Attia email: LDL-C, blood pressure, and CVD risk

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Attia email: LDL-C, blood pressure, and CVD risk

Postby SoCalGuy » Sun Nov 10, 2019 10:01 am

Here's Peter Attia's latest email article. Very interesting read with regard to lowering LDL-C and blood pressure. It also ties in nicely with his interview with Francisco Gonzalez-Lima.

Email link: https://peterattiamd.com/191110/
Podcast link: https://peterattiamd.com/franciscogonzalezlima/

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Re: Blood Pressure Treatment Drastically Reduces Alzheimer’s Incidence

Postby Kenny4/4 » Sun Nov 10, 2019 8:43 pm

SoCalGuy wrote:Here's Peter Attia's latest email article. Very interesting read with regard to lowering LDL-C and blood pressure. It also ties in nicely with his interview with Francisco Gonzalez-Lima.

Email link: https://peterattiamd.com/191110/
Podcast link: https://peterattiamd.com/franciscogonzalezlima/

Great stuff SoCalGuy!
Mendelian Randomization is quite the powerful tool when combined with advanced stats, computing power and large medical studies.
While I agree with the MR studies on BP and LDL on a certain level. I’m struggling with the much higher all cause mortality in Low Cholesterol populations.

On another issue-
Peter Attia wrote:

Having two copies (i.e., rs7412 T;T) means you’re an APOE 2/2, which is associated with a reduced risk for AD. So, if we were looking at AD risk and LDL-C levels in a Mendelian randomization study, it’s possible we might conclude that reduced risk of AD from this SNP is entirely due to its effect on LDL-C levels, when there are a number of other plausible mechanisms (though the evidence is pretty solid that lower LDL-C, which improves vascular health, lowers AD risk by reducing the risk of vascular disease in the brain, which was covered in my podcast with Francisco Gonzalez-Lima).
If this is the case ApoE 4 caused increases in CVD risk and Cerebrovascular risk would explain Alzheimer’s risk. I don’t see the risk ratios as the same unless the heart disease cerebrovascular risk is linear and the Alzheimer’s risk is geometric or exponential because the size of the vasculature in AD is geometrically smaller.
On a side note -not only is ApoE 4 associated with higher LDL but also higher Lp (a) and BP.

Great stuff, I really find his information useful.

Thank you.

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Re: Blood Pressure Treatment Drastically Reduces Alzheimer’s Incidence

Postby MarcR » Tue Nov 12, 2019 4:16 pm

Attia emphasizes the "mental gymnastics" required to understand Mendelian randomization (MR) and suggests that those of us who are intimidated by the work required ...
I had to print it out, put a spreadsheet together, and build my own model to fully digest it. It took a lot longer than I expected.
... should be impressed enough by the effort he invested to agree with his conclusions.

Unfortunately, like all statistical methods, MR cannot produce useful insights when the underlying data are inapplicable. Participants in the large population studies he cites overwhelmingly eat the Standard American Diet (SAD), which relies heavily on ultra processed food packed with sugar and seed oil.

What if you follow one of the popular non-SAD diets that emphasizes whole foods, pastured animal protein, and healthy fats? Work out and maintain a vibrant musculature? Restrict your daily feeding window to eight hours to ensure that your body mobilizes cellular fat stores each day and thereby demonstrates and maintains insulin sensitivity?

Many who do so find that HDL-C rises and triglycerides diminish while overall wellbeing soars. For this fraction of the population, what does LDL-C say about our future cardiovascular disease (CVD) prospects? According to the Framingham Heart Study data, not much - check out Table 2 at the top of page 4 of this paper:

Is Isolated Low High-Density Lipoprotein Cholesterol a Cardiovascular Disease Risk Factor?

All the risk appears in the low HDL-C stratification. Where HDL is high and trigs are below 100, the CVD odds ratios for all four LDL groupings are statistically identical (as per the confidence intervals).

Similarly, this paper ...

Low triglycerides-high high-density lipoprotein cholesterol and risk of ischemic heart disease

... concludes that "Men with conventional risk factors for IHD have a low risk of IHD if they have low TG--high HDL-C levels." If you visit Sci-Hub (currently accessible at mg.scihub.ltd) and search for 10.1001/archinte.161.3.361, Figure 1 in the upper-right corner of page 4 conveys the insignificance of LDL-C succinctly.

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Re: Blood Pressure Treatment Drastically Reduces Alzheimer’s Incidence

Postby Kenny4/4 » Tue Nov 12, 2019 8:52 pm

Marc, I agree that Mendelian Randomization Studies can have flaws, biases particularly if they don’t use a high number of genetic influence markers and those markers aren’t related to a confounding variable.

