The word cholesterol is inherent to heart disease. Just like Paris is the capital of France and the Moon orbits the Earth, so cholesterol is associated with heart disease.
And common knowledge extends further. Most people know that cholesterol is measured in blood and that there’s is supposed to be both good and bad cholesterol. Bad cholesterol may clog arteries, so by all means make sure it’s low.
Of course, most of us know there is only one type of cholesterol. The “good” and “bad” has to do with the lipoproteins that carry cholesterol molecules in our bloodstream.
A standard lipid panel provides numbers for total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C) (1) and high-density lipoprotein cholesterol (HDL-C)(2).
LDL-C is often termed “the bad cholesterol” because high levels are associated with increased risk of heart disease.
On the other hand, HDL-C is usually nicknamed “the good cholesterol” because high blood levels are associated with less risk of heart disease and low levels are associated with increased risk.
Recently many experts and non-experts have cast doubt on the role of cholesterol as a causative factor for cardiovascular disease (CVD). The internet is flooded with articles and books have been published with titles such as the “Cholesterol Conspiracy” and “The Great Cholesterol Myth”. Some have suggested that the fat hypothesis is the biggest lie in medicine.
The opposite view is usually found among medical professionals. Cholesterol is regarded as a key player when it comes to cardiovascular disease;dietary recommendations aim at lowering LDL-C and cholesterol lowering drugs are often prescribed.
In a paper (3) published 2010 in the American Journal of Cardiology, William C. Roberts, editor-in-chief of the American Journal of Cardiology for the last 33 years wrote: “The lower the LDL cholesterol, the better, and this principle has been established repeatedly despite voices of the anticholesterol, antistatin fallacy mongers! It’s the cholesterol, stupid!“
I believe healthy scepticism is the lifeblood of modern science. It is not about choosing teams and ignoring evidence that contradict our believes. Dogmatic assertions may get in the way of scientific progress.
So, let’s have a quick look at recent scientific results that may strengthen our understanding of the role of lipid measurements in assessing the risk of cardiovascular disease.
Lipid Combinations
It is well known that high levels of LDL-C, low levels of HDL-C and high levels of triglycerides (TG) are each by itself a major risk factor for developing CVD (4,5,6).
But what about lipid combinations. What if both LDL-C and HDL-C are high? Will high HDL-C wipe out the risk associated with high LDL-C? And what about TG? How do they affect the mixture?
Interestingly these questions have not been addressed until lately. A paper published in the American Heart Journal in December 2014 (7) reports results from the Framingham Heart Study Offspring Cohort where the association between different lipid combinations and the long-term risk of cardiovascular disease was studied.
The study addressed 3,501 healthy middle-aged individuals without any history of cardiovascular disease who were followed for a median of 20 years.
The authors defined levels of high LDL-C as >130 mg/dL (3.4 mmol/L), high TG as > 150 mg/dL (1.7 mmol/L), and low HDL-C as < 40 mg/dL (1.0 mmol/L).
The participants were grouped into eight distinct groups according to “normal”, or “low” or “high range” values of LDL-C, HDL-C, and TG.
The group with normal LDL-C, normal HDL-C and normal TG had a 5.9% risk of cardiovascular events (age- and sex-adjusted 10 year CVD incidence) compared to 18.4% in the group with high LDL-C, low HDL-C and high TG.
Evidently, lipid combinations can tell us quite a lot about the risk of developing CVD.
What Is Most Important, LDL-C, HDL-C or TG?
Interestingly, low HDL-C alone or in combination with a high LDL-C and/or high TG was the category associated with the greatest risk of CVD.
When compared with HDL-C, LDL-C alone was associated with only a marginally increased risk of CVD. For example, the hazard ratio for the group with low HDL-C but normal LDL-C and normal TG was 1.93 while the group with high LDL-C but normal HDL-C and normal TG had a hazard ratio of 1.28.
In contrast to HDL-C or LDL-C alone, no increase in CVD risk was associated with high TG alone.
In my opinion, the most interesting finding of this study is that a lipid combination with low HDL-C is associated with a much higher risk than a lipid combination with high LDL-C. If HDL-C is low, it makes a little difference whether LDL-C is high or not.
On the other hand, it can be argued that lowering LDL-C with statins seems to reduce CVD risk while raising HDL-C has not been found to be helpful.
How can this discrepancy be explained?
HDL-C and Insulin Resistance
The authors of the above paper cite two recent studies that suggest that HDL-C is a surrogate marker (8,9). This may imply that low HDL-C is not problematic in itself but is associated with some other factor that can increase risk. But, where is the missing link?
It is known that low HDL-C and high TG commonly occur together. In fact, the TG/HDL-ratio (10) is strongly associated with the incidence (11) and the extent (12) of coronary artery disease.
Low HDL-C and high TG are very often related to obesity and metabolic syndrome. These situations are characterised by the phenomenon we call insulin resistance.
Insulin resistance is a condition in which cells fail to respond to the normal actions of insulin. Most people with this condition have high levels of insulin in their blood. Insulin resistance appears to play an important role in CVD and is associated with increased mortality (13).
Interestingly, previously published data from the Framingham Heart Study have shown that the risk associated with low HDL-C or high TG is increased only in the presence of insulin resistance (14) .
Another study showed the benefit of fibrate therapy was much less dependent on levels of HDL-C or TG than on the presence or absence of insulin resistance (15).
Accordingly, there is evidence that in the absence of insulin resistance, low HDL-C is much less relevant as a marker of risk than when insulin resistance is present. Therefore, insulin resistance may be the missing link between low HDL-C and the risk of CVD.
So, possibly, to reduce the risk of low HDL-C, we should aim at reducing insulin resistance instead of targeting low HDL-C in itself.
Should These Findings Affect Modern Dietary Advice?
For fifty years, dietary advice has aimed at lowering LDL-C. Therefore, a low-fat diet rich in fruits, vegetables, nuts, legumes, whole grains, low-fat dairy products, fish, and lean cuts of meat is recommended to lower the risk of CVD.
