Cardiovascular Health

[BarryAllen]

Greetings:
I asked the Medical AI - OpenEvidence.com: Is there is an ApoB level below which plaque regression occurs. The answer follows:

While lower apolipoprotein B (apoB) levels are associated with reduced atherosclerotic cardiovascular disease (ASCVD) risk and plaque burden, there is no universally established apoB threshold below which plaque regression reliably occurs; guideline-recommended targets are <90 mg/dL for high-risk primary prevention and <80 mg/dL for very high-risk patients, as outlined by the National Lipid Association and the American College of Cardiology. Clinical studies using intravascular imaging demonstrate that reductions in apoB, particularly in statin-treated patients, are linked to greater plaque delipidation and regression, but do not define a specific apoB cutoff for regression; some observational data suggest lower cut points such as 65 mg/dL may be beneficial in certain populations, though these findings are not definitive and require further validation.

ApoB is a superior marker of atherogenic particle number and residual risk compared to LDL-C, especially in patients with diabetes, metabolic syndrome, or high triglycerides, but guideline targets are based on risk reduction rather than direct evidence of plaque regression at a specific level. No randomized controlled trial has established a definitive apoB threshold for plaque regression, and further research is needed to clarify if a specific level guarantees regression across populations. In summary, while aggressive lowering of apoB is associated with favorable changes in plaque characteristics, no specific apoB level has been proven to reliably induce plaque regression.

[Davin8r]

@BarryAllen

definitive apoB threshold for plaque regression

That’s why I just follow the “lower the better” model.

[tananth]

Mechanistically even at very low apoB levels, the apoB can still deposit soft plaque at a low rate, but there is some other mechanism that is constantly dissolving soft plaque at some genetically determined slow rate and getting picked up by HDL particles to be recycled in the liver. Unfortunately it is not clear what determines the rate at which soft plaque is picked up, but it may be related to the level of HDL. There are some low quality studies suggesting that on average soft plaque starts regressing below ApoB = 50, but there is a lot of variability between individuals.

[A_User]

@tananth

Unfortunately it is not clear what determines the rate at which soft plaque is picked up, but it may be related to the level of HDL.

For what it’s worth CETPi trials and genetic mutations that increase HDL but doesn’t decrease LDL hasn’t shown any benefits on cardiovascular outcomes.

[BarryAllen]

However, Obicetrapib, a new CETPi will likely change this
Obicetrapib has no off target effects which have limited the results for prior medications in this class

Obicetrapib: There is still Life in the CETP Inhibitor! - PMC

[A_User]

Yup, it’s because it massively lowers LDL.

[relaxedmeatball]

@tananth

Humans evolved rising serum LDL (with age) to improve rapid wound healing (which requires massive amounts of LDL),

Do you have evidence of this? I’ve heard the speculation that lipoproteins may have been beneficial in wound healing and fighting viral infections, but I haven’t seen any good evidence of that.

To my knowledge, I’m also not aware of any evidence that people who are aggressively lowering circulating LDL-C have worse wound healing. But I’ll be happy to be corrected. I did ask GPT-5, and it said there’s no evidence, aside from in people who have low lipoprotein levels due to malnutrition or severe systemic diseases, which would obviously massively impact wound healing.

@tananth

Blood vessels (even in the brain) are outside the BBB

Not really correct, if we’re being picky. The blood vessels form part of the BBB, because the endothelial cells are linked by tight junctions to prevent passage of molecules. They also contain receptors to allow selective transport of molecules between the blood and the brain. However, the whole BBB is formed from a cooperation of endothelial cells, pericytes, glial cells, astrocytes and even neurones - the new word is “neurovascular unit”. The BBB isn’t some wall - it’s a dynamic system which controls what enters and what leaves.

You’re absolutely correct about hypertension being a major risk factor though, and I would assume/hope that anybody taking Rapamycin for health has already covered the absolute basics like controlling their BP.

@A_User

Basically, when you’re laying down plaque in arteries across the body it’s equally embedded in the brain. So when people want to “deliver LDL” that can’t even cross into the brain, all they’re doing is laying down plaque in the blood brain vessels for a delivery that never arrived.

Is that right? It’s correct that we do build atherosclerotic plaque in multiple arteries. The coronary artery is particularly vulnerable because it is under super high pressure (being basically the first branch off the aorta). Also, I’ve seen some presentations modelling this, and the places where plaque accumulates tend to be where you have branches and the blood needs to change direction, which applies shear forces. You of course can build plaque in other places, such as the carotid, or the middle cerebral artery which supply the brain. However, in brain capillaries (where the BBB is “located”) the flow is low pressure and very slow. I don’t think you’d build plaque or accumulate lipoproteins there.