I agree or should I say I don’t necessarily disagree with the low triglyceride high HDL-C hypothesis.

I will say I disagree at this point in time with anyone who says LDL levels don’t matter in a general sense. Too much really good data is out there. Many of these studies that show high LDL cholesterol as neutral or good suffer from horrible sampling bias. If half the older middle aged adult population is on statins (for high cholesterol AND high risk factors) and you eliminate these people from your sample population you have biased the high cholesterol pool by selecting the very healthiest of high cholesterol people because most of the high risk high cholesterol group is not included because of their statin use. I hope I explained well enough this significant flaw in some of these studies.
Last edited by Kenny4/4 on Tue Nov 12, 2019 8:57 pm, edited 1 time in total.

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Re: Blood Pressure Treatment Drastically Reduces Alzheimer’s Incidence

Postby cdamaden » Wed Nov 13, 2019 9:23 am

What wasn't clear to me in reading Peter Attia's analysis email or the paper was whether it was the people who had SNPs that lead to lower LDL-C or was it the people who had low LDL-C who were less likely to have cardiovascular disease. In the first case, it seems immaterial what my actual LDL-C is - just what my genes contribute. If it is the second case, why do all the research on what my SNPs are, just look at those people who gets cardiovascular disease and look at their lifetime LDL-C (adjusting for those who smoke, etc.). My question is, if I have a hereditary inclination to high LDL-C but I maintained a low LDL-C would I be any better off than my twin brother who didn't maintain a low LDL-C?
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Re: Blood Pressure Treatment Drastically Reduces Alzheimer’s Incidence

Postby Kenny4/4 » Wed Nov 13, 2019 10:40 am

To answer your first question it’s both but in the case of Mendelian Randomization specifically the answer is just those with the SNP’s that lower it. If those lowering SNP’s and SNP’s for a higher LDL show positive correlation in a very large sample size with multiple independent SNP’s it illustrates a much higher likelihood of causation and eliminates some confounding and reverse causation.

Last question-all things equal a lower LDL equates to a lower CHD-CVD risk. How much? Are other variables more important? It depends. It’s like cards you may get dealt 2 aces in hold em -low LDL and someone else gets dealt a 8,4 high LDL but the 8,4 low LDL never gets heart disease and the 2 aces High LDL does ......but overall and over time 2 aces wins the vast majority of the time and doesn’t get heart disease unless the player really plays the hand stupidly or person engages in poor lifestyle choices.

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Re: Blood Pressure Treatment Drastically Reduces Alzheimer’s Incidence

Postby MarcR » Thu Nov 14, 2019 6:26 pm

Kenny4/4 wrote:all things equal a lower LDL equates to a lower CHD-CVD risk.
The evidence suggests otherwise.

This 8-year study of 100,000+ people aged 50+ without preexisting diabetes or heart disease is the only high-powered study I have seen that focuses on the lipids of healthy older people. I am skeptical of the studies that support the high LDL -> disease link primarily because they include so many sick people. By excluding young people and those with preexisting diabetes, heart disease, or statin prescriptions, the study shows us a cross-section of people who navigated the contemporary nutritional minefield reasonably well to 1997. The subsequent experiences of this relatively insulin-sensitive population therefore seem more relevant to this question - how does LDL drive mortality when insulin is low?

It turns out that low LDL-C conforming to conventional recommendations correlates with greatly INCREASED mortality. LDL-C high enough to prompt many doctors to prescribe statins correlates with greatly REDUCED mortality. The effect is not small. As per Table III, here are the hazard ratios for LDL-C levels in mg/dL:

50-60 years
<97: 1
97-116: 0.57
116-154: 0.44
>154: 0.44

60-70 years
<97: 1
97-116: 0.67
116-154: 0.49
>154: 0.45

>70 years
<97: 1
97-116: 0.71
116-154: 0.60
>154: 0.52

So if you're between the ages of 60 and 70, don't have diabetes and are not on a statin, having an LDL-C in excess of 154 mg/dL puts you in a group whose members are only 45% as likely to die as those with supposedly ideal LDL-C.

So, "all things equal", higher LDL-C = longer life in relatively healthy populations. If you want to parse it further, the two studies I cited in my previous post above show that LDL-C has no relationship with CVD event risk as long as one is insulin sensitive (low trigs/HDL ratio). The disappearance of the correlation in metabolically healthy people tells me that LDL-C is a marker of CVD risk in metabolically dysfunctional people, not a cause. And the huge reduction in all cause mortality as LDL-C rises suggests that plentiful LDL may offer benefits for overall health even though it has no effect on CVD risk.