But what if low HDL-C is a stronger marker of risk than LDL-C as suggested by the above study. Should we approach individuals with low HDL-C with the same dietary approach? Is a “Prudent” low-fat diet best for individuals with insulin resistance?
Today there is abundant evidence available suggesting that carbohydrate restriction is more effective than a low-fat approach to treating insulin resistance (16).
Therefore, modern dietary recommendations have to take into account recent scientific evidence suggesting that a low fat approach may not always be the best advice to cut the risk of CVD.
Don’t misunderstand me though. I’m not suggesting we should skip fresh foods such as fruits, vegetable, fish and nuts.
However, evidence suggests we have to abandon the fat phobia, the fear of saturated fat, and the view that preferring carbs rather than fat is always the best option to reduce the risk of CVD.
But, should we abandon LDL-C and the low-fat approach? Absolutely not. There are situations when lowering LDL-C is of prime importance.
But, it is time we broaden our perspective.
Interesting read, I think you’re onto something with the idea it’s insulin resistance magnifying the risks in the presence of low HDL and high TG.
A couple points:
“In my opinion, the most interesting finding of this study is that a lipid combination with low HDL-C is associated with a much higher risk than a lipid combination with high LDL-C. If HDL-C is low, it makes a small difference whether LDL-C is high or not.”
Many vegetarians/vegans end up having low HDL, presumably their LDL is so low that they don’t need as many garbage trucks to remove the LDL if you’ll allow the analogy. Or perhaps the increase in carbs drives it down. Either way, don’t they as a group have lower CVD risk? Do you suppose that it’s no insulin resistance at work here too?
“However, evidence suggests we have to abandon the fat phobia, the fear of saturated fat, and the view that preferring carbs rather than fat is always the best option to reduce the risk of CVD.”
I’m still not convinced in the absolution of sat fats, particularly in the case of apoe4 status. I know they rocket up my own lipid profile but that’s just me.
regards
Hi Bill
You’re right. There’s evidence suggesting that plant based diets reduce the risk of CVD compared with a traditional Western dietary pattern. There may be multiple underlying mechanisms. Lowering of LDL-C may play a role as well as less risk of insulin resistance. Polyphenols in fruit and vegetables—such as vitamin C, carotenoids, and flavonoids may play a role. These have been shown to prevent the oxidation of cholesterol and other lipids in the arteries and to increase the formation of prostacyclin with positive effects on arteries and blood clotting. Reduction in blood pressure may also play a role. Fruit and vegetables are good sources of magnesium and potassium, which have been inversely associated with mortality in some studies.
I’ve also seen a number of cases with high LDL-cholesterol when large amounts of saturated fats are consumed. Well of course we don’t really know whether that’s bad or not because HDL-C also goes up and LDL particle size usually increases which may be good. But anyway, abandoning the fear of saturated fat doesn’t imply that we should eat copious amounts. However, if slightly increasing the amount of saturated fats cuts our consumption of added sugar and refined carbs we’re probably fine.
Thanks for the comment.
What exactly is “A standard lipid panel” Do you by any chance mean this bunch of crooks, many of whom are paid vast amounts by pharmaceuticals to tell us to take our daily dose of toxic statins??
https://lipidsonline.org/site/editorial.cfm
No, I didn’t mean that. The term “standard lipid panel” just covers standard measurements of lipids in blood.
Hi there Doc, your article is the first I read in a while. Again nothing about HeFH – we are legion and WE are the ones to look at but … NOTHING. I no longer care whether “normal” genetic markers need statins or not. Then what about US?
My son at 34 got quintuple bypass surgery last christmas and it pulled the rug from under us. BOTH my boys have it. I didn’t worry because the females in my family who have it have lived longer than anyone else (WITHOUT statins on board).
LCHF halved my awful cholesterol numbers, but I can’t get my boys on the diet they are too afraid. So what’s the point. You guys have a GREAT opportunity with us. (In South Africa it wreak havoc under the Afrikaans whites, the Indian and Jewish population). We get told to go onto 80 mg Crestor and ‘gbye – hope you make it – kind of attitude. 80 milligrams will kill us all off very quickly with rhabdomyolysis. No, don’t want to hear about healthy people who have LOTS of options at hand. My heart is too sore to read it.
Hi Judit
You’re right. I haven’t written much about Heterozygous Familial Hypercholesterolemia (HeFH). I’m sorry to hear about your problems. Maybe I’ll be able to write something on the issue but I know it won’t provide any major solutions for you.
Hopefully, the new PCSK9 inhibitors that are being tested in clinical trials will help individuals with HeFH. See here.
Thank you for replying – the others without exception stay mum whenever the subject is broached. Cheers J
If its true what you wrote above, hen why do people with familial hypercholesterolemia, where are raised LDL levels (while remaining lipids are usually at normal levels, not low HDL and not hight TG), suffers coronary artery diseases? Why is that, since
Rafal
I never said that LDL-C doesn’t matter. Only that other measures matter as well and may even sometimes be more important or tell you more in terms of risk assessment. High LDL-C and high LDL particle number are certainly important, particularly in familial hypercholesterolemia as you imply.
Phew (smile) I was getting worried again NOT ——
Having been diagnose with T2DM and worked at getting my BGL’s into a non-diabetic range via a LCHF lifestyle … yet still managing to give my poor GP terrible worries as my cholesterol numbers indicate a pending heart attack – I was so pleased to see the following……
Accordingly, there is evidence that in the absence of insulin resistance, low HDL-C is much less relevant as a marker of risk than when insulin resistance is present. Therefore, insulin resistance may be the missing link between low HDL-C and the risk of CVD.
So, possibly, to reduce the risk of low HDL-C, we should aim at reducing insulin resistance instead of targeting low HDL-C in itself.
I now register as perfectly NON DIABETIC and my Triglycerides are sitting at 1.3….. I refuse statin drugs and intend to continue to do so after suffering mental and physical problems from them years ago…..
I do wish more GP’s would read your papers Doc….. until they do it is up to the patients to inform them 🙂
Thanks C
Appreciate your interest.
