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Is High LDL-c Harmless in Otherwise Healthy People?


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[Moderator's Note: I moved the first two posts in this thread from here, where they was off-topic. --Dean]

On 3/7/2021 at 5:26 AM, Dean Pomerleau said:

But I wonder just how generalizable and healthy your diet and lifestyle practices are long-term for people without your life threatening genetic condition.

 

I wonder the same thing about CR.  It often works wonders especially in the short term.  Some struggle to sustain success long term.  And there are cases of it spiraling into disaster typically attributed to bad luck, bad genes or bad execution.

I find it fairly compelling that a large and growing number of people (and mice too!) have found benefits with similar approaches to mine for numerous diseases such as MS, MD, ALS, SMA, CMT, Parkinson's, Alzheimer's and Huntington's as well as many forms of cancer.  And Virta Health and others have rapidly growing successful businesses treating common problems such as obesity, diabetes and heart disease using various forms of ketogenic diets as foundational aspects of their therapies.

It appears the most common pitfall of ketogenic diets, especially high saturated fat or animal based, is an extreme rise in LDL perhaps affecting 20 to 30% of those who stick with it long term.  I fall into this group as my LDL has already more than doubled and is rising, perhaps into the range of 500 to 800 if I sustain my current practices and trajectory.  But despite much looking I have yet to see compelling evidence high LDL is harmful in the context of good metabolic health (low BP, low bodyfat, high HDL, low triglycerides, low insulin, stable blood sugar w/ low HbA1C, normal thyroid, low inflammation, etc.).

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3 hours ago, Todd Allen said:

I wonder the same thing about CR.  It often works wonders especially in the short term.  Some struggle to sustain success long term.  And there are cases of it spiraling into disaster typically attributed to bad luck, bad genes or bad execution

Perfectly true. Hardcore CR should be attempted only with great care and is not recommended for people with risk factors for an eating disorder.

3 hours ago, Todd Allen said:

It appears the most common pitfall of ketogenic diets, especially high saturated fat or animal based, is an extreme rise in LDL perhaps affecting 20 to 30% of those who stick with it long term.  I fall into this group as my LDL has already more than doubled and is rising, perhaps into the range of 500 to 800 if I sustain my current practices and trajectory.  

Wow. Good luck with that.

3 hours ago, Todd Allen said:

But despite much looking I have yet to see compelling evidence high LDL is harmful in the context of good metabolic health (low BP, low bodyfat, high HDL, low triglycerides, low insulin, stable blood sugar w/ low HbA1C, normal thyroid, low inflammation, etc.).

The average person in this study's [1] cohort may not have had quite as favorable markers of metabolic health (besides LDL) as you do, but they were categorized as "low risk" for CVD based on such markers (their median estimated 10-year risk of developing (let alone dying from) CVD was only 1.3%) and they didn't have nearly as high LDL as you do (median LDL-C of 205 in the highest quintile).

Nevertheless those otherwise-low-CVD-risk people who were in the highest LDL quintiles died from CVD at a 50-80% higher rate during ~30 years of followup than folks with study participants with LDL less than 100. Here is the graph of CVD mortality stratified by LDL quintile:

Screenshot_20210308-153753_Chrome.jpg

You can certainly try to argue such a study doesn't apply to you, either because of your underlying disease (KD) and/or because you are metabolically healthier than those in the upper LDL quintiles in [1].

But I would consider that a stretch and would personally be very reluctant to take the chance that very high LDL is harmless in otherwise healthy people, especially given the additional evidence from:

  1. People with familial hypercholesterolemia (who are the only population I know of whose LDL approaches yours) who have a 22x higher risk of developing heart disease than people with LDL < 130 [2].
  2. Mendelian randomization studies (e.g. [3]) which have found that in otherwise well-matched populations, the lifetime risk of CVD in people with genetic mutations that modestly elevate their LDL is 50% higher per 38mg/dl increase in LDL.   

--Dean

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[1] Circulation. 2018 Nov 20;138(21):2315-2325. doi: 

10.1161/CIRCULATIONAHA.118.034273.

Long-Term Association of Low-Density Lipoprotein Cholesterol With Cardiovascular 
Mortality in Individuals at Low 10-Year Risk of Atherosclerotic Cardiovascular 
Disease.

Abdullah SM(1)(2), Defina LF(3), Leonard D(3), Barlow CE(3), Radford NB(4), 
Willis BL(3), Rohatgi A(1), McGuire DK(1), de Lemos JA(1), Grundy SM(1)(2), 
Berry JD(1), Khera A(1).

