#111

Related:

The oxidation of LDL was considered the main atherogenic modification of LDL within the vascular wall for decades. However, recent investigations provided a growing body of evidence in support of the multiple LDL modification theory. It suggests that LDL particles undergo numerous modifications that change their size, density, and chemical properties within the blood flow and vascular wall. Oxidation is the last stage in this cascade resulting in the atherogenic properties. Moreover, recent investigations have discovered that oxLDL may have both anti-inflammatory and pro-inflammatory properties. Oxidized LDL can trigger inflammation through the activation of macrophages and other cells. After all, oxidized LDL is still a promising object for further investigations that have the potential to clarify the unknown parts of the atherogenic process. In this review, we discuss the role of oxLDL in atherosclerosis development on different levels.

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#112

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https://twitter.com/Drlipid/status/1623033709615058976

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#113

Apolipoprotein B-100 (APOB) is a component of fat- and cholesterol-transporting molecules in the bloodstream. It is the main lipoprotein in low-density lipoprotein cholesterol (LDL) and has been implicated in conditions that end healthspan (the interval between birth and onset of chronic disease). However, APOB’s direct relationship with healthspan remains uncertain. With Mendelian randomization, we show that higher levels of APOB and LDL shorten healthspan in humans. Multivariable Mendelian randomization of APOB and LDL on healthspan suggests that the predominant trait accounting for the relationship is APOB. In addition, we provide preliminary evidence that APOB increases risk for Alzheimer’s disease, a condition that ends healthspan. If these relationships are causal, they suggest that interventions to improve healthspan in aging populations could include strategies targeting APOB. Ultimately, given that more than 44 million people currently suffer from Alzheimer’s disease worldwide, such interventions are needed.

Mendelian randomization reveals apolipoprotein B shortens healthspan and possibly increases risk for Alzheimer’s disease, 2024

Ultimately, our findings support the possibility that APOB underlies the causal effects of APOB-containing lipoprotein traits in ending healthspan and increasing the risk for AD. A finer-grained analysis of molecular mechanisms, unfortunately, is beyond our scope but should be part of future research efforts. For now, our results make it considerably more difficult to imagine that maximal strategies for improving healthspan and maintaining optimal cognitive function can ignore APOB.

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#114

Moreover, patients totally deficient for the native LDL receptor are still able to store large amounts of cholesterol in their macrophages. Consequently, they suggested that the classic LDL receptor is not involved in the uptake of modified LDL

From @RapAdmin paper posted above.

So if i measure total LDL mass (via centrifuge) and then use a PCSK9 (or statin) to lower that number, am i removing OxLDL (which promotes ASCVD) as well as LDL (which may not be an issue) to an LDL of say 30, am i depriving myself of some benefit or protection? Or is the risk of ASCVD so great that it dwarfs other risks?

Also, if i take 12mg astraxanthin daily, plus GlyNAC (for glutathione production) daily, does this diminish my risk of LDL being OxLDL and thus my LDL could be higher without the same level of ASCVD risk?

From the quote above: don’t PCSK9 inhibitors reduce “classic” LDL receptors? So we may be managing to a lab value (as the CEO of a mid-sized biotech told me regarding TC) instead of reducing the actual risk?

Asking for a friend….

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#115
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#116

This has been discussed here:

It’s not good

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#117

Every time I see this thread title I just see a big fat

:skull: :skull_and_crossbones:

So I will just mute this thread

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#118

Just one quick aside on the video. Chris Masterjohn mentioned recently ( I forgot where) that his DunedinPACE was .6 something on test 1. I don’t know where you go from there.

#119

I’ve just found this, which is a bit more recent. Looks like they’re inching forwards in this area but i don’t think they’re there yet (in terms of finding oxldl as a better target than apob). It looks like ox-ldl antibodies, if present, modify the risk. So a target may need to include that metric too.

“In addition to oxLDL as a candidate biomarker for CVD, there is a growing body of literature showing the potential role of anti-oxLDL antibodies and other oxLDL-related moieties for CVD risk stratification and promising therapeutic targets”

“The results demonstrated that oxLDL is significantly increased in participants with CVD in the setting of chronic inflammatory conditions. This meta-analysis suggests that oxLDL may be a useful biomarker in risk stratifying cardiovascular disease in chronically inflamed patients.”

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#120

Low LDL-C levels are associated with risk of mortality in a Chinese cohort study

Jie-Ming Lu et al. Endocrine. 2021 Sep.

