Yes, there are some people who will never develop plaque even with very high LDL-C. But no medication exists that specifically strengthens the cell walls. Medications/supplements that lower triglycerides have shown promise in studies (e.g. omega 3) while drugs that were developed to increase HDL-C have consistedly failed so far. Until further studies come out I remain sceptical.
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ng0rge
#11
Here is another tremendous resource for RapaNews users. It’s based around ApoE4 but that allele also affects CVD and lipid levels. There’s some great info there about blood glucose and insulin because as we know those have wide ranging effects.
https://wiki.apoe4.info/wiki/Main_Page
Cholesterol, Lipids and Treatments, including statins
“This is a horrendously complex topic…GLYCAEMIC CONTROL TRUMPS LIPIDS, EVERY TIME. (Read Insulin Resistance for info on glycemic control). You have been dealt a hand of cards. You need to play them cleverly. IR (Insulin Resistance) is far more damaging than a high LDL, but LDL still matters. We are on a seesaw trying to balance these two. The balance point will be different in everyone.” - Stavia, as posted in the Primer. E4s are at higher risk of cardiovascular disease, yet cholesterol is an important component in brain health. How do we resolve the two?
My question is…Why?
If high LDL-C/ApoB is both necessary AND sufficient, why do these people not get plaque? and the corollary…how long can they go with high ApoB and no plaque?
My posts above show they can go at least 4-5 years with zero plaque.
They are genetic outliers. Perhaps their cell walls are incredibly resistant to plaque formation or they have an optimal clearance system in place. Nothing we can simulate with drugs yet, sadly.
If high LDL-C/ApoB is both necessary AND sufficient
It is definitely necessary and approximately sufficient (for the vast, vast majority of people).
Those people are, in my opinion, no more common than centenarians who smoke and drink alcohol every day. But we will need further studies to explore this.
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ng0rge
#13
The 2019 Danish study I posted above looked at 23,143 patients and of the ones with LDL-C levels of at least 190 mg/dL, 46.2% had a zero CAC score. That doesn’t seem like a small number.
Results A total of 23 143 patients with a median age of 58 (IQR, 50-65) years (12 857 [55.6%] women) were included in the analysis. During median follow-up of 4.2 (IQR, 2.3-6.1) years, 1029 ASCVD and death events occurred. Across all LDL-C strata, absence of CAC was a prevalent finding (ranging from 438 of 948 [46.2%] in patients with LDL-C levels of at least 190 mg/dL
I certainly think that it’s worth taking a closer look at what’s happening here. Not only will we learn more about the process but there also may be new therapeutic solutions.
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A positive CAC score is the late stage progression of ASCVD where existing plaque has calcified to prevent it from bursting. That doesn’t equal there being no soft plaque.
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ng0rge
#15
I thought you read it. Yes, you’re right but the difference was negligible.
“Across all LDL-C strata, rates were similar and low in those with CAC scores of 0, regardless of whether they had no plaque or purely noncalcified plaque.”
By the way, even lipidologists are taking Lean Mass Hyper-Responders seriously enough to comment on. Here, from the Journal of Clinical Lipidology:
Journal of Clinical Lipidology on Lean Mass Hyper Responders.pdf (214.8 KB)
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Across all LDL-C strata, absence of CAC was a prevalent finding (ranging from 438 of 948 [46.2%] in patients with LDL-C levels of at least 190 mg/dL to 4370 of 7964 [54.9%] in patients with LDL-C levels of 77-112 mg/dL) and associated with no detectable plaque in most patients, ranging from 338 of 438 (77.2%) in those with LDL-C levels of at least 190 mg/dL to 1067 of 1204 (88.6%) in those with LDL-C levels of less than 77 mg/dL.
438/948 (54.9%) people with high LDL-C have no calcified plaque and 338/948 (35.6%) people with high LDL-C have no detectable plaque.
1204/2430 (49.5%) people with low LDL-C have neither calcified nor any plaque at all. So a higher proportion of the low LDL-C group developed no plaque.
Also, the high LDL-C group was fewer in size than the other comparison groups.
