Why in the world can't there be multiple causative factors?
We have a mountain of evidence that LDL-C/Lp(a) are causal regardless of hsCRP levels, both from medications that don't lower hsCRP, LDL-C/Lp(a) are direct causal factors for local inflammation themselves, and MR genetic studies show them as independent risk factors as well.
https://pmc.ncbi.nlm.nih.gov/articles/PMC4876179/
https://pubmed.ncbi.nlm.nih.gov/36779348/
https://www.nejm.org/doi/full/10.1056/NEJMoa1109034
https://pmc.ncbi.nlm.nih.gov/articles/PMC5483508/
https://europepmc.org/article/med/20032323
https://journals.plos.org/plosmedicine/article%3Fid%3D10.137...
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.
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.)
Presumably one of “time spent working in asbestos factories” and “cigarette pack years” is more predictive of lung cancer incidence than the other. Does this being the case mean that either smoking or inhaling asbestos particles isn’t causally implicated in lung cancer? If the answer is “no”, then presumably you can see why the inference you’re making is faulty.
I don't think anyone would argue that inflammation is a cause of heart disease. Inflammation is always a body's response to some underlying condition. The cholesterol hypothesis argues that dietary cholesterol is the important factor causing heart disease.
My argument specifically is not that inflammation causes heart disease and dietary cholesterol does not. That seems to be what you were arguing against.
> If the data here is correct and inflammation is a better indicator of heart disease than cholesterol levels, it should raise questions whether cholesterol levels are correlative rather than causal.
But, as with the asbestos and smoking example, I don’t think an argument with this structure is valid. What I’m arguing against is your claim that the existence of one exposure/outcome relationship with a stronger association entails casting doubt on other exposures’ relationship with the same outcome.
Does that make sense, and do you have a good argument as to why we should believe that it casts doubt?
We know from studies that if you get your LDL low enough, such as <50 (and don't have high Lp(a)), you not only see plaque stop being deposited, you even see regression of existing soft plaque, regardless of other factors like inflammation. MR studies show people that don't produce LDL/Lp(a) in significant quantities basically just don't die of atherosclerosis related heart-disease.
We have medications that can lower systemic inflammation, but local inflammation can still allow for plaque deposition in the presence of high LDL/Lp(a) and can be caused by a wide variety of things, and then plaque deposition itself causes more local inflammation via foam cells and cytokines.
We have medications today that let us drive LDL down to extremely low levels - combo statin/pcsk9 inhibitors, statin/ezetimibe/bempedoic acid, etc. - and the current evidence points towards doing this as being extremely efficacious for prevent atherosclerosis without significant side effects. Lp(a) isn't as great of a story yet - the pcsk9 inhibitors do make a ~30% dent in it, but we have other meds in phase 3 trials right now that are more like 80-90%. We're going to be able to remove the vast majority of atherogenic particles from the bloodstream well before we have any way to prevent all of the potential ways your endothelial walls can be inflamed (if that will ever even be possible.)