Sincerely hope your health keeps improving.
Keep up the good work 🙂
As a medical doctor specializing in family medicine (GP) I can assure you some of us are picking up on this “new” trend and looking into LCHF. There are very convincing studies that show greater effect treating DM2 (and as a supportive treatment of DM1) with high-fat diets while restricting carbs. We are spreading the word, but old habits die hard. Best regards.
[reply] I am happy that some GP’s are finally looking at Low Carb Healthy Fat Lifestyles as a way of putting into remission DM…. must just be the Aussie ones (some of them) who are behind the eight ball as it were :-)…. he is happy BGL numbers are into the ‘healthy’ range and horrified LDL is too high (must be the fats!)….. Cannot even relate to nice healthy NORMAL triglycerides as they seem locked into the TC and LDL numbers down here….. Congratulations on being more up to date and spreading the word.
Doctor Sigurdsson,
I have had low HDL-C (29-40) for over 20 years but it was never highlighted as a real concern since my total cholesterol has ranged from 95-114 and TG from 85-106.
However, I had a lipid panel run this past December and my PCP suggested a statin drug since my HDL-C was 35.
My lipid panel was:
Total Cholesterol 114
Triglycerides 106
HDL 35
LDL 58
VLDL 21
T Chol/HDL 3.3
Non-HDL 79
Your article states “low HDL-C is much less relevant as a marker of risk than when insulin resistance is present”.
I do not have any of the markers/symptoms of insulin resistance so interpret your article as indicating my low HDL-C is much less relevant as a risk.
BTW, I had a Thallium Stress Test five years ago. I was told results were good but never saw any detail. Does this test show coronary artery health?
I am going to discuss this with my PCP and will take this and your Non HDL-C article with me. What types of treatment other than statins would be suggested? I am not wanting to take a statin drug but am concerned about my risk for CVD after seeing low HDL-C alone can be a substantial risk.
Thanks,
Walter
Hi Walter, I hope you don’t mind if I jump in here. Do you take fish oil or astaxanthin? Both of these can increase HDL and also reduce triglycerides. 10g of fish oil, and 12mg of astaxanthin have increased my HDL from 47 to 64. My TG has gone from 147 to 98.
John, Thanks. I have just recently started 1000 mg of fish oil tablets per day. I will certainly try astaxanthin. Any particular brand? I appreciate your comments.
Walter
Hi Walter
In fact statins do very little for HDL-C. Your LDL-C is very low. It is unusual to prescribe statins if LDL-C is below 70.
How do you know you don’t have insulin resistance?
A TG/HDL-C ratio above 3 may suggest insulin resistance, but it doesn’t have to. Have you had Hemoglobin A1c tested? Do you have central obesity or any other signs of metabolic syndrome?
Hi Doctor,
Thanks for responding! I do not see Hemoglobin A1c on any of my blood tests. My Glucose Serum has run 79-84 in the past. My BMI is 28, not good but not obese and my stomach does not look like the photos I see for central obesity. My TG/HDL-C ratio has run from 2 to 3.02 on previous tests. I had a banana just an hour prior to my recent lipid panel. Could that have had any effect on my results? Can my PCP do specific insulin resistance testing? Would the Thallium Stress test in 2010 have shown any CVD indications? I had always thought my low total cholesterol was a really good thing.I appreciate your input. It sounds like statins are not the right answer for me.
Regards,
Walter
I agree Walter. I think your lipid profile is low risk. Total cholesterol is low, LDL-C and Non-HDL cholesterol are both low. Yes a normal Thallium stress test should indicate that there are no narrowings/blockages in the coronary arteries.
Best of luck.
I think Framingham Offspring data showed that LDL-P is more important than LDL-C. I saw a survival graph where, after 18 years, the highest survival rates were with low LDL-P and either high or low LDL-C. The worst survival was for high LDL-P and low LDL-C. I will try to find the reference.
Here is a link to the study. Look at Fig 2. (I don’t know how to post it here.)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2720529/
Correction: It was 16 years, no 18. And notice the sharp drop-off during the last year for high LDL-P/low LDL-C.
Hi Elliot
Thanks for the comment. Actually I did cite the study in another article.
Interestingly, TG/HDL ratio may help predict LDL particle number as discussed here.
“On the other hand, it can be argued that lowering LDL-C with statins seems to reduce CVD risk while raising HDL-C has not been found to be helpful.”
I cringe whenever I read statements like this. It can only be argued that taking statins seems to reduce CVD risk. It might be due to lowered inflammation, decreased endothelial dysfunction, stabilization of vulnerable plaque or some other beneficial side effects of statins.
Hi Elliot
You’re right. It has been debated how much of the effect of statins is due to lowering of LDL-C and how much is through other mechanisms. The recently published IMPROVE-IT trial suggests that lowering of LDL-C will reduce risk further among patients with coronary heart disease who are already on statins.
No, he really isn’t. A statin that lowers LDL-C more than another statin is more effective in reducing CVD events. The pleiotropic effects are totally secondary. See e.g.
https://www.ncbi.nlm.nih.gov/pubmed/16286171/
Concerning the HDL “paradox”: a very good post Axel! In addition, I’d like to point out that e.g. your reference 9 (its Table 1) shows more or less why HDL-C lowering hasn’t been that much to talk about:
– the effect of lifestyle interventions on HDL-C is minuscule – thus, no benefti to be expected
– the effect of drug treatments mostly too, with the exception of torcetrapib – and in this case the disappointing results were due to detrimental side effects which severely attenuated the findings –> the same as above
Plus then, of course, your point concerning the patient population: DM2/met.syndrome tends to mess HDL function, which is probably at least as important a factor as HDL levels.
Therefore, you really cannot say that HDL per se doesn’t matter. What you CAN say is that HDL modification/increasing HDL-C with current treatment options hasn’t been shown to offer benefits over current guidelines.
[I don’t see a reply button for Mie’s post so I’ll put this here]
“No, he really isn’t. A statin that lowers LDL-C more than another statin is more effective in reducing CVD events. The pleiotropic effects are totally secondary.”