I would say it would be interesting to study the LMHRs and split them into 3 groups: 1 eats a keto diet, 1 eats a “healthy” carb diet and 1 eats whatever they want but takes medication. Then follow them for 5 years or so and check how plaque progresses compared to the general population.
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ng0rge
#17
Yes, definitely. I’m a big believer in the science of lipidology and have read extensively. Lower LDL-C (fuel), particularly ApoB, when combined with a spark will cause less plaque and it will accumulate slower. But for those, a significant number, with all that fuel (ApoB) floating around in their circulation, how do they avoid a spark? And is that something we can control? The Keto LMHRs may be onto something, the control, but Keto has it’s own problems, namely saturated fat, but maybe that’s not part of what’s making it work that way.
More notably, LM’s data demonstrate that the LMHR phenotype can exist in the context of a CRD that is relatively low in saturated fat. While this possibility was suggested by our cohort data (given the low likelihood that lean metabolically healthy participants selectively consumed CRDs richer in saturated fat, as compared with those with higher BMI and TG/HDL-C ratio on CRDs), we were previously unable to demonstrate that high relative intake of saturated fat is not required to produce the LMHR phenotype. However, LM’s dietary fat profiles were >80% unsaturated prior to the drawings of his two highest LDL-C (August and September 2020). Conversely, LM’s most recent labs, drawn following both weight gain and a marked increase saturated fat intake, reveal a relative decrease in LDL-C from peak. Thus, saturated fat intake is not a primary driver of LDL-C change in LM.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9048595/
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We could simulate that with SGLT2 inhibitors that have shown benefit for heart disease treatment despite slightly raising lipids. Though it’s unclear whether this effect comes from increased ketogenesis, lower blood sugar levels or lower salt levels.
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ng0rge
#19
Keto is interesting…I haven’t looked into it that much. You might be able to tweak it to make it much better. Certainly it seems replacing most of the saturated fat with unsaturated would help. Then maybe adjusting the amount of carbs to your individual needs, by testing, might yield the optimal situation. Carbs are problematic, mainly their direct effect on blood sugar, but that goes on to affect your brain and cardiovascular. I’m not totally opposed to pharmaceuticals, I’m on a statin, but as I’ve said before, I’d like to know how far, in longevity and health, you could get without them. Just using the so-called “natural” interventions - diet, exercise, sleep, no stress/ positive mental state. We know much more about those now and how to tweak them for optimal results. I’m happy to take rapamycin because it’s pleiotropic and I don’t think caloric restriction could replace it. But if they ever come up with a “natural” routine that allows you to live as long and be as healthy (without being miserable) as rapamycin/pharmaceuticals…I’m all for it!
Clearly, of all the major diseases, cardiovascular appears to be the one we’re biologically (at least men) most disposed to. It has my attention and I want to understand it in as much detail as possible.
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ng0rge
#21
It’ interesting that Thomas Dayspring in his latest presentation really downplays the importance of HDL-C and Triglycerides, implying that they don’t matter.
https://videosolutions.mediasite.com/Mediasite/Play/2b86463212f34235b77446f05783f9021d
I found this page to have a lot of good info.
https://www.levels.com/blog/the-ultimate-guide-to-understanding-your-cholesterol-panel-and-metabolic-blood-tests
Triglyceride-to-HDL Ratio
Why is it important?
Dr. Hyman: This test is the best way to check for insulin resistance other than the insulin response test. According to a paper published in Circulation , the most powerful test to predict your risk of a heart attack is the ratio of your triglycerides-to-HDL. If the ratio is high, then your risk for a heart attack increases 16-fold—or 1,600 percent! This is because triglycerides go up and HDL or good cholesterol goes down with diabesity (insulin resistance).
Dr. D’Agostino: Triglycerides to HDL-cholesterol ratio has been shown to show the strongest association with cardiovascular disease than any other lipid marker or ratio.
Dr. Maloof: Triglyceride-to-HDL-C ratio is an important indicator of heart disease risk from standard testing.
Dr. Lustig: The triglyceride to HDL ratio is the best biomarker of small dense LDL, the best biomarker of cardiovascular disease, and the best surrogate marker of insulin resistance and metabolic syndrome.
