心血管健康

[AnUser]

LDL-c causes heart disease via apoB, independent of any pleiotropic effect of a medication like statins.

The Low-Density Lipoprotein Cholesterol Hypothesis: An Update

[Joseph_Lavelle]

Yes, I understand it’s particle count and time (age). No doubt other variables are in play but high apoB times many years is enough to kill a person most of the time.

[Neo]

Could be as simple as massive lowering of Apo B dominates any (smaller) hs-CRP increase?

How big is the CRP increase with those? (My hs-CRP on now full dose repatha is still below the lowest threshold of the test so I don’t know if mine has changed).

[AnUser]

@Neo

Could be as simple as massive lowering of Apo B dominates any (smaller) hs-CRP increase?

I think that is the case. Statins increase Lp(a), as well, but still have a worthwhile effect (probably primarily) due to the decrease in apoB, and hs-CRP and other pleiotropic effects contribute some.

[L_H]

This is interesting. Psk9 inhibiting genes have lots of pleiotropic benefits

“Investigations in animals and humans suggest that the impact of PCSK9 inhibition is not limited to reduction in LDL-C but also affects other aspects of lipoprotein metabolism, inflammation, thrombosis, and immune function.”

https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.116.023687

[AnUser]

@John_Hemming

I don’t think there is any doubt that CVD is a disease of aging,

If that is the case then few young people should have atherosclerosis, same source as above:

“We know that atherosclerosis begins early in life. In fact, a study from the 1990s looked at 111 casualties of the Korean War who died from non-cardiac trauma. 78.3% of these relatively healthy individuals with a mean age of 26 years showed coronary atherosclerosis. Over one-fifth had greater than 50% narrowing and just as many had left main or significant two and three-vessel involvement suggesting that ASCVD begins much earlier in life than usually presumed [58].”

I don’t think atherosclerosis has much to do with aging, it is proven it has everything to do with time and exposure to sub-optimal levels of apoB.

How do you know whether something is an age or time based disease?

Suboptimal levels of apoB have large effects with time. That’s all you need to know, practically.

[scta123]

@AnUser

Suboptimal levels of apoB have large effects with time. That’s all you need to know, practically.

How do you explain that some people with familial hypercholesterolemia die or have advanced disease in their thirties and some with same level of lipids have no sign of ASCVD into the old age?

[Virilius]

Some people are genetically more resistant to plaque formation than others. That’s the same reason why some obese cake-munchers never go on to develop diabetes.

[scta123]

@Virilius

Some people are genetically more resistant to plaque formation than others.

This prompts me to ask how these genetic differences work. What does this mean mechanistically? Would you care to explain? Did you intend for this statement to have no real significance, or does it hold some meaning?

[AnUser]

First, can you post some statistics how many with familial hypercholestrolemia who are untreated, have no sign of ASCVD into old age?

[scta123]

There isn’t any statistical evidence only anecdotal cases of individuals with FH only becoming aware of their condition when their children are diagnosed with advanced ASCVD. Typically, people become aware of their ASCVD when they start experiencing symptoms or are diagnosed with the condition. It’s crucial to explore alternative explanations and approaches when traditional hypotheses reach limitations. Certainly, when the LDL-C hypothesis reaches a dead end, alternative explanations become elusive.

[AnUser]

@scta123

There isn’t any statistical evidence

So how do I know whether what you said is true? How do you know?

@scta123

How do you explain that some people with familial hypercholesterolemia die or have advanced disease in their thirties and some with same level of lipids have no sign of ASCVD into the old age?

[scta123]

@AnUser

So how do I know whether what you said is true? How do you know?

From anecdotal reports by people familiar with the field. One was suggested by you, John Kastelein.

[AnUser]

Do you have a link to the timestamp where he says what you say?

[scta123]

No. (Post must be at least 20 characters)

[scta123]

I see, thank you for clarifying.

[AnUser]

It was unclear to me whether he meant there were few people who were immune to ASCVD throughout their lives despite high apoB, or if they were just immune to premature ASCVD as that is what Attia asked. But Kastelein meant he has had cases in old age as you said.

It sounded like it was only women, who weren’t smoking, physically active and with high HDL, and they were only 5 percent of people with FH. It’s possible to have protective factors, whether it is genetic or environmental that modify the risk. That’s why it’s the necessary cause of ASCVD, but not sufficient.