A statin that lowers LDL-C more than another statin might also have stronger pleiotropic effects. The study mentioned looked at “5 diet, 3 bile acid sequestrant, 1 surgery, and 10 statin trials”. It is possible that bile acid sequestrants have similar pleiotropic effects as statins. I don’t know the details of the diet studies but they might have some other effects. I didn’t even know you could lower LDL via surgery.
Eliot.
The replies can only go three levels deep. Then the reply button disappears.
The best thing is to reply to the comment Mie replied to. Then your comment will appear below his/hers.
Remember to scroll down a bit to find the text-box after you push the reply button.
Thanks for another interesting post. Your #7 reference is particularly interesting. A significant (but as far as I know, unknown) proportion of folks on a low carb diet present with very high LDL-C/LDL-P but typically low TG and high HDL. Do you know of any studies that grouped participants to shed any light on those sort of folk?
I find the opening paragraph very offensive…. likening cholesterol to something so pretty… Im struggling with obesity and its consequences… Its no walk in the park and theres certainly nothing pretty about it. I hope you will consider more carefully which words you use in the future..
Really sorry to hurt your feelings. I would never have imagined this paragraph could be offensive. Anyway, maybe you’re just joking. That’s fine with me. But if not, please accept my apologies.
But look at it this way. Cholesterol is just a part of nature. It’s essential for human life. It’s part of our cell membranes and without it we wouldn’t exist. So cholesterol is just a part of nature. Like the sun, the moon and the stars. So, it can’t be all that bad can it?
I don’t thnk you’ve said anything offensive Doc at all. My gripe was only that doctors never cover HeFH and I can understand it fully since it is so cery complicated. Obese is obese. My old mother of 83 has a natural cholesterol of 13 (we inherited the gene from my side of the family) the women live very long but the men.. well my heart just goes into a fast beat when I mention it. I am terrified for my beautiful sons. BUT, on ketosis it my cholesterol came down from 13 to 6, period. NOT a single cardiologist would take it on board or want to even KNOW about it – my GP was elated though. But right now, I can’t do the diet for a while – am still getting over my son’s dilemma and taking fibrates. Statins are not for us we wil surely die on them. And hey, MY family are now officionado’s on ALLLL of statin- and fibrate-dom. BEEN through them all. AND, some almost killed us off before the cholesterol could. Cheers doc. Ye do no hve to apologise – truth be told..
Most low carbers get Triglyceride well below 150 ! Mine sits at 50 to 70 with HDL up near 70
I would also consider Trgs at 150 way too high for anyone on a LCHF lifestyle .
So it would have been very interesting to see the numbers rerun with a lower cutoff for triglyceride.
High HDL with Trgs at 70 or below then possibly even more significant than when Trgs are only 150 or below.
Trgs at 70 or below could also then start to be a significant factor on there own too.
When I see people with Triglyceride above 100 who are doing Low carb – They often need to tweak the lifestyle and do better.
I also like to see low readings on the liver enzymes ALT and GGT.
but but but, your LDL goes large and bouncy so it doesn’t matter, although mine fell right down on ketosis. In metric also my trigs came down to 0.7 and I am also genetically hypertrigliseremic (spelling??). Have to somehow get back onto LCHF, but I find it slightly cruel, though easy to maintain. Guess what, EYE bake wedding cakes for a living. oh sigh…. If you have your LDL mri-ed and you’re on LCHF you will find the molecules lovely and big and non sticky.
I’m sorry, but even if large LDL particles were less atherogenic, they would not be non-atherogenic. They are still small enough to deposit in the arterial wall. See the National Lipid Association’s “Clinical utility of inflammatory markers and advanced lipoprotein testing: advice from an expert panel of lipid specialists”: https://www.lipid.org/sites/default/files/articles/expert_panel_paper.pdf.
Anyway, you don’t necessarily need to go on a LCHF diet to reduce small, dense LDL’s (“A simple change of ≈25% of energy load from fat to carbohydrate in a meal significantly improves postprandial pro-atherogenic factors in obese boys.”: https://www.sciencedirect.com/science/article/pii/S0939475311000032).
purely anecdotal I know, but my 83 year old mother was diagnosed with breast cancer 15 years ago. She ate mostly carbs and vegetables at the time. She was typically not feeling well, bloated and tired. Once she went through chemo, her diet changed. She experienced chemo related problems including a fast heart beat and some minor kidney issues. By changing her diet and taking supplements for her heart, she is as healthy I have ever seen her. If you peak into her refrigerator, all you will see is eggs, butter, cream and chicken salad. Fish and some veggies are on the menu as is fruit and not much red meat, but all in all not quite the diet that is normally recommended. Sugar is absolutely avoided as she believes that is the primary fuel of cancer.
Thanks.
Ding dong!
[merrily on high, the truth is now emerging.]
Online grocery shopping is all the rage, and home delivery no truly commonplace. The goods in those shopping bags travelled many hundreds of miles, probably, some by air, some in shipping containers, many by road in refrigerated big-wheeled articulated lorries, and finally it came from shop to your door in the kind of van frequently termed a ‘transit’. The way goods are transported, and the type of vehicles used, has to reference the network routes they may follow, and the kind of access at the various ‘nodes’ where they may be received or handled. Eighteen wheeled big-rigs are not used to deliver goods to your door, thank the lord.
The naming of lipoproteins is a bit misleading because they do not fall into the discrete categories the names suggest, instead the ‘densities’ or sizes of lipoprteins describe a spectrum. it seems plain to me that chylomicrons (the largest members of the lipoprotein family do the ‘trunking’ which is equivalent to big-rigs hauling between big distribution depots while smaller members such as LDL & HDL may be more interactive with the final delivery and recollections points.
members of the medical profession can bag on as long as they like about HDL being good, and LDL being bad but if liporpteins are considered like distribution vehicles, and the type of class of vehicle used is application or destination sensitive then any supposed association involving LDL and supposed LDL receptors informs nothing. VLDL and IDL and triglyscerides would not associate simply because they do not interact with ‘receptors’, just in the same way big-rigs should come to your door with grocery shopping.
