I have a tough time using mendelian randomization as the final step required to meet a causal requirement for two reasons, Firstly, while it claims to eliminate confounders, that would not be true in an environment whereby a large proportion (say 60% or more) of a population followed a set of dietary guidelines provided to them or more eating a SAD. If a higher ldl showed an issue with this group of people, it may be a secondary response to the poor metabolic health. Hard for me to eliminate the predominant dietary program as a confounder. Secondly, I find the Bradford Hill criteria in general to be insufficient to guarantee a root cause as opposed to actively involved and thereby defined as causal. As a possible example, suppose that people with very high ldl have an injury rate higher than the resolution rate such that soft plaque begins to form. As many note, if ldl is the ambulance, then perhaps, much like an allergy is an immune system over-reaction, the ldl over-reacts to the injury and thereby too many ldl attempt to clean up the issue and end up causing morer plaque buildup than in those with a lower LDL. LDL could then be defined as causal by the criteria, but yet not be a root cause, as it is only a reaction to a root cause. I have a set of over 700 papers on heart disease I am using for my deep dive. Well, or I was in the process, but now that I JUST got a CCTA showing zero soft or hard plaque with zero CAC, it is hard to stay motivated to complete the reading to become fully versed enough to defend my positions with multiple published links (atm).
Discussion of dietary cholesterol and cardiovascular disease
There is definitely some irony in the fact that people who do keto probably have some of the highest levels of LDL with arguably lower incidence of ASCVD. I get what youâre saying in that environmental factors that cause damage to artery walls are more the culprit in this disease. So, while generally the higher your LDL, the more likely it is that there will be plaque build up, if you have no damage to fix, then the LDL wonât have any reason to exacerbate it. So âcausalâ here is somewhat of a hype word. I shouldnât take credit for that either, it was from Peter Attiaâs podcast that I took it 
While a positive correlation (more A <â> more B) cannot by itself establish proof of causality, a negative correlation (more A <â> less B) is sufficient proof of non-causation. So the fact that there are people with high LDL running around who have no cardiovascular disease is pretty good proof that LDL does not cause cardiovascular disease.
A fact that I find intriguing is that something like 75% of people who show up in the emergency room with their first heart attack have either normal or low LDL. To me, this means that their cardiovascular disease could not have been caused by their LDL. Of course, a statin manufacter looks at that statistic and says, âSee? Itâs deadlier than we thought! Everyone should be using our product.â
Oh my, the man with maybe the highest level of cognitive dissonanceâŚever? Listened to a podcast when he had discussed a woman with extremely high LDL yet a zero score on a CAC scan (meaning a low level of atherosclerosis), yet said â literally a minute later â âBut we know LDL causes atherosclerosisâ. Ah, what?
I stopped listening to him after that.
Being eager to learn what I can from the links provided above, I admit to being a bit stymied by this opening sentence from the second paper cited above (after the first one blew well over my head) âŚ
"There can be no doubt now that there is a continuum of in-
creasing risk for complications of atherosclerosis when plasma
cholesterol levels exceed 160-180 mg/dl. Many types of ex-
perimental and clinical evidence substantiate the "cholesterol
hypothesis."
Perhaps Iâve missed a beat, but I thought the âcholesterol hypothesisâ has been sufficiently debunked? 
There is a correlation between high cholesterol, but that is not causation. There are people running around with ânormalâ cholesterol levels, and heart disease. I believe the correlation is because abnormal LDL is being confounded with native LDL.I believe oxidized LDL or oxLDL is the primary cause of most heart disease seen currently. I donât know where that quote came from, but risk is not causation. I do not worry about my cholesterol numbers at all - other than trying to keep my oxLDL levels down, because I believe science has sufficiently implicated oxLDL in the disease process. It has been found in the foam cells which start the plaque process. It is why the macrophage shows up. This is now clear from the science.
My own belief, though I doubt I could justify it, is that even oxidised LDL is associated with cardiovascular disease, but not causal.
I suspect that Ravnskov and Diamond are on to something when they identify the causal factor as hyper-coagulability of the blood, because the same factors that increase the coagulability of the blood also increase the oxidation and glycation rates of everything else, as well.
But so long as we consider glucose our friend and fat our enemy, our interpretation of the data will be distorted to fit that belief.
Fully agree, based on my reading of seemingly reliable studies. (The quote is the opening of one of the papers you cited above.)
Iâd agree with your idea. I think the same thing can be said about sub-types of LDL or HDL, as these probably just indicate the personâs diet, and diet likely affects coagulability of the blood. (Though I think I have a genetics issue for HDL for me; my HDL has gone up, but the sub-types of HDL I need to get a good âscoreâ on LPIR have not.)
Paul Mason is generally well regarded on this site, and he explains it somewhat here:
I agree with him on the issue of oxLDL being a problem. I somewhat disagree with him on how LDL gets oxidized. He has an unsupported hypothesis, which I believe is only partially true. He tries to blame it on phytosterols if memory serves. I believe oxidized PUFAs are much more scientifically proven to be the main cause, but elevated blood sugar can be a primary cause. Elevated triglycerides may contribute to heart disease as well by getting deposited into the arterial wall muscle, and eventually causing elevated blood pressure. It seems heart disease is probably a multi-factorial disease related to several foods and cooking methods in the SAD.
