1/ Time for another monster thread aimed at adding a bit of nuance to Twitter. This one is about Lean Mass Hyper-Responders, HDL, and it's topic might surprise you: Is ⬆️HDL-C in #LMHR bad? Read on to have thoughts provoked...
https://twitter.com/nicknorwitz/status/1474371478644826114
2/ Something I have intentionally yet to point out (but plan to include in upcoming writings) regards the potential adverse effects of high HDL-C in #LMHR? What?! High HDL is bad? Well, based on the epidemiology, yes. Multiple studies...
3/ including Copenhagen City Heart and CANHEART, report a U-shaped mortality curve whereby very low or very high HDL levels are associated with increased mortality. The most striking example is the blue line, which is all-cause mortality in CANHEART. 
4/ Look at how ~60 mg/dL HDL-C is “ideal” and levels higher than that are, well, more death. In fact, levels of ~115 are about as “good” as ~40, based on these correlations. (and some of you might know from prior disclosure what my levels run, but let's stay on topic...)
5/ The reason I point this out is because many #LMHR have HDL this high. Mean HDL among the 100 LMHR in the #LMHRpaper was 99mg/dL.
academic.oup.com/cdn/advance-ar…
So, 1 could make the case, that not only high LDL but also high HDL in #LMHR is likely to be associated with more death
academic.oup.com/cdn/advance-ar…
So, 1 could make the case, that not only high LDL but also high HDL in #LMHR is likely to be associated with more death
6/ But, this brings me to the question, that I repeatedly try to pose
“Is high genetic X the same as high X due to a metabolic response?” W.r.t LDL the clear distinction would be between those with FH and LMHR w/ similar LDL-C.
I certainly don’t know that the latter case is
“Is high genetic X the same as high X due to a metabolic response?” W.r.t LDL the clear distinction would be between those with FH and LMHR w/ similar LDL-C.
I certainly don’t know that the latter case is
7/ I certainly don’t know that the latter case is associated with lower risk, but I think it’s a possibility to be explored.
Similarly, the high HDL observed in present population-level data is likely due to genetics, rather than a metabolic response, and I hypothesize openly
Similarly, the high HDL observed in present population-level data is likely due to genetics, rather than a metabolic response, and I hypothesize openly
8/ I hypothesize openly that the distinct causes of high HDL could result in differences in functionality and, therefore, risk
Indeed, when HDL functionality is assessed in those with extremely high HDL who are not low-carb and likely do not exhibit the LMHR triad, an inverse-U
Indeed, when HDL functionality is assessed in those with extremely high HDL who are not low-carb and likely do not exhibit the LMHR triad, an inverse-U
9/ inverse U is seen in cholesterol transfer capacity from TG-rich lipoproteins to HDL. Again, the sweet-spot looks to be about 50-60 mg/dL in parallel to the Copenhagen City Heart and CANHEART data.
pubmed.ncbi.nlm.nih.gov/31840535/
pubmed.ncbi.nlm.nih.gov/31840535/
10/ But is high HDL in LMHR associated with dysfunctional LMHR, or does the high HDLin LMHR as part of a dietary response and the lipid triad reflect an increase in flux and function? I don’t know, but I’m curious to find out. So, boiling this all down to a caution and hypothesis
11/ Caution-high HDL-C in LMHR might be dangerous (surprise). Hypothesis: or perhaps, high HDL-C profile reflects the body meeting a metabolic need and increased function, contrasting strongly with the epidemiological data that’s primarily influenced by genetics.
12/ Compiled...
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