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Re: Blood Pressure Treatment Drastically Reduces Alzheimer’s Incidence

Postby SusanJ » Fri Nov 15, 2019 6:05 am

MarcR wrote:So, "all things equal", higher LDL-C = longer life in relatively healthy populations.


I think that "healthy" is the key here, since LDL helps the innate immune system fight viruses, microbes and their toxins. For example, my current doc is convinced that once I fix some small house issues and clear high arsenic levels, my immune system can send a mild EBV flare packing, and my LDL will come down some.

So there might be a corollary that you don't want high LDL with the presence of infection or toxins.

Have you seen this one? I haven't tried to track down the full paper.

The purpose of this review is to elucidate how low blood cholesterol promotes mitochondrial dysfunction and mortality by the loss of thioretinaco ozonide from opening of the mitochondrial permeability transition pore (mPTP). Mortality from infections and cancer are both inversely associated with blood cholesterol, as determined by multiple cohort studies from 10 to 30 years earlier. Moreover, low-density lipoprotein (LDL) is inversely related to all-cause and/or cardiovascular mortality, as determined by followup study of elderly cohorts. LDL adheres to and inactivates most microorganisms and their toxins, causing aggregation of LDL and homocysteinylated autoantibodies which obstruct vasa vasorum and produce intimal microabscesses, the vulnerable atherosclerotic plaques. The active site of mitochondrial oxidative phosphorylation and adenosine triphosphate (ATP) biosynthesis is proposed to consist of thioretinaco, a complex of two molecules of thioretinamide with cobalamin, oxidized to the disulfonium thioretinaco ozonide and complexed with oxygen, nicotinamide adenine dinucleotide (NAD+), phosphate, and ATP. Loss of the active site complex from mitochondria results from the opening of the mPTP and from decomposition of the disulfonium active site by electrophilic carcinogens, oncogenic viruses, microbes, and by reactive oxygen radicals from ionizing and non-ionizing radiation. Suppression of innate immunity is caused by the depletion of adenosyl methionine because of increased polyamine biosynthesis, resulting in inhibition of nitric oxide and peroxynitrite biosynthesis. Opening of the mPTP produces a loss of thioretinaco ozonide from mitochondria. This loss impairs ATP biosynthesis and causes the mitochondrial dysfunction observed in carcinogenesis, atherosclerosis, aging and dementia. Cholesterol inhibits the opening of the mPTP by preventing integration of the pro-apoptotic Bcl-2-associated X protein (BAX) in the outer mitochondrial membrane. This inhibition explains how elevated LDL reduces mitochondrial dysfunction by preventing loss of the active site of oxidative phosphorylation from mitochondria.

https://www.ncbi.nlm.nih.gov/pubmed/31471331

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Re: Blood Pressure Treatment Drastically Reduces Alzheimer’s Incidence

Postby MarcR » Fri Nov 15, 2019 11:44 am

That looks like a terrific new paper, Susan - great find! I didn't have any luck acquiring the full paper as it does not yet seem to be on Sci-Hub. Fortunately the abstract does a great job of hitting the high points.
SusanJ wrote:So there might be a corollary that you don't want high LDL with the presence of infection or toxins.
Puzzled ... seems the paper explains that high LDL is a desirable functional response to infection or toxins. We don't want infection or toxins, but if we do have them, we also want high LDL, right?

I see a parallel between the emerging story of LDL functionality and that of amyloid beta. For decades it was almost impossible to get funding for Alzheimer's research that didn't focus on aβ reduction. Only in recent years after hundreds of failed drug trials that reduce aβ but deliver no or negative clinical results has the medical research establishment begun conceding that aβ is merely associated with dementia and is not the cause. Aβ now seems more likely to be a harm mitigating response to injury rather than a root cause.

Similarly, we're learning that LDL has multiple functions, that our bodies wisely produce more or less as needed, and that we manipulate it at peril.

Which view is more plausible? Attia's mental gymnastics and just trust me because I'm so smart statistical analysis or any of Malcolm Kendrick's lucid and accessible explanations? Those of us tempted to believe Attia really should give Kendrick a read. His latest:

What causes heart disease – part 67 – The Blood Brain Barrier

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Re: Blood Pressure Treatment Drastically Reduces Alzheimer’s Incidence

Postby SusanJ » Fri Nov 15, 2019 7:01 pm

MarcR wrote:We don't want infection or toxins, but if we do have them, we also want high LDL, right?


To be more precise, I was thinking that higher LDL could be suggestive of an infection, so, it's worth ruling out any infection just to make sure you're on the healthy side of higher LDL.


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