be bad news. There was no selection effect to eliminate the gene in Limone sul Gardo because the population here was already doing something very right. Probably living on Lardo.
The impression I get from Franceschini is that he is proposing the opposite hypothesis. Because apoA1 Milano results in low HDL, people with it should have been sick, so there is magic in the single amino acid change which stops people with low HDL getting heart disease, so long as it's the Milano type HDL they have. Magic. Cranks up their trigs too, but still no problems. Super magic. This was back in 1985 and I don't see that Franceschini would be knocking the "HDL is good" hypothesis at that stage. The fact that Milano is different to normal apoA1 allowed this hypothesis to float briefly.
There's another genetic error resulting in low HDL, a problem with the gene for LCAT (Lecithin Cholesterol Acyltransferase). LCAT takes free cholesterol from tissues/lipoproteins and esterifies it ready for placing in to HDL particles. The mutation leads to cholesterol build up in some tissues and very low HDL levels in the blood. If you can't put cholesterol in to HDL, there won't be much HDL cholesterol. And what little HDL is present will have a normal apoA1 on it's surface. Nothing Milanesque about it. It's a dribble of that same HDL that keeps anyone with high HDL free of CVD, if you believe that. You would have thought this was an absolute cert of a recipe for atherosclerosis. It's not.
Franceschini's group did the work and were again good enough to publish in a journal with free access. The abstract is here. Just click on the PubMed link for full text.
It turns out that if you have a double dose of the defective LCAT gene you will be walking around with an HDL of around 9mg/dl. The standard deviation around this mean is almost 5mg/dl. Go figure how low some of these people must be on the HDL front. People with the LCAT mutation are rare, but are not clumped in anywhere particularly pleasant like Limone sul Gardo. They live in a nasty world of pasta and sugar based ice cream.
So what about arteriosclerosis?
The study used carotid intima-media thickness as a surrogate for arteriosclerosis. This seems reasonable to me. This is what was found:
"The average and maximum IMT values in the carriers were 0.07 [average] and 0.21 mm [maximum] smaller than in controls (P=0.0003 and P=0.0027), respectively. Moreover, the inheritance of a mutated LCAT genotype had a remarkable gene-dose-dependent effect in reducing carotid IMT (P=0.0003 for average IMT; P=0.001 for maximum IMT)."
I'll translate that. The lower the HDL the less the arteriosclerosis, p<0.0003. Count the zeros.
I think it's also worth mentioning that HDL transfers both apoprotein C2 and apoprotein E to VLDLs. No HDL means poor processing of VLDLs, exactly as for the Milano carriers. Do these victims also have high trigs, as well as low HDL? You bet they do. The lower the HDL and the higher the trigs, the less arteriosclerosis. Even though their HDL:trig ratio is appalling. Go figure. And you thought trigs were sticky and caused...
That's really all I wanted to say about papers. Having a high HDL might or might not be good or bad. If you are a sort of average person with sort of average genes the level of HDL in you bloodstream reflects the amount of fat, particularly saturated fat, in your diet. It's a surrogate. It seems a perfectly reasonable point of view that it is the saturated fat that is good and the HDL merely reflects this, an epiphenomenon. Get a gene for low HDL but do what, in anyone else, should raise HDL and perhaps you will still get the benefits, without the "marker" of high HDL. This seems to be a perfectly reasonable hypothesis to me.
Other than eating saturated fat, accessing saturated fat by weight loss or mimicking ketones by taking niacin, you don't have many levers left to raise HDL anyway. Torcetrapib excepted, and we all know about poor old torcetrapib.
This was all floating around the desktop but the post was triggered by Lynn's comments on the previous post. She has an elevated sdLDL number, the evil incarnate sort of LDL, despite a very sensible eating pattern. So you have to ask whether what matters is the eating pattern or the lipoprotein pattern. Does it matter what your lipids are, if you are eating real food such as eaten by Lynn or even the Kitavans?
Personally I'm a little envious of Lynn's calcium score of zero despite the sdLDL. Only an n=1 anecdote, but I like it. I feel this calcium score might matter more than a sdLDL number. After all, people try and lower their sdLDL to achieve what she already possesses...
Never forget that originally total cholesterol was evil incarnate, then LDL was bad, now sdLDL is bad, what will be the next bodge? I tend to favour purple spotted sdLDL as the problem. Anyone with the pink tinged sdLDL will be fine. Until the next ad hoc is floated.
Oh, and just an addendum on apoA1 Milano and my favourite cardiologist Dr Nissen:
Nissen is using apoA1 Milano as "Drano" [©Kendrick] to unblock coronary arteries. His logic, as far as logic goes, appears to have been that the low HDL in a few members of a generally heart disease free population must have been due to some magic in its structure to produce protection using just this miniscule amount of special HDL. The fact that the whole population was particularly heart healthy seems to have escaped him. And of course, if he'd been interested enough to find out why that population was healthy he might have succeeded in preventing heart disease. But that's not a lot of use when you can make money from a cure. Nissen can get atherosclerosis regression with intravenous apoA1 Milano, a cure!
So how does apoA1 Milano Drano work? You could say it doesn't, and Nissen is a crook, but I would never say anything like that. Obviously apoA1 Milano really does hoover cholesterol out of atheroma and transport it back to the liver. Err, like yeah.
What have people other than Nissen found out about apoA1 Milano? How about this:
"In fact, in some systems, acceptors containing the Milano variant of apoA-I promoted significantly less efflux than the acceptors containing wild-type apoA-I (apoA-I(wt)). Additionally, intracellular cholesteryl ester hydrolysis in macrophage foam cells was not different in the presence of either apoA-I(Milano) or apoA-I(wt). CONCLUSION: Collectively these studies suggest that if the Milano variant of apoA-I offers greater atheroprotection than wild-type apoA-I, it is not attributable to greater cellular lipid mobilization."
Translation: However the Drano works (oops, I mean IF the Drano works... sceptics, these folks), it's not by reverse cholesterol transport. Poof, what's that I hear, another patch on the lipid hypothesis bursting?
So how does apoA1 Milano work to alter the thickness of abnormal arteries on ultrasound scan?
These people seem to have some sort of an idea:
"In in vitro studies, incubation of platelets with apoA1 Milano reduced ADP-induced platelet aggregation by about 50%, but apoA1 Milano had no direct effect on vasoreactivity. This study provides further evidence for critical role of platelets in thrombosis. Use of apoA1 Milano offers a novel approach to inhibit arterial thrombosis."
Translation: apoA1 Milano is an antithrombotic agent. A bit like statins really. Or, dare I mention anything this cheap, aspirin. The thrombosis theory of arteriosclerosis got a bit sidelined by the cholesterol fed rabbit. Amazing what people believe.
Peter
Wednesday, August 12, 2009
Shazia and Dr Clifton
The following is pure fantasy. If it's too offensive I'll take it down. Blame George for forwarding the link to me. Better read the original text before going on to my travesty.
Here's the original.
Here's the travesty:
Dr Peter Clifton, a human nutrition researcher from Adelaide, has recently made surgical history as the first nutrition researcher to receive a functional human brain.
The newly implanted brain, inserted during a 15 hour neurosurgical procedure, has allowed him perceptive thought for the first time in his life. Looking back on his most recent research presentation using his newly acquired brain, he was interviewed by Shazia Qureshi for DGDispatch.
