I intend spending some time reading up on LDL and HDL at some stage. My understanding is that LDL provides C to tissues whilst HDL returns excess C to the liver. I would assume, therefore, that there is some messaging system (possibly a peptide) which passes around information as to the need for C. Hence I would like to look at the research to see what this might be and how it may be influenced.
I have experimented with monacolin K (aka lovastatin), but I think it causes me memory issues so I stopped.
My underlying view is that CVD is caused by a failure in endothelial cells which is exacerbated by LDL-C (and all the other factors being relevant ApoB Lp(a) etc). However, it is the failure (which I assume to be a failure of differentiation and a move to senescence) that underlies it.
My own personal LDL-C floats around for various reasons and tends to be either just under or just over the UK 3mmol/L threshold for intervention/concern. Hence I don’t see a need for urgent action if I can sort out the endothelial failure issue which as it stands I have no good way to measure. (which is an issue).
I do, however, think that if the body provides C to tissues from the liver there is a good reason for this.
Results: Among individuals with low levels of circulating CD34-positive cells, LDL-c levels were significantly inversely correlated with CAVI and positively correlated with circulating CD34-positive cells. No significant correlations were observed among the participants with high levels of circulating CD34-positive cells. Among low levels of CD34-positive cells, the adjusted standardized parameter (β) and p value were −0.24 (p = 0.021) for CAVI and 0.41 (p < 0.001) for CD34-positive cells, whereas among high levels of CD34-positive cells, the corresponding values were 0.03 (p = 0.738) and −0.09 (p = 0.355).
Conclusion: LDLc has a beneficial influence on endothelial health among individuals with low endothelial repair activity, possibly by stimulating the proliferation of hematopoietic stem cells.
The hard part is that LDL-C is providing C which is used to tissues. C is otherwise produced via the SLC25A1 - Acetyl-CoA pathway. Hence inefficient mitochondria will result in less intracellular C.
There needs to be a Netflix documentary like this to give it a larger audience. Right now, there are far too many normal people thinking high LDL is healthy, including friends of mine who are health conscious. There needs to be a strong message conveyed about the dangers of high LDL/ApoB with compelling data (which we know there is plenty). It seems the bad info has become so mainstream.
It’s sort of unclear to me how serum LDL levels impact brain LDL (and thus endothelial function and ICH). AIUI, LDL particles do not readily cross the BBB and the brain produces its own cholesterol.
That’s an interesting point. Hence a statin that can pass the BBB will affect brain cholesterol.
This strikes me as short and not too AI sloppy
Here is a list of common statins, categorized by their ability to cross the blood-brain barrier (BBB), primarily based on lipophilicity and experimental evidence (including animal and human studies):
Lipophilic Statins – Likely or known to cross the BBB
These statins are more lipophilic (fat-soluble), enabling them to penetrate the BBB more readily.
Statin
BBB Penetration
Notes
Simvastatin
Yes (high)
Crosses BBB; studied for CNS effects, including Alzheimer’s disease
Lovastatin
Yes (moderate-high)
Crosses BBB; evidence in animals and humans
Atorvastatin
Partial/Yes
Crosses to some extent; detected in brain tissue
Cerivastatin
Yes (withdrawn)
Withdrawn due to rhabdomyolysis risk; was lipophilic and crossed BBB
Hydrophilic Statins – Do not significantly cross the BBB
These are more water-soluble and have very limited brain penetration.
Statin
BBB Penetration
Notes
Pravastatin
No (very low)
Poor CNS penetration; minimal CNS side effects
Rosuvastatin
No (very low)
Highly hydrophilic; negligible BBB crossing
Fluvastatin
/Partial (low)
Low lipophilicity; minimal CNS exposure
Pitavastatin
/Unclear
Intermediate properties; evidence is limited
Mechanistic Note
Lipophilicity is the main factor influencing BBB crossing.
However, active transporters (e.g., P-glycoprotein) can limit CNS accumulation even for lipophilic statins.
Simvastatin (especially in lactone form) has the highest CNS penetration.
Clinical Relevance
Cognitive effects (e.g., memory issues, confusion) have occasionally been reported, especially with lipophilic statins, but large trials (e.g., PROSPER, STAREE) generally find no strong adverse CNS effect.
Neuroprotective studies are ongoing for simvastatin and atorvastatin in Alzheimer’s, MS, and other CNS disorders.
Let me know if you’d like references or want to compare statins by half-life, potency, or metabolism.
Thinking “why would this be”. I think the answer is that by reducing neural cholesterol production more acetyl-CoA is available to fix the splicing problems that cause Alzheimers and the others linked to splicing (I think myelin creation may be in with this, but myellin uses cholesterol so I would be surprised if MS is improved by a statin).
Statins and Bempedoic Acid: Different Actions of Cholesterol Inhibitors on Macrophage Activation
Caveat: Chinese study.
