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Mike Lustgarten

LDL: What's Optimal For Health And Longevity?

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On 12/25/2020 at 11:04 AM, Todd Allen said:

Dr. Attia has stated quite clearly he believes LDL is not sufficient for atherosclerosis.  LDL might be essential for atherosclerosis although it is essential for life and can't be eliminated. Dr. Attia advises keeping LDL low on the basis that the medical system currently isn't very good at evaluating or modulating other essential factors of CVD such as endothelial injury and inflammation.  He has also stated he has patients following low carb diets with very high LDL who decline his advice to address it.

While LDL may not be the end-all factor for developing atherosclerosis, the preponderance of the evidence I've seen indicates that it is a significant factor.

As mentioned above, LDL particle size is likely to affect large population studies looking at just LDL, as up to 40% of those with normal or low LDL levels have significantly elevated small, dense LDL particles which can help explain the higher CVD incidence among them.

I was spurred by this discussion to check my LDL-P and am waiting for the results from Quest Diagnostics Cardio-IQ test, which is relatively inexpensive. Here is a sample table of the test:

Screen Shot 2020-12-30 at 13.23.58.png

Edited by Ron Put

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47 minutes ago, Mike Lustgarten said:

Even better than associations for LDL or LDL particle size is a coronary artery calcium score, which will tell you how much calcification that you have. Getting that done is on my list for 2021.

When you make the appointment try to find out what machine they use.  I've read the newest are much better with a radiation dose little more than a chest X-ray while older machines can be 20 times higher or more.

I've also read CAC scans show hardened calcified plaques but don't show soft plaques.  Some believe soft plaques are more dangerous because they can break up and instigate clotting.  Statins have been shown to accelerate calcification of soft plaques and some speculate this and other pleiotropic effects are more valuable in reducing cardiac incidents than the lowering of cholesterol which is rarely found beneficial when done by means other than statins.  And I've read that the rate of calcification is much more predictive of future cardiac events than a given score so for example going from 0 to 200 in a year might put someone at much higher risk than another person who has been stable at a score of 1000 for the past 10 years.  Which would suggest one should plan on follow up scanning if there is reason for concern.

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6 hours ago, Todd Allen said:

... the lowering of cholesterol which is rarely found beneficial when done by means other than statins.  

Todd, 

I'm very skeptical of this statement. For example, see [1] which shows that genetic variations that result in even modest increases in LDL-c are associated with a significant increase in risk of heart disease. I suspect that the key is lifelong low LDL and that by the time someone with higher LDL gets treated they have already built up a lot of plaque. 

--Dean 

-----

[1] ] Neurology. 2019 Mar 12;92(11):e1176-e1187. doi: 10.1212/WNL.0000000000007091.Epub 2019 Feb 20.

Relative effects of LDL-C on ischemic stroke and coronary disease: A Mendelianr andomization study.

Valdes-Marquez E(1), Parish S(1), Clarke R(1), Stari T(1), Worrall BB(1);

METASTROKE Consortium of the ISGC,, Hopewell JC(2).

 

OBJECTIVE: To examine the causal relevance of lifelong differences in low-density

lipoprotein cholesterol (LDL-C) for ischemic stroke (IS) relative to that for

coronary heart disease (CHD) using a Mendelian randomization approach.

METHODS: We undertook a 2-sample Mendelian randomization, based on summary data, to estimate the causal relevance of LDL-C for risk of IS and CHD. Information

from 62 independent genetic variants with genome-wide significant effects on

LDL-C levels was used to estimate the causal effects of LDL-C for IS and IS

subtypes (based on 12,389 IS cases from METASTROKE) and for CHD (based on 60,801 

cases from CARDIoGRAMplusC4D). We then assessed the effects of LDL-C on IS and

CHD for heterogeneity.

RESULTS: A 1 mmol/L higher genetically determined LDL-C was associated with a 50%

higher risk of CHD (odds ratio [OR] 1.49, 95% confidence interval [CI] 1.32-1.68,

p = 1.1 × 10-8). By contrast, the causal effect of LDL-C was much weaker for IS

(OR 1.12, 95% CI 0.96-1.30, p = 0.14; p for heterogeneity = 2.6 × 10-3) and, in

particular, for cardioembolic stroke (OR 1.06, 95% CI 0.84-1.33, p = 0.64; p for 

heterogeneity = 8.6 × 10-3) when compared with that for CHD.

CONCLUSIONS: In contrast with the consistent effects of LDL-C-lowering therapies 

on IS and CHD, genetic variants that confer lifelong LDL-C differences show a

weaker effect on IS than on CHD. The relevance of etiologically distinct IS

subtypes may contribute to the differences observed.

 

DOI: 10.1212/WNL.0000000000007091 

PMCID: PMC6511103

PMID: 30787162 

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2 hours ago, InquilineKea said:

Centenarians (and their offspring) tend to be more likely to have HDLs of 100 and LDLs in their 50s...

-Not true: few (not most!) of the centenarians from Nir Barzilai's studies have HDL > 100,. Average HDL for female and male centenarians was HDL 52 and 48, respectively:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4087084/

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On 12/31/2020 at 4:38 AM, Dean Pomerleau said:

Todd, 

I'm very skeptical of this statement. For example, see [1] which shows that genetic variations that result in even modest increases in LDL-c are associated with a significant increase in risk of heart disease. I suspect that the key is lifelong low LDL and that by the time someone with higher LDL gets treated they have already built up a lot of plaque. 

--Dean 

-----

[1] ] Neurology. 2019 Mar 12;92(11):e1176-e1187. doi: 10.1212/WNL.0000000000007091.Epub 2019 Feb 20.

Relative effects of LDL-C on ischemic stroke and coronary disease: A Mendelianr andomization study.

Valdes-Marquez E(1), Parish S(1), Clarke R(1), Stari T(1), Worrall BB(1);

METASTROKE Consortium of the ISGC,, Hopewell JC(2).

 

OBJECTIVE: To examine the causal relevance of lifelong differences in low-density

lipoprotein cholesterol (LDL-C) for ischemic stroke (IS) relative to that for

coronary heart disease (CHD) using a Mendelian randomization approach.

METHODS: We undertook a 2-sample Mendelian randomization, based on summary data, to estimate the causal relevance of LDL-C for risk of IS and CHD. Information

from 62 independent genetic variants with genome-wide significant effects on

LDL-C levels was used to estimate the causal effects of LDL-C for IS and IS

subtypes (based on 12,389 IS cases from METASTROKE) and for CHD (based on 60,801 

cases from CARDIoGRAMplusC4D). We then assessed the effects of LDL-C on IS and

CHD for heterogeneity.

RESULTS: A 1 mmol/L higher genetically determined LDL-C was associated with a 50%

higher risk of CHD (odds ratio [OR] 1.49, 95% confidence interval [CI] 1.32-1.68,

p = 1.1 × 10-8). By contrast, the causal effect of LDL-C was much weaker for IS

(OR 1.12, 95% CI 0.96-1.30, p = 0.14; p for heterogeneity = 2.6 × 10-3) and, in

particular, for cardioembolic stroke (OR 1.06, 95% CI 0.84-1.33, p = 0.64; p for 

heterogeneity = 8.6 × 10-3) when compared with that for CHD.

CONCLUSIONS: In contrast with the consistent effects of LDL-C-lowering therapies 

on IS and CHD, genetic variants that confer lifelong LDL-C differences show a

weaker effect on IS than on CHD. The relevance of etiologically distinct IS

subtypes may contribute to the differences observed.

 

DOI: 10.1212/WNL.0000000000007091 

PMCID: PMC6511103

PMID: 30787162 

This point is often confused. What the research supports is that “changes in HDL cholesterol caused by diet or drug treatments can no longer be directly linked to changes in CVD, and therefore, the LDL cholesterol–raising effect should be considered on its own.” (1) The context here is caution in the context of coconut oil until more research is done, since coconut raises HDL as well as LDL. (There are many other arguments pertaining to coconut oil on both sides of the debate, but this is not the focus of this post). But in that context the Presidential Advisory from the AHA was essentially taking the position that we cannot be as confident that raising HDL via diet will compensate for the increase in LDL. In contrast, elevated HDL achieved via weight loss and exercise does have a consistent favorable profile. [“because coconut oil increases LDL cholesterol, a cause of CVD, and has no known offsetting favorable effects, we advise against the use of coconut oil.”].

The basis of this skepticism of a rise in HDL outside of established benefit via lifestyle intervention was described earlier in (1): “However, unlike LDL cholesterol, genetic variation that affects HDL cholesterol is not associated with expected differences in CVD unless LDL cholesterol or triglyceride is also affected by the genetic variants84 or reverse cholesterol transport is impaired.85 Still, these genetic studies, often called mendelian randomization, may not be capturing important loci for the protective effect of HDL that may be reflective in HDL cholesterol raising by dietary fats compared with carbohydrates. Although increases in HDL cholesterol by some pharmacological treatments have not decreased CVD,86,87 this does not directly pertain to the effects of dietary fat because the underlying mechanisms of effects of drugs such as a cholesterylester transfer protein inhibitor and nicotinic acid are probably not the same as those affected by dietary fats and carbohydrates. The HDL field is working toward a functional approach to CVD risk prediction and treatment. For example, a small experimental study showed that consumption of saturated fat reduces the anti-inflammatory potential of HDL and impairs arterial endothelial function. In contrast, the anti-inflammatory activity of HDL improves after consumption of polyunsaturated fat.”

An editorial in Circulation by Frank Sacks (2) subsequently reaffirmed this position, ie, “Although coconut oil increases plasma HDL cholesterol, it is impossible to know if this is a beneficial mechanism in cardiovascular disease.7 Although HDL cholesterol is a robust risk marker for cardiovascular disease, genetic studies and HDL-raising drugs have not so far supported a causal relationship between HDL cholesterol and cardiovascular disease. HDL, the lipoprotein, is composed of a huge array of subparticles that may have adverse or beneficial actions.7,8 It is unknown which, if any, foods or nutrients that raise HDL cholesterol do so in a way that reduces atherosclerosis and coronary events. Thus, effects on cardiovascular disease of foods or nutrients cannot be judged from changes in HDL cholesterol.”

As the Harvard Heart letter noted (3) , the track record for HDL raising drugs is particularly dismal with “To date, five major clinical trials that sought to raise HDL levels with drugs have failed to lower heart disease risk” Lipidologist Dr. Thomas Dayspring & others have speculated it is more of an HDL function story, still poorly characterized as of now.

(1) https://www.ahajournals.org/doi/full/10.1161/CIR.0000000000000510

(2) https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.119.044687

(3) https://www.health.harvard.edu/heart-health/rethinking-good-cholesterol

Further reading (primary sources of said publications):

  • Sacks FM, Jensen MK. From high-density lipoprotein cholesterol to measurements of function: prospects for the development of tests for high-density lipoprotein functionality in cardiovascular disease.Arterioscler Thromb Vasc Biol2018; 38:487–499. doi: 10.1161/ATVBAHA.117.307025LinkGoogle Scholar
  •  

 

  • Furtado JD, Yamamoto R, Melchior JT, Andraski AB, Gamez-Guerrero M, Mulcahy P, He Z, Cai T, Davidson WS, Sacks FM. Distinct proteomic signatures in 16 HDL (high-density lipoprotein) subspecies.Arterioscler Thromb Vasc Biol2018; 38:2827–2842. doi: 10.1161/ATVBAHA.118.311607LinkGoogle Scholar

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If you have very little inflammation and very low blood pressure, the risk of hemorrhagic stroke shouldn't be a concern with having very low cholesterol.

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Bottom line. It’s associated with liver disease and certain cancers. Low ldl does NOT INCREASE MORTALITY! Rather some disease states lower ldl. 

Edited by Mike41

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He makes an interesting point about stains either reducing (or no change) all-cause mortality risk in response to lowering TC, but that's in CVD-related populations. Also, in the study with 12.8 million subjects, ~2 million were 18-34y, and < 150 for TC was associated with an increased all-cause mortality risk for men. There were ~67,000 deaths in that age and TC group . His argument would be that 67,000 young adults had a pre-existing illness that caused lower TC and death, which I find that hard to believe. Also, there are many studies in older adults where those with lower TC have an increased all-cause mortality risk.

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On 2/3/2021 at 2:45 PM, Mike Lustgarten said:

Also, in the study with 12.8 million subjects, ~2 million were 18-34y, and < 150 for TC was associated with an increased all-cause mortality risk for men. There were ~67,000 deaths in that age and TC group .

Hm, if my math is right, at 67k dead, this is a rather high morbidity group.... 67k is close to 3.5% of 2 million while the expected mortality rate of that age group should be less than 0.2%. Unless I am missing something?

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On 2/3/2021 at 5:45 PM, Mike Lustgarten said:

He makes an interesting point about stains either reducing (or no change) all-cause mortality risk in response to lowering TC, but that's in CVD-related populations. Also, in the study with 12.8 million subjects, ~2 million were 18-34y, and < 150 for TC was associated with an increased all-cause mortality risk for men. There were ~67,000 deaths in that age and TC group . His argument would be that 67,000 young adults had a pre-existing illness that caused lower TC and death, which I find that hard to believe. Also, there are many studies in older adults where those with lower TC have an increased all-cause mortality risk.

Why would it be surprising if indeed cancer before you even know you have it lowers the cholesterol levels? Young people do get cancer. So out of almost 13 million people one would expect liver and cancer issues in a small 1/2 of 1 percent. Also Consider the heavy use of  drugs, alchohol, smoking in that group.

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16 hours ago, Ron Put said:

Hm, if my math is right, at 67k dead, this is a rather high morbidity group.... 67k is close to 3.5% of 2 million while the expected mortality rate of that age group should be less than 0.2%. Unless I am missing something?

I agree, which is why reverse causation as an explanation for that age group with lower TC may not be the easy answer.

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5 hours ago, Mike41 said:

Why would it be surprising if indeed cancer before you even know you have it lowers the cholesterol levels? Young people do get cancer. So out of almost 13 million people one would expect liver and cancer issues in a small 1/2 of 1 percent. Also Consider the heavy use of  drugs, alchohol, smoking in that group.

There's no way to know cause and effect-did cancer or other diseases cause low TC and death in the young group, or did low TC contribute to an increased disease risk?

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32 minutes ago, InquilineKea said:

Looks like moderately high TC is optimal for longevity too: https://www.nature.com/articles/s41598-018-38461-y

Notice that study was done on people from South Korea, where on 5% of people die of heart disease compared with 23% in the US. So the applicability of that result is questionable for those of us who live in the US.

--Dean

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On 2/5/2021 at 12:30 PM, Mike Lustgarten said:

I agree, which is why reverse causation as an explanation for that age group with lower TC may not be the easy answer.

Possibly, but with morbidity higher than 3% the 18-34 group is rather unusual (I am looking at the 67k death rate out of 2 million). The average death rate for that age group should be about 0.2%

The higher death rate in the sample would suggest that the sample had comorbidities that may have caused the drop in total cholesterol.

I believe that I've seen at least one study showing generally lower TC levels in centenarians (LDL of 97 if I recall correctly). There is also a lot of evidence that lower cholesterol is healthier, so I'd be leery of these U-shaped population curves for TC, or BMI for that matter.