Eh, now that is reaching. Diabetes is a huge risk factor for ASCVD but the clinically accepted marker for it is high blood sugar or, more specifically, high HbA1c.
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ng0rge
#23
This is what’s important, and the difference between large, fluffy LDL particles which aren’t a problem because they don’t cross the endothelium into the intima of the arterial wall.
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Every apoB particle size increases risk, sdLDL-p just slightly more so than lfLDL-p and lp(A) is obviously the worst.
LDL Cholesterol: Heart Disease Risk? Does size matter? [Study 171 - 180 Analysis] (youtube.com)
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ng0rge
#25
I just watched the whole hour&20min Physionic video and did not find it convincing. One of his worst that I’ve seen (but it was a year ago). He spends almost the whole video showing how much worse small, dense LDL particles are, and then right at the end says - “but I think large LDL particles still matter”…WTF!!! The video was also pretty simplistic relative to the detail that I’ve been presenting. OK, maybe it’s wrong to say “large, fluffy LDL particles aren’t a problem” but I can and will post numerous studies that show particle size does matter (for both LDL and HDL) and that small, dense LDL particles are vastly more important in starting plaque.
Because the predominance of small, dense LDL has been accepted as a bona fide cardiovascular risk factor,1 this result suggests that we should not estimate the risk of CAD from the LDL-C level alone.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2929871/
Small dense low-density lipoprotein particles (sdLDLs) are associated with an increased risk of cardiovascular disease and events. They are a better indicator of CVD risk than LDL-cholesterol. The smaller, denser LDL particles are more prone to oxidation and other modifications that make them more atherogenic. Elevated sdLDLs are also associated with elevated triglycerides, metabolic syndrome, diabetes, and arthritis. A healthy diet and a variety of nutrition supplements can help lower sdLDLs. A low level of sdLDLs is considered healthy
https://www.optimaldx.com/research-blog/lipoprotein-biomarkers-small-dense-ldl-particles
Small, dense low-density lipoprotein cholesterol (sdLDL-c), a type of smaller LDL-c, is considered an emerging risk factor for T2DM and CVD. SdLDL-c levels have been found the association with elevated triglyceride (TG) levels and low HDL-c concentrations, constitutes the ‘proatherogenic lipoprotein phenotype’, a common feature of T2DM and MetS [15,16,17]. The potential mechanism maybe partly because of the lower affinity for the LDL receptor and its multiple atherogenic modifications in blood [18]. And subjects with higher sdLDL-c levels have been shown to be associated with an increased risk factor for cardiovascular disease both in cross-sectional and prospective observational studies.
https://nutritionandmetabolism.biomedcentral.com/articles/10.1186/s12986-019-0334-y
The science has clearly established that particle size matters.This is just a start, I can post many more.
.
.
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This study just says that sdLDL-p tracks better with ASCVD than LDL-C but it doesn’t say that it tracks better than just raw apoB count.
The number of apoB particles that enter the arterial wall is determined primarily by the number of apoB particles within the arterial lumen. However, once within the arterial wall, smaller cholesterol-depleted apoB particles have a greater tendency to be trapped than larger cholesterol-enriched apoB particles because they bind more avidly to the glycosaminoglycans within the subintimal space of the arterial wall. Thus, a cholesterol-enriched particle would deposit more cholesterol than a cholesterol-depleted apoB particle whereas more, smaller apoB particles that enter the arterial wall will be trapped than larger apoB particles. The net result is, with the exceptions of the abnormal chylomicron remnants in type III hyperlipoproteinemia and lipoprotein (a), all apoB particles are equally atherogenic.
Apolipoprotein B Particles and Cardiovascular Disease: A Narrative Review - PubMed (nih.gov)
In summary, more sdLDL-p get stuck than the lfLDL-p but they deliver the same amount of cholesterol overall.
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ng0rge
#27
Yes, good article (I read the full text version). This section addresses the complxities of what I’m looking at.
