Hacker News Reader

Comment by FollowingTheDao | Hacker News Reader

For the last time. I am not saying that lowering cholesterol does not lower the risk of CVD. I am saying that it is oxidized cholesterol that causes CVD, and by lowering cholesterol you are also lowering oxidized cholesterol. Cholersterol good. oxidized cholesterol bad.

pubmed.ncbi.nlm.nih.gov/18625445/

Oxidative modification of low-density lipoprotein (LDL) is one of the earliest events in atherosclerosis.

https://www.frontiersin.org/journals/cardiovascular-medicine...

The point of the original article is we should be focusing more on lowering oxidative stress (inflammation) instead of focusing on lowering cholesterol since 75% of people who have heart attacks have normal cholesterol.

Also, CVD mortality is lowered, but other causes of death increase.

View on HN

Where we agree is that oxidation of LDL is part of the atherogenesis pathway.

However, I’m not aware of any evidence showing that higher oxLDL vs higher LDL entails greater risk. IIRC there is a paper that compared oxLDL to ApoB where ApoB was more strongly associated with risk, which doesn’t seem like it would be expected on your hypothesis.

The response to retention hypothesis and the mechanistic evidence supporting it point to oxidation being inevitable once ApoB tagged lipoproteins are trapped in the arterial wall. That being the case, it would be moot whether it entered the wall in an oxidised state or not.

So yes, oxLDL is one of the early stages of atherogenesis, but I’m not aware of any evidence that having LDL pre-oxidised before it’s trapped vs regular LDL increases risk.

I’m always open to new evidence that would change my view, but that’s my understanding of the research landscape at the moment.

MR studies rule out the idea that inflammation is the sole causal factor, and we have a lot of them.

We have MVMR studies that look at multiple variables

https://journals.plos.org/plosmedicine/article%3Fid%3D10.137...

https://www.thelancet.com/journals/lanhl/article/PIIS2666-75...

Some MR looking specifically at CRP actually dispute the idea of a causal link altogether

https://www.bmj.com/content/342/bmj.d548

https://www.ahajournals.org/doi/10.1161/01.atv.0000258869.48...

Factorial MR show strong evidence that the risk is additive, in the case of these that look at atherogenic particles and IL-6 signaling

https://www.ahajournals.org/doi/10.1161/JAHA.121.023277

MR looking at specific genes that reduce LDL-C through a variety of mechanisms, including some that lower inflammation, show basically identical reduction of risk per LDL-C lowered.

https://pubmed.ncbi.nlm.nih.gov/25770315/

https://www.nejm.org/doi/full/10.1056/NEJMoa1604304

Reply on news.ycombinator.com