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6 minutes ago, Mike Lustgarten said:

TC increases towards midlife, then declines towards the end of life. In support of that, offspring of centenarians had TC = 196, whereas their centenarian parents had lower TC (156 - 172)

Fair point, but this can be due to changes in lifestyle between parents and offspring.  For instance, the traditional Okinawan diet all but disappeared in the 1970s and it is likely that the offspring discovered Fritto Lays, while the parents stuck to purple yams.

Also, it is possible that that higher TC during mid-life produces long-term damage and that the parents were less prone to it because of dietary limitations during their lifetime. There is a significant genetic component to longevity, but epigenetic changes produced by diet and environment are likely to have an impact as well.

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Definitely lots of factors can influence TC, but other studies have shown that generally higher LDL are associated with a lower all-cause mortality risk when compared with < 100 mg/dL. For ex., in 74 yr olds: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6919530/

If the hypothesis that higher TC produces long-term damage, we'd expect to see a higher mortality risk in association with the higher LDL for the 74 yr olds in that study. but that's not what the data shows...

Similarly, in 94yr olds, relatively higher LDL was associated with a reduced 3-yr mortality risk: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4441211/.

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21 hours ago, Dean Pomerleau said:

Notice that study was done on people from South Korea, where on 5% of people die of heart disease compared with 23% in the US. So the applicability of that result is questionable for those of us who live in the US.

 --Dean

Most of us CRONites have more to fear from dementia than from heart disease. Cholesterol may be good for the brain and bad for the heart. Also future interventions for heart disease will be **much** easier to come by that future interventions for dementia.

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52 minutes ago, InquilineKea said:

Most of us CRONites have more to fear from dementia than from heart disease. Cholesterol may be good for the brain and bad for the heart. Also future interventions for heart disease will be **much** easier to come by that future interventions for dementia.

Those are reasonable points Alex. But how good is the evidence that high(er) cholesterol is beneficial against dementia?

You are right that I don't fear heart disease much. But then again much of that lack of  fear results from the fact that I eat an extremely health, whole food vegan diet which is low in saturated fat, which happens to keep my LDL and total cholesterol on the low side (~70 and ~150 mg/dl, respectively).

I may be wrong, but personally I would not be inclined to substitute refined fats (e.g. coconut oil or even EVOO) for other healthy foods in my diet to raise my cholesterol level based on the evidence I've seen.

--Dean

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Cholesterol and dementia: Nothing conclusive yet. Low cholesterol may predispose people to depression, but this is probably orthogonal to dementia. Given cholesterol's importance in maintaining cell fluidity and in segregating lipid rafts, I would not be surprised if cholesterol improved cognition (and if low cholesterol decreased it).

So like, don't SFAs also increase the percent of cell membrane that *is* saturated, and more resistant to oxidative stress? Animals with higher SFA/MUFA ratios in their cell membranes are more likely to live longer. It's much easier to desaturate SFAs (SCD1 and the other desaturase enzymes) than it is to turn MUFAs into SFAs in the cell membrane.

https://fireinabottle.net/dietary-monounsaturated-fat-the-scd1-theory-of-obesity-part-3/ (this is just for weight loss but it has interesting links regardless)

Everything I've seen is indicative of encouraging higher MUFA to SFA ratio consumption, but I sometimes do wonder if this ratio may be different for the longest lived individuals who are resistant to heart disease in other ways (SFAs do increase oxidative stress => satiation) through other weird mechanisms I can't *quite* understand.

I'm practically vegan too and recently had a lipids panel that showed surprisingly high LDL/cholesterol (normally my levels are like yours, but a recent test showed elevated levels and I felt less concerned as a result). Anyways, saturated fats *can* curb appetite which can reduce calorie consumption.

FWIW I've started to eat more Beyond meat burgers and sausages (they have some SFAs but not a high SFA to MUFA ratio), and these may be increasing my lipid panels, but I'm not sure if I should feel concerned. 

Edited by InquilineKea

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