@Beth

What do you recommend other than the medicines

Nothing. Let’s take a few things as facts:

1. Her current ApoB/Lp(a) level is still enough to build soft plaque. The CTA proves it.

2. You said she already has a great diet and exercises. So we’d assume there’s not much additional room to reduce risk by cutting saturated fat, lowering her BP etc.

The only thing left is lowering her ApoB, from wherever it is now, down to something low enough that she stops building more plaque. Tinkering with an already good diet, or adding supplements isn’t going to make a big difference. The only thing that will significantly move the needle is medication. (I’m aware that you already know this, haha. But some people just need to push to finally start taking the damn pills).

May also be worth her doing a Lp(a) test, just to see whether that might also be involved?

@tananth

There are some low quality studies suggesting that on average soft plaque starts regressing below ApoB = 50, but there is a lot of variability between individuals.

A researcher I know that me that she thinks it’s diffusion. If cholesterols are lower in the blood than in the artery wall, some will leave down the concentration gradient. (Of course some will be trapped, don’t have a diffusion pathway etc)

[A_User]

@relaxedmeatball

Is that right?

Dunno.

@relaxedmeatball

However, in brain capillaries (where the BBB is “located”) the flow is low pressure and very slow. I don’t think you’d build plaque or accumulate lipoproteins there.

But where do the initiation of strokes happen? Is it in places with similar historical concentration of lipoprotein as rest of the circulation e.g affected by cholesterol lowering drugs?

[tananth]

There are 2 types of stroke:

1. Hemorrhagic stroke: This is NOT caused by LDL or plaque, but by injury/damage to the blood vessel walls by high blood pressure or head trauma. LDL may actually help speed healing of injured blood vessels.

2. Ischemic stroke, caused by blockage of the blood vessels in the brain, either from plaque in the brain OR (more commonly) from blood clots OR plaque pieces travelling from blood vessels elsewhere in the body where plaque has torn lose causing bleeding and clotting.

Overall, Ischemic stroke is much more common than Hemorrhagic stroke, so it is likely that high LDL will actually increase overall mortality from all types of stroke, even if it reduced mortality from Hemorrhagic stroke.

[A_User]

We do want to know the quantity (percent) of strokes are caused where and by what, if necessary the magnitude of the stroke, and if the initiation area were subject to systemic LDL concentration. I’m suspecting the majority even adjusted for magnitude of strokes were initiated in places with the same LDL particles count that is clogging up the heart.

[BarryAllen]

All that’s good, but may not be enough for those with strong family history of early MIs and with non zero CAC Scans. LP(a) can be reduced if elevated although that’s expensive. What about inflammatory contributors to heart disease? hsCRP elevation is not good, and increases risk associated with whatever your apoB level is. Keeping kidneys healthy would be reflected in good eGFR levels ( > 60), which would allow urine discharge of TMAO - hence minimal TMAO associated risk. If TMAO is elevated, a WFPB diet work. It would also be wise to look at your OxLDL levels, since this is an active molecule that enhances plaque formation. Note that elevated TMAO is likely to increase OxLDL while statin use is shown to lower OxLDL levels, as does Ezitimibe.

[Agetron]

Here you go. I know the scientist who did this research.

Rapamycin enhances neurovascular, peripheral metabolic, and immune function in cognitively normal, middle-aged APOE4 Carriers: genotype-dependent effects compared to non-carriers - PMC

Rapamycin enhances neurovascular, peripheral metabolic, and immune function...

[Barnabas]

Four weeks at 1mg per day is a nice proof of concept, but it would be nice to get a follow up tracking 6mg per week for six months.

[A_User]

Sure you can lower hsCRP if you can.

TMAO has no effect on heart disease risk.

[Davin8r]

@A_User

TMAO has no effect on heart disease risk

The preponderance of evidence would seem to disagree with you.

OpenEvidence - Is there evidence showing that elevated levels of TMAO has no...

[A_User]

I was thinking about a MR study showing or detecting no effect.

[A_User]

We used genetic variants as instruments to test the causal associations. Genetically predicted higher TMAO and carnitine were not associated with higher odds of T2DM, AF, CAD, MI, stroke, and CKD after Bonferroni correction (P ≤ 0.0005). However, we observed that genetically increased choline showed a suggestive association with higher risk of T2DM (odds ratio 1.84 [95% CI 1.00-3.42] per 10 units, P = 0.05). In contrast, genetically predicted higher betaine (0.68 [0.48-0.95] per 10 units, P = 0.023) was suggestively associated with a lower risk of T2DM. We observed a suggestive association of genetically increased choline with a lower level of body fat percentage (β ± SE -0.28 ± 0.11, P = 0.013) but a higher estimated glomerular filtration rate (0.10 ± 0.05, P = 0.034). We further found that T2DM (0.130 ± 0.036, P < 0.0001) and CKD (0.483 ± 0.168, P = 0.004) were causally associated with higher TMAO levels. Our Mendelian randomization findings support that T2DM and kidney disease increase TMAO levels and that observational evidence for cardiovascular diseases may be due to confounding or reverse causality.

https://diabetesjournals.org/diabetes/article/68/9/1747/39628/Assessment-of-Causal-Direction-Between-Gut

[relaxedmeatball]

@A_User

We do want to know the quantity (percent) of strokes are caused where and by what, if necessary the magnitude of the stroke, and if the initiation area were subject to systemic LDL concentration. I’m suspecting the majority even adjusted for magnitude of strokes were initiated in places with the same LDL particles count that is clogging up the heart.

