I realize this is going to ruffle some feathers. I spent over a month reading/analyzing these studies, and I'm sure there will be a small, vocal minority that will strongly disagree with my work here, but I take pride in my work and I put a ton of effort into this, so if you disagree, feel free, but be respectful and let's have a discussion instead of assuming I'm paid off, or I'm an idiot, or the like. That said, I also had a lot of fun doing this one, because I learned a ton about LDL and the different sizes - I hope it's informative for you!
@Yuri R. Most all of the crowd saying "experts are wrong!" prove in the long run to be bogus and just playing on lack of knowledge and emotion. IF information is designed to get you pissed off at "the system", "the experts", or "them" in general, you are likely, not always but likely, being manipulated.
@Yuri R. Unfortunately his "appeal to authority" fallacy is disrupting his work. I'm obviously disappointed. Focusing on the statistics is why I like this channel, suggesting conclusions as a result leaves things open for critical thinking and discussion(versus proclamations). Saying "I have a degree, you don't" is in effect anti critical thinking. That's a shame.
yes diagram labeling sizes is the key;; and unlike many presenters this at least mention LDL out path from liver and HDL as return path. I would love to see my own LDL particle sizes in histogram form.. aparrently this is a std test in Austrailia check out Ken Sikaris cholesterol talk. Personally i will NOT take a statin since it ameliorates any Nicotinamide benefit (something i learned here)
Only at start and liked just based on transparency and (true) unbiased nature of review. Rare now. Appreciated. Edit: study looking at drugs targeting cholesterol in brain for cancer. Also ones looking at neg effect of sat on blood brain barrier. Brilliant job. I’ll re-watch and pass on. Def signing up for insiders.
total LDL is a weak predictor of CVD. In statistics correlation =2 in order to consider it worth to further study. Mandelian studies have been addressed by scientists even on yt and they're not so enthusiastic about them. LDL level is so weak that it has miniscule clinical effect. It is well established that aggressive treatment for lowering LDL gives about 0.4% absolute rate reduction of heart attacks per year. But statins have large side-effects including induction of diabetes and mild cognitive impariment, ALzheimer and even increasing deaths of cancer and pneumonia ("Low Serum LDL Cholesterol Levels and the Risk of Fever, Sepsis, and Malignancy"). We know that cummulative effect of high LDL on CVD is about 27% per 10 yeras on average. But low HDL rises risk 3 times (300%) regardles of LDL level. Triglicerydes rise risk 3.8 times when above 2.3 mmol. That is why ratio Total cholesterol to HDL, or TG/ HDL ratio have more predictive value and more favouralbe effect when addressed by diet. The most important single factor is insulinemia and related to this glycemic load. Glycemic load of 300 grams of carbohydrate per day gives rise of CVD 6 times above basal level. Every 60 grams produce rise of 44%. That is why insulin resistance is the most important factor to address. There are PCSK9 inhibotors and studies have been made. Dr Nadi Ali presented on yt one of these studies. Lowering LDL level to 30 mg% resulted in increased rate of incidents compared to control group. So lower is not always better. The conclusion is: LDL has some impact, but its impact is relatively small so that in many cases it is not worthy to deal with it. Pareto rule should be applied here in my opinion. We have several elephants in the room but main stream physicians still focus on gnat.
I concur that LDL is a weak predictor, but it is still a factor. I'd be interested in hearing what these scientists have to say about mendelian trials, because the 20+ scientists I've read and heard from have been blown away by their utility. I think the absolute values aren't nuanced enough, because there are many factors that play a role in LDL lowering effectiveness (the delta, the duration, the time of implementation, etc.). Still, I do believe that the risk reduction is modest, but if we expand the scope to the broader category of ApoB (which LDL is a big part of), we start seeing greater effects. Not only that, the argument isn't 'is LDL the *only* risk factor', it's 'is it a risk factor of any level' - the answer is yes. The relationship with lowering LDL and cancer, pneumonia, etc. is confounded massively by the sample those studies are performed on - I even covered one study that acknowledged higher rates of pneumonia in people with low LDL, but one sentence later also mentioned there were higher rates in people with high LDL, as well. There's a lot of context we're missing here. There are studies that have been done in people that have accounted for insulin/insulin sensitivity and have still determined that LDL increases rates of heart attacks independent of insulin (my video on Dr. Saladino discusses this in brief). In total, I agree with you on some points like yes, LDL is not the only factor and may not even be the major factor to CVD, but it is a contributor - more so than people acknowledge, but not the only factor. Additionally, the absolute risk reduction in the mendelian trials is huge considering it's only one factor. Still, I agree we shouldn't be insular in our focus of LDL.
@@Physionic I don't know any scientist of practitioner claiming that LDL has nothing to do with cardiovascular incidents. But many of low-carb physicians maintain that for majority of patients LDL is not issue to worry about. Unfortunatelly I can't recall where did I see lecture on mendelian studies. I suspect that this was some from low carb under. However I found on my disk fantastic narrative review I wanted to post the last one, about mechanisms of arterial plaque formation. I encourage you to download and read it because it is worthy. "The critical issue linking lipids and inflammation: Clinical utility of stopping oxidative stress"
I really appreciate your channel, thank you for all of your work. Per your comment at the start of the video, I focused on your video at the start of 1 hour and 5 minutes in. I just want to point out the difference is wall thickness of the intima between what appears to be the "extremes" of the study is around 10%, or in inches(converted from microns), around .004 to .005" of an inch, around the thickness of 2 human hairs. (again, if I'm reading this correctly) When you bring up that a debate on the wall thickness itself might still be something to consider, I agree. (even if most everyone leans to accepting wall thickness as the root cause of heart disease at this time). This topic is interesting, but I can't help but refer to the large scale sauna study in Finland that showed tremendous reduction in cardiovascular events(and stroke, which to me is related- but digress) dependent on frequency of sauna use. I've "onced over" the study some time ago, but I seem to recall that there was little in the way of controlling factors accounted for(lifestyle choices/activity outside of the sauna use for example),but the result were so significant it's hard to ignore the results(it was conducted on around 2300 middle aged participant over 20 years) and further I think has significant implications on the role of wall thickness of arteries, LDL, etc. et al regarding heart disease and it's causes. Keep up the great work!
I love this, Nick. I appreciate you doing the math on that. I can appreciate how miniscule that is, but we're forgetting the other side of the equation here - what's the size of an artery, and then even more importantly, what's the size of an arteriole? Keep in mind, most plaque formation likely isn't a huge issue if its found in a large artery (and, plaque build up can vary based on where the artery is located, like the coronary), but if a thrombus forms, it can freely float through the larger diameter arteries, yet may easily get stuck in a much smaller arteriole, like that found in the brain (stroke), legs (peripheral artery disease). The size of arteriole ranges from 100um to 7um - now we're getting into a territory where 2 hairs thickness is a problem. Additionally, the progression of the plaque bows outwards more dramatically once calcification and ECM is overlaid on top of the initial plaque formation. Finally, the study ran for 8 or 10 years, and cardiovascular disease is a progressive disease taking decades, so is it possible the problems compound on one other with each decade? Oh, and one more thing - as for the sauna data, I have not looked at it in the slightest, but keep in mind that LDL is one risk factor, it isn't a 1:1 (high LDL therefor you will die) - it's a major facet out of several factors (weight, hypertension, physical activity, pollutants, and much more), so the sauna data can indicate a positive effect while this LDL data can also show an effect. I'll have to look into it sometime. Thanks for the thoughtful comment!
@@Physionic Yes, the Finnish sauna study would be a great opportunity for you to further your channel IMO. I'd be interested to see your take on it. Thank you for the note, I agree with your point on specific artery size, especially when it comes to "strokes" for example. Artery blockage as a function of LDL is definitely a cause/effect conundrum in that we don't fully understand the mechanisms at play obviously.
Thanks for putting this together, it’s very informative. In your initial image, above "Tissue of the body" you included the brain. My understanding is that the cholesterol pool in the brain (made in situ by astrocytes and oligodendrocytes) is independent from the other two pools in our body, that is, cholesterol produced by the liver and that produced by peripheral cells. As far as i know LDL particles either do not cross the blood-brain barrier, or they do so in very small amounts. Also, positive and negative charges refer to electrical charges. A magnet does not have charges, they have poles. A south and a north pole, to be precise. Electric and magnetic fields are two different things (though they are associated one to the other, but that’s a different conversation).
Thank you. Now I have the arguments to talk to the people, that are convinced saturated fat is not bad, since it only increases the large LDL-P's. Very interesting. There are even MD's with this standpoint on youtube, I could not believe that.
Hi Nicholas, thanks for your great work. It would be very interesting (for me at least) for the purposes of objectivity to review the studies quoted by the statin skeptics that cast a shadow on the legitimacy of the studies that have authored the narrative that saturated fat is bad and the benefits of statins are being overstated. I'm aware of the dangers of echo chambers but having available someone like yourself to bridge the different schools of thought would be a valuable contribution to consumers.
Hey Craig - thanks. I expect to cover statins at some point, but I really need to take a lot of time on it, because people are really polarized on the topic. In time, I will, though.
this was as difficult to keep watching as many of my philosophy lessons on Kant. i had to break often to get through to the end. much appreciated, but really a mental exercise that at my age, is like doing push-ups
Haha, Kant isn't easy - I can appreciate that from my own philosophy courses way back when. Still, the mental workload helps keep those neurons healthy - appreciate the effort, Paul.
Hi Nick, so glad that your program pops up on my CZcams and glad to have come to know your channels, which I m interested to dig in more. I m coming 60, have been having issue of high LDL (7.18 mmoI/L) since few decades that I came to know ( so is my whole family where most of my 7 siblings are having same issue). Would you be kind to point the link to me , if you have , on subject of how to combat high LDL ? Sincerely look forward to… Tqvm..🙏
Really great lecture, Nick! I've seen another study(maybe from you) that indicated the endothelial "gaps" allow penetration of particles up to 70 mm. Seems to support the "more trucks cause more accidents" theory Wish I'd learned this 20 yrs sooner.
no, it's more like the endothelium is designed to allow transit of molecules. As a primary part of its normal function. (ie, allowing lipoproteins to deliver cholesterol and triglycerides that needs it)
Thank you for your work, it is contentious that small particle size isnt the villain when it comes to elevated cholesterol but science is science. Food for thought. I'll certainly get a particle test over LDL C
I was hoping you'd go into the claims by Paul Mason about the ratios of trig, HDL, and LDL being the best proxy for cvd risk. He seems to know what he's talking about.