I would phrase it differently. Phytosterols are involved with lowering cholesterol levels, and they have unpredictable, sometimes dangerous effects on cells that take them in. I donât believe they contribute directly to atherosclerosis, however, any more than the consumption of cholesterol does.
Oxidative stress, however, whether from the consumption of oxidised fatty acids, or from a rise in free radicals in the blood, is a major cause of the formation of blood clots. Clotting is a necessary part of dealing with arterial damage, of course, yet we donât want the clotting to get out of control and block the artery. Or worse, for the clot to break loose and do damage by getting stuck somewhere.
Oxidised blood cells of all types are likelier to clot, and red blood cells with glycated haemoglobin are even likelier to do so. And blood that can clot simply from going around a corner is especially dangerous, for obvious reasons.
So it is getting clearer and clearer that high levels of oxidative stress probably cause atherosclerosis. It is not just oxidised lipoproteins that are the problem, however, though they are certainly a part of it. A high-glucose diet, airborne contaminants, oxidised seed oilsâthey all help cause cardiovascular disease. Anything that causes hyperinsulinaemia/insulin-resistance will also contribute, since hyperinsulinaemia directly increases blood pressure and inhibits the bodyâs production of endogenous anti-oxidants, both of which result in more oxidation and more stress on the arteries.
Dr. Malcolm Kendrick has a far more detailed explanation of how this all works, and there was an interview with him posted recently in another thread. Ravnskov and Diamond hypothesise that under healthy conditions, with a decent low-carbohydrate diet and pure air and water, the body is capable of handling the arterial damage that probably occurs quite routinely; it is the piling up of damaging factors that leads to atherosclerosis and calcification as responses with the goal of containing a higher rate of damage.
Anybody had any luck getting a doctor to be OK with high LDL on keto? I fit the LMHR parameters. The leaner and stronger I get, and as my diet gets under 20 total carbs, TG go down, HDL goes up, VLDL goes down, and LDL goes upâŚwayyyy up 
I choose the very low carb because it keeps my RA away. 50 net carbs is enough to cause inflammation symptoms, and thatâs itâs own heart disease risk.
You might be able to get a CAC scan and go from there. But my doctor wanted me on statins with a score of zero on a CAC scan, and a mere 130 LDL. So, itâll depend.
CAC scan sounds like a great idea to put everyoneâs fears to rest. (130 LDL is so reasonable!)
The âhealthyâ limit was 150, back in 2018. When I was a young man, (* cough-cough *) years ago, it was around 200.
Iâm carnivore and no, my doctor is not on board with my diet or my high (in his opinion) cholesterol but since high LDL has no correlation with heart disease I couldnât care less how he feels about it.
Not only that, but mine has been below or near 100 for many years. I get one of 130, and my doctor suddenly freaks.
Personally, Iâd like to see it higher. But Iâm not lean, that works against me. (Iâm slowly getting leaner, which might be why my LDL went up.)
I do a lot of body weight training, and used to be a pseudo-body builder, meaning that I have larger muscles. Not huge, but bigger than most. The LMHR paradigm tends for fail for people with larger muscles, and Dave Feldman had some theories about why. So, that works against me in terms of raising LDL.
I also have lower ferritin, due to a genetics anomaly, but Iâve been trying to get that up via B vitamins and no longer giving blood. Thereâs some evidence that raising ferritin, which Iâve done (gone from near 20 to over 100), can cause higher LDL. But the evidence is epidemiological, and also not all evidence aligns with this.
Anyway, Iâd like some higher LDL, but weâll see what happens. And I donât relish a fight.
There are studies of people with zero scores for CAC, and how statins donât provide a benefit for those people. But again, my doctor gave me all this explanation about why statins were good even for those people.
So, I generally agree here Paul. Yes, high oxidative stress appears to be a major if not THE major player in heart disease. The question is why? As I see it oxidized seed oils are going to go into the liver, and the liver is going to try to pack these fatty acids into LDL particles, yes? So, mind you at this point we havenât even talked about oxidized cholesterol. You mention a high-glucose diet. Well, yes, the evidence shows that can lead to high insulin, and IR. I believe once this leads to uncontrolled blood sugar, and maybe even before, you will see more glycated LDL or gLDL. gLDL is like 6 times more likely to become oxidized as well. This pretty much exactly corresponds to the higher chance of CVD in diabetic patients. I just havenât seen much, if any evidence that blood clotting starts the process. I am all eyes and ears for some.
Nevertheless, it doesnât hurt to lower the oxidative stress level, and the oxLDL level, which has been my own personal goal, and I believe I have seen and experienced positive observations in my own body⌠Lower(almost too low) BP, disappearing pain from a major varicose vein, and less observable blue spider viens in my right foot. Oh, and btw, I began supplementing with ubiquinol too, which is a major antioxidant for LDL⌠So my new motto is I worry about the quality of my LDLâŚnot my quantity.
I think high glucose damages the endothelium:
Thatâs most likely the cause.
The ârepairâ comes in from LDL or the like, but thatâs not the cause.
If high blood glucose (possibly caused or exacerbated by high insulin resistance) causes endothelium damage and oxidized LDL at the same time, is oxidized LDL merely a bystander?
What we need is someone fed a keto diet but one very high in PUFAs, which also supposedly cause oxidized LDL.
If high oxLDL are the culprits, weâd find out. Even this outlook seems to imply the culprit is a damaged endothelium:
