#2952

I think Atherosclerosis is partially caused by a failure of cellular function driven by genome failures. Hence if you fix those Atherosclerosis is less likely.

Only one of my labs tests for ApoB. It has also bounced around a little (between 77 and 97) although my most recent value was 77 and the oldest 97 I also had a 77 a good few months ago. Hence I am unsure as to the consistency of the testing process. (Questions as to the precision of the test, questions as to normal metabolic changes in ApoB level, not sure as to what the cause of variation is, but it means I am not going to see too much in a single value of 77).

I did have some Red Yeast Rice with Monacolin K (a statin) in them for a bit, but I stopped and am not doing anything specific at the moment to reduce ApoB.

My key target remains cellular function more generally and what I would say about ApoB is that it is a single value. If it were to be haywire in some way I may be more focussed on it, but if it is in the bounds of reasonable values I am not inclined to skew my metabolism to further reduce it.

I thought I would copy in the results I have had since June 23 (the first time I tested this) so people can see how it bounces around a bit. This is all one lab.

	97				89				77				90												84							90				87				93						92						89														77
3 Likes
#2953

What dose of beta cyclodextrin are you using? Have you seen any side effects?

#2954

Ok, see under each my thoughts and ā€œfeelingsā€

1 atherosclerosis is completely avoidable with apo b levels above 50.

  • This might be true, but I donā€™t think we know that in any given individual, so itā€™s very different from believing that statement could be true vs using it as an assumption for one self or oneā€™s loved ones. Unless their are massive advances I think the likelihood for that being true in an individual to pushes through their 80s, 90s and into their 100-120s.

Apob is necessary but not sufficient for atherosclerosis.

  • Probably correct from a practical model to see these things from

2 And that apob of say, 30 isnā€™t a guarantee of no atherosclerosis. (MRandomization studies)

  • Yes, I do not thing it is a guarantee. I do think it continues to
    Change the risks by a lot vs even 50-60 - when look looks at the total exposure that difference would mean over the course of decades
  1. If inflammation is low, and oxidation risk highly reduced by exercise, evoo, fibre etc there is very little benefit and maybe no or negative benefit from reducing apob from 55 to 30.
  • Do not agree. Also our ways to measure and gauge true inflammation levels are limited and most of even the people on this forum are not using more than perhaps hs-CRP, homocysteine and perhaps IL-6 to measure their inflammation - so almost no one truly knows if they have optimally low inflammation
  1. I donā€™t think we should discount the downside risk of extremely low cholesterol completely either, just yet. The science isnā€™t settled and certainly not for a 30+ year period.
  • That is true. On the good side we do not have to commit today do a 30+ year time period. Iā€™ve basically only committed to what Iā€™m doing this month and am constantly following literature and thought leaders to obtain updated information and would change is the balance of how I should weigh the totally of understanding the world has today vs in future months, years and decades
  1. All pharma has potential side effect risks especially v. long term use. Psk9i are newish and Iā€™d love to see more long term data. Statins are likely to have some (small) downside over v long term use.
  • I agree that there could be unknown, unknowns. See point above that if the evidence shifts in a way on a year or 5 years then I would change my decisions. The nice thing is that if you have not used say a PCSK9i or Bemp Accid before and where to start now (or last year for me) it means that one would be riding behind a decade or so of longer term data and that moved in time, so when you potentially get to have used it for 5 years there will not be 15 years of experience from others and so on. (Iā€™m not sure if statin side effects have more negative ones than positive ones - there are those also).
  1. Using pharma and optimizing lifestyle is possible but confidence in the pharma is likely to lead to worse lifestyle.
  • Not sure I understand. For me I think it has been the opposite so far.
  1. within 10 years weā€™ll have a much better understanding of the mechanisms of atherosclerosis including the role of inflammation and oxidation and therefore weā€™ll have better targets than apoB.
  • I already look at massive amounts of other measures than Apo B (also including cardio MRI, non frequent CT scan/Cleerly, ultrasound and many other types of blood work). I manage those other things too, eg Homoceistine, Omega 3 index and DHA/EPA fractions, etc, etc.
  • And yes, as mentioned in (4) no one has to can to commit to doing any action for longer than the action they are taking today and everyone can and should constantly be taking in the updates to the worldā€™s understanding and using that to update our measurements and actions.
  1. Someone who achieves say, apo b 65 with exercise, fibre, evoo, fish, nuts etc is likely to have a much lower risk of ascvd than someone who achieved it with say, a statin
  • yes, but I donā€™t thing that is relevant. The question should not be OR, but rather about AND
  • the question whether (A) vs (B) is better is the relevant I think? Ie which is better:
    (A) person achieves say, apo b 65 with exercise, fibre, evoo, fish, nuts etc
    (A) same person achieves materially lower, apo b than 65 with the same exercise, fibre, evoo, fish, nuts etc AND and optimal, well thought through use of pharmaceutical agent(s)

9.edit: risk of atherosclerosis doesnā€™t increase exponentially with age for individuals with zero risk factors

  • perhaps, but no human that becomes 90-120 will have zero risk factors (without massive technological/medical advances)
6 Likes
#2955

Could you explain more please. Are you thinking of mitchondrial function/metabolism? Are there any specific drugs/side effects you have in mind? And do you have any concerns about psk9i?

1 Like
#2956

The normal action of statins is to inhibit HMC-CoA. I am not inclined to do this.

#2957

Thereā€™s 8 ml of liquid which contains 6 grams hydroxypropyl-beta-cyclodextrin. On the package it says you can absorb 1 gram in 30 minutes retention. It doesnā€™t say how much you absorb if you retain it forever. I would expect some of it to be turned into short chain fatty acids by the bacteria. Itā€™s a starch and that is food for them.

No side effects except for the obvious. If you can ignore that itā€™s a miracle.

1 Like
#2958

@L_H can I ask you the same question back - which of my responses to the 9 items do you agree with, and in the cases where you donā€™t agree, why?

#2959

This is further information on one strand of this conversation.

I have long been of the opinion that inflammation plays a causal role in cardiovascular disease. At times, I thought it might have been a necessary condition. The following does not rule this interpretation out but the consensus on proportions (20-25%) you see in the following suggests that there might be better explanations of the full causal chain.

  • In the JUPITER trial, approximately 25% (1,013 out of 4,060) of major cardiovascular events occurred in individuals who had baseline hsCRP levels < 0.5 mg/L.

  • In the Pravastatin Inflammation/CRP Evaluation (PRINCE) study, about 21% (195 out of 919) of the cardiovascular events were in those with hsCRP < 0.5 mg/L at enrollment.

  • A post-hoc analysis of the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) found that nearly 20% of major coronary events happened in those with baseline hsCRP < 0.5 mg/L.

These studies indicate that a substantial proportion of cardiovascular events can still occur even with very low CRP levels, thereby reducing the testā€™s value as a lone risk predictor. I was unable to secure comparable data on other common measures of inflammation.

7 Likes
#2960

CRP and hsCRP are always identical if checked at the same time. CRP increases with any inflammation, infection, exercise and many other factors. I agree that it is ā€œnot a valuable lone predictorā€ of cardiovascular events.

2 Likes
#2961

C Reactive Protein is driven by two things.
a) infection
b) the background level of SASP

hence you need multiple measurements so that an upswing from infection can be excluded.

4 Likes
#2962

The apoB increase was transient and self resolving. There was no need to address this as it was an expected side effect and if it would persist I would certainly address it although apoB of 84 without any confounding risk factors does not need any radical decisions.
I had my ASCVD health assessed in clinic and their conclusion was that ATM my lifetime risk is low and even aggressive 40% lowering of apoB would reduce it marginally per know data we have from studies. Assessment included ultrasound assessment of carotid and peripheral arteries and ambulatory BP, heart stress test among other tests and there is no sign atherosclerotic plaques or arterial wall thickening. I am almost 50.
Yes I have been reading a lot and listening to PA and co. and was tempted to try to lower my apoB especially when I hit 84 mg/dl 3 months into rapamycin regimen. But as ASCVD can not be generalized and recommendations are really more case to case I discussed it with few doctors and reading a lot of literature and possible risks involved I identified two possible drugs that I could potentially use, ezetimibe and fibrates, but since my lipid composition favors apoA1, I have really low TG and lp(a) I did not decide to try fibrates, ezetimibe is still there as an option. At this moment I do try to optimize lifestyle interventions, I have low BP (median 24h is 106/65) my apoB is 58, my HbA1c is 4.8-4.9%, I donā€™t smoke, I exercise daily, eat mostly home cooked Mediterranean diet, trying to lower saturated fats and sodium and I donā€™t see much benefit in going lower with medicines. I think every medicine has unwanted side effects and risk assessment of potential side effects vs. benefits should be taken into consideration very carefully in wanting to prevent something that you are low risk to begin with. I know that Attia uses argument that 30% of all first MI are fatal and that starting with lipid lowering when you already have ASCVD is far worse than preventing it. If I were in my thirties my position would probably be different but entering into fifth decade without any sign of ASCVD and no close family members dying of ASCVD or having advanced ASCVD gives me a bit more confidence that maybe my genotype and phenotype is protective against it, but if any of risk factors changes I will reconsider. I am also open to arguments that donā€™t generalize ASCVD and donā€™t use catchy one liners or fear mongering.

4 Likes
#2963

Yes, really interesting replies thank you. You make a good point that we need only commit short term to any intervention at any one point in time. My counterthought to it would be that to work, blood lipid interventions need to be long term, so Iā€™m more drawn to experimenting with food and lifestyle rather pharma because I know that if they work Iā€™ll find it easy and risk and worry free to continue with them indefinitely.

I think the areas of disagreement are mainly:
A. The scale of the benefit from moving to v.low from low (say apob 55 to 30). The mendelian randomization studies suggest a lifetime impact of 20-25%. Thatā€™s obviously great but it may not be generalizable to psk9 inhibitors, and it equates to whole of life apob not middle age+ intervention. And it comes from population typical lifestyles, and I assume the % doesnā€™t hold for people hyperfocussed on minimizing inflammation and oxidation. And the absolute benefit will be small for those people too, even at age 90+
The risk of atherosclerosis seems fairly linear with age (not exponential), and being in the best 2% for apob (apob <55) and low inflammation/oxidation would seem to give you extremely good odds of avoiding atherosclerosis given the population level incidence.

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B. Whether we should worry more about a. missing out on the potential benefit of hitting extremely low Apob or b. the potential side effects of pharma to get us there. I suspect this is highly unknowable. But I veer towards ā€˜first do no harmā€™. And Iā€™m also sure that I would eat less well if i were on say, a psk9i, so that is an added side effect.

C. Whether we can avoid atherosclerosis risk factors into old age. I think we can, as long as we remain metabolically healthy

D. Our theoretical models for atherosclerosis probably differ too. I believe oxidation and inflammation are also necessary but not sufficient. I appreciate they canā€™t be targeted as well as apo b. But i think thereā€™s a danger focussing too heavily on the things we can measure because it typically is at the detriment of the things we canā€™t target easily. In most multi-factoral diseases itā€™s better to focus broadly on all risk factors rather than trying to solve the problem by targeting a single risk factor to extremes.

I suspect the main difference between us is one of biases. I have no family history of heart disease, grandparents all reached 90s or 100+, Iā€™ve grown up on a high fibre med diet etc. So I believe my atherosclerosis risk is very small compared to other hallmarks of aging. So I feel confident in my future arterial health, less in my future kidneys, mitochondria, brain, cancer risk etc.

Some back of envelope calculations: letā€™s assume 25% is the baseline risk of ascvd at age 75. An apo b of 55 would already put me below 5%. Plus family history, low inflammation, low oxidation and Iā€™m well into low single digit% - reducing that risk by a further say, 10-15% with a psk9i (used only middle age +) doesnā€™t seem large to me - weā€™re talking well under 0.5% absolute benefit. Even at 90 years+ the risk reduction benefit is likely to be under 0.5%. Whereas my mitochondria and brain are more likely than not to be compromised at 90 years+ So any potential side effects which impact those, Iā€™d love to avoid!

3 Likes
#2964

Masterjohn here links a study showing that MK-4 is localized in the membranes of liver cells especially to the mitochondrial inner membrane, and jumps to the conclusion that MK-4 taken as an oral supplement will go there (and not just in the liver). He has presented no evidence that such is the case, and I could find one. He also assumes that oral supplemental CoQ will be delivered to mitochondria, and this is not at all clear after years of investigation, and seems unlikely granted that it fails to do anything about statin-induced myopathy.

1 Like
#2965

We certainly have much better long-term intervention study data for hard outcomes and side effects for lowering apo B to very low levels with current pharmaceuticals than we have for K2, exercise, or fiber to do it ā€” since we have none for the latter three. The studies you link or could point to are all epidemiology, not intervention trials. Indeed, most trials of K2 for CVD indications have failed, and were only looking at surrogate outcomes to begin with.

3 Likes
#2966

You may have misunderstood. Iā€™m not trying to lower my apo b to extreme levels with food and exercise etc.

Iā€™m saying that food and exercise will both lower my apob moderately and reduce my inflammation and ldl oxidation.

I hold food and exercise to a lower standard compared to a drug. Partly because it doesnā€™t lower apob to extreme levels. But also because i only opt for non-extreme diet and exercise. Med diet and 250 mins of moderate exercise with a little high intensity and body weight resistance.

Admittedly, Vitamin k2 is in supplement form now, but originally i ate natto. It noticeably improved the texture of my teeth and so i switched to a supplement when my easy supply of natto disappeared during covid.

I am very interested in any RCTs for lowering apob to extreme levels if there are any that havenā€™t been posted.

1 Like
#2967

Indeed, are there ongoing or planned trials about intensive apoB reduction? (similar to the trials for intensive BP reduction that led the ACA/AHA to lower its hypertension threshold)

#2968
#2969

All of the PCSK9 inhibitor trials have lowered from already low LDL, around 70 mg/dl (already on max dose statins etc) iirc.

Of course there is regression in plaques etc from it and decrease in heart attacks, following the linear relationship as expected.

#2970

Yes, but this is not the same thing as doing a trial where you ask doctors to put ALL patients under, letā€™s say, 50 mg/dL using whatever drugs they want and then see the outcome.

#2971

Do you mean adjusting the dosage so everyone gets below 50 mg/dl? Why not just stratify based on achieved LDL reduction and see what happens to those with lower LDL (which they have in both statin and PCSK9 trials I think)?

Example of a post-hoc analysis on plaque regression:

image

The PCSK9 trials tend to lower from around 90 mg/dl-70 mg/dl to 30 mg/dl and have a reduction in events. There are statins studies stratifying on achieved LDL as well.

1 Like