Abstract

Background and aims: Although low-density lipoprotein cholesterol (LDL-C) has been considered as a risk factor of atherosclerotic cardiovascular disease, limited studies can be available to evaluate the association of LDL-C with risk of mortality in the general population. This study aimed to examine the association of LDL-C level with risk of mortality using a propensity-score weighting method in a Chinese population, based on the health examination data.

Methods: We performed a retrospective cohort study with 65,517 participants aged 40 years or older in Ningbo city, Zhejiang. LDL-C levels were categorized as five groups according to the Chinese dyslipidemia guidelines in adults. To minimize potential biases resulting from a complex array of covariates, we implemented a generalized boosted model to generate propensity-score weights on covariates. Then, we used Cox proportional hazard regression models with all-cause and cause-specific mortality as the dependent variables to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs).

Results: During the 439,186.5 person years of follow-up, 2403 deaths occurred. Compared with the median LDL-C group (100-130 mg/dL), subjects with extremely low LDL-C levels (group 1) had a higher risk of deaths from all-cause (HR = 2.53, 95% CI:1.80-3.53), CVD (HR = 1.84, 95% CI: 1.28-2.61), ischemic stroke (HR = 2.29, 95% CI:1.32-3.94), hemorrhagic stroke (HR = 3.49, 95% CI: 1.57-7.85), and cancer (HR = 2.12, 95% CI: 1.04-4.31) while the corresponding HRs in LDL-C group 2 were relatively lower than that in group 1.

Conclusions: Low LDL-C levels were associated with an increased risk of all-cause, CVD, ischemic stroke, hemorrhagic stroke, and cancer mortality in the Chinese population.

PubMed Abstract

Full Text (Paywall)

#121

Low density lipoprotein cholesterol and all-cause mortality rate: findings from a study on Japanese community-dwelling persons

Ryuichi Kawamoto et al. Lipids Health Dis. 2021.

Abstract

Background: Low-density lipoprotein cholesterol (LDL-C) independently impacts aging-related health outcomes and plays a critical role in cardiovascular diseases (CVDs). However, there are limited predictive data on all-cause mortality, especially for the Japanese community population. In this study, it was examined whether LDL-C is related to survival prognosis based on 7 or 10 years of follow-up.

Methods: Participants included 1610 men (63 ± 14 years old) and 2074 women (65 ± 12 years old) who participated in the Nomura cohort study conducted in 2002 (first cohort) and 2014 (second cohort) and who continued throughout the follow-up periods (follow-up rates: 94.8 and 98.0%). Adjusted relative risk estimates were obtained for all-cause mortality using a basic resident register. The data were analyzed by a Cox regression with the time variable defined as the length between the age at the time of recruitment and that at the end of the study (the age of death or censoring), and risk factors including gender, age, body mass index (BMI), presence of diabetes, lipid levels, renal function, serum uric acid levels, blood pressure, and history of smoking, drinking, and CVD.

Results: Of the 3684 participants, 326 (8.8%) were confirmed to be deceased. Of these, 180 were men (11.2% of all men) and 146 were women (7.0% of all women). Lower LDL-C levels, gender (male), older age, BMI under 18.5 kg/m2, and the presence of diabetes were significant predictors for all-cause mortality. Compared with individuals with LDL-C levels of 144 mg/dL or higher, the multivariable-adjusted Hazard ratio (and 95% confidence interval) for all-cause mortality was 2.54 (1.58-4.07) for those with LDL-C levels below 70 mg/dL, 1.71 (1.15-2.54) for those with LDL-C levels between 70 mg/dL and 92 mg/dL, and 1.21 (0.87-1.68) for those with LDL-C levels between 93 mg/dL and 143 mg/dL. This associatioparticularly significant among participants who were male (P for interaction = 0.039) and had CKD (P for interaction = 0.015).

Conclusions: There is an inverse relationship between LDL-C levels and the risk of all-cause mortality, and this association is statistically significant.

From the full text:

"The main finding of this cohort study is that LDL-C is a significant and independent predictor of all-cause mortality in community-dwelling adults. After adjustment for possible confounding factors, the results showed that participants with the very low LDL-C levels (< 70 mg/dL) were at a significantly higher risk for all-cause mortality than those with high LDL-C levels (≥ 144 mg/dL).

Pubmed Abstract

Full Text - Open Access

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#122

Low Levels of Low-Density Lipoprotein Cholesterol and Mortality Outcomes in Non-Statin Users

Ki-Chul Sung et al. J Clin Med. 2019.