Qureshi: Dr Clifton, what do you now think about the elevation in LDL cholesterol that was found in the low carbohydrate, high saturated fat arm of your study?
Dr Clifton: Well Shazia, I can't believe I've been such a berk. We've known since the 1980s that saturated fat increases the size of LDL particles, to give the large fluffy non atherogenic type, which can typically give an increase in calculated LDL of 20% or more but with a marked reduction in cardiovascular risk. Of course, before my brain implant I simply assumed a 19% rise in LDL implied 19% more bad stuff. I'd never read the literature and had no idea there could be good LDL. Just stupidity, pure and simple. I'm so embarrassed.
Qureshi: How about the change in HDL cholesterol? Was this adversely affected by the saturated fat diet?
Dr Clifton: God no, Shazia, it improved dramatically, by 21%, on the saturated fat diet, that's over 4 times as much as the low fat group who only achieved a 5% increase. Now I can see the low fat group only managed their pityful 5% rise because they were accessing their own supplies of saturated fat due to weight loss. If we'd not starved the poor buggers their HDL would certainly have dropped. Now I realise that HDL always drops on low fat diets unless there is weight loss. What a pillock I've been!
Quershi: Tell me more about the weight loss.
Dr Clifton: Well of course it was greater in the low carbohydrate group, but luckily the difference didn't make statistical significance. Sheesh, at least I didn't come over as such a drongo on that one. Bit of a relief really.
Qureshi: What about the flow mediated dilation?
Dr Clifton: Well again, bit of a pillock on this one. Of course we've known for decades that flow mediated arterial dilation is blunted by free fatty acids. And, because I have always recommended low fat diets, the only way anyone could have any amount of free fatty acids in their circulation is if they are in advanced metabolic syndrome and have started to spill un-needed and uncontrolled free fatty acids from their adipose tissue. Of course these people are in trouble cardiovascular wise. I should know, I've gotten them there by telling them that fructose is great stuff as it's low in fat and a bit is found in fruit, so a giant Pepsi is fine... If only I'd had this brain sooner.
With a brain all you have to do is ask yourself: What substance is a low carbohydrate dieter going to run their metabolism on? It's not going to be glucose is it? And if they are loosing adipose tissue as free fatty acids and getting even more fat from their diet, it's obvious that there is going to have to be a higher level of free fatty acids in their bloodstream. God knows why I didn't measure them. Oh, guess that's because I didn't have a brain... It's not clear why free fatty acids blunt flow mediated dilation. I guess that's mostly because the research on this subject was done by people like me. I should have realised my boo boo when we got the pulse wave velocity results.
Qureshi: Yes, you measured the stiffness of the aorta using the time taken for the pressure wave from the heart beat to reach the lower limbs. This must have been much worse in the saturated fat group, with all that elevated LDL cholesterol clogging everything up and no ability to dilate arteries after they've had a tourniquet on their arm.
Dr Clifton: You'd have thought that I'd have realised I was talking a load of bollocks about cholesterol and flow mediated dilation when the low carbohydrate group improved their pulse wave velocity as much as the low fatters. But don't forget, I had no brain in those days. This is so embarrassing. I actually said long-term consumption of a low-carb diet may have detrimental effects on cardiovascular risk.
Do you think anyone might have noticed?
Qureshi: I hope not.
Here's the original.
Here's the travesty:
Dr Peter Clifton, a human nutrition researcher from Adelaide, has recently made surgical history as the first nutrition researcher to receive a functional human brain.
The newly implanted brain, inserted during a 15 hour neurosurgical procedure, has allowed him perceptive thought for the first time in his life. Looking back on his most recent research presentation using his newly acquired brain, he was interviewed by Shazia Qureshi for DGDispatch.
Qureshi: Dr Clifton, what do you now think about the elevation in LDL cholesterol that was found in the low carbohydrate, high saturated fat arm of your study?
Dr Clifton: Well Shazia, I can't believe I've been such a berk. We've known since the 1980s that saturated fat increases the size of LDL particles, to give the large fluffy non atherogenic type, which can typically give an increase in calculated LDL of 20% or more but with a marked reduction in cardiovascular risk. Of course, before my brain implant I simply assumed a 19% rise in LDL implied 19% more bad stuff. I'd never read the literature and had no idea there could be good LDL. Just stupidity, pure and simple. I'm so embarrassed.
Qureshi: How about the change in HDL cholesterol? Was this adversely affected by the saturated fat diet?
Dr Clifton: God no, Shazia, it improved dramatically, by 21%, on the saturated fat diet, that's over 4 times as much as the low fat group who only achieved a 5% increase. Now I can see the low fat group only managed their pityful 5% rise because they were accessing their own supplies of saturated fat due to weight loss. If we'd not starved the poor buggers their HDL would certainly have dropped. Now I realise that HDL always drops on low fat diets unless there is weight loss. What a pillock I've been!
Quershi: Tell me more about the weight loss.
Dr Clifton: Well of course it was greater in the low carbohydrate group, but luckily the difference didn't make statistical significance. Sheesh, at least I didn't come over as such a drongo on that one. Bit of a relief really.
Qureshi: What about the flow mediated dilation?
Dr Clifton: Well again, bit of a pillock on this one. Of course we've known for decades that flow mediated arterial dilation is blunted by free fatty acids. And, because I have always recommended low fat diets, the only way anyone could have any amount of free fatty acids in their circulation is if they are in advanced metabolic syndrome and have started to spill un-needed and uncontrolled free fatty acids from their adipose tissue. Of course these people are in trouble cardiovascular wise. I should know, I've gotten them there by telling them that fructose is great stuff as it's low in fat and a bit is found in fruit, so a giant Pepsi is fine... If only I'd had this brain sooner.
With a brain all you have to do is ask yourself: What substance is a low carbohydrate dieter going to run their metabolism on? It's not going to be glucose is it? And if they are loosing adipose tissue as free fatty acids and getting even more fat from their diet, it's obvious that there is going to have to be a higher level of free fatty acids in their bloodstream. God knows why I didn't measure them. Oh, guess that's because I didn't have a brain... It's not clear why free fatty acids blunt flow mediated dilation. I guess that's mostly because the research on this subject was done by people like me. I should have realised my boo boo when we got the pulse wave velocity results.
Qureshi: Yes, you measured the stiffness of the aorta using the time taken for the pressure wave from the heart beat to reach the lower limbs. This must have been much worse in the saturated fat group, with all that elevated LDL cholesterol clogging everything up and no ability to dilate arteries after they've had a tourniquet on their arm.
Dr Clifton: You'd have thought that I'd have realised I was talking a load of bollocks about cholesterol and flow mediated dilation when the low carbohydrate group improved their pulse wave velocity as much as the low fatters. But don't forget, I had no brain in those days. This is so embarrassing. I actually said long-term consumption of a low-carb diet may have detrimental effects on cardiovascular risk.
Do you think anyone might have noticed?
Qureshi: I hope not.
Tuesday, August 11, 2009
Nicotine on the move
Just a quick post about moving, I was reminded by Tom Naughton's current post on his move.
We used a national company for the move, the driver plus three local helpers loaded the truck in Berkshire, he drove it up and two guys helped him unload at the Glasgow end.
