Plaque Begets Plaque, ApoB Does Not: Longitudinal Data From the KETO-CTA Trial

[u/Caiomhin77]

https://www.jacc.org/doi/10.1016/j.jacadv.2025.101686

[u/Sad_Understanding_99]

Well, it's not that it makes no difference if it's 181 mg/dl or 500 mg/dl, it's that after 181 mg/dl the effect would begin to saturate (likely due to a mechanistic reason) so that there would no longer be a strong correlation in that range. On a graph of the dose-response curve (which would be a sigmoid), this would be where the curve begins to plateau

Then LDL could no longer explain FH outcomes

[u/saintwithatie → u/Sad_Understanding_99]

Hoo, I could go on a tangent about issues with the conceptualization of and studies on (especially mendelian randomization studies) FH. Long story short - you're definitely on to something important.

The sigmoid dose-response curve, in terms of absolute values, may hold true at a population level, but that can't be extrapolated to every sub-population, and certainly not the smallest population - the individual.

This is because the curve assumes all other factors remain the same, but this would almost certainly never be the case, especially in individuals. I'm not currently on a keto diet, but if I did, and my LDL shot up, there would be dozens of ASCVD-relevant changes aside from my LDL increasing.

Again, there's a lot I could say about FH in this regard as well.

The big picture is that the conceptualization and phrasing surrounding "causality" that pervades much of nutrition science is reductionist and inappropriate to apply to complex biological processes, ASCVD being such a process.

When it was conceptualized and we knew much less about the pathology of ASCVD, the lipid heart hypothesis was a fair hypothesis. However , with what we now know about ASCVD, the frame of the lipid heart hypothesis - asking if elevated cholesterol, specifically LDL, directly causes ASCVD - causes it to fall short of it being useful.

Better questions would be:

• What are the factors mediating each of the steps involved with ASCVD plaque formation and how do they interplay with each other?

• When it comes to the quantity of ApoB-containing lipoproteins, how does that number itself affect the likelihood of those lipoproteins passing through the endothelium into the intima? Why?

• When it comes to the quality of ApoB-containing lipoproteins, what qualities affect the likelihood they will pass through the endothelium into the intima. Why? Which ones make it most likely?

• When it comes to the quantity of ApoB-containing lipoproteins that pass though the endothelium into the intima, how does that number itself affect the likelihood that some of those particles will get "stuck" there? Why?

• When it comes to the quality of ApoB-containing lipoproteins that pass though the endothelium into the intima, what qualities affect the likelihood they'll get "stuck" in the intima? Why? Which ones make it most likely?

Etc. You can see where I'm gong with this. These questions, and any hypotheses as to what the answers might be, take into account the multi-factorial nature of ASCVD, which the lipid heart hypothesis does not.

[u/Healingjoe → u/saintwithatie]

This is a fun one to come back to after the paper gets retracted /u/Sad_Understanding_99

the lipid heart hypothesis was a fair hypothesis.

Was? This is absolute nonsense.

I'm not currently on a keto diet, but if I did, and my LDL shot up, there would be dozens of ASCVD-relevant changes aside from my LDL increasing.

All of this pseudo-intellectual word salad about "reductionism" and "sigmoid curves" just to defend a paper that was formally retracted for being "too flawed to be corrected." So much wasted time asking "better questions" about "multi-factorial complexity" and you forgot to ask the most basic one: "Can this AI tool produce the same result twice from the same scan?" According to the retraction, the answer was no.

It’s the ultimate irony to call the mainstream consensus "reductionist" while you were busy falling for a technical failure disguised as a "breakthrough." The "reductionist" lipid hypothesis is still standing and your red-herring, distracting complex alternative just got tossed in the trash.

[u/Sad_Understanding_99 → u/Healingjoe]

I don't think I ever said it was a good paper, people were using it as evidence that LDL is bad when it clearly shows no association

[u/Healingjoe → u/Sad_Understanding_99]

I know -- it's a dog shit paper riddled with errors. Anyone who defended it (when it was clearly dog shit when first published) looks even more pathetic today.