It is very interesting, thanks. I come from a family with genetically-high cholesterol and triglicerides values (and no systematic habit for seed oils or ultra-processed food); however in my family there have never been major CVDs, except for one person (who had a very bad eating habit and smoked up to one packet of sigarettes per day). The grandparents almost reached 100 years. Still, I would like to pay attention to the blood work; yet maybe, *maybe*, total cholesterol and LCD is not what I should focus on, risking to lose health elsewhere (e.g. once I followed one strict diet that lowered my total cholesterol to 180 mg/dl, but that was allegedly way worse as my HDL was extremely low). After years of dietary efforts, I found a significant blood work improvement with a low-carb/keto OMAD-2MAD diet. Even my stress and overall quality of life improved. Let’s consider that I was relatively fit even before (72-74kg / 178cm, but with a constant “effort” to maintain the weight). With the LC/keto diet I moved effortlessly to 67-68kg (without willing to do that, 43:17 intentionally). The hunger went away; possibly, the nutrients I am getting from the LC/keto diet are also more balanced for my body (?) as often in the previous diets (including low-fat ones), I always felt that something “was missing”, even if sated. BP, glucose, triglycerides, HDL, mood, stress, joints pain, and energy all improved. It seems that at least in my case the LC/keto diet had good effects. Alas also LDL increased. I would really not want to go back to the trial&error dietary regime again, just because of LDL: I feel really good now. Of course I do not want to increase too much the risk of CVD.l, on the other hand. In the search for the optimal compromise of benefits/risks, is there a way to know the quantitative weight of LDL in the total CVD risk, alone or in combination with other factors? That would help. Cheers
Well, besides the expected comment that these studies are observational, I have something else to say, ask or suggest. First, it is incorrect to only talk about relative risks. A simple illustration as to why. You chance of winning a lottery is about one in eight million. If you buy two tickets you double your chance. Yet, the chance is still very low. In fact, it is still negligible if you buy ten tickets, increasing your relative chances ten times. How much lower was the absolute incidence of cardiac events in people with these mutations? Second, while there is a reduction in cardiac risk, you cannot conclude that this is because of lower LDL. It could be another (or many) factor that is connected to LDL and which is also affected by these genes. For example, anti-inflammatory effect. LDL is an inflammatory marker, and is the corollary variable of these genes' correlation with cardiac morbidity. So while these studies do point out at the connection between LDL and heart disease, it is not possible to conclude of the precise mechanism. Finally, while it is possible that LDL plays causative role in heart disease, the practical implication of these studies is unclear. Reduction of cholesterol by itself has variable effect on cardiac morbidity, from positive to negative. Early studies with fenofibrate showed increased cardiac mortality. Half of patients admitted to the emergency rooms with infarcts have normal or low cholesterol. The reduction of cardiac events seen with statins is not related to the degree of cholesterol reduction. Real life is messier than an epidemiological study.
Dismissing the genetic research as merely correlational is incorrect, in my estimation (for the reasons mentioned in the video). As for relative risk and absolute - that's a good point: I calculated the absolute risk for just one of the genetic mutations (PCSK9) and it came out as follows: 1 in 10 people with normal LDL experience a heart attack, while only 1 in 60-85 with reduced LDL experience a heart attack. A big difference. And, yes, it's exclusively due to LDL - I think you don't understand how mendelian randomization studies work, I addressed those points in the video, there is no pleiotropy with those genes, please rewatch.
Out of interest, how did you arrive to the absolute risk reduction values? The Mendelian randomisation study does not mention the incidence of CHD and related events, and RR varies between 0.86 and 0.94 (0.72 8n one study). You are claiming 6 - 8 times reduction in CHD, which means RRs should be around 0.12 - 0.15.
Myocardial infarctions cause cholesterol to decline. Measuring someone's blood cholesterol levels after a heart attack is unlikely to deliver a figure that accurately represents their blood cholesterol level prior to their heart attack.
You are not considering the LDL that are oxidized because those are the LDL that make it into the intima. You have also not looked into how oxLDL get through the endothelial monolayer to get to the intima. So inflammation is the key. What drives the ROS that oxidized the LDL! Start by understanding how TRPV4 and piezo channels on endothelial and immune cells work. This will show how TRPV4 breaks open the endothelial monolayer and on macrophages -> M1 macrophage. Look at how TRPV1 brings glucose into cells independent of insulin and the insulin receptor that leads to too much oxidation for the cell to handle and the mevalonate pathway that increases cholesterol. Stimulation of the piezo channel on monocytes directly takes them to an endothelial inflammatory reaction. Without stimulating these TRP and piezo channels and consuming too much glucose there is a far different LDL, cholesterol story. Lastly, people live longer with normal, native unmodified LDL. Cholesterol makes our immune and hormone systems. We cannot live healthy lives without them.
Ok. Where are the studies to back up your assertions? Your last two sentences make me wonder if you have started with a conclusion and worked backwards from there.
The LDL particles have to be retained BEFORE they oxidize. Thus, oxidation is a downstream effect from retention. And you get retention from high particle numbers, which occupies air high LDL/ApoB levels. Lower particle numbers enough and you get less to no retention.
@@BlahBlahPoop617 I respectfully disagree. Too much TRPV1 at the cytoplasmic membrane on the cell puts glucose into the cell even when the cell is resistant to the insulin receptor thus the metabolism of glucose is in excess of the cell’s antioxidants. Too much TRPV1 on the mitochondrial membrane causes too much reactive oxygen species to be produced and as we know a fundamental function of mitochondria is lipid oxidation. This is where the excess oxLDL comes from. Additionally, too much TRPV1 causes too much calcium into the mitochondria and damages the mitochondria and along with more insulin resistance leads to apoptosis of the cell. Too much TRPV1 -> hyponatremia/hypoosmolality that stimulates TRPV4 on vascular smooth muscle cells (VSMC) and along with klf4 leads to the dangerous inflammatory phenotype when the VSMC dedifferentiate from contractile VSMC to macrophage-like VSMC that make up 50% of the plaque and osteoblast-like VSMC that put calcium in the lesion. Unfortunately this phenotype is associated with a dangerously thin fibrous cap over the lesion with significant risk of rupture. The condition when the transcriptome does not have klf4 or TRPV4 but has OCT4 instead has a good thick fibrous cap.
@@BlahBlahPoop617 you are incorrect in fact the lean mass hyper responder evidence shows this. LMHR have high LDL, high total Cholesterol and high apoB. LMHR have good triglycerides and HDL. I know, I am one. On the low carb diet my plaque reduced from moderate to mild in one artery and from mild to no significant finding in a couple other arteries. My calcium decreased across the board. My lipid fraction profile is type A on multiple tests with high apoB but my lp(a) is
@@BlahBlahPoop617 And what purpose or reasoning do you have to "Lower" or manipulate the number of lipoprotein particles in the blood? Don't you think its rather inappropriate and risky to go toying with homeostasis without understanding the full picture? Clearly you don't understand the full picture or you would immediately list the possible side effects of suggesting something like "lowering particle numbers"
Very good analysis, thanks you. One thing I wonder about is about CoQ10. CoQ10, which is important for the heart, is transported by LDL, so the lower the level of LDL, the lower the CoQ10 level is going to be, which is what we see with the use of statin. So is a very low LDL a factor for heart desease, not due to arterial stenosis but due to lack of energy production in the heart? Also, on top of that, from looking at the chart at 1:07, a very low LDL-p ( small + large LDL particles ) seems to increase increase IMT. That threshold below which it happens seems to be around 700 ( corresponding to say the 2 white bars on the left ).
If on Cholesterol and Triglycerides lowering medications, old school Neurology and Cardiology University Professors recommend briefly to supplement with CoQ10 200 mg or higher. Patients rarely follow their advice as they typically don't measure CoQ10 Levels and other Vitamins (including Vit Bs and Iron and Vit D3) during Metabolic Blood Panel and Liver Enzymes Panels which are usually required for getting these Statins, Ezetimibe, Nexlizet, and PCSK9 Inhibitors Repatha or Praluent. Ideally they should be including checking for CoQ10 Levels and most likely the reason why they don't is hidden in the way Cholesterol lowering medications are having side effects not beneficial for Big Pharma to disclose to their younger and younger patients (20-60 old)...
I always thought the distinction between LDL and Small dense LDL was nonsense. Small dense LDL is simply oxidized or glycated LDL. Call it what it is. If you have blood sugar, then there is a risk of glycating the apob100 of LDL. The more blood sugar you have, the higher the risk of this. When the APOB100 is damaged, the LDL will circulate till it gets picked up by macrophages in the vessel wall. This gives lots of time for the contents to oxidize. The more polyunsaturated fats you have in your diet, the higher the oxidation risk. Some fats are worse than others, such as Linoleic Acid and it's oxidized metabolites, 4-HNE and 9 and 13 HODE. In either case it's the oxidation and glycation that is the issue. Higher blood sugar and excess PUFA are the primary factors. Of course, having more LDL can also mean more APOB100 to be glycated. , This if you have a higher PUFA diet, then a higher LDL could lead to increased risk also.. and their study populations have a diet of excessive PUFA on average... So results not surprising. I'm still skeptical this is an issue with ancestral levels of Linoleic acid consumption.. so I guess more data needed on that population...
Please consider "Small Dense Low-Density Lipoprotein as Biomarker for Atherosclerotic Diseases" Oxid Med Cell Longev. 2017; 2017: 1273042. Published online 2017 May 7. doi: 10.1155/2017/1273042 PMCID: PMC5441126 PMID: 28572872 Conclusion "The results of recent studies demonstrate that LDL fractions have different atherogenicity, with sdLDL being more atherogenic than larger LDL subfractions."
@Ray. Carbon is the basic building block of life as we know it. If I dumped a truckload of carbon ashes on you, you'd be crushed. See how this works? We are only acclimated to a certain range of anything under the sun, including sunlight.
@@raywang7551 yes your calcium score is crucial for atherosclerosis risk but there are a group of ppl who have good genetics that can live with high LDL as he mentioned and never have problems and you are likely one of them. Not everyone is that lucky.
@@raywang7551 there are many people who have high LDL's who are now dead before 70 and there is a ton of evidence in many trials over the past 2 decades. If you are eating healthy and exercising and your LDLs are still high but you have a low calcium score then you do not have much to worry about. You are one of the lucky ones. There is a safe range to be in - not too high and not too low, and as they always say, it's good to be safe than sorry.
@@raywang7551 Definition of Syndrome is a group of signs and symptoms that occur together and characterize a particular abnormality or condition so the answer is no. If you want more info of your own risk, ask your physician because this is not based on meta-analysis but personalized medicine and based on your other factors as well including your TG's, BSL, your HDL, total cholesterol and your diet and exercise. I won't be responding anymore to this thread so if you are still concerned, just ask your doctor for his opinion.
@@Physionic You got me there. The truth is that I have read a few models, but none of them fulfill the basics of a molecular model for a disease. For starters, any model that when applied predicts that every millimeter of every artery will develop plaque has to be wrong (I hope!). I find it hard to buy a slow inevitable progression model for a disease that almost did not exist 100 years ago.
Interesting. I don't know about the models. The papers I covered seemed pretty uniform in how they were describing things. As for heart disease 100 years ago, the life expectancy was 47 years old - most people don't develop noticeable heart disease until their 60s or beyond (of course, there are exceptions). Edit: Just looked it up - the average heart attack occurs around 65.
@@PhysionicThe main critique some will pose to that average life expectancy number is that it is misleading because the higher level of infant mortality distorts from the typical age of death of the elderly population. I still haven’t found a good number for what the typical life expectancy was for those that lived past say 50 years old. Heart attacks are also not a peaceful way to go which is what makes me wonder why there doesn’t seem to be reports from those that went beyond the 65 threshold.
@@el_argent0 What are u talking about? 100 years? As long as they lived long enough and were exposed to high ldl they would developed atherosclerosis. Who developed it u might ask? Let's see someone rich enough to eat lots of meat and fat and dairy and refined grains and sugar and honey or white bread with zero fiber. Someone rich enough to live past 60 or even in 70. And we need their bodies too. Is there anyone like that? Oh, the royal family, the mummies An article in the Lancet[1] in 2013 with whole body computed tomography (CT) scans of mummies from four different geographical regions (ancient Egypt, ancient Peru, Ancestral Puebloan of Southwest, and the Unangan of the Aleutian Islands) showed that atherosclerosis may be very ancient. The time period spanned more than 4000 years. The investigators found probable or definite atherosclerosis in 34% of the 137 mummies studied. you are so busted
Nice work here. Thanks for that. So basically, carnivore followers are headed for trouble due to all the saturated fat they eat? I'm also not sure how that large LDL is harmless thing caught so much momentum online but I've heard it many times as well
Based on my work looking at saturated fat, I'd say yes. There may be some nuance on the type of saturated fat, but as one lump sum, saturated fat raises LDL, and LDL raises heart disease risk.
@@Physionic Thank you sir. Do you have any expertise in the area of glycation as it relates to dietary choices? If so, I think that would be an interesting video for the future to hear your take on it
Yes, when the prominent online Carnivores start dropping, their followers will do somersaults trying to come-up with excuses. Most-likely, they will either blame genetics and/or pre-Carnivore diet and lifestyle. I’ve seen it already.
@MegaVegan There's little to no long term studies done on the carnivore diet. I expect that pattern will continue. People get a few years in at most and then start adding healthy carbs and fiber... Wonder why?
@@limitisillusion7 Not even a few years in. Most of these people are dishonest and eventually admit that they cheated on the diet and would eat blueberries or lettuce and tomatoes with burgers for example. So it wasn't them eating "just meat and meat fat" as they claim
Hi Nick. The genetic information is good evidence, but wouldn’t you have to know the amount of embryos formed with that genotype who don't make it to term and development and whether the rest of the genome is important for that to get a perfect comparison? This is what I hear denialists commonly say with regards to the genetic studies such as the one you provided.
@@Physionic Hello! I have heard critiques say that if the scientist is taking two equal groups and making one have just that one change going forward, it isn’t exactly testing cause. Just one example but in these cases you aren’t testing “people with genetic mutation X” but “people with mutation X who were born.” We don’t know how many people have this or that mutation and that causes a high level of miscarriage, as just one example. So there’s already a selection there outside of a pure randomization. And probably others. There are a lot of mutations people make in animals that would be great to study but the animals end up sterile or they don't develop. So then things like cre-loxp were developed to induce a mutation after offspring reach a certain level, but of course that can't be done on humans. I’ve heard critiques of the genetic research say that when you are studying a genetic mutation such as this research, you aren't studying that per se, you're studying that mutation in the population you can observe. This leaves out people for whom that mutation proved lethal early in life, particularly miscarriage. Many miscarriages are from genetic issues or other developmental hiccups, but could get those babies to term they may have some disease resistance. It could be that ApoB mutations are really dangerous in X amount of host genotypes. But those might never be known because they never make it to the sample. So imagine in the future we have a gene editing technology, and everyone goes out and mutates their ApoB because of all of this great "controlled" research showing it's good to have that mutation.
Gotcha. I understand the concept of embryonic lethal and have studied LoxP extensively throughout my PhD, but I don't see how that argument applies to studying humans who want to know if LDL is causative to heart disease? Whatever mutations lead to embryonic lethality don't matter in the slightest to the people who are alive and want to know about their heart health. If a mutation exists that leads to embryonic lethality, so what? You'll never see it, so it doesn't matter (those with the mutation won't exist and those without the mutation don't have it, so they don't care). As for mutating ApoB - that's where there is concern related to what you're talking about, the mendelian trials aren't anything related to that, so I'm confused how that's an argument against these MRTs.
@Physionic And now, some speculation... Some say that inflammation causes the endothelial layer to allow lipoproteins to enter. Could it be age? Could cells be damaged during their reproduction? Why don't babies have arterial plaques? What causes arterial inflammation besides sugar and nicotine? Could a carb-based diet cause LDL to circulate more than it should, since cells need to get rid of sugar and cannot consume fat?
One explanation I've seen for this is that older people are more likely to be sick with certain diseases that lead to low cholesterol levels. For example, a cancer patient isn't going to have a huge appetite, so they are likely to be losing weight which usually lowers cholesterol.
I've read that right after an event like a heart attack, the LDL will often drop. So it would appear the person had low LDL when they didn't. It's kind of like blood pressure dropping before you pass out. The person could have had very high blood pressure before they fainted. So that's the comparison I've read why many people who've died from a coronary event show low LDL. Plus as others mentioned, high LDL is only one risk factor. There are other risk factors. Low LDL doesn't mean a person can't get CVD. It just lowers the risk.
@Physionic I agree 100% with you in that video, as you didn't say “cause” at any point, but just “it's associated”. At minute 19, you say that the proposed mechanism is that the lipoprotein is attracted to the intima... Which study proposed this and, most importantly, what was the proposed reason for this attraction? I understand the attraction between lipoproteins and proteoglycans, positive and negative, but these charges exist since we are born. Why, at some point, do endothelial cells allow lipoprotein to enter the intima? The answer to this question will lead us to the cause of atherosclerosis.
Could you please cite the mechanistic studies that would support the description of atherogenesis that you have outlined in the beginning of your video?
My pleasure. I hope to make specific content looking at some of the experimental methods and show you the data more forthright in the future (so much to do!).
I think small ldl is rusult from 1 insulin resistant or 2 liver has problem to recycle ldl such as fatty liver LDL stay too long in the blood so it get smaller and oxidezed.
I have a question about the mutations that reduce the risk of heart disease. Say we are talking about rs11591147. According to the video, there's a huge decrease in heart disease associated with the mutation. Does that mean that people who have it live longer or healthier lives in general, or does it mean that they just die of heart disease less often and instead die of other things like accidents, suicide, cancer, etc, but in the end don't really do much better than the other people?
We basically have no reasonable method of predicting any event in humans based on any measurements let alone genetics which is _extra difficult_ to predict. In fact even labelling genes as "decrease in heart disease" is like you say, merely associated, and could be compeltely unrelated
Could there be an issue with the tight junction in the endothelial cells that allows the LDL through? Is the real issue the compromised tight junction not the LDL?
That's an interesting idea, and there could be something to that, Ed. However, LDL doesn't just cross the endothelial layer between the cells, but can also transcytose through the endothelial cells according to study 179, so while tight junction misfunction could contribute, it likely wouldn't eliminate the problem entirely. Great idea, though.
@@Physionic This I found was interesting. However, the oxLDL hypothesis of coronary heart disease does not get at the root cause, that is, what causes LDL to become oxidised in the first place? It was later discovered that the oxidation of LDL was initiated by the oxidation of linoleic acid contained within the LDL particles.13 Indeed, linoleic acid is the most common oxidised fatty acid in LDL.14 Once linoleic acid becomes oxidised in LDL, aldehydes and ketones covalently bind apoB, creating LDL that is no longer recognised by the LDL receptors in the liver but is now recognised by scavenger receptors on macrophages leading to the classic foam cell formation and atherosclerosis.13 15 16 Hence, the amount of linoleic acid contained in LDL can be seen as the true ‘culprit’ that initiates the process of oxLDL formation as it is the linoleic acid that is highly susceptible to oxidation. Additionally, an increase in the intake of linoleic acid intake increases the linoleic acid content of very-low-density lipoprotein (VLDL) and high-density lipoprotein (HDL) increasing their susceptibility to oxidise, which further increases the risk of cardiovascular disease.17-19 Thus, expanding on the oxLDL theory of heart disease, a more comprehensive theory, the ‘oxidised linoleic acid theory of coronary heart disease’, is as follows: dietary linoleic acid, especially when consumed from refined omega-6 vegetable oils, gets incorporated into all blood lipoproteins (such as LDL, VLDL and HDL) increasing the susceptibility of all lipoproteins to oxidise and hence increases cardiovascular risk.20 (an extract from openheart.bmj.com/content/5/2/e000898)
@@Physionic The endothelium doesn’t need to be damaged or inflamed for LDL particles to transcytose. They can get through even with a healthy endothelium (I learned that from Dr. Thomas Dayspring’s 3-part series with Simon Hill). That’s why elevated LDL/ApoB is a causal in atherosclerosis. Obviously, a damaged endothelium will exacerbate the problem.
Great question. One, I haven't looked at that data, but I'd say multiple things: First, looking at associative data that doesn't account for other common variables is a far cry from studies that are more rigorous (like the genetic studies I point out here); secondly, LDL is one factor of heart disease, but it isn't the only factor. So, is it possible that Japanese people are far more active? Have less stress? etc. etc., which ultimately mitigates some of the risk of high LDL? Probably pretty likely. Still, until I actually look at that data, I can't give you any specific answer.
@@PhysionicI really love the topic, also an important role I think is the prevalent use of fermented food, natto included. Did you check the effects of the nattokinase in the cardiovascular system? It's very interesting. Hope inspires you.
@@megavegan5791atherosclerosis is pretty much the leading cause of death world wide however, japan has the lowest rate of Cardiovascular disease in the world. they eat more eggs than anyone. if they eat the most eggs it stands to reason, they must eat chickens. ramen is a popular dish in japan.noodles cooked in bone broth with a hard boiled egg, and a bit of fatty pork. they also seem to smoke tobacco quite a bit. i personally think it's genetics more than anything.
Really well presented Nick. Particularly interested in the IMT results. I've had 2 (annual) cIMTs after a nasty CAC. Their ability to pick out the plaque densities gives them great utility. For feedback, in a couple videos, including this one, you seem to emphasize the build up of plaque over time clogging the artery to cause a heart attack "eventually" over the more acute danger of a newer soft plaque rupturing, resulting often (30-50%)in ones sudden, tragic, early death. Please don't take this as a criticism. Ive had cardiologists skim over this detail. You're doing good work, thank you!
I don't take it as criticism. It's an important point. I plan on addressing it in the future (working on a multi-video series on LDL, oxidation, and inflammation's role in cardiovascular disease). I appreciate it, CJP!
I'm not following your logic on LDL lowering genes. How do we know that's the only thing they're doing? Couldn't these genes be driving some other health improvement and then that improvement is driving an observed reduction in LDL in those with the gene?
Good question. We can verify by mass data sets that have the sensitivity to compare those with and without the mutation. Additionally, we can run genome sequencing to determine if there is linkage between genes (in this case, there is none). Finally, we can look for interactions between the protein of interest (say, the LDL-R or PCSK9) and potential targets to test for affinity and/or reaction speed.
@@Physionic but how do we know the pathway is: gene -> LDL -> health outcome? Couldn't it also be: gene -> health outcome -> LDL? For example, let's say a gene reduces chronic inflammation. Then (due to reduced inflammation) those people happen to have lower LDL when measured. Or do we have some other way of knowing the details of the mechanism here?
We can't know. Ever. You need to control the individual from birth to know anything about what their genes are doing unless its _extremely_ obvious like Huntington's. Where it's not obviously affected by environment ever and there is a finite set of outcomes. Have disease or don't have disease
I'm 27 my LDL is out of the chart with good diet and sports so I'm just gonna start rosuvastatin 5mg daily with my grandma 😂 and dodge the risk while I'm young
"If you have high LDL you are at risk" - these are empty words, my friend, it means absolutely nothing. What is high LDL? Would you want to lower any number just because "high LDL = risk"? Would ZERO LDL be the best? The U-shaped relation between levels of LDL-C and mortality is well established by now. "Large buoyant LDL particles increase heart disease risk" - what is the mechanism then? When You say A say B, why don't you??? "The higher your blood LDL particle levels the greater your risk of heart disease" Statins and PCSK9 inhibitors curb LDL and their absolute risk reduction of any CV event (stroke, heart attack, etc) is basically minuscule (regardless of the fact Big Pharma is in charge of what is disclosed and what is not when it comes to data THEY collect from the trials THEY carry out). This topic in general might be WAY TOO BIG for you at this stage (no offence)..... Besides, besides, besides... focusing just on LDL (whether it is buoyant or petite) leaving out HDL, triglycerides, and insulin resistance in relation to CVD is just plain silly, isn't it? By going low-carb for instance you may increase large buoyant LDL but so your HDL would spike, triglycerides drop and IR would improve. Are you trying to say low-carb/high fat detrimental to cardiovascular health overall?
I've read that HDL is actually a more reliable predictor of heart/stroke issues than LDL in a few places as well. I think it has something to do with HDL's ability to transport LDL based on current understanding. It's a very complex topic to your point.
I think you either didn't understand the whole video or you're purposefully ignoring some of the information I provided. Obviously, no LDL means death - we need some level of LDL for cholesterol and triglyceride transport, we agree there. The U-shaped relationship is also driven by the fact that many diseases reduce cholesterol/particles and those people end up in the hospital before death. To your other points - I keep having to repeat myself here, but people get so caught up on the mechanisms without acknowledging the more important aspect - the clinical end point (heart attacks, death, cardiovascular disease progression). As I explained, and showed the data, lbLDL is also a risk, and although I didn't go into the mechanisms much (I provided one, briefly), the end result is still the same, according to the data. I didn't discuss statins once in this video, but statin data is often misunderstood - I'll likely make content explaining why once people have jumped down my throat about this topic. Your point about relative vs absolute risk is a good one, but I calculated the absolute risk for the genetic studies I gushed over and the absolute risk is actually dramatic (1 in 10 vs 1 in 65 or something like that in the PCSK9 SNP individuals). I not only explained why elevated LDL, independent of all other factors, is a heart disease risk, but I also included some data showing that accounting for those risk factors (HDL, triglycerides, etc.), there was still an elevated risk of LDL (this is where I'm wondering if you watched the video? I mention this multiple times across multiple studies). I have videos explaining the nuances of a low carbohydrate diet and how it can be done safely so as not to increase heart disease risk, so no, I'm not saying all low carb diets increase heart disease risk. Finally, if the topic is too big for me (a person who dedicates their life to analyzing research, who is on the cusp of multiple advanced degrees in this area, and who has real world experience publishing studies), how are you so confident?
@@nickb3968 it is. On top of that you have to take into consideration the state of your endothelial cells with its supportive extracellular matrix. I strongly believe there is too much commotion around LDL-C (obviously because we have drugs to lower it, we still do not have any to raise HDL for instance) plus I just can not figure out how a native LDL (not modified by sugars or oxygen) could cause arteriosclerosis.
@@matkagrogan5251 "we still do not have any to raise HDL for instance"- actually, as an "fyi", niacin in the form of nicotinic acid(which I take in lieu of a statin as I'm close to 52 years old), does raise HDL at therapeutic dosages. Just as an "fyi", I think you should try to tone your comments down as you make some good points but they could be lost on a perceived "rudeness" and that would be shame. Mr. Verhoeven puts a tremendous amount of time and energy into his channel obviously and I don't think most here would want to dissuade him from doing that even if they disagree with some aspects of his videos. I imagine it would very difficult to spend a month of your time reviewing studies and creating videos and feel like it's not appreciated- it's the whole "disagreeing without being disagreeable" thing that if mastered, is a great skill to have.
@@Physionic It is too big because you focus on epiphenomenon, downstream effects, etc. You are making the whole video with humongous statements about LDL causing atherosclerosis, but you just can not underpin that? If you can you should come up with the mechanism. You made a cause-and-effect statement. There are floating LDL particles (big? small? modified? oxidized? etc) and then there is a plaque buildup in arteries (inflamed? swollen? etc) So many scenarios in between! I don't have to be confident, I'm not making big statements on youtube, you are so you should be. Mentioned statins because they target LDL, that's obvious, with puny outcomes but not so puny side effects. I delved into a couple of these studies and the ARR for CVE was usually between 1 out of 50 to 1 out of 125. Dire numbers indeed (still without any positive effects on all-cause mortality). Yes, you mentioned one study that is 173, unfortunately, I can not download it, my loss. Sorry, I do not understand your statement about the U-shape curve. A recent gigantic study from Denmark (among 110 k individuals) proved U-shape explicitly ("The concentration of LDL-C associated with the lowest risk of all-cause mortality was 3.6 mmol/L (140 mg/dL) in the overall population and in individuals not receiving lipid-lowering treatment"). And among older generations (70+) the correlation (higher LDL & increased lifespan) is even more striking. Guess what, LDL has many other functions apart from delivering lipids and cholesterol. I wish your channel more critical thinking, less pedantry : )
@@Physionic ●President Dwight Eisenhower had a heart attack in 1955. he had many heart attacks but later died in 1969. ●John Yudkin posited that sugar was culprit for heart disease in 1957. ●Ancel Keys was on the cover of time magazine swaying the public that cholesterol was the culprit for heart disease in 1961. ●The Sugar Research Foundation paid scientists to say that sugar consumption was not culprit for heart disease in 1967. ●seed oils became popular in america in 1911. ●americas were eating increasingly amount of sugar of by 1900s. ● the cereal grain year is unclear to me but Kellogg "changed breakfast forever" since 1898. 🌈 the more you know of course i am speaking about American history. America was traumatized when Eisenhower died, they were vulnerable. heart attacks werent as common in those days. but i am saying that 'the power' decades ago shifted america. with intent of making people eating more industrialized food. they have the wealth. when you see studies demonizing cholesterol, you know its sugar companies that funded that research. research studies are very expensive. ☆mostly importantly, in those studies you presented never had a group of people have been only eating clean meat and fat for decades. honest people for most of their life, believe the greatest lie ever told. in general people are kind. i don't think that people are malicious. i think you do what you do to survive. some people are willing to sell their integrity more than others. ● high fructose cornsyrup become popular in 1970?
@@Physionic @Physionic correction president dwight Eisenhower didnt die in 1955, he died in 1969. he had a heart attack that shook america though in 1955. the american heart association recommended that people stop eating saturated animal fats and replace them with vegetable oils, they were paid, of course, by proctor and gamble to say that.
![Oxidized LDL: Heart Disease Risk? [Study 184-189 Analysis]](http://i.ytimg.com/vi/1m8D5ewuw6g/mqdefault.jpg)
![Oxidized LDL: Heart Disease Risk? [Study 184-189 Analysis]](/img/tr.png)
![Diabetes & Mitochondria: How Nutrition Connects the Two. [Study 32]](http://i.ytimg.com/vi/x6EOhTzVKsE/mqdefault.jpg)
I realize this is going to ruffle some feathers. I spent over a month reading/analyzing these studies, and I'm sure there will be a small, vocal minority that will strongly disagree with my work here, but I take pride in my work and I put a ton of effort into this, so if you disagree, feel free, but be respectful and let's have a discussion instead of assuming I'm paid off, or I'm an idiot, or the like. That said, I also had a lot of fun doing this one, because I learned a ton about LDL and the different sizes - I hope it's informative for you!
After reading the actual studies with an education in statistical analysis and research design, I disagree.
@Yuri R. Most all of the crowd saying "experts are wrong!" prove in the long run to be bogus and just playing on lack of knowledge and emotion. IF information is designed to get you pissed off at "the system", "the experts", or "them" in general, you are likely, not always but likely, being manipulated.
@Yuri R. Unfortunately his "appeal to authority" fallacy is disrupting his work. I'm obviously disappointed. Focusing on the statistics is why I like this channel, suggesting conclusions as a result leaves things open for critical thinking and discussion(versus proclamations). Saying "I have a degree, you don't" is in effect anti critical thinking. That's a shame.
@@raywang7551 That’s why only the ApoB-containing lipoproteins are atherogenic.
I used to believe in low carb nonsense.
Mendellian randomization is what brought me back.
Glad to see it mentioned
Best explanation of VLDL ,IDL, LDL shrinkage/transformation and liver output I've seen on CZcams. Thanks!
yes diagram labeling sizes is the key;; and unlike many presenters this at least mention LDL out path from liver and HDL as return path. I would love to see my own LDL particle sizes in histogram form.. aparrently this is a std test in Austrailia check out Ken Sikaris cholesterol talk. Personally i will NOT take a statin since it ameliorates any Nicotinamide benefit (something i learned here)
Thanks for all the hard work putting that together. I appreciate your thoroughness, honesty and integrity
Thanks, Peter.
Only at start and liked just based on transparency and (true) unbiased nature of review. Rare now. Appreciated. Edit: study looking at drugs targeting cholesterol in brain for cancer. Also ones looking at neg effect of sat on blood brain barrier. Brilliant job. I’ll re-watch and pass on. Def signing up for insiders.
Thank you, j mc!
Excellent topic, Nicholas. There’s lots of misinformation on this. Looking forward to your study analysis!
Thanks, Suj! It was a fun one - I learned a lot.
total LDL is a weak predictor of CVD. In statistics correlation =2 in order to consider it worth to further study. Mandelian studies have been addressed by scientists even on yt and they're not so enthusiastic about them. LDL level is so weak that it has miniscule clinical effect. It is well established that aggressive treatment for lowering LDL gives about 0.4% absolute rate reduction of heart attacks per year. But statins have large side-effects including induction of diabetes and mild cognitive impariment, ALzheimer and even increasing deaths of cancer and pneumonia ("Low Serum LDL Cholesterol Levels and
the Risk of Fever, Sepsis, and Malignancy"). We know that cummulative effect of high LDL on CVD is about 27% per 10 yeras on average. But low HDL rises risk 3 times (300%) regardles of LDL level. Triglicerydes rise risk 3.8 times when above 2.3 mmol. That is why ratio Total cholesterol to HDL, or TG/ HDL ratio have more predictive value and more favouralbe effect when addressed by diet. The most important single factor is insulinemia and related to this glycemic load. Glycemic load of 300 grams of carbohydrate per day gives rise of CVD 6 times above basal level. Every 60 grams produce rise of 44%. That is why insulin resistance is the most important factor to address. There are PCSK9 inhibotors and studies have been made. Dr Nadi Ali presented on yt one of these studies. Lowering LDL level to 30 mg% resulted in increased rate of incidents compared to control group. So lower is not always better. The conclusion is: LDL has some impact, but its impact is relatively small so that in many cases it is not worthy to deal with it. Pareto rule should be applied here in my opinion. We have several elephants in the room but main stream physicians still focus on gnat.
I concur that LDL is a weak predictor, but it is still a factor. I'd be interested in hearing what these scientists have to say about mendelian trials, because the 20+ scientists I've read and heard from have been blown away by their utility. I think the absolute values aren't nuanced enough, because there are many factors that play a role in LDL lowering effectiveness (the delta, the duration, the time of implementation, etc.). Still, I do believe that the risk reduction is modest, but if we expand the scope to the broader category of ApoB (which LDL is a big part of), we start seeing greater effects. Not only that, the argument isn't 'is LDL the *only* risk factor', it's 'is it a risk factor of any level' - the answer is yes. The relationship with lowering LDL and cancer, pneumonia, etc. is confounded massively by the sample those studies are performed on - I even covered one study that acknowledged higher rates of pneumonia in people with low LDL, but one sentence later also mentioned there were higher rates in people with high LDL, as well. There's a lot of context we're missing here. There are studies that have been done in people that have accounted for insulin/insulin sensitivity and have still determined that LDL increases rates of heart attacks independent of insulin (my video on Dr. Saladino discusses this in brief).
In total, I agree with you on some points like yes, LDL is not the only factor and may not even be the major factor to CVD, but it is a contributor - more so than people acknowledge, but not the only factor. Additionally, the absolute risk reduction in the mendelian trials is huge considering it's only one factor. Still, I agree we shouldn't be insular in our focus of LDL.
@@Physionic I don't know any scientist of practitioner claiming that LDL has nothing to do with cardiovascular incidents. But many of low-carb physicians maintain that for majority of patients LDL is not issue to worry about. Unfortunatelly I can't recall where did I see lecture on mendelian studies. I suspect that this was some from low carb under. However I found on my disk fantastic narrative review I wanted to post the last one, about mechanisms of arterial plaque formation. I encourage you to download and read it because it is worthy. "The critical issue linking lipids
and inflammation: Clinical utility
of stopping oxidative stress"
I really appreciate your channel, thank you for all of your work. Per your comment at the start of the video, I focused on your video at the start of 1 hour and 5 minutes in. I just want to point out the difference is wall thickness of the intima between what appears to be the "extremes" of the study is around 10%, or in inches(converted from microns), around .004 to .005" of an inch, around the thickness of 2 human hairs. (again, if I'm reading this correctly)
When you bring up that a debate on the wall thickness itself might still be something to consider, I agree. (even if most everyone leans to accepting wall thickness as the root cause of heart disease at this time).
This topic is interesting, but I can't help but refer to the large scale sauna study in Finland that showed tremendous reduction in cardiovascular events(and stroke, which to me is related- but digress) dependent on frequency of sauna use. I've "onced over" the study some time ago, but I seem to recall that there was little in the way of controlling factors accounted for(lifestyle choices/activity outside of the sauna use for example),but the result were so significant it's hard to ignore the results(it was conducted on around 2300 middle aged participant over 20 years) and further I think has significant implications on the role of wall thickness of arteries, LDL, etc. et al regarding heart disease and it's causes.
Keep up the great work!
I love this, Nick. I appreciate you doing the math on that. I can appreciate how miniscule that is, but we're forgetting the other side of the equation here - what's the size of an artery, and then even more importantly, what's the size of an arteriole? Keep in mind, most plaque formation likely isn't a huge issue if its found in a large artery (and, plaque build up can vary based on where the artery is located, like the coronary), but if a thrombus forms, it can freely float through the larger diameter arteries, yet may easily get stuck in a much smaller arteriole, like that found in the brain (stroke), legs (peripheral artery disease). The size of arteriole ranges from 100um to 7um - now we're getting into a territory where 2 hairs thickness is a problem. Additionally, the progression of the plaque bows outwards more dramatically once calcification and ECM is overlaid on top of the initial plaque formation.
Finally, the study ran for 8 or 10 years, and cardiovascular disease is a progressive disease taking decades, so is it possible the problems compound on one other with each decade?
Oh, and one more thing - as for the sauna data, I have not looked at it in the slightest, but keep in mind that LDL is one risk factor, it isn't a 1:1 (high LDL therefor you will die) - it's a major facet out of several factors (weight, hypertension, physical activity, pollutants, and much more), so the sauna data can indicate a positive effect while this LDL data can also show an effect. I'll have to look into it sometime.
Thanks for the thoughtful comment!
@@Physionic Yes, the Finnish sauna study would be a great opportunity for you to further your channel IMO. I'd be interested to see your take on it.
Thank you for the note, I agree with your point on specific artery size, especially when it comes to "strokes" for example. Artery blockage as a function of LDL is definitely a cause/effect conundrum in that we don't fully understand the mechanisms at play obviously.
Thanks for putting this together, it’s very informative.
In your initial image, above "Tissue of the body" you included the brain.
My understanding is that the cholesterol pool in the brain (made in situ by astrocytes and oligodendrocytes) is independent from the other two pools in our body, that is, cholesterol produced by the liver and that produced by peripheral cells.
As far as i know LDL particles either do not cross the blood-brain barrier, or they do so in very small amounts.
Also, positive and negative charges refer to electrical charges. A magnet does not have charges, they have poles. A south and a north pole, to be precise. Electric and magnetic fields are two different things (though they are associated one to the other, but that’s a different conversation).
Thank you very much for this video. You’ll be at 2 million subs and on Joe Rogan in no time
Absolute brilliant masterclass.
Condensed and easy to understand.
Keep going, thinking about insiders
Thanks, Pavel - saw your message in the community. Hope to see you in the Insiders.
Thank you. Now I have the arguments to talk to the people, that are convinced saturated fat is not bad, since it only increases the large LDL-P's. Very interesting. There are even MD's with this standpoint on youtube, I could not believe that.
and a couple of chiropractors as well 😂
Hi Nicholas, thanks for your great work. It would be very interesting (for me at least) for the purposes of objectivity to review the studies quoted by the statin skeptics that cast a shadow on the legitimacy of the studies that have authored the narrative that saturated fat is bad and the benefits of statins are being overstated. I'm aware of the dangers of echo chambers but having available someone like yourself to bridge the different schools of thought would be a valuable contribution to consumers.
Hey Craig - thanks. I expect to cover statins at some point, but I really need to take a lot of time on it, because people are really polarized on the topic. In time, I will, though.
this was as difficult to keep watching as many of my philosophy lessons on Kant.
i had to break often to get through to the end.
much appreciated, but really a mental exercise that at my age, is like doing push-ups
Haha, Kant isn't easy - I can appreciate that from my own philosophy courses way back when. Still, the mental workload helps keep those neurons healthy - appreciate the effort, Paul.
I Kant stand him... ha!... yeah... ok .. I'll uh.. I'll see myself out...
Hi Nick, so glad that your program pops up on my CZcams and glad to have come to know your channels, which I m interested to dig in more. I m coming 60, have been having issue of high LDL (7.18 mmoI/L) since few decades that I came to know ( so is my whole family where most of my 7 siblings are having same issue). Would you be kind to point the link to me , if you have , on subject of how to combat high LDL ? Sincerely look forward to… Tqvm..🙏
Really great lecture, Nick! I've seen another study(maybe from you) that indicated the endothelial "gaps" allow penetration of particles up to 70 mm. Seems to support the "more trucks cause more accidents" theory
Wish I'd learned this 20 yrs sooner.
no, it's more like the endothelium is designed to allow transit of molecules. As a primary part of its normal function. (ie, allowing lipoproteins to deliver cholesterol and triglycerides that needs it)
Thank you for your work, it is contentious that small particle size isnt the villain when it comes to
elevated cholesterol but science is science. Food for thought. I'll certainly get a particle test over LDL C
I was hoping you'd go into the claims by Paul Mason about the ratios of trig, HDL, and LDL being the best proxy for cvd risk. He seems to know what he's talking about.
Based on what "he seems to know what he's talking about"?
@@Sobchak2 He seems. It's an opinion I have from listening to him. No sources to cite. 😶
It is very interesting, thanks. I come from a family with genetically-high cholesterol and triglicerides values (and no systematic habit for seed oils or ultra-processed food); however in my family there have never been major CVDs, except for one person (who had a very bad eating habit and smoked up to one packet of sigarettes per day). The grandparents almost reached 100 years. Still, I would like to pay attention to the blood work; yet maybe, *maybe*, total cholesterol and LCD is not what I should focus on, risking to lose health elsewhere (e.g. once I followed one strict diet that lowered my total cholesterol to 180 mg/dl, but that was allegedly way worse as my HDL was extremely low).
After years of dietary efforts, I found a significant blood work improvement with a low-carb/keto OMAD-2MAD diet. Even my stress and overall quality of life improved. Let’s consider that I was relatively fit even before (72-74kg / 178cm, but with a constant “effort” to maintain the weight). With the LC/keto diet I moved effortlessly to 67-68kg (without willing to do that, 43:17 intentionally). The hunger went away; possibly, the nutrients I am getting from the LC/keto diet are also more balanced for my body (?) as often in the previous diets (including low-fat ones), I always felt that something “was missing”, even if sated.
BP, glucose, triglycerides, HDL, mood, stress, joints pain, and energy all improved. It seems that at least in my case the LC/keto diet had good effects. Alas also LDL increased.
I would really not want to go back to the trial&error dietary regime again, just because of LDL: I feel really good now. Of course I do not want to increase too much the risk of CVD.l, on the other hand.
In the search for the optimal compromise of benefits/risks, is there a way to know the quantitative weight of LDL in the total CVD risk, alone or in combination with other factors?
That would help.
Cheers
Well, besides the expected comment that these studies are observational, I have something else to say, ask or suggest. First, it is incorrect to only talk about relative risks. A simple illustration as to why. You chance of winning a lottery is about one in eight million. If you buy two tickets you double your chance. Yet, the chance is still very low. In fact, it is still negligible if you buy ten tickets, increasing your relative chances ten times. How much lower was the absolute incidence of cardiac events in people with these mutations? Second, while there is a reduction in cardiac risk, you cannot conclude that this is because of lower LDL. It could be another (or many) factor that is connected to LDL and which is also affected by these genes. For example, anti-inflammatory effect. LDL is an inflammatory marker, and is the corollary variable of these genes' correlation with cardiac morbidity. So while these studies do point out at the connection between LDL and heart disease, it is not possible to conclude of the precise mechanism. Finally, while it is possible that LDL plays causative role in heart disease, the practical implication of these studies is unclear. Reduction of cholesterol by itself has variable effect on cardiac morbidity, from positive to negative. Early studies with fenofibrate showed increased cardiac mortality. Half of patients admitted to the emergency rooms with infarcts have normal or low cholesterol. The reduction of cardiac events seen with statins is not related to the degree of cholesterol reduction. Real life is messier than an epidemiological study.
Dismissing the genetic research as merely correlational is incorrect, in my estimation (for the reasons mentioned in the video). As for relative risk and absolute - that's a good point: I calculated the absolute risk for just one of the genetic mutations (PCSK9) and it came out as follows: 1 in 10 people with normal LDL experience a heart attack, while only 1 in 60-85 with reduced LDL experience a heart attack. A big difference. And, yes, it's exclusively due to LDL - I think you don't understand how mendelian randomization studies work, I addressed those points in the video, there is no pleiotropy with those genes, please rewatch.
Out of interest, how did you arrive to the absolute risk reduction values? The Mendelian randomisation study does not mention the incidence of CHD and related events, and RR varies between 0.86 and 0.94 (0.72 8n one study). You are claiming 6 - 8 times reduction in CHD, which means RRs should be around 0.12 - 0.15.
Myocardial infarctions cause cholesterol to decline. Measuring someone's blood cholesterol levels after a heart attack is unlikely to deliver a figure that accurately represents their blood cholesterol level prior to their heart attack.
Can you make video about vitamin K2 how it interact with D3 and calcium
What are the conflict of interest in each study?
the intima is composed of two components, the endothelial cell layer and the sub-endothelial connective tissue layer
You are not considering the LDL that are oxidized because those are the LDL that make it into the intima. You have also not looked into how oxLDL get through the endothelial monolayer to get to the intima. So inflammation is the key. What drives the ROS that oxidized the LDL! Start by understanding how TRPV4 and piezo channels on endothelial and immune cells work. This will show how TRPV4 breaks open the endothelial monolayer and on macrophages -> M1 macrophage. Look at how TRPV1 brings glucose into cells independent of insulin and the insulin receptor that leads to too much oxidation for the cell to handle and the mevalonate pathway that increases cholesterol. Stimulation of the piezo channel on monocytes directly takes them to an endothelial inflammatory reaction. Without stimulating these TRP and piezo channels and consuming too much glucose there is a far different LDL, cholesterol story. Lastly, people live longer with normal, native unmodified LDL. Cholesterol makes our immune and hormone systems. We cannot live healthy lives without them.
Ok. Where are the studies to back up your assertions? Your last two sentences make me wonder if you have started with a conclusion and worked backwards from there.
The LDL particles have to be retained BEFORE they oxidize. Thus, oxidation is a downstream effect from retention. And you get retention from high particle numbers, which occupies air high LDL/ApoB levels. Lower particle numbers enough and you get less to no retention.
@@BlahBlahPoop617 I respectfully disagree. Too much TRPV1 at the cytoplasmic membrane on the cell puts glucose into the cell even when the cell is resistant to the insulin receptor thus the metabolism of glucose is in excess of the cell’s antioxidants. Too much TRPV1 on the mitochondrial membrane causes too much reactive oxygen species to be produced and as we know a fundamental function of mitochondria is lipid oxidation. This is where the excess oxLDL comes from. Additionally, too much TRPV1 causes too much calcium into the mitochondria and damages the mitochondria and along with more insulin resistance leads to apoptosis of the cell.
Too much TRPV1 -> hyponatremia/hypoosmolality that stimulates TRPV4 on vascular smooth muscle cells (VSMC) and along with klf4 leads to the dangerous inflammatory phenotype when the VSMC dedifferentiate from contractile VSMC to macrophage-like VSMC that make up 50% of the plaque and osteoblast-like VSMC that put calcium in the lesion. Unfortunately this phenotype is associated with a dangerously thin fibrous cap over the lesion with significant risk of rupture. The condition when the transcriptome does not have klf4 or TRPV4 but has OCT4 instead has a good thick fibrous cap.
@@BlahBlahPoop617 you are incorrect in fact the lean mass hyper responder evidence shows this. LMHR have high LDL, high total Cholesterol and high apoB. LMHR have good triglycerides and HDL. I know, I am one. On the low carb diet my plaque reduced from moderate to mild in one artery and from mild to no significant finding in a couple other arteries. My calcium decreased across the board. My lipid fraction profile is type A on multiple tests with high apoB but my lp(a) is
@@BlahBlahPoop617 And what purpose or reasoning do you have to "Lower" or manipulate the number of lipoprotein particles in the blood? Don't you think its rather inappropriate and risky to go toying with homeostasis without understanding the full picture? Clearly you don't understand the full picture or you would immediately list the possible side effects of suggesting something like "lowering particle numbers"
Thank you again for incredible content
Thanks for the kind words!
Very good analysis, thanks you.
One thing I wonder about is about CoQ10. CoQ10, which is important for the heart, is transported by LDL, so the lower the level of LDL, the lower the CoQ10 level is going to be, which is what we see with the use of statin. So is a very low LDL a factor for heart desease, not due to arterial stenosis but due to lack of energy production in the heart?
Also, on top of that, from looking at the chart at 1:07, a very low LDL-p ( small + large LDL particles ) seems to increase increase IMT. That threshold below which it happens seems to be around 700 ( corresponding to say the 2 white bars on the left ).
If on Cholesterol and Triglycerides lowering medications, old school Neurology and Cardiology University Professors recommend briefly to supplement with CoQ10 200 mg or higher. Patients rarely follow their advice as they typically don't measure CoQ10 Levels and other Vitamins (including Vit Bs and Iron and Vit D3) during Metabolic Blood Panel and Liver Enzymes Panels which are usually required for getting these Statins, Ezetimibe, Nexlizet, and PCSK9 Inhibitors Repatha or Praluent. Ideally they should be including checking for CoQ10 Levels and most likely the reason why they don't is hidden in the way Cholesterol lowering medications are having side effects not beneficial for Big Pharma to disclose to their younger and younger patients (20-60 old)...
I always thought the distinction between LDL and Small dense LDL was nonsense.
Small dense LDL is simply oxidized or glycated LDL. Call it what it is.
If you have blood sugar, then there is a risk of glycating the apob100 of LDL. The more blood sugar you have, the higher the risk of this.
When the APOB100 is damaged, the LDL will circulate till it gets picked up by macrophages in the vessel wall.
This gives lots of time for the contents to oxidize. The more polyunsaturated fats you have in your diet, the higher the oxidation risk. Some fats are worse than others, such as Linoleic Acid and it's oxidized metabolites, 4-HNE and 9 and 13 HODE.
In either case it's the oxidation and glycation that is the issue. Higher blood sugar and excess PUFA are the primary factors.
Of course, having more LDL can also mean more APOB100 to be glycated. , This if you have a higher PUFA diet, then a higher LDL could lead to increased risk also.. and their study populations have a diet of excessive PUFA on average... So results not surprising.
I'm still skeptical this is an issue with ancestral levels of Linoleic acid consumption.. so I guess more data needed on that population...
cool hypothesis
evidence when?
don't tell me u get this info from this youtuber, that dr on YT channel blabla.
Please consider "Small Dense Low-Density Lipoprotein as Biomarker for Atherosclerotic Diseases" Oxid Med Cell Longev. 2017; 2017: 1273042. Published online 2017 May 7. doi: 10.1155/2017/1273042 PMCID: PMC5441126 PMID: 28572872
Conclusion "The results of recent studies demonstrate that LDL fractions have different atherogenicity, with sdLDL being more atherogenic than larger LDL subfractions."
Great work and excellent analysis. Can you also please consider the effects of coffee on liver health in your future projects?
Does the liver produces the sdLDL or it is a continuation of the increase in density from VLDL?
Yep, liver produces it.
Can we turn on that forever-low LDL gene with CRSPR or any other gene editing tools?
thank you for your work
Thank you!
i'll listen on my way to work.
@Ray. Carbon is the basic building block of life as we know it. If I dumped a truckload of carbon ashes on you, you'd be crushed. See how this works? We are only acclimated to a certain range of anything under the sun, including sunlight.
Awesome studies and analysis. Thanks for all the LDL relevations! I guess moral of the story: keep 'em all low :)
Thanks, Talia - maybe I should have summarized it like you did. :)
@@raywang7551 there's a lower limit. Just check the medical ranges and keep in between.
@@raywang7551 yes your calcium score is crucial for atherosclerosis risk but there are a group of ppl who have good genetics that can live with high LDL as he mentioned and never have problems and you are likely one of them. Not everyone is that lucky.
@@raywang7551 there are many people who have high LDL's who are now dead before 70 and there is a ton of evidence in many trials over the past 2 decades. If you are eating healthy and exercising and your LDLs are still high but you have a low calcium score then you do not have much to worry about. You are one of the lucky ones. There is a safe range to be in - not too high and not too low, and as they always say, it's good to be safe than sorry.
@@raywang7551 Definition of Syndrome is a group of signs and symptoms that occur together and characterize a particular abnormality or condition so the answer is no. If you want more info of your own risk, ask your physician because this is not based on meta-analysis but personalized medicine and based on your other factors as well including your TG's, BSL, your HDL, total cholesterol and your diet and exercise. I won't be responding anymore to this thread so if you are still concerned, just ask your doctor for his opinion.
Somebody has to figure out the mechanism that kick starts the plaque, until that is done there is no rationale to heart disease research
I explain it in the video? But, your comment is 10 minutes after the video is live, so I imagine you haven't gotten to that point..
@@Physionic You got me there. The truth is that I have read a few models, but none of them fulfill the basics of a molecular model for a disease. For starters, any model that when applied predicts that every millimeter of every artery will develop plaque has to be wrong (I hope!). I find it hard to buy a slow inevitable progression model for a disease that almost did not exist 100 years ago.
Interesting. I don't know about the models. The papers I covered seemed pretty uniform in how they were describing things. As for heart disease 100 years ago, the life expectancy was 47 years old - most people don't develop noticeable heart disease until their 60s or beyond (of course, there are exceptions).
Edit: Just looked it up - the average heart attack occurs around 65.
@@PhysionicThe main critique some will pose to that average life expectancy number is that it is misleading because the higher level of infant mortality distorts from the typical age of death of the elderly population.
I still haven’t found a good number for what the typical life expectancy was for those that lived past say 50 years old.
Heart attacks are also not a peaceful way to go which is what makes me wonder why there doesn’t seem to be reports from those that went beyond the 65 threshold.
@@el_argent0 What are u talking about?
100 years?
As long as they lived long enough and were exposed to high ldl they would developed atherosclerosis.
Who developed it u might ask?
Let's see
someone rich enough to eat lots of meat and fat and dairy and refined grains and sugar and honey or white bread with zero fiber.
Someone rich enough to live past 60 or even in 70. And we need their bodies too.
Is there anyone like that? Oh, the royal family, the mummies
An article in the Lancet[1] in 2013 with whole body computed tomography (CT) scans of mummies from four different geographical regions (ancient Egypt, ancient Peru, Ancestral Puebloan of Southwest, and the Unangan of the Aleutian Islands) showed that atherosclerosis may be very ancient. The time period spanned more than 4000 years. The investigators found probable or definite atherosclerosis in 34% of the 137 mummies studied.
you are so busted
Nice work here. Thanks for that. So basically, carnivore followers are headed for trouble due to all the saturated fat they eat? I'm also not sure how that large LDL is harmless thing caught so much momentum online but I've heard it many times as well
Based on my work looking at saturated fat, I'd say yes. There may be some nuance on the type of saturated fat, but as one lump sum, saturated fat raises LDL, and LDL raises heart disease risk.
@@Physionic Thank you sir. Do you have any expertise in the area of glycation as it relates to dietary choices? If so, I think that would be an interesting video for the future to hear your take on it
Yes, when the prominent online Carnivores start dropping, their followers will do somersaults trying to come-up with excuses. Most-likely, they will either blame genetics and/or pre-Carnivore diet and lifestyle. I’ve seen it already.
@MegaVegan There's little to no long term studies done on the carnivore diet. I expect that pattern will continue. People get a few years in at most and then start adding healthy carbs and fiber... Wonder why?
@@limitisillusion7 Not even a few years in. Most of these people are dishonest and eventually admit that they cheated on the diet and would eat blueberries or lettuce and tomatoes with burgers for example. So it wasn't them eating "just meat and meat fat" as they claim
Hi Nick. The genetic information is good evidence, but wouldn’t you have to know the amount of embryos formed with that genotype who don't make it to term and development and whether the rest of the genome is important for that to get a perfect comparison? This is what I hear denialists commonly say with regards to the genetic studies such as the one you provided.
I'm unclear on the argument, but I'd like to know more - can you elaborate?
@@Physionic
Hello! I have heard critiques say that if the scientist is taking two equal groups and making one have just that one change going forward, it isn’t exactly testing cause. Just one example but in these cases you aren’t testing “people with genetic mutation X” but “people with mutation X who were born.” We don’t know how many people have this or that mutation and that causes a high level of miscarriage, as just one example. So there’s already a selection there outside of a pure randomization. And probably others.
There are a lot of mutations people make in animals that would be great to study but the animals end up sterile or they don't develop. So then things like cre-loxp were developed to induce a mutation after offspring reach a certain level, but of course that can't be done on humans.
I’ve heard critiques of the genetic research say that when you are studying a genetic mutation such as this research, you aren't studying that per se, you're studying that mutation in the population you can observe. This leaves out people for whom that mutation proved lethal early in life, particularly miscarriage. Many miscarriages are from genetic issues or other
developmental hiccups, but could get those babies to term they may have some disease resistance.
It could be that ApoB mutations are really dangerous in X amount of host genotypes. But those might never be known because they never make it to the sample. So imagine in the future we have a gene editing technology, and everyone goes out and mutates their ApoB because of all of this great "controlled" research showing it's good to have that mutation.
Gotcha. I understand the concept of embryonic lethal and have studied LoxP extensively throughout my PhD, but I don't see how that argument applies to studying humans who want to know if LDL is causative to heart disease? Whatever mutations lead to embryonic lethality don't matter in the slightest to the people who are alive and want to know about their heart health. If a mutation exists that leads to embryonic lethality, so what? You'll never see it, so it doesn't matter (those with the mutation won't exist and those without the mutation don't have it, so they don't care).
As for mutating ApoB - that's where there is concern related to what you're talking about, the mendelian trials aren't anything related to that, so I'm confused how that's an argument against these MRTs.
@@Physionic
I see. Makes sense. Thanks, Nick!
What are your thoughts about the ongoing study of lean mass hyper responders from Dave Feldman?
I have a video on it, but I'm interviewing him on Saturday
Hi Nick, have you looked into what Dr. Malcolm Hendrick is saying about CVD? I'd love to get your input.
The liver is the coolest organ of all the organs? Really? Cooler than the Hammond B3? Nah!
:-P
@Physionic And now, some speculation... Some say that inflammation causes the endothelial layer to allow lipoproteins to enter. Could it be age? Could cells be damaged during their reproduction? Why don't babies have arterial plaques? What causes arterial inflammation besides sugar and nicotine?
Could a carb-based diet cause LDL to circulate more than it should, since cells need to get rid of sugar and cannot consume fat?
Why do some studies find an inverse relationship between total cholesterol and mortality in older adults?
One explanation I've seen for this is that older people are more likely to be sick with certain diseases that lead to low cholesterol levels. For example, a cancer patient isn't going to have a huge appetite, so they are likely to be losing weight which usually lowers cholesterol.
I think disease states use up a lot of cholesterol in the body as well, causing lower levels.
I've read that right after an event like a heart attack, the LDL will often drop. So it would appear the person had low LDL when they didn't. It's kind of like blood pressure dropping before you pass out. The person could have had very high blood pressure before they fainted. So that's the comparison I've read why many people who've died from a coronary event show low LDL.
Plus as others mentioned, high LDL is only one risk factor. There are other risk factors. Low LDL doesn't mean a person can't get CVD. It just lowers the risk.
Very good.
@Physionic I agree 100% with you in that video, as you didn't say “cause” at any point, but just “it's associated”.
At minute 19, you say that the proposed mechanism is that the lipoprotein is attracted to the intima...
Which study proposed this and, most importantly, what was the proposed reason for this attraction?
I understand the attraction between lipoproteins and proteoglycans, positive and negative, but these charges exist since we are born.
Why, at some point, do endothelial cells allow lipoprotein to enter the intima? The answer to this question will lead us to the cause of atherosclerosis.
Could you please cite the mechanistic studies that would support the description of atherogenesis that you have outlined in the beginning of your video?
5:37 - those are the studies/reviews I got my information from for that section.
@@Physionic Thanks!
My pleasure. I hope to make specific content looking at some of the experimental methods and show you the data more forthright in the future (so much to do!).
I think small ldl is rusult from
1 insulin resistant or
2 liver has problem to recycle ldl such as fatty liver
LDL stay too long in the blood so it get smaller and oxidezed.
I have a question about the mutations that reduce the risk of heart disease. Say we are talking about rs11591147. According to the video, there's a huge decrease in heart disease associated with the mutation. Does that mean that people who have it live longer or healthier lives in general, or does it mean that they just die of heart disease less often and instead die of other things like accidents, suicide, cancer, etc, but in the end don't really do much better than the other people?
We basically have no reasonable method of predicting any event in humans based on any measurements let alone genetics which is _extra difficult_ to predict. In fact even labelling genes as "decrease in heart disease" is like you say, merely associated, and could be compeltely unrelated
Could there be an issue with the tight junction in the endothelial cells that allows the LDL through?
Is the real issue the compromised tight junction not the LDL?
That's an interesting idea, and there could be something to that, Ed. However, LDL doesn't just cross the endothelial layer between the cells, but can also transcytose through the endothelial cells according to study 179, so while tight junction misfunction could contribute, it likely wouldn't eliminate the problem entirely. Great idea, though.
@@Physionic This I found was interesting.
However, the oxLDL hypothesis of coronary heart disease does not get at the root cause, that is, what causes LDL to become oxidised in the first place? It was later discovered that the oxidation of LDL was initiated by the oxidation of linoleic acid contained within the LDL particles.13 Indeed, linoleic acid is the most common oxidised fatty acid in LDL.14 Once linoleic acid becomes oxidised in LDL, aldehydes and ketones covalently bind apoB, creating LDL that is no longer recognised by the LDL receptors in the liver but is now recognised by scavenger receptors on macrophages leading to the classic foam cell formation and atherosclerosis.13 15 16 Hence, the amount of linoleic acid contained in LDL can be seen as the true ‘culprit’ that initiates the process of oxLDL formation as it is the linoleic acid that is highly susceptible to oxidation. Additionally, an increase in the intake of linoleic acid intake increases the linoleic acid content of very-low-density lipoprotein (VLDL) and high-density lipoprotein (HDL) increasing their susceptibility to oxidise, which further increases the risk of cardiovascular disease.17-19 Thus, expanding on the oxLDL theory of heart disease, a more comprehensive theory, the ‘oxidised linoleic acid theory of coronary heart disease’, is as follows: dietary linoleic acid, especially when consumed from refined omega-6 vegetable oils, gets incorporated into all blood lipoproteins (such as LDL, VLDL and HDL) increasing the susceptibility of all lipoproteins to oxidise and hence increases cardiovascular risk.20 (an extract from openheart.bmj.com/content/5/2/e000898)
@@edharding8372 this makes sense but the link doesn’t work. I’d like to know more about that
@@Physionic The endothelium doesn’t need to be damaged or inflamed for LDL particles to transcytose. They can get through even with a healthy endothelium (I learned that from Dr. Thomas Dayspring’s 3-part series with Simon Hill). That’s why elevated LDL/ApoB is a causal in atherosclerosis. Obviously, a damaged endothelium will exacerbate the problem.