All were thin as rakes. Obviously exercise makes you thin. Duh. These guys were exercising alright. Getting as many books as we own up the stairs, for storage in the bedroom cupboard, was no minor feat. This was almost certainly done on a diet of carbs and alcohol (not on the job of course, but one chap's comment was that he wouldn't want to attempt our Glasgow stairs on a Saturday night, crashing on the couch would be needed!).
At least that was how it seems on the surface. But in reality there is another factor involved. It brought home to me Gary Taubes' comment about nicotine releasing free fatty acids from adipocytes to allow humans access to the energy stored in their fat cells. Nicotine is an archetypal slimming drug.
Every 60 minutes there was an obligatory "fag break" as it was described. My impression was that they were automatically maintaining a fixed level of nicotine in their blood. Whether this was a fluke and we just happened to have six nicotine addicts in our crew, or whether people in hard manual labour accidentally discover that smoking makes the job a darn sight easier is open to speculation. But a few free fatty acids, irrespective of your insulin levels, might come in useful when you have to shift heavy stuff for hours at a time.
I doubt I'd have noticed anything without Gary Taubes giving the pointer.
Peter
We used a national company for the move, the driver plus three local helpers loaded the truck in Berkshire, he drove it up and two guys helped him unload at the Glasgow end.
All were thin as rakes. Obviously exercise makes you thin. Duh. These guys were exercising alright. Getting as many books as we own up the stairs, for storage in the bedroom cupboard, was no minor feat. This was almost certainly done on a diet of carbs and alcohol (not on the job of course, but one chap's comment was that he wouldn't want to attempt our Glasgow stairs on a Saturday night, crashing on the couch would be needed!).
At least that was how it seems on the surface. But in reality there is another factor involved. It brought home to me Gary Taubes' comment about nicotine releasing free fatty acids from adipocytes to allow humans access to the energy stored in their fat cells. Nicotine is an archetypal slimming drug.
Every 60 minutes there was an obligatory "fag break" as it was described. My impression was that they were automatically maintaining a fixed level of nicotine in their blood. Whether this was a fluke and we just happened to have six nicotine addicts in our crew, or whether people in hard manual labour accidentally discover that smoking makes the job a darn sight easier is open to speculation. But a few free fatty acids, irrespective of your insulin levels, might come in useful when you have to shift heavy stuff for hours at a time.
I doubt I'd have noticed anything without Gary Taubes giving the pointer.
Peter
Monday, August 10, 2009
Heart failure and insulin resistance
While I was off line for several weeks I had a browse through some of the random texts lying around my hard drive. This one in particular caught my eye and has started of a train of thought which seems interesting. This is the basics of the paper:
The healthy heart likes non esterified fatty acids:
"NEFA are the preferred metabolic substrate because of the high yield of ATP when NEFA are fully oxidized"
NEFA burn primarily in the mitochondria. But without oxygen there is no possibility of doing this, you cannot oxidise fats without oxygen. Glucose to lactate, an anaerobic process, yes:
"However, under circumstances of increased myocardial work or limited oxygen availability, the heart turns to glucose as the more efficient fuel for ATP generation"
Glycolysis, with its poor ATP yield, is better than no ATP at all and quite logical when there is insufficient oxygen to keep the mitochondria working. But when the heart is going in to failure it comes to prefer glucose, ultimately even at tickover:
"When the heart is injured and left ventricular (LV) function is depressed on a chronic basis, there is a shift to glucose as the preferred substrate under basal circumstances"
Why should this be? Why not stick with fat. NEFA are the devil you know and a very benign devil they are too... The problem is that the whole system for burning NEFA, from the cell surface receptor to the mitochondrial transport system has, by this stage, already been deliberately shut down:
"this shift in substrate preference is a highly regulated transcriptional event. Importantly, the changes in gene transcription involve down-regulation of transport mechanisms and enzymes involved in fatty acid oxidation. This includes decreases in the NEFA receptor—peroxisome proliferator activated receptor- alpha (PPAR alpha)—and its co-factor, the retinoic acid receptor RXR, as well as a series of enzymes, including carnitine palmitoyltransferase-1 (CPT-1), which is rate limiting in the transport of fatty acid coenzyme A (CoA) to the inner mitochondrial membrane".
You have to wonder why this is. It's not some accidental failure. The heart is sitting in a sea of both NEFA and glucose, and it carefully shuts down it's NEFA processsing equipment to rely on glucose, then shuts off glucose uptake and dies. This is not an adaptive process!
The shut down of glucose usage probably comes back to good old fatty acids causing insulin resistance. The body has sensors for detecting a decreased cardiac output. On an evolutionary basis the assumption is that a serious fall in cardiac output is due to a serious loss of blood volume. Fluid retention and increased sympathetic nervous system activity are standard adaptive responses to blood loss. Increased sympathetic nervous system activity not only boosts cardiac work (hence increases cardiac output to compensate for low blood volume, mimicked by the failing myocardium) at the cost of increased oxygen demand, but also releases free fatty acids from adipocytes to supply the evolutionarily preferred heart fuel. Actually, the NEFA will supply a large proportion of the whole body needs because if you been mauled by a tiger you're not going to go grubbing for tubers to run your metabolism on glucose. Free fatty acids are taken up by the heart down a concentration gradient. If they accumulate in the cytoplasm because the heart has shut down its fat burning system it's easy to see why triglycerides accumulate in the cell. This signals insulin resistance. There is enough fat, no need for glucose. This makes the heart say no to glucose, that's understandable.
Unfortunately, if the fatty acid burning system has been carefully and inappropriately shut down, saying no to glucose becomes catastrophic. Which it is.
The whole drive of the paper is to develop techniques to get the heart back running on glucose in the face of myocardial insulin resistance, for which we can read due to a failure to burn NEFA. Obviously a supra physiological infusion of insulin would overcome this, but it's a big volume to give to a heart failure patient and causes issues with sodium retention anyway, another post there. So insulin sensitisers are high on the priority list. Pity Actos and Avandia cause heart failure! Interestingly among the several postulated mechanism of action suggested for metformin, one is increasing fatty acid oxidation. In my simplistic view this would decrease intracellular triglycerides and allow a reduction in insulin resistance. Thiazolidinediones and other insulin sensitisers are the drugs the paper is thinking about:
"At present, concerns about peripheral edema have limited the use of TZDs (Thiazolidinediones [Actos and Avandia]) in patients with heart failure, although the mechanisms of this phenomenon have not been elucidated. An attractive alternative might involve the derivatives of the proglucagon family, the glucagonlike peptides, which possess insulinotropic, insulinomimetic, and glucagonostatic properties. Importantly, these naturally occurring incretins are largely devoid of hypoglycemic risks, as their insulinotropic properties are attenuated when plasma glucose falls below 70 mg/dL. The short duration of action requires continuous subcutaneous infusion, which constitutes a potential drawback to chronic treatment"
OK, hands up who has spotted the missing idea? Yes, right in one, ketone bodies. Straight to the mitochondria without insulin, CD38 or CPT-1. Increased cardiac work/output without increased oxygen demand. They completely by pass insulin resistance. So they're a nice sticking plaster on a much more interesting problem.
The interesting problem is: Why did the myocardium decide to shut down its fat burning system?
I think you can argue that it is because glucose is so toxic when it is present in high levels in the blood stream that it has to be burned first. While it is still within the power of the pancreas to force glucose in to muscles cells, those cells burn it rather than having it lying around glycating every protein in sight. A little can be stored as glycogen, but if you are on the SAD (including the 3.00am refrigerator raids, and that's not roast beef in the fridge...) and chronically hyperglycaemic/hyperinsulinaemic, glycogen stores are going to be more than full. No, chronic excess glucose oversupply needs burning as fast as possible, you can pack away the far burning system if blood glucose concentration is always being pushed upwards. Maintain this for long enough and it becomes a way of life, and eventually a way of death. Burning glucose in the face of increasing insulin resistance due to the sympathetic nervous system freeing up NEFA, being unaware of the catastrophic loss of fat burning ability, is a non starter.
Ketosis and normolgycaemia would allow the unpackaging of that stored fat burning system. It's not gone for ever, the genes are still there.... Given a few tools NEFA no longer need be the enemy, rather the preferred fuel once again. As the primary fuel the fact that they are present in the cytoplasm signalling the rejection of glucose by signalling insulin resistance is no problem. With efficient fat burning, as soon as the NEFA supply drops cytoplasm trigycerides will drop and insulin can get back to work to allow glucose to be used.
Things can get back to the way they were meant to be with NEFA as the primary fuel with the additional facility to use glucose in dire circumstances.
More on the shutting down of fat burning next.
Peter
The healthy heart likes non esterified fatty acids:
"NEFA are the preferred metabolic substrate because of the high yield of ATP when NEFA are fully oxidized"
NEFA burn primarily in the mitochondria. But without oxygen there is no possibility of doing this, you cannot oxidise fats without oxygen. Glucose to lactate, an anaerobic process, yes:
"However, under circumstances of increased myocardial work or limited oxygen availability, the heart turns to glucose as the more efficient fuel for ATP generation"
Glycolysis, with its poor ATP yield, is better than no ATP at all and quite logical when there is insufficient oxygen to keep the mitochondria working. But when the heart is going in to failure it comes to prefer glucose, ultimately even at tickover:
"When the heart is injured and left ventricular (LV) function is depressed on a chronic basis, there is a shift to glucose as the preferred substrate under basal circumstances"
Why should this be? Why not stick with fat. NEFA are the devil you know and a very benign devil they are too... The problem is that the whole system for burning NEFA, from the cell surface receptor to the mitochondrial transport system has, by this stage, already been deliberately shut down:
"this shift in substrate preference is a highly regulated transcriptional event. Importantly, the changes in gene transcription involve down-regulation of transport mechanisms and enzymes involved in fatty acid oxidation. This includes decreases in the NEFA receptor—peroxisome proliferator activated receptor- alpha (PPAR alpha)—and its co-factor, the retinoic acid receptor RXR, as well as a series of enzymes, including carnitine palmitoyltransferase-1 (CPT-1), which is rate limiting in the transport of fatty acid coenzyme A (CoA) to the inner mitochondrial membrane".
You have to wonder why this is. It's not some accidental failure. The heart is sitting in a sea of both NEFA and glucose, and it carefully shuts down it's NEFA processsing equipment to rely on glucose, then shuts off glucose uptake and dies. This is not an adaptive process!
The shut down of glucose usage probably comes back to good old fatty acids causing insulin resistance. The body has sensors for detecting a decreased cardiac output. On an evolutionary basis the assumption is that a serious fall in cardiac output is due to a serious loss of blood volume. Fluid retention and increased sympathetic nervous system activity are standard adaptive responses to blood loss. Increased sympathetic nervous system activity not only boosts cardiac work (hence increases cardiac output to compensate for low blood volume, mimicked by the failing myocardium) at the cost of increased oxygen demand, but also releases free fatty acids from adipocytes to supply the evolutionarily preferred heart fuel. Actually, the NEFA will supply a large proportion of the whole body needs because if you been mauled by a tiger you're not going to go grubbing for tubers to run your metabolism on glucose. Free fatty acids are taken up by the heart down a concentration gradient. If they accumulate in the cytoplasm because the heart has shut down its fat burning system it's easy to see why triglycerides accumulate in the cell. This signals insulin resistance. There is enough fat, no need for glucose. This makes the heart say no to glucose, that's understandable.
Unfortunately, if the fatty acid burning system has been carefully and inappropriately shut down, saying no to glucose becomes catastrophic. Which it is.
The whole drive of the paper is to develop techniques to get the heart back running on glucose in the face of myocardial insulin resistance, for which we can read due to a failure to burn NEFA. Obviously a supra physiological infusion of insulin would overcome this, but it's a big volume to give to a heart failure patient and causes issues with sodium retention anyway, another post there. So insulin sensitisers are high on the priority list. Pity Actos and Avandia cause heart failure! Interestingly among the several postulated mechanism of action suggested for metformin, one is increasing fatty acid oxidation. In my simplistic view this would decrease intracellular triglycerides and allow a reduction in insulin resistance. Thiazolidinediones and other insulin sensitisers are the drugs the paper is thinking about:
"At present, concerns about peripheral edema have limited the use of TZDs (Thiazolidinediones [Actos and Avandia]) in patients with heart failure, although the mechanisms of this phenomenon have not been elucidated. An attractive alternative might involve the derivatives of the proglucagon family, the glucagonlike peptides, which possess insulinotropic, insulinomimetic, and glucagonostatic properties. Importantly, these naturally occurring incretins are largely devoid of hypoglycemic risks, as their insulinotropic properties are attenuated when plasma glucose falls below 70 mg/dL. The short duration of action requires continuous subcutaneous infusion, which constitutes a potential drawback to chronic treatment"
OK, hands up who has spotted the missing idea? Yes, right in one, ketone bodies. Straight to the mitochondria without insulin, CD38 or CPT-1. Increased cardiac work/output without increased oxygen demand. They completely by pass insulin resistance. So they're a nice sticking plaster on a much more interesting problem.
The interesting problem is: Why did the myocardium decide to shut down its fat burning system?
I think you can argue that it is because glucose is so toxic when it is present in high levels in the blood stream that it has to be burned first. While it is still within the power of the pancreas to force glucose in to muscles cells, those cells burn it rather than having it lying around glycating every protein in sight. A little can be stored as glycogen, but if you are on the SAD (including the 3.00am refrigerator raids, and that's not roast beef in the fridge...) and chronically hyperglycaemic/hyperinsulinaemic, glycogen stores are going to be more than full. No, chronic excess glucose oversupply needs burning as fast as possible, you can pack away the far burning system if blood glucose concentration is always being pushed upwards. Maintain this for long enough and it becomes a way of life, and eventually a way of death. Burning glucose in the face of increasing insulin resistance due to the sympathetic nervous system freeing up NEFA, being unaware of the catastrophic loss of fat burning ability, is a non starter.
Ketosis and normolgycaemia would allow the unpackaging of that stored fat burning system. It's not gone for ever, the genes are still there.... Given a few tools NEFA no longer need be the enemy, rather the preferred fuel once again. As the primary fuel the fact that they are present in the cytoplasm signalling the rejection of glucose by signalling insulin resistance is no problem. With efficient fat burning, as soon as the NEFA supply drops cytoplasm trigycerides will drop and insulin can get back to work to allow glucose to be used.
