I didn't say there can't be multiple causal factors, and in anything related to biology I would expect there to be multiple factors.

The cholesterol hypothesis never left that room on the table though. The argument made was that dietary cholesterol was the cause of heart disease and that we could measure current risk levels via blood tests, with later additions of related tests meant to measure cholesterol and plaque build up.

My point wasn't that cholesterol is entirely unrelated to heart disease. I was only showing appreciation that research questioning cholesterol's outsized focus in heart disease is finally gaining traction. I'm actually a but surprised that appreciation was controversial, science is always better off when we give space for alternative explanations.

The cholesterol hypothesis certainly leaves room on the table for multiple causal factors, and from very early on we knew that inflammation was key to plaque actually being deposited on arterial walls. The cholesterol hypothesis has always been that serum cholesterol are linked and that decreasing serum cholesterol significantly reduces heart disease. It is not that serum cholesterol is the sole source of heart disease.

We also know that very low levels of LDL, even in the presence of inflammation, will regress soft plaque build up, and from MVMR and 2x2 factorial MR studies that populations with genetically low LDL/Lp(a) levels see hugely reduced CVD risk regardless of other variables.

We've got more and more science around PCSK9 inhibitors that showing evidence that there are no health risks in dropping ApoB levels to near 0. We have additional treatments in phase 3 trials that are showing 80%+ reductions in Lp(a) as well, so soon even people with the unlucky Lp(a) genetics will be able to get their ApoB numbers down to extremely minimal numbers.

Without the ability to completely remove inflammation or stress to arterial walls, LDL can deposit, increase foam cell activation and cytokine signaling, and then cause more localized inflammation which then repeats the process.

Treating inflammation, both systemic and local, of course reduces the ability to for plaque to deposit. But if we have no or very few atherogenic particles in our bloodstream to begin with, there's nothing to deposit. It's not been practical to drop LDL to that level until PCSK9 inhibitors came into existence, but it is now.

Many experts are arguing that just like blood pressure (which was recently revised down again, to <120/<80 as normal, 120/80+ pre-hypertensive, etc. etc.) we have set the acceptable levels of LDL too high and that targets should be lower, and treatment starting earlier.

There's of course a variety of other health impacts from having significant levels of inflammation - so treating it makes a lot of sense too. Not saying we shouldn't. But when we can basically ignore inflammation at a low enough ApoB because plaque is actively regressing, it makes it hard to argue that the focus is outsized, at least when it comes to atherosclerosis.

(I've got 20+ reference links to RCTs, multiple MR types, large meta analysis, study reviews, etc. that I feel like I've reposted like 500 times in here so I apologize for not doing so yet again, but if you check my recent comments you can find supporting data for all of the claims I've made.)