CardioLipid

[CardioLipid @sciencenoteasy]

@YounisJoseph @ZentrixHQ Disagree

[CardioLipid @sciencenoteasy]

@Kansanparantaja @raphaels7 Never heard him say exactly that. Also just to note : getting shot in the head is not sufficient for death (as rarely some people survive)

[CardioLipid @sciencenoteasy]

@venkmurthy Can’t forget the social determinants of health from David Gordon

[CardioLipid @sciencenoteasy]

@gcfmd @DrDerekConnolly @kewatson @rblument1 @CBallantyneMD @AnnMarieNavar @HeartDocSadiya @DrMarthaGulati @dmljmd @JohnKastelein If there was truly a reason high HDL leads to more mortality one needs to have a good explanation as to why if a healthy person does X and HDL rises this leads to more dysfunction / harm. Low HDL seems to be an epiphenomenon

[CardioLipid @sciencenoteasy]

@gcfmd @DrDerekConnolly @kewatson @rblument1 @CBallantyneMD @AnnMarieNavar @HeartDocSadiya @DrMarthaGulati @dmljmd @JohnKastelein Unfortunately this doesn’t address the question of WHY increasing HDLC would lead to more biological harm. Confounding can explain why - alcohol raises HDLC and increase chance of CVD. Drug trials it seems some had off target effects (niacin) , some affected RCT of HDL-c.

[CardioLipid @sciencenoteasy]

@5_utr @JiaJennyLiu Agreed seldomly if ever is there a single gene to be targeted !

[CardioLipid @sciencenoteasy]

@gcfmd @DrDerekConnolly @kewatson @rblument1 @CBallantyneMD @AnnMarieNavar @HeartDocSadiya @DrMarthaGulati @dmljmd @JohnKastelein To quote @JohnKastelein “At the ends of a Gaussian distribution there are few individuals and this artificially inflates risk or absence of risk for an outcome and dementia and very high HDL are both immensely multifactorial ; to think you can avoid confounding is not realistic”

[CardioLipid @sciencenoteasy]

@gcfmd @DrDerekConnolly @kewatson @rblument1 @CBallantyneMD @AnnMarieNavar @HeartDocSadiya @DrMarthaGulati @dmljmd @JohnKastelein Agreed,but if we are to say that raising HDL or high HDL is associated with increased CVD / ACM then mechanism would need to make sense. Here it seems there is no reason why raising = more dysfunction which leads me to think potentially confounding explains the observational data

[CardioLipid @sciencenoteasy]

@robertlufkinmd respectfully the study was not powered for ACM, and stopping CVD events is enormous benefit given how life debilitating MIs can be. As people age chances of mortality increase from cancer , liver disease kidney disease etc , statins help reduce CVD disease … that a huge positive

[CardioLipid @sciencenoteasy]

@gcfmd @DrDerekConnolly @kewatson @rblument1 @CBallantyneMD @AnnMarieNavar @HeartDocSadiya @DrMarthaGulati @dmljmd @JohnKastelein Thanks for response ,I wonder why when HDL raised why does it become dysfunctional. And is this a proven phenomenon , why can’t someone with normal HDL have lots of dysfunction. My understanding is we have no way of knowing. But still would wonder why raising it = dysfunction

[CardioLipid @sciencenoteasy]

@gcfmd @DrDerekConnolly @kewatson @rblument1 @CBallantyneMD @AnnMarieNavar @HeartDocSadiya @DrMarthaGulati @dmljmd @JohnKastelein Interesting, this seems like dysfunctional HDL. The questions I have now are (1) are any tests / assays being developed to detect this dysfunction (2) why does this happen specifically when HDL RAISED (why can’t a person with “normal” HDL level have lots of pro-inflammatory HDL

[CardioLipid @sciencenoteasy]

@gcfmd @DrDerekConnolly @kewatson @rblument1 @CBallantyneMD @AnnMarieNavar @HeartDocSadiya @DrMarthaGulati @dmljmd @JohnKastelein Agreed, I would also ask what any proposed mechanisms are for why high HDL would contribute to ACM… this perplexes me … all I will say is I NEVER call HDL good cholesterol (for many reasons!!)

[CardioLipid @sciencenoteasy]

@gcfmd @DrDerekConnolly @kewatson @rblument1 @CBallantyneMD @AnnMarieNavar @HeartDocSadiya @DrMarthaGulati @dmljmd @JohnKastelein Very interesting , I was under impression that dysfunctionaliry was due to proteome + inflammatory function of HDL. Hence even raising cholesterol efflux capacity may not change this hence no extra benefit perhaps? Also what level of HDL wouldn’t suggest one not to exceed !!

[CardioLipid @sciencenoteasy]

@gcfmd @DrDerekConnolly @kewatson @rblument1 @CBallantyneMD @AnnMarieNavar @HeartDocSadiya @DrMarthaGulati @dmljmd @JohnKastelein They also consider reverse causation as a limitation that could explain it !!

[CardioLipid @sciencenoteasy]

@gcfmd @DrDerekConnolly @kewatson @rblument1 @CBallantyneMD @AnnMarieNavar @HeartDocSadiya @DrMarthaGulati @dmljmd @JohnKastelein Also isn’t the RCTs showing they don’t raise mortality just confirmation that HDLs may be dysfunctional hence higher value confers no evidence as to whether their cardioprotective effects are pertinent

[CardioLipid @sciencenoteasy]

@gcfmd @DrDerekConnolly @kewatson @rblument1 @CBallantyneMD @AnnMarieNavar @HeartDocSadiya @DrMarthaGulati @dmljmd @JohnKastelein Have heard John say that SCARB1 etc are very rare and he believes most of the right part of the U explained by residual confounding. Do any RCTs show the J shape that aren’t explained by off target effects of drugs or alcohol.

[CardioLipid @sciencenoteasy]

@gcfmd @DrDerekConnolly @kewatson @rblument1 @CBallantyneMD @AnnMarieNavar @HeartDocSadiya @DrMarthaGulati @dmljmd @JohnKastelein Appreciate this response and fully agree. Have heard @JohnKastelein talk about how the right hand part of the U curve he believes is caused by residual confounding. Would be interested to know if there is consensus on this.

[CardioLipid @sciencenoteasy]

@gcfmd @DrDerekConnolly @kewatson @rblument1 @CBallantyneMD @AnnMarieNavar @HeartDocSadiya @DrMarthaGulati @dmljmd @JohnKastelein Thank you for response, only question is why can’t we account for all the confounding with LDLc and mortality unlike with HDLc and ASCVD , you said adjustment should flatten HDLc curve but it doesn’t. Why doesn’t adjusting flatten the LDLc curve and ACM.

[CardioLipid @sciencenoteasy]

@gcfmd @DrDerekConnolly @kewatson @rblument1 @CBallantyneMD @AnnMarieNavar @HeartDocSadiya @DrMarthaGulati @dmljmd @JohnKastelein @JohnKastelein very interested for your thoughts here. May I ask we also we see U shaped curve with LDL-c , do you think that’s a true relationship ? Most agree there is confounding , survivorship bias and reverse causation. Why is HDL different in this regard ?

[CardioLipid @sciencenoteasy]

@gcfmd @DrDerekConnolly @kewatson @rblument1 @CBallantyneMD @AnnMarieNavar @HeartDocSadiya @DrMarthaGulati @dmljmd @JohnKastelein is this true? I thought this is mostly confounding due to alcohol?