Things can get back to the way they were meant to be with NEFA as the primary fuel with the additional facility to use glucose in dire circumstances.
More on the shutting down of fat burning next.
Peter
Thursday, August 06, 2009
Cholesterol: statins and oxLDL
I would just like to recap the lipid hypothesis for a moment. The basic idea is that an elevated level of LDL cholesterol, estimated by the Friedewald equation, makes these lipoprotein particles stick to your arterial walls, causes plaque to develop and eventually rupture. Saturated fat is the main dietary cause of heart disease because it is purported to elevate LDL cholesterol.
The key to treating heart disease is to lower LDL to below some arbitrary figure, mostly determined by the need for profit of Astra Zeneca or their ilk.
The most effective drugs to do this are the statins, which inhibit the synthesis of a basic metabolic precursor of many substances, one of which happens to be cholesterol. All tissues, particularly the liver, are then so desperate for cholesterol that they up-regulate the expression of genes coding for the LDL receptor and so pull in as much cholesterol as they can get by ingesting circulating LDL particles.
This lowering of LDL lipoproteins by statins is what is supposed to protect against, and even reverse, arteriosclerosis. Although some cardiologists accept that statins do have other effects, the lipid hypothesis says that dropping LDL is the core effect.
So, while taking a statin drug, we have cholesterol depleted cells sporting every LDL receptor they can muster to make up their deficit and this leads to a fall in plasma LDL level. Instead of there being 100 LDL particles per unit volume of blood there are now only 60 LDL particles, and hey presto, atheromatous plaque suddenly starts throwing its rancid lipids back in to those few LDL particles which still remain in the circulation!
Summary: At an LDL of 100mg/dl cholesterol packs in to arterial walls, at an LDL of 60mg/dl this very same lipoprotein becomes a magical hoover, sucking oxidised lipids out of the arterial wall.
You can even measure how good the statin is by how much oxidised phospholipid there is in your LDL lipoproteins!
If this seems to be a little far fetched, you are obviously not a cardiologist! Just check out here and here.
It is simply a fact that statinating people routinely increases the degree of oxidation of their few remaining LDL particles. Because statins are good, this change must be good too. It must be a marker of atheroma regression!
If the concept of an LDL particle sucking oxidised phospholipids out of atheroma sounds implausible, what is happening in statinated people to elevate their oxLDL? Is it good or bad?
Unadulterated LDL is non artherogenic and is taken up readily by cells which need cholesterol via their LDL receptors. Oxidised LDL is atherogenic but is NOT taken up by the LDL receptor because the glycation of the apoB100 protein, which also leads to LDL oxidation, stops it interacting with the LDL receptor.
So oxLDL tends to be left in the circulation while native LDL is taken up by cells affected by statins. There may be less oxLDL, but what is left is very sticky.
Perhaps this is good? Personally, while I think there are all sorts of considerations here, the overall answer seems to be that oxLDL is a Bad Thing. If you take a person who is exquisitely sensitive to simvastatin you can drop their TC from > 260mg/dl to < 160mg/dl. This will probably give an LDL of around 80mg/dl. And a six times greater risk of cardiovascular death than if their TC only dropped to 210mg/dl. Much of that residual LDL with be highly oxidised
An LDL of 60-80mg/dl, produced by removing ONLY the non-atherogenic component of LDL from the plasma, is going to be bad news. This is what statins do.
Never mind Nissen and his 500 victims, look at J-LIT and the 50,000. This gives a much better idea of what having a circulation with no LDL other than oxLDL does for you.
Does it seem incomprehensible that we could have made such a mistake with statins?
Yes, I think so.
Peter
The key to treating heart disease is to lower LDL to below some arbitrary figure, mostly determined by the need for profit of Astra Zeneca or their ilk.
The most effective drugs to do this are the statins, which inhibit the synthesis of a basic metabolic precursor of many substances, one of which happens to be cholesterol. All tissues, particularly the liver, are then so desperate for cholesterol that they up-regulate the expression of genes coding for the LDL receptor and so pull in as much cholesterol as they can get by ingesting circulating LDL particles.
This lowering of LDL lipoproteins by statins is what is supposed to protect against, and even reverse, arteriosclerosis. Although some cardiologists accept that statins do have other effects, the lipid hypothesis says that dropping LDL is the core effect.
So, while taking a statin drug, we have cholesterol depleted cells sporting every LDL receptor they can muster to make up their deficit and this leads to a fall in plasma LDL level. Instead of there being 100 LDL particles per unit volume of blood there are now only 60 LDL particles, and hey presto, atheromatous plaque suddenly starts throwing its rancid lipids back in to those few LDL particles which still remain in the circulation!
Summary: At an LDL of 100mg/dl cholesterol packs in to arterial walls, at an LDL of 60mg/dl this very same lipoprotein becomes a magical hoover, sucking oxidised lipids out of the arterial wall.
You can even measure how good the statin is by how much oxidised phospholipid there is in your LDL lipoproteins!
If this seems to be a little far fetched, you are obviously not a cardiologist! Just check out here and here.
It is simply a fact that statinating people routinely increases the degree of oxidation of their few remaining LDL particles. Because statins are good, this change must be good too. It must be a marker of atheroma regression!
If the concept of an LDL particle sucking oxidised phospholipids out of atheroma sounds implausible, what is happening in statinated people to elevate their oxLDL? Is it good or bad?
Unadulterated LDL is non artherogenic and is taken up readily by cells which need cholesterol via their LDL receptors. Oxidised LDL is atherogenic but is NOT taken up by the LDL receptor because the glycation of the apoB100 protein, which also leads to LDL oxidation, stops it interacting with the LDL receptor.
So oxLDL tends to be left in the circulation while native LDL is taken up by cells affected by statins. There may be less oxLDL, but what is left is very sticky.
Perhaps this is good? Personally, while I think there are all sorts of considerations here, the overall answer seems to be that oxLDL is a Bad Thing. If you take a person who is exquisitely sensitive to simvastatin you can drop their TC from > 260mg/dl to < 160mg/dl. This will probably give an LDL of around 80mg/dl. And a six times greater risk of cardiovascular death than if their TC only dropped to 210mg/dl. Much of that residual LDL with be highly oxidised
An LDL of 60-80mg/dl, produced by removing ONLY the non-atherogenic component of LDL from the plasma, is going to be bad news. This is what statins do.
Never mind Nissen and his 500 victims, look at J-LIT and the 50,000. This gives a much better idea of what having a circulation with no LDL other than oxLDL does for you.
Does it seem incomprehensible that we could have made such a mistake with statins?
Yes, I think so.
Peter
Wednesday, August 05, 2009
Back on line
BT have finally strung the necessary two tin cans and piece of string to our rental house in Bearsden and we are back on line. A bit of reading to do and then I'll get to a few replies and posts.
Glasgow is excellent. There are really weird things like not having to pay at railway station car parks or for parking anywhere else outside the city centre, a train service to town where you don't look at the time table, just pole up and wait for a train, there are hills pushing in to the suburbs, it's light much longer than down south (until the equinox) but the really strange thing is how polite everyone is. A minor near collision with a supermarket trolley is grounds for profuse apologies on both sides. It's not like the M4 corridor! Just weird. But nice.