To continue the theme if bad apples arriving with your grocery are an issue for you then neither the bags nor the vehicle that arrives with them can inform you whether bad apples are present or not. To spot a bad apple one has to look inside the bag, and it is the same with proteins to discern if any lipoprotein harbours any ‘badness’, you have to look to its contents.
If you look to the contents of a lipoprotein and there is cholestane-3B,5a,6B-triol present then there is en evidence backed risk that may lead to necrosis of smooth muscle cells in arterial tissues, and it may be that LDL is the final carrier that makes the delivery. If you look inside a lipoprotein and there is 25-hydroxycholesterol present than there exits an evidential basis to wonder in that might ramp up biosynthesis of cholesterol in hepatocytes (liver cells) and perhaps elevate levels of blood cholesterol. Likewise if that 25-hydroxycholesterol is delivered to macrophages its effect upon macrophages may have them ramp up cholesterol synthesis and become bloated with cholesterol. This eventuality has had them earn the nick-name ‘foam cells’. Necrotic and dgenerate smooth muscle cells present with foaming macrophages are key features witnessed in atherosclerotic tissues.
Now, if any 25-hydroxycholesterol (25-HC) present becomes converted by the process of sulphation to sulphated 25-hydroxycholesterol (25-HCS) then its worth knowing that 25-HCS has the opposite effect upon cholesterol synthesis and ramps it back. Diets deficient in sulphur could be an issue. Icelandic soils are rich in sulphur, and the Icelandic diet may incorporate sulphur rich foods (beets and cruciferous veg) and that might be deemed ‘good’.
Anitschkow and Chalatov were the first to report positive induction of experimental atherosclerosis in 1913. When Keys made his giant leap of faith circa 1950 and concluded that cholesterol must be the cause of this experimental effect he discounted the possibility that certain cholesterol oxides present could confound the experimental results. Insufficient was known about cholesterol oxides until Imai et al reported on them in relation to experimental atherosclerosis in 1974, their write up encouraged further research, news of which has travelled far enough.
It is a little known fact that cholesterol can form around 49 alternate cholesterol oxides, many of which appear to have legitimate biological purpose. Certain cholesterol oxides appear to form too readily, there are around ten, and of these ten some appear to be able to convey deleterious effects.
Dr Stephanie Seneff has peened a very good essay, ‘Could It Be Sulphur’, available on the web, and that points to some of these themes.
When you finally come down form that fence you sit on Axel, there are professional colleagues who will think you have crossed to the dark side when in reality you will have found one great enlightenment in cardiology.
One small step for man; one giant leap for Axel.
One more thing, Axel.
Did you know that the acetyl and mevalonate pathway is common to plants and animals? Mevalonate sits half way along a ladder that has glucose as the first rung and cholesterol higher up? Mevalonate requires the action of an enzyme to make it. That enzyme is HMG-CoA reductase. There may be exceptions but this enzyme is common to the majority of plants as well as to all animals. This should be sobering news, because implications should have it that HMG-CoA reductase is easily 1 billion years old, and this very same enzyme is the one cholesterol lowering drugs called statins act upon. To endure for 1 billion years an not face extinction very strongly implies this enzyme has contributed only good to biology and human physiology. Are you now truly ready to jump off that fence?
Richard.
“Incoherent” is the word that comes to my mind when reading this comment. I have no idea what you’re getting at. I’m probably stuck on that fence as you say. You’re not the first one to tell me about my limitations.
I’ll let the comment stand for a while in case someone else makes any sense out of it.
Haaa ha ha ha I was also wondering about this comment – is it someone very angry or cynical or frustrated. BUT, did make me smile.
“I have no idea what you’re getting at .. “
Then why not read Peng and Morins book, ‘ Biological Effects of Cholesterol Oxides’ [3] to bring yourself up to speed? Why not acquaint yourself with some of the steps in the history of the formation of the cholesterol hypothesis? And why not simply visit an online encyclopedia to reacquaint yourself with the acetyl and mevalonate pathway and its perceived pertinence to the primary prevention of cardiovascular disease? Why not have a fresh look at what a lipoprotein is and what it is comprised of? Then wonder if something riding within a lipoprotein might compromise its otherwise good nature? And if there can exist something inside a lipoprotein, under certain conditions, that can compromise its otherwise wholesome nature, then wonder if all that mumbo jumbo about ‘ratios’ is really all that pertinent. And before you rush to think that the remark makes no sense, pause to wonder if there might exist something that you might be missing that might help you make sense of it?
The first step Keys took to fashioning his cholesterol hypothesis referenced Anitschkows and Chalatovs reporting of experimental atherosclerosis. [1,2] They achieved this by doctoring rabbit feed with cholesterol. But cholesterol is a highly labile molecule. It can be refashioned to form things like the steroid hormones, vitamin D, and around 49 alternate cholesterol oxides. Greatly improved knowledge about cholesterols highly labile nature did not come until the 1980s but in the 1950s Dr Ancel Keys rushed to assume that Anitschows and Chalatovs atherosclerotic rabbits had developed atherosclerosis as a result of the added cholesterol in the feed. However cholesterol can readily oxidise if exposed to air, and so doctoring feed risks the prospect of oxidation. Indeed simply refining cholesterol samples and storing them risks prospects of oxidation, hence cholesterol under storage may turn progressively more rancid. [3]
Some cholesterol oxides result from the action of enzymes on cholesterol, some result from contact with hyperoxides, and some results from simple autoxidation upon contact with air. To my mind the involvement of enzymes suggests that some of the 49 possible alternate oxides have legitimacy within biology, that’s to say they are involved in process necessarily for the workings of bodies. However simple autoxidation (contact with air) can account for the formation of around 10 of the 49 alternate cholesterol oxides. Hence these are the ones that can form in stored cholesterol samples in a time dependent manner. Likewise these are the ones most likely to form when feed is doctored with cholesterol.
