That trial was specifically for familial types of hypercholesterolemia, which are strongly genetic. Not clear that it would also work for run-of-the-mill high cholesterol, although it is possible.
Fair point. I subscribe to the idea that LDL causes heart disease:
> Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel https://pubmed.ncbi.nlm.nih.gov/28444290/
The trial inhibited PCSK9, and this study says "other PCSK9 mutations result in unusually low concentrations of plasma LDL cholesterol and a reduced risk of atherosclerotic disease". https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5079795/ I'm optimistic about this.
As far as I know, ApoB is the only "necessary but not sufficient" molecule, and that's mostly in LDL. There's also IDL and VLDL, but AFAIK those are in insufficient quantities to have clinical significance - please LMK if you know otherwise. There's also Lp(a), but PCSK9 inhibitors also work there:
> For PCSK9 inhibitors a small reduction of Lp(a) levels could be shown, which was associated with a reduction in cardiovascular events, independently of the effect on LDL cholesterol. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8469722/
I hate to sound like I'm only focused on PCSK9i - there's also ezetimibe/bempedoic acid/statins, but AFAIK only PCSK9 has been shown to be a viable target of CRISPR. Perhaps that's your point, but I wonder what would happen if we flattened ApoB starting at age, say, 25. Perhaps the residual Lp(a) wouldn't be enough to cause any MACE.
...gum disease can be caused by 20 to 30 different types of bacteria... and it is increasingly thought that gum disease is probably an independent risk factor for heart disease.
I'm not condescending. Chagas disease is a class of trypanosomiasis which currently the medical establishment doesn't know how to treat. It's due to a parasite. Parasites living in your heart and feeding on the tissue is not a good thing independent of whether or not it is related to fatty deposits in the vessels.
I'm genuinely baffled that in a discussion of heart disease, actual infection is being handwaved off as irrelevant and only another possible means to cause fatty deposits.
I'm sure our backgrounds are really different. I'm a knowledgeable layperson and a lot of people are dismissive of me because of that.
It doesn't mean your "level" is somehow implicitly above mine anymore than one language is inherently "superior" to another. Language is a tool. Its purpose is communication. If one chooses language that fails to adequately communicate with the target audience, the failure is on the speaker.
Let me add that while I clearly am not as well versed in fatty deposits in the circulatory system as you are, I am leery of any plan to globally suppress any class of molecule.
The brain has the most cholesterol of any organ in the body. If we suppress fats globally to "prevent heart disease," what might this do to the brain?
Bone marrow is fatty. It's a critical part of the immune system where white blood cells are produced. If we suppress fat globally, what does this do to our immune system?
They invented antibiotics not that many decades ago and announced "the end of disease." Fast forward to today and we are wrestling with antibiotic resistant infections and drug shortages.
I'm leery of any claim that "this one neat trick will be the end of this entire class of disease." In this case, I readily know of actual diseases that specific one neat trick wouldn't help at all which are pertinent to the category known as heart disease.
I encourage you to reflect on your prior statements.
> I'm leery of any claim that "this one neat trick will be the end of this entire class of disease."
Sure, I overspoke. My usage of the word eliminate is strong - there are always edge cases in biology. And I should've been more specific with my language and specified ASCVD instead of the more broad "heart disease". That would, kinda by definition, scope what I'm talking about to fatty deposits. However, I think we're deep in pedantic territory and I hope you forgive me my excess. I didn't mean to enter "one neat trick' territory, though I can see how I came off that way.
> chagas
I'm also a layman and accept there are gaping holes in my knowledge, which is why I asked you a genuine question: "What do you suggest is the mechanism of action behind that?". My interpretation is that high levels of chronic inflammation leads to endothelial damage which leads to the formation of cholesterol plaques as the immune system attempts to fix the damage it caused. I'm going to assume here that "Infection chewing on the heart is a problem." means you think the parasite literally eats holes in blood vessels? I don't know what you think, which is why I asked. If you know the pathogenesis of heart disease with Chagas, I'd love to learn.
> I am leery of any plan to globally suppress any class of molecule.
A fair concern. I would note that healthy children have an LDL of 23.8 mg/dl https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5529694/ and they manage to supply their greedy brains. Note too that circulating (blood) cholesterol is not "global" cholesterol:
> The body has four distinct “pools” of cholesterol, in which tissues have regulatory mechanisms to maintain their respective homeostasis. In order of size, these pools of cholesterol consist of: peripheral tissues, red blood cells, liver, and lipoproteins. It turns out that the brain synthesizes its own cholesterol and does not exchange cholesterol with the other aforementioned pools, which means that cholesterol concentrations outside the brain have no direct impact on brain cholesterol. https://peterattiamd.com/does-low-cholesterol-cause-cognitiv...