On another topic I would be interested to find out what the three percent of people who avoid positive CAC scores above 70 yrs old, what their lipids are. I wouldn’t like if 20-30 mg/dl apoB, for instance, throughout most of my life would not protect CAC from going positive above 70 yrs old.

[Ericross2]

I’m not sure this is how we should approach this in general. Did someone do a search on this topic and came up with no solid papers? — then saying “i can’t” find any support for this, can you please send over some sources for this?” might be a better way to volley the discussion back. I get it: some people can come off in a message as abrasive (or i haven’t eaten breakfast) and i want to say “i am not your librarian” (which i have, once, here) but providing the sources as you would if you were on a Journal Of Organic Chemistry forum, arguing a topic with other professionals: you have professional respect for the other participants, so providing sources is a normal courtesy, and necessary to make tour point. Or maybe at 53 I’ve become Don Quixote. .

To go further: I feel like many of this “discussions” on this forum have recently become “arguments”, @RapAdmin; its starting to feel more like Reddit/etc where there is much more one-upmanship and “gotchas” and less civility and respect in what are extremely complex and thus-undecided conclusions within the scientific community . This is getting annoying to read. Maybe i never noticed (certainly my wife would argue thusly) but i feel there was more of a scientific discourse as we all probed to find the correct answers.

I’m probably in the minority, but I’d also love to see more emphasis on credentials. I’d love to know if the person whom i reading is a doctor (and thus has a great understanding of the human systems biology but perhaps less experience in scientific research methods), a practicing medical professional (for instance an aestertrician who has 30 years under her belt is definitely equipped to lecture us on skin health), a research scientist, someone who studied science in school but hasn’t actually performed research, and then the rest of us who read papers and connect the dots, but may or may not be connecting them correctly. This is not to say that a “novice” cannot be the most respected person in the forum: i am (occasionally) on another non-longevity (buy highly technical) forum in which one of the very most respected members is a retired steel worker with exactly zero expertise or credentials, but he has made this topic his passion upon retirement and is among the first when members want to check the voracity of a fact. I’d love a feature in the bios where we can see who are are listening to (reading) and what they (potentially) bring to the table. I’m officially pitching this to @RapAdmin .

[AnUser]

@scta123 did give a source later on, which was Kastelein.

[Neo]

@adssx

PCSK9i increase it though

How sure are we about that - I was just reflecting and cannot remember my cardiologist mentioning any negative impact on inflammation of Repatha and we had a long conversation about the pros and cons and that should have come on as a con.

So I looked at it more now and it seems trending to decrease or at least neural on hs-CRP - not increasing?

Impact of PCSK9 monoclonal antibodies on circulating hs-CRP levels: a systematic review and meta-analysis of randomised controlled trials

Ten studies involving 4198 participants were identified. PCSK9-mAbs showed a slight efficacy in reducing hs-CRP (−0.04 mg/L, 95% CI: −0.17 to 0.01) which was not statistically different. The results did not altered when subgroup analyses were performed including PCSK9-mAb types (alirocumab: 0.12 mg/L, 95% CI: −0.18 to 0.43; evolocumab: 0.00 mg/L, 95% CI: −0.07 to 0.07; LY3015014: −0.48 mg/L, 95% CI: −1.28 to 0.32; RG7652: 0.35 mg/L, 95% CI: −0.26 to 0.96), treatment duration (≤12w: 0.00 mg/L, 95% CI: −0.07 to 0.07; >12w: −0.11 mg/L, 95% CI: −0.45 to −0.23), participant characteristics (familial hypercholesterolaemia: 0.00 mg/L, 95% CI: −0.07 to 0.07; non-familial hypercholesterolaemia: 0.07 mg/L, 95% CI: −0.12 to 0.26; mix: −0.48 mg/L, 95% CI: −1.28 to 0.32) and treatment methods (monotherapy: 0.00 mg/L, −0.08 to 0.07; combination therapy: −0.08 mg/L, −0.37 to 0.21). Meta-regression analyses suggested no significant linear correlation between baseline age (p=0.673), sex (p=0.645) and low-density lipoprotein cholesterol reduction (p=0.339).

Impact of PCSK9 monoclonal antibodies on circulating hs-CRP levels: a...