Peter
Glasgow is excellent. There are really weird things like not having to pay at railway station car parks or for parking anywhere else outside the city centre, a train service to town where you don't look at the time table, just pole up and wait for a train, there are hills pushing in to the suburbs, it's light much longer than down south (until the equinox) but the really strange thing is how polite everyone is. A minor near collision with a supermarket trolley is grounds for profuse apologies on both sides. It's not like the M4 corridor! Just weird. But nice.
Peter
Monday, July 20, 2009
Here we go
OK, the move begins tomorrow. Apologies for the several non answered emails, I'll get to them when we're a bit unpacked and have got net access up and running in Bearsden!
Peter
Peter
Tuesday, July 07, 2009
May 2009: ASTEROID destroys lipid hypothesis!
Here's a nice quote from this paper:
"Atheroma regression occurred in most patients and was not linked to the LDL cholesterol achieved"
Read that line very carefully. Now read it again. That's it, the rest of the post is just rambling on my part.
But is the lipid hypothesis dead? To quote Malcolm Kendrick from 2005 on a different study:
"The great ship Cholesterol-Lowering has ripped its guts out on the harsh rocks of evidence, but still it does not sink"
ASTEROID was a mini version of the J-LIT study (see below) with three modifications. First it was only 501 patients, so there was never any possibility of looking at clinical outcomes, good or bad. Second was it was only run for two years, which repeats point one but with underlining. Third is that they used a crippling dose of statin, sufficient to drop the mean LDL cholesterol level to 60mg/dl.
Luckily there were minimal adverse reactions to this, if you believe Nissen, which I don't:
"Adverse events were infrequent and similar to other statin trials"
Anyway, they went looking for adverse reactions by level of LDL cholesterol, much as did J-LIT. As might be expected there was no graduation of adverse reactions by cholesterol level because, as Nissen might say, there weren't any!
"Adverse events occurred infrequently during the trial, and no pattern appeared relating the frequency of any adverse event to the achieved LDL cholesterol"
Dying of cancer is difficult in 2 years in the USA. Try five years in Japan, or 10 years in Japan, and use over a 40,000 rather than 500 patients. The excess deaths in the lowest LDL groups will be there, just don't expect them to show in 500 patients.
Final quote:
"Similarly, the on-treatment atheroma volume, change in atheroma volume, and high percentage of subjects with atheroma regression did not differ by the achieved LDL cholesterol"
This is a classic. If the lowering of LDL does not correlate with atheroma volume decrease, why do people believe that lowering LDL is what shrinks atheroma? And if the statin per se is causing atheroma shrinkage, which it certainly is, how come long term large studies of the same design show an increasing body count from cardiac causes when statinating to very low levels of LDL? That's what happened in J-LIT and it's what will happen in ASTEROID if they keep going, except 500 people is far to small to separate the occasional death from chance. Is statin induced atheroma shrinkage beneficial? J-LIT suggests not and ASTEROID is too miniscule to look at clinical outcomes. They will be bad.
Executive summary: lower LDL cholesterol has no linkage to shrinkage of plaque.
Peter
"Atheroma regression occurred in most patients and was not linked to the LDL cholesterol achieved"
Read that line very carefully. Now read it again. That's it, the rest of the post is just rambling on my part.
But is the lipid hypothesis dead? To quote Malcolm Kendrick from 2005 on a different study:
"The great ship Cholesterol-Lowering has ripped its guts out on the harsh rocks of evidence, but still it does not sink"
ASTEROID was a mini version of the J-LIT study (see below) with three modifications. First it was only 501 patients, so there was never any possibility of looking at clinical outcomes, good or bad. Second was it was only run for two years, which repeats point one but with underlining. Third is that they used a crippling dose of statin, sufficient to drop the mean LDL cholesterol level to 60mg/dl.
Luckily there were minimal adverse reactions to this, if you believe Nissen, which I don't:
"Adverse events were infrequent and similar to other statin trials"
Anyway, they went looking for adverse reactions by level of LDL cholesterol, much as did J-LIT. As might be expected there was no graduation of adverse reactions by cholesterol level because, as Nissen might say, there weren't any!
"Adverse events occurred infrequently during the trial, and no pattern appeared relating the frequency of any adverse event to the achieved LDL cholesterol"
Dying of cancer is difficult in 2 years in the USA. Try five years in Japan, or 10 years in Japan, and use over a 40,000 rather than 500 patients. The excess deaths in the lowest LDL groups will be there, just don't expect them to show in 500 patients.
Final quote:
"Similarly, the on-treatment atheroma volume, change in atheroma volume, and high percentage of subjects with atheroma regression did not differ by the achieved LDL cholesterol"
This is a classic. If the lowering of LDL does not correlate with atheroma volume decrease, why do people believe that lowering LDL is what shrinks atheroma? And if the statin per se is causing atheroma shrinkage, which it certainly is, how come long term large studies of the same design show an increasing body count from cardiac causes when statinating to very low levels of LDL? That's what happened in J-LIT and it's what will happen in ASTEROID if they keep going, except 500 people is far to small to separate the occasional death from chance. Is statin induced atheroma shrinkage beneficial? J-LIT suggests not and ASTEROID is too miniscule to look at clinical outcomes. They will be bad.
Executive summary: lower LDL cholesterol has no linkage to shrinkage of plaque.
Peter
Tuesday, June 30, 2009
Gluten and schizophrenia SPECT scan
I've been meaning to post about the gluten schizophrenia paper in Nutrition and Metabolism, prompted by the paper itself, a forward from Bloggeier and now a reminder on the THINCS formum by Bogdan. But it turned in to an epic with lots of threads to interweave so, while I get it sorted, here's a quick one liner on the joys of a gluten based diet that I can fit in over a coffee break now I've run out of filler and floor board timber.
Take one adult established schizophrenic with recent onset diarrhoea and weight loss. For some reason do a SPECT scan to look at the blood flow within their brain and note that it is abnormal in the left frontal lobe.
Place on gluten free diet.
Re-scan a little while later and re-biopsy the gut.
All cured, including the "schizophrenic" disorder.
You don't have to be mad to eat bread, but you might end up that way!
Peter
BTW it's possible to speculate whether the blood flow is a vascular phenomenon due to the gluten affecting the arteries in the brain or a hypoperfusion due to abnormal brain metabolism, ie a direct neural effect. I'd never really considered that the gluten effects on the brain might be vascular...
Take one adult established schizophrenic with recent onset diarrhoea and weight loss. For some reason do a SPECT scan to look at the blood flow within their brain and note that it is abnormal in the left frontal lobe.
Place on gluten free diet.
Re-scan a little while later and re-biopsy the gut.
All cured, including the "schizophrenic" disorder.
You don't have to be mad to eat bread, but you might end up that way!
Peter
BTW it's possible to speculate whether the blood flow is a vascular phenomenon due to the gluten affecting the arteries in the brain or a hypoperfusion due to abnormal brain metabolism, ie a direct neural effect. I'd never really considered that the gluten effects on the brain might be vascular...
Saturday, June 27, 2009
Alzheimers and BSE: Prions are not Tau
While sniffing around BSE research in the aftermath of the Tau protein paper find I came upon this quite interesting review. A quick pubmed of the author suggests that BSE is, in her book, a viral infection by a currently uncharacterised virus about 25nm across. I'm not experienced enough at looking at electron micrographs to tell how convincing her pictures are, but they certainly look OK to me.