There is no way of establishing this as a fact with total certainty, but with hindsight and knowledge of cholesterols propensity to form up to ten alternate oxides by simple autoxidation it seems that cholesterol oxides could have been a feature of Anitschkows and Chalatovs experiment. In 1974 Hideshige Imai et al [4] reported findings that cholesterol samples that had been purified and administered to rabbits by gastric gavage (to limit prospects of autoxidation) did no harm to their rabbits whatsoever. However, when aged cholesterol that had not been purified was administered to rabbits sacrifice and study revealed extensive necrosis of smooth muscle cells in aortic tissues. Likewise when the extracted impurities were administered smooth muscle cells were compromised.
There had been a confounding error early in the history of cholesterol science. Once one accounts for the confounding error cholesterol has never been implicated as a causal agent in in any positive induction of atherosclerosis under experimental conditions.
Imais results reported in 1974 provoked interest into how aged cholesterol becomes contaminated and what substances might be identified as contaminants. Peng & Morin take up the story from there, which is why their book [3] is a landmark publication.
This list represents the common autoxidation derivatives of cholesterol. Enter them in to the database search engines with the correct terms and you may get results indicating degrees of biological toxicity. They have been investigated in vivo and in vitro in relation to atherosclerosis and cancer.
For’ a’ read alpha; for ‘B’ read beta (the more relaxed or ‘trivial’ names in brackets).
Cholest-5-ene-3B,7a-diol (7a-Hydroxycholesterol-)
Cholest-5-ene-3B,7B-diol (7B-Hydroxycholesterol-)
3B-Hydroxycholesten-5-ene-7-one (7-Ketocholesterol)
5a-Cholestane-3B,5a,6B-triol (Cholestanetriol)
Cholest-5-ene-3B,25-diol (25-Hydroxycholesterol)
20S-Cholset-5-ene-3B,20-diol (20a-Hydroxycholesterol)
5,6a,-Epoxy-5a-cholestan-3B-ol (Cholesterol 5a,6a-epoxide)
5,6B,-Epoxy-5a-cholestan-3B-ol (Cholesterol 5B,6B-epoxide)
3B,5-Dihydroxy-5a-cholestan-6-one (6-Ketodihydroxycholesterol)
Cholest-4-ene-3-one (4-Choestene-3-one)
There, it took around 20 minutes to populate that list, hence you can see why a person might show reticence at the prospect of itemising them.
I might have trivialised slightly the meaning of ‘autoxidation’ in order to keep matters simple. Smith [5] had been a key figure researching the subject, and what it boils down to is damage to cholesterol molecules by free radicals, and where the damaged cholesterol molecules exist in generally trace amounts. Although the event initiating the formation of free radicals are not completely understood, many agents, including azo compounds, peroxides, hyperoxides, transition metal ions, and excited molecular oxygen species could promote this step. [3, p.3] I’ll be plain, specific meaning intrinsic to that sentence is lost on me too, while I do get the general gist. The sentence itself is not incoherent nor impenetrable, but if I want to extract the specifics I readily accept I might have to put my brain into gear and be prepared to work at it. The day may arise when I might need to.
So, the list is one of cholesterol derivatives that have been ‘radicalised’ and whose potential for harmful cytological attacks is deserving of research. Peng & Morin summarised the extent of understanding as of 1991. How much do you know about them, Axel?
SUMMARY:
# The notion that cholesterol is a concentration dependent atherogen is a falsehood whose origins can be traced to a confounding error.
# Cholesterol took the blame for effects that certain oxides of cholesterol replicate under experimental conditions and when undertaken with more care.
# Cholesterol does not contribute to risk of heart disease.
# Damage by free radicals that might result in proliferation of certain oxidised progeny of cholesterol appears to account for features that associate with atherosclerotic lesions, namely degeneration and necrosis of smooth muscle cells in arterial tissues, and over-synthesis of cholesterol in macrophages that earns them the name ‘foam cells’.
# We ought to be thinking, ‘it ain’t cholesterol, might it be certain cholesterol oxides?’.
# Since the perception of cholesterol as being a concentration dependent athrogen is a falsehood the perceived wisdom of prescribing cholesterol lowering protocols and medications ought to be subjected to question.
# Since cholesterol is fashioned, after several steps, from a biochemical called mevalonate, and since mevalonate accounts for the provenance of other important biochemicals we should wonder if limiting synthesis of mevalonate with drugs called statins is a good idea.
# The formation of mevalonate requires the action of an enzyme, that enzyme is HMG-CoA reductase, This is true for humans, for all animals, and for a great many plants. All the family of sterols (around 200 in number) are made from mevalonate. mevalonate is a very important biochemical throughout biology and no less imp[ortant for humans.
# We should expect any that any attack upon that enzyme, HMG-CoA reductase would do harm because it would interfere with production of vital mevalonate and with the production of other biochemicals derived from mevalonate.
# Cholesterol lowering drugs called statins target the enzyme called HMG-CoA reductase.
# There ain’t no evidential justification from lwering choleserol because cholesterol does not provoke atherosclerosis in a concentration dependent manner, but when cholesterol has contact with free radicals and is converted to certain of its 49 possible alternate oxides then changes arise in cells that are part of arterial tissues and that feature in atherosclerotic lesions.
# Stains target HMG-CoA reductase and mevalonate without any necessity or justification, while the ubiquity of mevalonate across biology would strongly imply that it is a very important biochemical.
# Any person that might wonder (for long enough) would realise the emergence of the zoosterols within the family of sterols (which all derive from mevalonate) would realise that they represent a great step forwards in the advance of biological diversity. The arrival of cholesterol was a major transition point in the evolution of species and diversity. In the time when only phytosterols existed then plants existed without animals.
# Ergo: Stains are toxins.
# Lipoproteins are ingenious natural ‘vehicles’ that overcome the thorny issue of distributing valuable cholesterol, fats, and fat-soluble biochemicals and anti-oxidants (lipophiles and hydrophobes), around an essentially aqueous (lipophobic and hydrophilic) network.