Abstract

We aimed to test the association between low-density lipoprotein cholesterol (LDL-C) and cardiovascular disease (CVD), cancer, and all-cause mortality in non-statin users. A total of 347,971 subjects in Kangbuk Samsung Health Study (KSHS.57.4% men, mean follow up: 5.64 ± 3.27 years) were tested. To validate these associations, we analyzed data from another cohort (Korean genome and epidemiology study, KoGES, 182,943 subjects). All subjects treated with any lipid-lowering therapy and who died during the first 3 years of follow up were excluded. Five groups were defined according to baseline LDL-C concentration (<70, 70-99, 100-129, 130-159, ≥160 mg/dL). A total of 2028 deaths occurred during follow-up in KSHS. The lowest LDL-C group (LDL < 70 mg/dL) had a higher risk of all-cause mortality (HR 1.95, 1.55-2.47), CVD mortality (HR 2.02, 1.11-3.64), and cancer mortality (HR 2.06, 1.46-2.90) compared to the reference group (LDL 120-139 mg/dL). In the validation cohort, 2338 deaths occurred during follow-up. The lowest LDL-C group (LDL < 70 mg/dL) had a higher risk of all-cause mortality (HR 1.81, 1.44-2.28) compared to the reference group. Low levels of LDL-C concentration are strongly and independently associated with increased risk of cancer, CVD, and all-cause mortality. These findings suggest that more attention is needed for subjects with no statin-induced decrease in LDL-C concentrations.

PubMed Abstract

Full Text - Open Access

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#123

Cells produce cholesterol starting with acetyl-CoA. Statins hold back the conversion of acetyl-CoA into cholesterol, but if there is an initial shortage of acetyl-CoA, the individual concerned will face considerable health problems. That is probably where this association comes from (viz a shortage of acetyl-CoA).

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#124

Relationship of serum cholesterol levels in man infected with parasites has drawn the attention of various workers. Since it has been shown in-vitro studies that parasites like Giardia and Entamoeba can grown in lipid rich media in the absence of serum, it would be interesting to determinate the mechanism of lipid/cholesterol utilization. Recent studies have shown elevated levels of lipoproteins like high density lipoprotein (HDL), low density lipoprotein (LDL) and total cholesterol in patients suffering from parasitic infection (4). In human body cholesterol is synthesized in liver, which incidentally happens to be a major extraintestinal site of infection with Entamoeba histolytica . Keeping this in view, the following queries arise (i) is there any correlation between cases of amoebic liver abscess (ALA) with cholesterol synthesis in liver? (ii) in case of intestinal amoebiasis, what is the source of cholesterol? (iii) how do the amoebae utilize cholesterol in these two different areas (iv) what is the role of cholesterol in enhancing virulence and pathogenecity of E. histolytica (v) does cholesterol help in cyst formation?

Role of cholesterol in parasitic infections - PMC (nih.gov)

From this study I draw the conclusion that people who defend high cholesterol are controlled by the brain parasite Toxoplasma gondii.

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#125

Association of lipoprotein levels with mortality in subjects aged 50 + without previous diabetes or cardiovascular disease: a population-based register study

Lise Bathum et al. Scand J Prim Health Care. 2013 Sep.

Abstract

Objective: This study aimed to investigate the association of lipoprotein and triglyceride levels with all-cause mortality in a population free from diabetes and cardiovascular disease (CVD) at baseline. The European Guidelines on cardiovascular disease prevention state that in general total cholesterol (TC) should be < 5 mmol/L (190 mg/dL) and low-density lipoprotein cholesterol (LDL-C) should be < 3 mmol/L (115 mg/dL).

Design: A population-based register study in the period 1999-2007 including 118,160 subjects aged 50+ without statin use at baseline. All-cause mortality was related to lipoprotein and triglyceride levels and adjusted for statin use after inclusion.

Results: All-cause mortality was lower in the groups with TC or LDL-C above the recommended levels. Compared with subjects with TC < 5 mmol/L, adjusted hazard ratios for the group aged 60-70 years ranged from 0.68 (95% confidence interval (CI) 0.61-0.77) for TC 5-5.99 mmol/L to 0.67 (95% CI 0.59-0.75) for TC 6-7.99 mmol/L and 1.02 (95% CI 0.68-1.53) for TC ≥ 8 mmol/L in males and from 0.57 (95% CI 0.48-0.67) to 0.59 (95% CI 0.50-0.68) and 1.02 (95%j CI: 0.77-1.37) in females. For triglycerides, ratios comparednn with the group < 1 mmol/L in the females agedb 60-70 years ranged from 1.04 (95% CI 0.88-1.23) to 1.35 (95% CI 1.10-1.66) and 1.25 (95% CI 1.05-1.48) for triglycerides 1-1.39 mmol/L, 1.4-1.69 mmol/L, and ≥ 1.7 mmol/L, respectively. Statin treatment after inclusion provided a survival benefit.

