Thanks for your thoughtful comments. I have to admit, though, that I’m not quite sure whether I get the point you want to make. So, allow me to respond to some of the issues you raised that deserve further discussion.
First off, my article addressed the issue of statin prescription for the purpose of reducing CVD risk. I argued that the statistical support for the current practice of population-wide prescription is questionable at best.
As such, individual pathways, like the one via RBCs, are subsumed in that overall picture. Readers and I are interested in the evidence for cholesterol-lowering via statins favorably affecting CVD outcomes. As an aside, our knowledge about the role of RBCs in cholesterol transport is still in its infancy, and as your reference confirms, of in-vitro nature, not in-vivo (yet). BTW, it would be very helpful if in future you could include the full references (or at least their doi, not just the names of the first author and year which makes searching for them a rather time-consuming exercise).
But you are correct, the RBC’s role within the cholesterol transport chain is indeed an interesting area of research since RBCs are the only cells that do not manufacture their own cholesterol.
What we observe in RBCs may have an implication on how we need to improve cholesterol measurements because there is a differentiation to be made between accessible and non-accessible cholesterol in RCBs (only accessible cholesterol will have an impact on cholesterol transport and downstream CV outcomes).
First, cholesterol accessibility in RBCs varies significantly among individuals, with a stable phenotype observed within individuals but a more than ten-fold range between different individuals. This variability is associated with demographic factors, particularly ethnic differences, suggesting that genetic and lifestyle factors may influence cholesterol metabolism and transport
Second, the level of accessible cholesterol does not correlate with the total cholesterol content of the RBC membranes. This suggests that accessible cholesterol acts as a distinct pool that is functionally different from the total cholesterol mass. This may have implications for downstream cellular function and disease processes. The observation that in patients on hemodialysis a higher percentage of accessible cholesterol in their RBC membranes correlates with CVD events. But we need to disentangle this relationship from a number of potential confounders in these patients.
All this indicates that improvement of cholesterol measurements may improve risk prediction in the future, which will mean that the prescription of cholesterol-lowering drugs can be tailored to a finer-grained cholesterol profiling. If that is capable to distinguish the high-cholesterol person having an elevated risk from the high-cholesterol person who does not share that risk level, it will inevitably mean less prescriptions than the current scattershot approach. A point I wanted to make with my article.
Just one more comment on your recommendation of supplementing with Arginine. I’m against it. I prefer the alternative of supplementing with citrulline. Here is why:
eNOS uses L-arginine as a substrate to produce nitric oxide (NO).
When L-arginine is converted to NO, citrulline is generated as a byproduct.
Citrulline can then be recycled back into L-arginine. Increasing the citrulline pool will increase arginine too.
The oral bioavailability of arginine is much lower than that of citrulline, and the evidence for beneficial effects of arginine supplementation is controversial. The improvements of endothelial function in diseased patients (PAD) that are seen with-term supplementation aren’t sustainable with long-term supplementation. So, it is a highly individualized response that needs to be monitored, ideally in a N-of-1 setting that I have explained in several of my posts.
I encourage you, though, to write an article about the intricacies of pathways that you mention.