I hope that helps address any ‘incoherence’, Axel. Your registration has responsibilities attached.
People once thought Einstein ‘incoherent’, and early papers on Relativity he submitted for peer review were rejected, until those fat-headed peers caught on.
Oh, I do so love a good debate in open and transparent settings.
Christopher Palmer, 15:30, 21-01-2015.
Notes:
1, Anitschkow, N., Uber die veranderungen der kaninachenaorta by experimenteller cholesteroleinsteatose, beitr. Pathol. anat. Alig. Pathol., 56, 379,1913.
2, 1 Anitschkow, N. N. , and S. Chalatov. 1913. Ueber experimentelle Choleserinsteatose und ihre edeutung fur die Entstehung einiger pathologischer Prozesse. Zentralbl. Allg. Pathol. 24:1—9
3, Biological Effects of Cholesterol Oxides, Peng & Morin; 1991. ISBN 0-8493-6776-X
4, Imai, H H., Werthessen, N.T., Taylor. C. B., and Lee, k. t., Angiotoxicity and and arteriosclerosis due to contamination of U.S.P. grade cholesterol. Acrh. Pathol. Lab. Med., 100, 565, 1976
5, Smith, L. L., Cholesterol autoxidation. Plenum Press, New York, 1981.
Insulin resistance usually results in more insulin circulating, why do you say insulin resistance is a risk and not just excess insulin? I am T2D on LCHF and in nutritional ketosis, my insulin levels are low. Dietary ketosis results in insulin resistance too. Are you suggesting I’m more or less at risk just based on this. Does the fact that my HDL/Trig ratio is ~1 influence your opinion?
Hi Mark
Increased insulin production is a reaction to insulin resistance. When the cells of the body become resistant to the action of insulin, the pancreas starts to produce more insulin in order to solve the problem (compensatory hyperinsulinemia). This is typical for T2D although insulin production usually diminishes again as time goes on.
Dietary ketosis will likely reduce insulin levels because less insulin is needed because you’re not eating sugar or carbs. A TG/HDL ratio of 1 is good (if you’re using US units) and doesn’t suggest insulin resistance.
Thanks for the reply and another great post.
Would eating less than 30 grams of carbs per day for 2 years, mask any signs of being insulin resistant?
Mark,
Just saw where vitamin A increases beta cells in mice. Might be worth a try if you think you are not getting enough A..
https://www.medicalnewstoday.com/articles/288199.php
“is it someone very angry or cynical or frustrated. BUT, did make me smile.”
Happy to have raised a smile.
In reality it was the work of pragmatist thoroughly frustrated at the persistence of dogma. The tone was intended to be encouraging. That’s to say it was intended to be appreciative of Axels additional steps that have him trending away from the dogma as resides in medicine. Medicine and medical science is great. Medicine can work wonders. Axel is great. Axel is great because whereas most of his colleagues are very conservative he is openly progressive.
Evidentially, the cholesterol hypothesis is nonsense because the ‘evidence’ is mere wil-o-the-wisp. Contextually the cholesterol hypothesis would appear to be barking up the wrong tree because cholesterol is a zoosterol. Sterols are vital to biology. Phytosterols permit the existence of plants, while zoosterols permit the existence (and evolutionary emergence) of animals. Cholesterol is the most important of the zoosterols. So ..
Where Axel says this; “But look at it this way. Cholesterol is just a part of nature. It’s essential for human life. It’s part of our cell membranes and without it we wouldn’t exist. So cholesterol is just a part of nature. Like the sun, the moon and the stars. So, it can’t be all that bad can it?”, he has gotten right back on the tread of the truth. He’s courageous. I commend him. If he hadn’t been in such a rush to call me ‘Richard’ or to direct that my remark was incoherent ‘without’ his realising just how much time an effort a truck driver has put into researching the topic I’d commend all the way to the moon and back.
The remark he referred to as ‘incoherent’ was my best effort at lending him a well-intentioned good steer to help on on his progressive way. I can forgive him. I like him. But if he calls me Richard again I’ll be booking my flight to Reykjavik to put some force behind any well-intentioned ambitions to help him on his way.
Pragmatism can be tricky message to put across. The reason is that it is inevitable less simple and less familiar than the dogma that stands in its way.
The stars account for the provenance of all the chemical elements above hydrogen. So there would exist no carbon without the life-cycles and death of stars. There could be no Earth and no moon. There could be no glucose. Glucose has earned its right to be considered the mother of all biochemicals. In time Axel will perceive the gravitas in this. glucose is clever. Energy conveyed in photons of light is captured and harvested, then it gets inserted into the energy carried by electrons in the particular way they bind carbon and hydrogen in a glucose molecule. Its photosynthesis, of course, but photosynthesis pulls off a clever trick. It makes a quantum investment in a quantum bank account. The bank account is glucose, the currency being deposited is added energy being pressed into the way electrons bind, or ‘bond’ hydrogen and carbon.
There are many steps but cholesterol is made from glucose. Mevalonate is an intermediary along the way. Cholesterol is fashioned from mevalonate, indeed all the 200 strong family of sterols are, though we have no need of the large number of possible phytosterols, while mevalonate is fashioned from glucose, though in several steps.
Cholesterols link with the stars that Axel mentioned is indeed verifiable. If enchantment with modern medicine comes at the price of losing faith and curiosity in nature then that is a very, very sad day indeed. So well done Axel for being so succinct in that short sentence.
As for being ‘angry’, not at all. Though in recent days my soon to be former employer, Moran Logistics, have given me grounds to lose my normally personable demeanour. People there can be slow to see sense too.
Realised that full well. Has he tried the banks yet – those arteries are clogged inside AND out, same as home affairs.
Dear Christopher (Dick)
I’m really sorry for the name confusion. It was purely unintentional . Probably a Freudian slip. Lengthy comments from one Richard (OrnishForLife) surfacing from my subconciousness. Can’t explain it otherwise.
I do appreciate your interest in my blog, don’t misunderstand me.
I also realise you’ve studied these matters a lot.