@A_User

But where do the initiation of strokes happen? Is it in places with similar historical concentration of lipoprotein as rest of the circulation e.g affected by cholesterol lowering drugs?

I am not a brain expert, but what I do know is that any form of atherosclerosis isn’t just about the systemic LDL-C concentration. The anatomy of the actual artery is important, and that obviously varies between people. (Plus all the usual variables like blood pressure, reactivity of your immune system etc). I have no idea how you’d measure historical concentration of lipoproteins though.

For ischaemic strokes, the initiation site is sometimes in the brain itself (middle cerebral artery etc) or immediately upstream of the brain (like the carotid, which is why people look at that by ultrasound as a clue to the condition of your arteries). You can also generate clots from other places, like in the heart if you have atrial fibrillation, and the clot can shoot up and lodge somewhere else.

Anyway, I think the larger point is that for most people, they’re more likely to die from ASCVD than anything else, and lowering your LDL-C is pretty much the best safeguard against that.

[A_User]

@relaxedmeatball

I have no idea how you’d measure historical concentration of lipoproteins though.

I’m differentiating which strokes we have control of with LDL-C lowering therapies and which strokes we don’t. Those strokes under the influence of systemic LDL concentration rather than past the BBB is what I mean, and since risk from LDL-C is never a snapshot but historical concentration, I mean what’s been in the past. Initiation because as you say the stroke can travel to the brain. So amount and magnitude of strokes in this area lets us know which ones we can prevent with reducing LDL-C solely.

This basically is the more precise question IMO.

gpt-oss-120b wrote RR reduction lifetime stroke risk is reduced by 80% by combining apoB to ~30, BP 115/80, no type 2 diabetes, normal weight. I should’ve added kidney function to the question.

[CronosTempi]

As promised I’m posting results of the n=1 experiment wrt. lipid medication. No changes in diet or exercise or other lifestyle factors, sleep, level of stress insofar as I can tell (low), supplements. The only med change was going from the Zydus brand sirolimus 6mg/1-week to Eris/Biocon brand same dose and schedule, have been on it ever since that test, so 8 weeks of the Eris for this test. This test (3) keeps pitavastatin 4mg/day but substitutes 10mg/day ezetimibe for the previous 180mg/day bempedoic acid.

So the tests are as follows - each intervention roughly 6 weeks with no washout period:

(1)pitavastatin 4mg/day alone (switched from atorvastatin 10mg/day)

(2)pitavastatin 4mg/day + bempedoic acid 180mg/day

(3)pitavastatin 4mg/day + ezetimibe 10mg/day - CURRENT RESULTS test on 08/08/25

And the next test is ongoing since 08/09/2025, the results will be in a blood test on 10/28/25:

(4)pitavastatin 4mg/day + bempedoic acid 180mg/day + ezetimibe 10mg/day

Pitavastatin 4mg/day alone vs pitavastatin 4mg/day + bempedoic acid 180mg/day vs pitavastatin 4mg/day + ezetimibe 10mg/day

Pita alone - 5 months; Pita + BA - 39 days.

Legend: Pita alone - PA; Pita + BA - P+BA; Pita + ezetimibe P+EZ

Total Cholesterol: PA - 228 mg/dL ; P+BA - 208 mg/dL; P+EZ - 195 mg/dL
LDL-C Calc: PA - 123 mg/dL ; P+BA 110 mg/dL; P+EZ - 99 mg/dL
Trig: PA - 93 mg/dL ; P+BA - 62 mg/dL; P+EZ - 82 mg/dL
HDL: PA - 89 mg/dL ; P+BA - 87 mg/dL; P+EZ - 81 mg/dL

I’m not thrilled with this. The decline in LDL is pretty marginal. No change in ApoB (delcine from 90 to 89). The trigs and HDL going in the wrong direction, as is the entire lipid profile (number of small LDL increase, size of LDL decrease etc.)

A truly bizarre result for Apolipoprotein A-1:

Apolipoprotein A-1:

"Apolipoprotein A-1 02 <3 Low mg/dL ref.101-178

Result confirmed on concentration."

My previous A-1 on 06/09/25 was 197 mg/dL. What??

A lot of other biomarkers going in the wrong direction.

For me ezetimibe 10mg/day has been an overall, FAIL.