If she is correct then Prof Ebringer is wrong on this one, as he feels that the TSEs are auto immune attacks comparable to MS.
The biggest problem with the virus hypothesis is the effect of converting the virus to ash and still having it retain its infectivity. I'm a bit puzzled as to how formalin fixation might enhance the virulence of a virus too. This is not typical behaviour of virus particles. Where as sticking ash or formalin fixed gunk in to a brain may do enough of the right sort of damage to trigger an auto immune attack.
On top of this there is the fact that SCID (severe combined immunodeficient) mice are extremely resistant to BSE. How many viral problems are blunted by having a crippled immune system?
The problem here for the auto immune hypothesis is that while SCID mice are very resistant to BSE, they are not completely so. This is less of a problem to me as even SCID mice have some residual functional immune tissue and auto immune attack does not seem to be wholly dependent on antibodies, it probably uses all sorts of cells.
But ultimately it is becoming clearer that the prion hypothesis is probably wrong because the better the purification of putative infectious prion proteins, the lower the infectivity. I would guess that synthetic prion proteins will prove to be fully harmless unless their injection in to a mouse's brain does as much damage as injecting ash.
Add to this the limited ability of the brain to produce disease specific pathologies (ie most end stage diseases look similar!). CJD looks VERY like MS to a histopathologist and simply injecting TNFalpha in to the eye produces lesions indistinguishable from CJD in the optic nerve!
I think the jury is definitely out on this one but it will be interesting to watch the progress of the prion hypothesis and whether prions turn out to be neurotoxic at all.
Peter
If she is correct then Prof Ebringer is wrong on this one, as he feels that the TSEs are auto immune attacks comparable to MS.
The biggest problem with the virus hypothesis is the effect of converting the virus to ash and still having it retain its infectivity. I'm a bit puzzled as to how formalin fixation might enhance the virulence of a virus too. This is not typical behaviour of virus particles. Where as sticking ash or formalin fixed gunk in to a brain may do enough of the right sort of damage to trigger an auto immune attack.
On top of this there is the fact that SCID (severe combined immunodeficient) mice are extremely resistant to BSE. How many viral problems are blunted by having a crippled immune system?
The problem here for the auto immune hypothesis is that while SCID mice are very resistant to BSE, they are not completely so. This is less of a problem to me as even SCID mice have some residual functional immune tissue and auto immune attack does not seem to be wholly dependent on antibodies, it probably uses all sorts of cells.
But ultimately it is becoming clearer that the prion hypothesis is probably wrong because the better the purification of putative infectious prion proteins, the lower the infectivity. I would guess that synthetic prion proteins will prove to be fully harmless unless their injection in to a mouse's brain does as much damage as injecting ash.
Add to this the limited ability of the brain to produce disease specific pathologies (ie most end stage diseases look similar!). CJD looks VERY like MS to a histopathologist and simply injecting TNFalpha in to the eye produces lesions indistinguishable from CJD in the optic nerve!
I think the jury is definitely out on this one but it will be interesting to watch the progress of the prion hypothesis and whether prions turn out to be neurotoxic at all.
Peter
Thursday, June 25, 2009
Alzheimers and Tau proteins
This report on the "spreadable" nature of Alzheimers within the brain is in New Scientist and came to me via Glyn Wainwright on the THINCS forum. It's interesting in it's own right but I rather liked the related paper it linked to about the "contagious" nature of misfolded Tau proteins.
I think it would be reasonable to summarise the abstract as claiming that Tau proteins are non pathogenic structural proteins present inside, and essential to, normal nerve cells. Tau protein aggregates, which are abnormal products, "are observed" outside cells. My assumption is that, as healthy Tau are normally intracellular proteins, they have to be either excreted or exocytosed. Or the cell has to die to released them, before they can be found outside cells. The latter seems the more believable option.
Placing healthy monomer Tau proteins outside neuronal cells in culture does nothing. Placing Tau aggregates outside cells promotes endocytosis of those aggregates and, once endocytosed, the aggregates are directly toxic ("induce fibrillization") to the normal intracellular structural Tau. When this cell then dies it too will release it's abnormal Tau aggregates, which will go on to kill further recipient cells.
OMG its a locally contagious protein! Except it's not, it's a toxic substance which triggers the production of the same toxic substance from healthy tissue on contact.
Where do the original Tau aggregates come from? I suspect that Blaylock would argue they are shrapnel from the death of a neurone killed by catastrophic energy failure, induced by excitotoxins hitting glutamate-receptor sporting cells. This will no doubt involve hyperphosphorylation of Tau and all of the other exciting co factors for Alzheimers. Oh, and might be avoidable by supplying alternative energy molecules such as ketones. The shrapnel is itself neurotoxic and the product of its damage is more of the same neurotoxic shrapnel. This is a chain reaction and Alzheimers then becomes the neurological equivalent of Hiroshima. At this point Blaylock must be feeling quite justified in his views.
The obvious comparison, which is made in the abstract, is to prion proteins as featured in BSE.
If misfolded prion proteins are endocytosed, as Tau proteins are, and are themselves toxic to normal prion proteins, you then have the mirage of a contagious protein.
BSE can be induced in the brain of almost any recipient species by injecting a slurrry from the brain of a BSE case, which contains misfolded prion protein. But what is the trigger for the initial misfolding?
If I was prof Ebringer I might strongly suggest that the original trigger for prion misfolding is an autoimmune attack on myelin basic protein, or a similar structural protein, in the brain. We're not thinking neat and tidy apoptosis here, more like sudden death and spill your contents. Once the misfolding chain reaction is started the progression to BSE via more misfolding and cell death might then follow on, exactly as the Tau aggregates spread.
There is then no need for a contagious protein. In fact, it is easy to "spread" BSE by injecting the ash from incinerated BSE brain (600 deg C in the presence of oxygen. This means incinerated!!!). All you need is for the ash to damage the recipient brain enough to trigger protein misfolding and you have "transmitted" BSE using ash. Thoroughly formalin fixed brain tissue does the job rather better than fresh brain tissue too!
You really have to wonder what is going on here and the Tau "transmission" abstract makes Prof Ebringer and Russell Blaylock look pretty good as proposers of the correct triggers for the respective diseases to me.
Fascinating stuff.
Peter
I think it would be reasonable to summarise the abstract as claiming that Tau proteins are non pathogenic structural proteins present inside, and essential to, normal nerve cells. Tau protein aggregates, which are abnormal products, "are observed" outside cells. My assumption is that, as healthy Tau are normally intracellular proteins, they have to be either excreted or exocytosed. Or the cell has to die to released them, before they can be found outside cells. The latter seems the more believable option.
Placing healthy monomer Tau proteins outside neuronal cells in culture does nothing. Placing Tau aggregates outside cells promotes endocytosis of those aggregates and, once endocytosed, the aggregates are directly toxic ("induce fibrillization") to the normal intracellular structural Tau. When this cell then dies it too will release it's abnormal Tau aggregates, which will go on to kill further recipient cells.
OMG its a locally contagious protein! Except it's not, it's a toxic substance which triggers the production of the same toxic substance from healthy tissue on contact.