However, I prefer short comments and they should also be related to the blog article at hand.
I usually reject long essays that are out of context.
Hope you continue visiting the website and I hope you’ll respect my policy regarding comments.
Best wishes
Axel F
Hello Doc,
I have CAD and had a stent placed about 11 years ago. I’m male 65 yo mean BMI and very active. I found out my FBG @112 was slightly elevated just over a year ago. Without medical intervention I researched this relentlessly and decided to eat LCHF. I lost 18 lbs., increased my HDL, also my LDL slightly, slashed my TG and VLDL.
I’ve been eating LCHF for about a year now, have tons of energy, feel terrific, I do strenuous hikes in the mountains weekly, work full time, and my heart health actually feels better, no bloating, etc.
My point is, I saw a new Cardiologist for the first time a month ago, outlined my high fat diet in a 2 page report, submitted 2 A1c results, 4 cardio and lipid panels from the last year for his review. He was amazed and also said “excited” to see a patient with so much interest in their health, and also one that appears so healthy. After a brief physical exam he also mentioned he will not require a stress test for me as he generally does with all new patients. My last was 7-9 years ago.
He could see first hand the results of a patient whose diet was predominately fat, hardly any carbs and little protein and back up what he saw with blood tests at 3 month intervals. My last A1c was 5.7 and if possible I’d like to get it into the high 4% or very low 5%. My doc has just prescribed 500mg Metformin to help more of what my LCHF diet is already doing and my FBG is dropping close to normal levels.
I am a 60 year old male on LCHF for 1 year, BMI of 20, LDL 298, HDL 58, Trig 130. Should I go on statins (again) to reduce my LDL, or not. Muscle aches were an issue previously, on simvastatin.
Doc,
see the new study which (again) highlights the issue of cumulative burden when it comes to LDL. Even modest elevation of non-HDL cholesterol at early adulthood is associated with elevated risk later on. This is an issue which you seem to overlook again and again.
https://circ.ahajournals.org/content/early/2015/01/15/CIRCULATIONAHA.114.012477.full.pdf+html
Martin B Katan, reknown Dutch epidemiologist explain why it is hard to take seriously the new studies allegedly casting doubt on saturated fat:
https://www.cspinet.org/nah/pdfs/covermay2014.pdf
Best,
R
Thanks. No, I don’t think I overlook the issue, at least not all the time, see here and here.
So, Doc,
what you are goin’ to do with your next FH -case, encourage the patient to increase his/her SFA intake and initiate a therapy targeting his/her blood-glucose levels?
LOL! Doc, I think you are a fucked-up denialist fraud, akin to people who promote Intelligent Design.
You are rude Sir. I have HeFH and an EXTREME Keto diet (very high in sat fats) halved my cholesterol – I reckon I was the first one in the entire world who, for my children’s sake tackled the diet and thought “if I die they need to know it’s the diet” and I would’ve died quickly since our types’ arteries clog up very quickly (though not in females for some reason). Thus I eat fat chops (unfortunately I don’t eat pork), beef, lots of butter, double cream only, etc. Would you tell those mothers whose epyileptic children benefited from this diet to not have done it? Too much vegetables very quickly will raise my LDL since they’re all a form of carbohydrate – so we stick to cabbage and it’s types and a bit of tomatoe and a strawberry now and then. My elated doctors would find you weird – THEY say the blood numbers never lie. There is a Dr. Ornish (linked to Clinton?) – perchance you are of his family? Hey whatever floats your boat, but stop the swearing. My ears hurt already. I have NEVER heard a low carb doc or scientist tell anybody to go onto the diet. In fact, our local champion of same, Dr. Tim Noakes, said if everyone went onto it, farmers would lose a lot so it’s only for those who do their homework and are fully persuaded.
Richard
I’ve been forced to not accept some of your comments lately.
I’ll let this one stand as a token of your attitude.
Otherwise, I will not accept impolite or rude comments. Lengthy posts that are out of context will also be rejected.
Best wishes
Doc
Good choice Doc. I think Richard needs to work on his Ornish meditation, otherwise he might blow an artery.
Again, Mr. RichardOrnishForLife, my mother is now 83. Only found out she carried the gene in her sixties – couldn’t tolerate statins at all. She outlived all 11 of her siblings. 2 of her brothers unfortunately carried the gene and died young. None of her other siblings (sans the two brothers) carried the mutation. The others had such very low cholesterol numbers and yet they died of diabetes. Both my sons carry the gene and I don’t care if the whole world swears at me – my sons need to beat this thing and they ARE too!
Hi. I am a 51 year old male. I am a non-smoker. Had a blood pressure of 145/100 for the last couple of years without medications. One month ago, my blood pressure read 160/100. I decided to visit a cardiologist after checking my lipid profile. The readings were:
T. Cholesterol: 260 mg/dl
Triglycerides: 94 mg/dl
HDL Cholesterol: 50 mg/dl
LDL Cholesterol: 191.2 mg/dl
The cardiologist prescribed a blood lowering medication, a statin (Crestor) and daily pill of baby aspirin. Starting taking Crestor for a couple of days made me feel terrible and decided to stop it; however the doctor says that it is necessary to take a statin to lower the high LDL. I started to go on a low fat, low carb diet and to exercise regularly instead of the statin drug with their side effects. But I am fine with the blood pressure medication. My blood pressure now after 10 days on medication is 130/80. But I do not want to go on statins. Could you pls. advise whether the lifestyle changes would be enough? The doctor says that life style changes are OK, but not enough to lower such a high LDL.
I have also made an Echocardiography and the conclusion says: Mild concentric LV remodeling and dilated aortic root. My doctor says that all other comments are normal and the dilated aortic root is due to my stage 1 hypertension for which I did not take any drugs.
I have read about the NMR which can also help determine the risk of heart disease but we do not have it in Egypt.
Very nice article and exchange of opinions… Very helpful thoughts specially for those who has cholesterol and heart problems but without enough information regarding their condition and doesn’t have proper knowledge in Healthcare.