Conclusion: These associations indicate that high lipoprotein levels do not seem to be definitely harmful in the general population. However, high triglyceride levels in females are associated with decreased survival.

From the Full Text:

The most striking finding was that compared with the reference levels, high TC, HDL-C, or LDL-C levels were associated with lower mortality in the elderly and this was the case for even very high levels. The finding that high TC or LDL-C levels were associated with a lower mortality is contrary to the general assumption that there is a higher mortality among subjects with high lipoprotein levels. Our findings could seem controversial. However, most studies performed in older adults show an inverse association between TC and mortality and a recent study demonstrated an inverse association between TC and non-cardiovascular mortality in a population free of CVD and statin use at baseline. These findings were significant from the age of 65 years and were largely due to an inverse association with non-HDL-C. Our study demonstrates the same significant inverse association between high levels of TC and its subfractions and mortality in all age groups from as early as 50 years.

PubMed Abstract

Full Text - Open Access

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#126

This is the data (per the corresponding author):

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image1117×768 86 KB

https://biobank.ndph.ox.ac.uk/ukb/field.cgi?id=30640

But I’m not clear on what you’re objecting to. Is ‘suggest’ too speculative? Given the linearity of the trend, seems like a reasonable speculation.

#127

Low and High-Density Lipoprotein Cholesterol and 10-Year Mortality in Community-Dwelling Older Adults: The Shanghai Aging Study

Wanqing Wu et al. Front Med (Lausanne). 2022.

Abstract

Background: The relationship between serum cholesterol and mortality remains disputed. This study aimed to examine the association of low and high-density lipoprotein cholesterol (LDL-C and HDL-C) with all-cause mortality among community-dwelling older adults in the Shanghai Aging Study.

Methods: We followed 3,239 participants free of lipid-lowering agents for a median of 10 years. Levels of LDL-C and HDL-C were measured at baseline using fasting blood samples. Survival status was confirmed by the local mortality surveillance system. The associations between the levels of LDL-C, HDL-C, and all-cause mortality were assessed by Cox proportional hazards models.

Results: The increment of LDL-C concentration was related to a lower risk of mortality (p for trend < 0.05). Using the highest quintile of LDL-C (≥4.10 mmol/L) as a reference, the lowest quintile of LDL-C (<2.61 mmol/L) was associated with the highest risk of mortality, after adjusting for confounders (HR 1.67; 95% CI 1.26-2.21), exclusion of death within the first 2 years of follow-up (HR 1.57; 95% CI 1.17-2.11), and exclusion of functionally impaired participants (HR 1.46; 95% CI 1.07-2.00). A U-shape relationship was found between HDL-C level and the mortality risk. Using the third quintile of HDL-C (1.21-1.39 mmol/L) as a reference, HR (95% CI) was 1.46 (1.09-1.95) for the lowest quintile (<1.09 mmol/L) and 1.45 (1.07-1.96) for the highest quintile (≥1.61 mmol/L) of HDL-C, after adjusting for confounders; and 1.57 (1.15-2.15) for the lowest quintile and 1.45 (1.04-2.01) for the highest quintile of HDL-C, after exclusion of death within the first 2 years of follow-up; and 1.55 (1.11-2.16) for the lowest quintile and 1.42 (1.00–2.02) for the highest quintile of HDL-C, after exclusion of functionally impaired participants.

Conclusions: We found an inverse association of LDL-C and a U-shape relationship of HDL-C with long-term all-cause mortality in a cohort with community-dwelling older Chinese adults. Levels of LDL-C and HDL-C are suggested to be managed properly in late life.

From the full text:

”Our finding is consistent with previous studies where an inverse association of LDL-C with all-cause mortality was found among older adults. […]
High LDL-C might not be a risk indicator at old age and thus be used to identify older adults at risk and start cardiovascular disease management. Instead, those with low LDL-C in late life might warrant further attention. An adjustment of diet may help to increase their level of LDL-C and avoid extra risk of all-cause mortality."

PubMed Abstract

Full Text - Open Access

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#128

I didn’t object to anything.

Yes that’s a speculation and we should be aware that it is nothing more than this. The curve below 0.7 mg/dL could go back up (the dreaded U shaped curve), be flat or continue to go down.

(By the way, I recently joined the “lower the better” team for LDL/ApoB and CVD (I didn’t have an opinion before) but come on, we should avoid defending hypotheses as facts and promoting theses in a religious way. We’re all trying to find the truth and to make the best possible decisions for ourselves, given the available evidence. It’s a common quest. It shouldn’t be a fight.)

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#129

Of course…

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#130

Best post in this thread (for me).

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