In addition, variations in glycosaminoglycan structure and perhaps other elements of the arterial wall might influence the avidity of binding of apoB and therefore increase fractional trapping of apoB particles. 64 Thus, the hypothesis that glycation of apoB particles promotes binding of apoB particles deserves further attention. 65 Finally, there is likely significant interindividual variation in the intensity of the innate and acquired immune responses, ie B and T cell responses, to apoB particles trapped within the arterial wall and therefore significant variation in in the inflammatory-mediated destruction of the arterial wall. 68
Accordingly, variance in the sequence of events after an apoB particle enters the arterial wall will account for much of the individual variance of risk at the same apoB. Nevertheless, everything first depends on the entry of an apoB particle into the arterial wall, and this depends, most of all, on the concentration of apoB particles in the arterial lumen.
Statins lower LDL-C more than non-HDL-C more than apoB 35 because larger cholesterol-rich LDL apoB particles interact more avidly with the LDL receptor than smaller cholesterol-depleted ones. 36 Therefore, their concentration will decrease more than the concentration of smaller cholesterol-depleted apoB particles.
Trapping of apoB lipoprotein particles within the arterial wall is the fundamental step that initiates and drives the atherosclerotic process from beginning to end, from the first appearance of fatty streaks to the ultimate development of the complex lesions that are vulnerable to the acute transformations, such as plaque rupture and endothelial erosion, that are the immediate precursors of clinical events. 1 The concentration of apoB particles within the arterial lumen is the primary determinant of the number of apoB particles that will be trapped within the arterial wall. But the proportion of apoB particles that are trapped within the arterial wall versus the proportion that pass harmlessly through is also influenced by the size of the apoB particles and by the structure of the glycosaminoglycans within the subintimal space of the arterial wall. Trapping of apoB particles deposits atherogenic cholesterol within the arterial wall.
I’m still not convinced of their conclusion that " all apoB particles are equally atherogenic."
Here’s an opposing view.
Several studies have reported that small dense low-density lipoprotein (sdLDL) levels increase the risk of ASCVD.[22–24] Ikezaki et al demonstrated that sdLDL is the most atherogenic lipoprotein parameter compared to other lipoprotein parameters, including low-density lipoprotein triglycerides, triglyceride-rich lipoprotein cholesterol, remnant lipoprotein particle cholesterol, direct LDL-C, Lp (a), large buoyant LDL-C, and VLDL-C.[24] The increased atherogenesis of sdLDL is associated with the specific biochemical properties of these particles. The small size makes penetration into the arterial wall easier, and smaller LDL particles have a decreased receptor-mediated uptake. Therefore, the half-life of sdLDL is longer than that of the large LDL particles. A longer circulation time increases the possibility of atherogenic modification of sdLDL in the blood.[25] The LDL-C/Apo B ratio has been identified as a marker of small dense low-density lipoprotein (sdLDL). Hirano et al found that an LDL-C/Apo B ratio of 1.2 corresponds to an LDL diameter of 25.5 nm, has been proposed as a cutoff value between sdLDL and large buoyant LDL.[26] A low LDL-C/Apo B ratio has been associated with increased ASCVD risk.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9829249/
There are no trials showing that independent reduction of sdLDL-p reduces events or acm yet and statins work well despite apparently working better on larger LDL-p. SGLT2i do cause a reduction in sdLDL-p while slightly increasing lfLDL-p and yet SGLT2i cause a reduction in events and acm, though SGLT2i have various effects on the kidneys, blood pressure and on cancer inhibition so it’s not clear which one of those is causing that effect.
From all this info I would say that even if LMHR genotypes do exist, they would still be well-advised to get on medication.
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curt504
#29
Just my opinions here. What if what if all this recent research into (my views) splitting of hairs re ApoB vs this vs that. Little mention of each scenario’s state of inflammation (CRP, Homocyctine etc) vs out come.
What if this is all just systems and not root cause?
What if the root cause was a new item that crept into our food chain that predisposes the body to these ends; heart / vacular issues, cancer etc.
What if seed oils, canola, excess linoleic acid in our diet weakening the cell membrane increasing insulin resistance…
An over view: https://www.youtube.com/watch?v=7kGnfXXIKZM
Prior to excess linoleic, 100yrs ago, subtracting out the death from disease, war, accident, death was not from heart or cancer…
Good luck to all, curt
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