Author information:
(1)Department of Internal Medicine, University of Texas Southwestern Medical 
Center, Dallas (S.M.A., A.R., D.K.M., J.A.D., S.M.G., J.D.B., A.K.).
(2)Veteran's Affairs North Texas Medical Center, Dallas (S.M.A., S.M.G.).
(3)The Cooper Institute, Dallas, TX (L.F.D., D.L., C.E.B., B.L.W.).
(4)The Cooper Clinic, Dallas, TX (N.B.R.).

BACKGROUND: The associations of low-density lipoprotein cholesterol (LDL-C) with 

cardiovascular disease (CVD) and coronary heart disease mortality in an 
exclusively low estimated 10-year risk group are not well delineated. We sought 
to determine the long-term associations of various LDL-C and non-high-density 
lipoprotein cholesterol (HDL-C) thresholds and CVD and coronary heart disease 
mortality in a large, low 10-year risk cohort.
METHODS: The study sample included participants of the CCLS (Cooper Center 
Longitudinal Study) without a history of CVD or diabetes mellitus and defined as 
low risk (<7.5%) for 10-year atherosclerotic CVD events
at baseline based on 
Pooled Cohort Risk Assessment Equations. The associations of fasting LDL-C and 
non-HDL-C with CVD mortality were tested with Cox proportional hazards models.
RESULTS: In 36 375 participants (72% men, median age 42) followed for a median 
of 26.8 years
, 1086 CVD and 598 coronary heart disease deaths occurred. Compared 
with LDL-C <100 mg/dL, LDL-C categories 100 to 129 mg/dL, 130 to 159 mg/dL, 160 
to 189.9 mg/dL, and ≥190 mg/dL were associated with a significantly higher risk 
of CVD death, with hazard ratios of 1.4 (95% CI, 1.1-1.7), 1.3 (95% CI, 
1.1-1.6), 1.9 (95% CI, 1.5-2.4), and 1.7 (95% CI, 1.3-2.3),
and mean reductions 
in years free of CVD death of 1.8, 1.1, 4.3, and 3.9, respectively. After 
adjustment for atherosclerotic CVD risk factors, LDL-C categories 160 to 189 
mg/dL and ≥190 mg/dL remained independently associated with CVD mortality, with 
hazard ratios of 1.7 (95% CI, 1.4-2.2) and 1.5 (95% CI, 1.2-2.1), respectively. 
In multivariable-adjusted models using non-HDL-C <130 mg/dL as the reference, 
non-HDL-C 160 to 189 mg/dL, 190 to 219 mg/dL, and ≥220 mg/dL were significantly 
associated with CVD death, with hazard ratios of 1.3 (95% CI, 1.1-1.6), 1.8 (95% 
CI, 1.4-2.2), and 1.5 (95% CI, 1.2-2.0), respectively. Restricting the cohort to 
those with 10-year risk <5% did not diminish the associations of LDL-C and 
non-HDL-C with CVD mortality.

CONCLUSIONS: In a low 10-year risk cohort with long-term follow-up, LDL-C and 
non-HDL-C ≥160 mg/dL were independently associated with a 50% to 80% increased 
relative risk of CVD mortality. These findings may have implications for future 
cholesterol treatment paradigms
.

DOI: 10.1161/CIRCULATIONAHA.118.034273
PMID: 30571575 [Indexed for MEDLINE]

-----------------

[2] J Am Coll Cardiol. 2016 Jun 7;67(22):2578-89. doi: 10.1016/j.jacc.2016.03.520. 

Epub 2016 Apr 3.

Diagnostic Yield and Clinical Utility of Sequencing Familial 
Hypercholesterolemia Genes in Patients With Severe Hypercholesterolemia.

Khera AV(1), Won HH(2), Peloso GM(3), Lawson KS(4), Bartz TM(5), Deng X(6), van 
Leeuwen EM(7), Natarajan P(1), Emdin CA(8), Bick AG(8), Morrison AC(4), Brody 
JA(9), Gupta N(8), Nomura A(10), Kessler T(11), Duga S(12), Bis JC(9), van Duijn 
CM(7), Cupples LA(6), Psaty B(13), Rader DJ(14), Danesh J(15), Schunkert H(11), 
McPherson R(16), Farrall M(17), Watkins H(17), Lander E(8), Wilson JG(18), 
Correa A(19), Boerwinkle E(4), Merlini PA(20), Ardissino D(21), Saleheen D(22), 
Gabriel S(8), Kathiresan S(23).