Efficacy and safety of bempedoic acid alone or combining with other lipid-lowering therapies in hypercholesterolemic patients: a meta-analysis of randomized controlled trials
Pharmacodynamic effect of bempedoic acid and statin combinations: predictions from a dose–response model
True, but mice also don’t get ASCVD or die from MI. Those other purported benefits are still related to ASCVD, like stabilising plaque, lowering arterial inflammation etc.
Except those with familiar hypercholesterolemia. I was at a conference learning about this recently. And guess what - those kids start to have heart attacks in their teens and early adulthood, unless treated with aggressive LDL-C lowering therapies. That is extremely compelling evidence of the LDL-C hypothesis IMO.
In addition, for the larger topic and the last 30 posts, I would say we need to remind ourselves that all these things are just playing probability games. Some people with high LDL-C go on and lead long lives with no CVD. Others with “normal” LDL-C die of early MI. But, you certainly decrease your chance of early death by lowering LDL-C/ApoB. (Similar story with Rapamycin, which reliably increases median lifespan but in every study, some of the mice on Rapamycin still died before other mice on placebo.)
So yes, maybe a super low LDL-C does increase risk of viral infection, or bleeding. However, in the larger context, CVD kills 1/4 of all humans, and for most people it’s a far larger risk than that of bleeding or viral infections.
But, as others have also said, the targets should be different depending on your history, other risk factors etc. If you have high Lp(a), evidence of plaque, or other risk factors, then you’d likely want ApoB as low as possible. If you’re older, have clean arteries (by CTCA), and low risk factors, then higher ApoB is probably fine. If you have stage 4 cancer, then you have bigger risks to deal with and the importance of ApoB is relatively less.
The inverse relationship between endogenous testosterone (natural levels) and heart disease is reported in the following study of elderly men. Given that lipid lowering drugs also reduce testosterone levels, I thought the study has merits for discussion under this topic heading. From the abstract: “Men in the highest quartile of testosterone (≥550 ng/dl) had a lower risk of CV events.”
We tested the hypothesis that serum total testosterone and sex hormone–binding globulin (SHBG) levels predict cardiovascular (CV) events in community-dwelling elderly men.
Background:
Low serum testosterone is associated with increased adiposity, an adverse metabolic risk profile, and atherosclerosis. However, few prospective studies have demonstrated a protective link between endogenous testosterone and CV events. Polymorphisms in the SHBG gene are associated with risk of type 2 diabetes, but few studies have addressed SHBG as a predictor of CV events.
Methods:
We used gas chromatography/mass spectrometry to analyze baseline levels of testosterone in the prospective population-based MrOS (Osteoporotic Fractures in Men) Sweden study (2,416 men, age 69 to 81 years). SHBG was measured by immunoradiometric assay. CV clinical outcomes were obtained from central Swedish registers.
Results:
During a median 5-year follow-up, 485 CV events occurred. Both total testosterone and SHBG levels were inversely associated with the risk of CV events (trend over quartiles: p = 0.009 and p = 0.012, respectively). Men in the highest quartile of testosterone (≥550 ng/dl) had a lower risk of CV events compared with men in the 3 lower quartiles (hazard ratio: 0.70, 95% confidence interval: 0.56 to 0.88). This association remained after adjustment for traditional CV risk factors and was not materially changed in analyses excluding men with known CV disease at baseline (hazard ratio: 0.71, 95% confidence interval: 0.53 to 0.95). In models that included both testosterone and SHBG, testosterone but not SHBG predicted CV risk.
Conclusions:
High serum testosterone predicted a reduced 5-year risk of CV events in elderly men.
Study: AI predicts patient odds of dying from sudden cardiac arrest
Researchers at Johns Hopkins found that the AI outperformed current clinical guidelines with 89% accuracy across all patients and a 93% accuracy rate for individuals ages 40 to 60.
The CaRi-Heart technology, developed by British Heart Foundation (BHF) spinout company Caristo Diagnostics, utilizes coronary computed tomography angiography (CCTA) scans already performed in clinical practice.
It uses AI and deep learning technology to produce a fat attenuation index score (FAI-Score), which accurately measures inflammation of blood vessels in and around the heart.
A BHF-funded study involving around 4,000 patients found those with an abnormal FAI were up to nine times more likely to die of a heart attack in the next nine years than those with normal FAI readings.
It also found that around one-third of patients initially considered low risk after a routine CCTA had a much higher risk after CaRi-Heart was applied to their scan.
Amazing. I hope this makes it stateside, as Cleerly is clearly inadequate especially that they don’t deign to release the full results of the test to the patient - highly condescending to people who purchase their test for a lot of $. In general there needs to be more competition and more development in the CT angio space. A lot more can be mined from the data in this test.
Lipophilic Statins – Likely or known to cross the BBB
Yes (high)
Hydrophilic Statins – Do not significantly cross the BBB
No (very low)
Mechanistic Note