Where do the original Tau aggregates come from? I suspect that Blaylock would argue they are shrapnel from the death of a neurone killed by catastrophic energy failure, induced by excitotoxins hitting glutamate-receptor sporting cells. This will no doubt involve hyperphosphorylation of Tau and all of the other exciting co factors for Alzheimers. Oh, and might be avoidable by supplying alternative energy molecules such as ketones. The shrapnel is itself neurotoxic and the product of its damage is more of the same neurotoxic shrapnel. This is a chain reaction and Alzheimers then becomes the neurological equivalent of Hiroshima. At this point Blaylock must be feeling quite justified in his views.
The obvious comparison, which is made in the abstract, is to prion proteins as featured in BSE.
If misfolded prion proteins are endocytosed, as Tau proteins are, and are themselves toxic to normal prion proteins, you then have the mirage of a contagious protein.
BSE can be induced in the brain of almost any recipient species by injecting a slurrry from the brain of a BSE case, which contains misfolded prion protein. But what is the trigger for the initial misfolding?
If I was prof Ebringer I might strongly suggest that the original trigger for prion misfolding is an autoimmune attack on myelin basic protein, or a similar structural protein, in the brain. We're not thinking neat and tidy apoptosis here, more like sudden death and spill your contents. Once the misfolding chain reaction is started the progression to BSE via more misfolding and cell death might then follow on, exactly as the Tau aggregates spread.
There is then no need for a contagious protein. In fact, it is easy to "spread" BSE by injecting the ash from incinerated BSE brain (600 deg C in the presence of oxygen. This means incinerated!!!). All you need is for the ash to damage the recipient brain enough to trigger protein misfolding and you have "transmitted" BSE using ash. Thoroughly formalin fixed brain tissue does the job rather better than fresh brain tissue too!
You really have to wonder what is going on here and the Tau "transmission" abstract makes Prof Ebringer and Russell Blaylock look pretty good as proposers of the correct triggers for the respective diseases to me.
Fascinating stuff.
Peter
Sunday, June 14, 2009
Bob Michell on meta-analysis
Quote of the century, from Bob Michell (taught me applied physiology many moons ago at the RVC and is a seriously bright guy).
"Meta-analysis of dross remains dross"
Ahhhhh that's good.
Peter
Edit: It's possibly as good as Malcolm Kendrick's definition of meta-analysis: one, two, skip a few, 99, one hundred.
"Meta-analysis of dross remains dross"
Ahhhhh that's good.
Peter
Edit: It's possibly as good as Malcolm Kendrick's definition of meta-analysis: one, two, skip a few, 99, one hundred.
Tuesday, June 02, 2009
Gluten: The NICE guidelines for UK diagnosis
For UK readers who want to go the mainstream route here are the NICE guidelines as supplied by Ali in the comments after the Gluten and MS post.
This is part of her comment:
"I am sure you will be pleased to note that the care pathway now includes the referral to a gastroenterologist of those with negative tests but persisting coeliac symptoms."
Yes, too right. I'd personally still go LC as part of my gluten free approach but not everyone wants to go that way. I suppose I went gluten free without anything other than reading the literature! But being armed with the information you are positively coeliac is an opportunity to avoid so many auto immune diseases. If you need a positive test to make the change, these guidelines will help you.
Thanks Ali.
Peter
This is part of her comment:
"I am sure you will be pleased to note that the care pathway now includes the referral to a gastroenterologist of those with negative tests but persisting coeliac symptoms."
Yes, too right. I'd personally still go LC as part of my gluten free approach but not everyone wants to go that way. I suppose I went gluten free without anything other than reading the literature! But being armed with the information you are positively coeliac is an opportunity to avoid so many auto immune diseases. If you need a positive test to make the change, these guidelines will help you.
Thanks Ali.
Peter
Monday, June 01, 2009
Gluten, coeliac and multiple sclerosis
These are a set of MRI images taken from a paper in Spanish entitled "Sustained clinical remission in a patient with remittent-recurrent multiple sclerosis and celiac disease gluten-free diet for 6 years". Something seems to have gotten lost in translation, but you get the gist. Pictures A are before gluten free eating and B after six years gluten free, I think.
Even on the relatively poor reproduction here you can see the white plaques typical of MS lesions on the left and their absence on the right is equally notable. Click to enlarge. That's as far as my Spanish (which is non existent) will take me with the paper.
Of course this may just be a complete fluke, MS does do remission. But I doubt it and anyone with MS or related problems can take note and realise that it is not necessarily a one way ticket, remission is possible, six years is a good start and eating gluten is probably your key to progression of the disease. It becomes debatable whether eating low carbohydrate is needed but, if nothing else, going low carb makes the avoidance of gluten about a million times easier than deciding whether to trust the labelling for complete freedom from gluten. No gluten in a home cooked steak.
For those who do have MS but don't have coeliac disease, I stumbled on this paper as a link related to the Spanish paper. It is almost impossible to describe how utterly, totally and completely cr*p the antibody tests for coelaic disease are. In the UK you will not get an intestinal biopsy unless you are antibody positive. You can have flat intestinal villi with a negative antibody titre. You can also have flat villi in large areas of your gut and the guy driving the endoscope might just biopsy the last six minute patches of normal mucosa you had left. Leaving you with no normal gut lining, a negative diagnosis and a label of over vivid imagination about gut pain. Conclusion: A deficiency of Prozac. The hydrogen breath test seems a lot better than serology, if you can get one done.
There is no need to believe you are coeliac negative. If you have MS it seems very unlikely you would be coeliac negative. Risking MS progression for toast is a pretty amazing trade off! There are no adverse reactions to a gluten free diet. Oh, once you are through the withdrawal syndrome that is, about 4-6 weeks.
Peter
Even on the relatively poor reproduction here you can see the white plaques typical of MS lesions on the left and their absence on the right is equally notable. Click to enlarge. That's as far as my Spanish (which is non existent) will take me with the paper.
Of course this may just be a complete fluke, MS does do remission. But I doubt it and anyone with MS or related problems can take note and realise that it is not necessarily a one way ticket, remission is possible, six years is a good start and eating gluten is probably your key to progression of the disease. It becomes debatable whether eating low carbohydrate is needed but, if nothing else, going low carb makes the avoidance of gluten about a million times easier than deciding whether to trust the labelling for complete freedom from gluten. No gluten in a home cooked steak.
For those who do have MS but don't have coeliac disease, I stumbled on this paper as a link related to the Spanish paper. It is almost impossible to describe how utterly, totally and completely cr*p the antibody tests for coelaic disease are. In the UK you will not get an intestinal biopsy unless you are antibody positive. You can have flat intestinal villi with a negative antibody titre. You can also have flat villi in large areas of your gut and the guy driving the endoscope might just biopsy the last six minute patches of normal mucosa you had left. Leaving you with no normal gut lining, a negative diagnosis and a label of over vivid imagination about gut pain. Conclusion: A deficiency of Prozac. The hydrogen breath test seems a lot better than serology, if you can get one done.
There is no need to believe you are coeliac negative. If you have MS it seems very unlikely you would be coeliac negative. Risking MS progression for toast is a pretty amazing trade off! There are no adverse reactions to a gluten free diet. Oh, once you are through the withdrawal syndrome that is, about 4-6 weeks.
Peter
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