@@megavegan5791 I thought that the endothelial damage activates the clotting cascade which draws LDL to the endothelium?
You could have talked about LDL pattern A or B. This is also a good indicator of CVD risk.
Those are just different terms for small and large LDL.
First time that I wasn’t into study.I was only listening and not looking at charts.can ldl number be associated with mortality
i haven't made it all the way thru. what about people that have high ldl and have a low risk of heart disease? japan for instance.
Great question. One, I haven't looked at that data, but I'd say multiple things: First, looking at associative data that doesn't account for other common variables is a far cry from studies that are more rigorous (like the genetic studies I point out here); secondly, LDL is one factor of heart disease, but it isn't the only factor. So, is it possible that Japanese people are far more active? Have less stress? etc. etc., which ultimately mitigates some of the risk of high LDL? Probably pretty likely. Still, until I actually look at that data, I can't give you any specific answer.
Two things that definitely help the Japanese, I think, are higher intakes of fish oil and vitamin K.
@@PhysionicI really love the topic, also an important role I think is the prevalent use of fermented food, natto included.
Did you check the effects of the nattokinase in the cardiovascular system?
It's very interesting.
Hope inspires you.
Japan is an affluent country with universal health care. They still get atherosclerosis too.
@@megavegan5791atherosclerosis is pretty much the leading cause of death world wide however, japan has the lowest rate of Cardiovascular disease in the world. they eat more eggs than anyone. if they eat the most eggs it stands to reason, they must eat chickens. ramen is a popular dish in japan.noodles cooked in bone broth with a hard boiled egg, and a bit of fatty pork.
they also seem to smoke tobacco quite a bit. i personally think it's genetics more than anything.
Really well presented Nick. Particularly interested in the IMT results. I've had 2 (annual) cIMTs after a nasty CAC. Their ability to pick out the plaque densities gives them great utility.
For feedback, in a couple videos, including this one, you seem to emphasize the build up of plaque over time clogging the artery to cause a heart attack "eventually" over the more acute danger of a newer soft plaque rupturing, resulting often (30-50%)in ones sudden, tragic, early death. Please don't take this as a criticism. Ive had cardiologists skim over this detail.
You're doing good work, thank you!
I don't take it as criticism. It's an important point. I plan on addressing it in the future (working on a multi-video series on LDL, oxidation, and inflammation's role in cardiovascular disease). I appreciate it, CJP!
I'm not following your logic on LDL lowering genes. How do we know that's the only thing they're doing? Couldn't these genes be driving some other health improvement and then that improvement is driving an observed reduction in LDL in those with the gene?
Good question. We can verify by mass data sets that have the sensitivity to compare those with and without the mutation. Additionally, we can run genome sequencing to determine if there is linkage between genes (in this case, there is none). Finally, we can look for interactions between the protein of interest (say, the LDL-R or PCSK9) and potential targets to test for affinity and/or reaction speed.
@@Physionic but how do we know the pathway is: gene -> LDL -> health outcome? Couldn't it also be: gene -> health outcome -> LDL?
For example, let's say a gene reduces chronic inflammation. Then (due to reduced inflammation) those people happen to have lower LDL when measured. Or do we have some other way of knowing the details of the mechanism here?
We can't know. Ever. You need to control the individual from birth to know anything about what their genes are doing unless its _extremely_ obvious like Huntington's. Where it's not obviously affected by environment ever and there is a finite set of outcomes. Have disease or don't have disease
So...LDL-C has nothing to do with increased CVD risk?
I knew it!
*JUST KIDDING ;-)*
I'm 27 my LDL is out of the chart with good diet and sports so I'm just gonna start rosuvastatin 5mg daily with my grandma 😂 and dodge the risk while I'm young
Carnivore ❤
Good luck! 🙂
"If you have high LDL you are at risk" - these are empty words, my friend, it means absolutely nothing. What is high LDL? Would you want to lower any number just because "high LDL = risk"? Would ZERO LDL be the best? The U-shaped relation between levels of LDL-C and mortality is well established by now. "Large buoyant LDL particles increase heart disease risk" - what is the mechanism then? When You say A say B, why don't you??? "The higher your blood LDL particle levels the greater your risk of heart disease" Statins and PCSK9 inhibitors curb LDL and their absolute risk reduction of any CV event (stroke, heart attack, etc) is basically minuscule (regardless of the fact Big Pharma is in charge of what is disclosed and what is not when it comes to data THEY collect from the trials THEY carry out). This topic in general might be WAY TOO BIG for you at this stage (no offence)..... Besides, besides, besides... focusing just on LDL (whether it is buoyant or petite) leaving out HDL, triglycerides, and insulin resistance in relation to CVD is just plain silly, isn't it? By going low-carb for instance you may increase large buoyant LDL but so your HDL would spike, triglycerides drop and IR would improve. Are you trying to say low-carb/high fat detrimental to cardiovascular health overall?
I've read that HDL is actually a more reliable predictor of heart/stroke issues than LDL in a few places as well. I think it has something to do with HDL's ability to transport LDL based on current understanding. It's a very complex topic to your point.
I think you either didn't understand the whole video or you're purposefully ignoring some of the information I provided. Obviously, no LDL means death - we need some level of LDL for cholesterol and triglyceride transport, we agree there. The U-shaped relationship is also driven by the fact that many diseases reduce cholesterol/particles and those people end up in the hospital before death.
To your other points - I keep having to repeat myself here, but people get so caught up on the mechanisms without acknowledging the more important aspect - the clinical end point (heart attacks, death, cardiovascular disease progression). As I explained, and showed the data, lbLDL is also a risk, and although I didn't go into the mechanisms much (I provided one, briefly), the end result is still the same, according to the data. I didn't discuss statins once in this video, but statin data is often misunderstood - I'll likely make content explaining why once people have jumped down my throat about this topic. Your point about relative vs absolute risk is a good one, but I calculated the absolute risk for the genetic studies I gushed over and the absolute risk is actually dramatic (1 in 10 vs 1 in 65 or something like that in the PCSK9 SNP individuals).
I not only explained why elevated LDL, independent of all other factors, is a heart disease risk, but I also included some data showing that accounting for those risk factors (HDL, triglycerides, etc.), there was still an elevated risk of LDL (this is where I'm wondering if you watched the video? I mention this multiple times across multiple studies).
I have videos explaining the nuances of a low carbohydrate diet and how it can be done safely so as not to increase heart disease risk, so no, I'm not saying all low carb diets increase heart disease risk.
Finally, if the topic is too big for me (a person who dedicates their life to analyzing research, who is on the cusp of multiple advanced degrees in this area, and who has real world experience publishing studies), how are you so confident?
@@nickb3968 it is. On top of that you have to take into consideration the state of your endothelial cells with its supportive extracellular matrix. I strongly believe there is too much commotion around LDL-C (obviously because we have drugs to lower it, we still do not have any to raise HDL for instance) plus I just can not figure out how a native LDL (not modified by sugars or oxygen) could cause arteriosclerosis.
@@matkagrogan5251 "we still do not have any to raise HDL for instance"- actually, as an "fyi", niacin in the form of nicotinic acid(which I take in lieu of a statin as I'm close to 52 years old), does raise HDL at therapeutic dosages. Just as an "fyi", I think you should try to tone your comments down as you make some good points but they could be lost on a perceived "rudeness" and that would be shame. Mr. Verhoeven puts a tremendous amount of time and energy into his channel obviously and I don't think most here would want to dissuade him from doing that even if they disagree with some aspects of his videos. I imagine it would very difficult to spend a month of your time reviewing studies and creating videos and feel like it's not appreciated- it's the whole "disagreeing without being disagreeable" thing that if mastered, is a great skill to have.
@@Physionic It is too big because you focus on epiphenomenon, downstream effects, etc. You are making the whole video with humongous statements about LDL causing atherosclerosis, but you just can not underpin that? If you can you should come up with the mechanism. You made a cause-and-effect statement. There are floating LDL particles (big? small? modified? oxidized? etc) and then there is a plaque buildup in arteries (inflamed? swollen? etc) So many scenarios in between! I don't have to be confident, I'm not making big statements on youtube, you are so you should be. Mentioned statins because they target LDL, that's obvious, with puny outcomes but not so puny side effects. I delved into a couple of these studies and the ARR for CVE was usually between 1 out of 50 to 1 out of 125. Dire numbers indeed (still without any positive effects on all-cause mortality). Yes, you mentioned one study that is 173, unfortunately, I can not download it, my loss. Sorry, I do not understand your statement about the U-shape curve. A recent gigantic study from Denmark (among 110 k individuals) proved U-shape explicitly ("The concentration of LDL-C associated with the lowest risk of all-cause mortality was 3.6 mmol/L (140 mg/dL) in the overall population and in individuals not receiving lipid-lowering treatment"). And among older generations (70+) the correlation (higher LDL & increased lifespan) is even more striking. Guess what, LDL has many other functions apart from delivering lipids and cholesterol. I wish your channel more critical thinking, less pedantry : )
big sugar funded that study.
Which one, be specific? I listed all the funding sources. It's 10 studies, which one are you referring?
@@Physionic
●President Dwight Eisenhower had a heart attack in 1955. he had many heart attacks but later died in 1969.
●John Yudkin posited that sugar was culprit for heart disease in 1957.
●Ancel Keys was on the cover of time magazine swaying the public that cholesterol was the culprit for heart disease in 1961.
●The Sugar Research Foundation paid scientists to say that sugar consumption was not culprit for heart disease in 1967.
●seed oils became popular in america in 1911.
●americas were eating increasingly amount of sugar of by 1900s.
● the cereal grain year is unclear to me but Kellogg "changed breakfast forever" since 1898.
🌈 the more you know
of course i am speaking about American history. America was traumatized when Eisenhower died, they were vulnerable. heart attacks werent as common in those days. but i am saying that 'the power' decades ago shifted america. with intent of making people eating more industrialized food. they have the wealth.
when you see studies demonizing cholesterol, you know its sugar companies that funded that research. research studies are very expensive. ☆mostly importantly, in those studies you presented never had a group of people have been only eating clean meat and fat for decades.
honest people for most of their life, believe the greatest lie ever told.
in general people are kind. i don't think that people are malicious. i think you do what you do to survive. some people are willing to sell their integrity more than others.
● high fructose cornsyrup become popular in 1970?
@@Physionic @Physionic
correction president dwight Eisenhower didnt die in 1955, he died in 1969. he had a heart attack that shook america though in 1955.
the american heart association recommended that people stop eating saturated animal fats and replace them with vegetable oils, they were paid, of course, by proctor and gamble to say that.