BACKGROUND: Approximately 7% of American adults have severe hypercholesterolemia 

(untreated low-density lipoprotein [LDL] cholesterol ≥190 mg/dl), which may be 
due to familial hypercholesterolemia (FH). Lifelong LDL cholesterol elevations 
in FH mutation carriers may confer coronary artery disease (CAD) risk beyond 
that captured by a single LDL cholesterol measurement.
OBJECTIVES: This study assessed the prevalence of an FH mutation among those 
with severe hypercholesterolemia and determined whether CAD risk varies 
according to mutation status beyond the observed LDL cholesterol level.
METHODS: Three genes causative for FH (LDLR, APOB, and PCSK9) were sequenced in 
26,025 participants from 7 case-control studies (5,540 CAD case subjects, 8,577 
CAD-free control subjects) and 5 prospective cohort studies (11,908 
participants). FH mutations included loss-of-function variants in LDLR, missense 
mutations in LDLR predicted to be damaging, and variants linked to FH in 
ClinVar, a clinical genetics database.
RESULTS: Among 20,485 CAD-free control and prospective cohort participants, 
1,386 (6.7%) had LDL cholesterol ≥190 mg/dl; of these, only 24 (1.7%) carried an 
FH mutation. Within any stratum of observed LDL cholesterol, risk of CAD was 
higher among FH mutation carriers than noncarriers. Compared with a reference 
group with LDL cholesterol <130 mg/dl and no mutation, participants with LDL 
cholesterol ≥190 mg/dl and no FH mutation had a 6-fold higher risk for CAD (odds 
ratio: 6.0; 95% confidence interval: 5.2 to 6.9), whereas those with both LDL 
cholesterol ≥190 mg/dl and an FH mutation demonstrated a 22-fold increased risk 
(odds ratio: 22.3; 95% confidence interval: 10.7 to 53.2).
In an analysis of 
participants with serial lipid measurements over many years, FH mutation 
carriers had higher cumulative exposure to LDL cholesterol than noncarriers.
CONCLUSIONS: Among participants with LDL cholesterol ≥190 mg/dl, gene sequencing 
identified an FH mutation in <2%. However, for any observed LDL cholesterol, FH 
mutation carriers had substantially increased risk for CAD.

Copyright © 2016 American College of Cardiology Foundation. Published by 
Elsevier Inc. All rights reserved.

DOI: 10.1016/j.jacc.2016.03.520
PMCID: PMC5405769
PMID: 27050191 [Indexed for MEDLINE]

-------------

[3] Sci Rep. 2020 Jun 8;10(1):9208. doi: 10.1038/s41598-020-66027-4.

In-depth Mendelian randomization analysis of causal factors for coronary artery 
disease.

Tan YD(1), Xiao P(1), Guda C(2).

Author information:
(1)Department of Genetics, Cell Biology & Anatomy in Nebraska University Medical 
Center, Omaha, NE, 68198, USA.
(2)Department of Genetics, Cell Biology & Anatomy in Nebraska University Medical 
Center, Omaha, NE, 68198, USA. babu.guda@unmc.edu.

Selecting a set of valid genetic variants is critical for Mendelian 
randomization (MR) to correctly infer risk factors causing a disease. We here 
developed a method for selecting genetic variants as valid instrumental 
variables for inferring risk factors causing coronary artery disease (CAD). 
Using this method, we selected two sets of single-nucleotide-polymorphism (SNP) 
genetic variants (SNP338 and SNP363) associated with each of the three potential 
risk factors for CAD including low density lipoprotein cholesterol (LDL-c), high 
density lipoprotein cholesterol (HDL-c) and triglycerides (TG) from two 
independent GWAS datasets. We performed in-depth multivariate MR (MVMR) analyses 
and the results from both datasets consistently showed that LDL-c was strongly 
associated with increased risk for CAD (β = 0.396,OR = 1.486 per 1 SD 
(equivalent to 38 mg/dL), 95CI = (1.38, 1.59) in SNP338; and β = 0.424, OR = 
1.528
per 1 SD, 95%CI = (1.42, 1.65) in SNP363)
; HDL-c was strongly associated 
with reduced risk for CAD (β = -0.315, OR = 0.729 per 1 SD (equivalent to 
16 mg/dL), 95CI = (0.68, 0.78) in SNP338; and β = -0.319, OR = 0.726 per 1 SD, 
95%CI = (0.66, 0.80), in SNP363). In case of TG, when using the full datasets, 
an increased risk for CAD (β = 0.184, OR = 1.2 per 1 SD (equivalent to 
89 mg/dL), 95%CI = (1.12, 1.28) in SNPP338; and β = 0.207, OR = 1.222 per 1 SD, 
95%CI = (1.10, 1.36) in SNP363) was observed, while using partial datasets that 
contain shared and unique SNPs showed that TG is not a risk factor for CAD. From 
these results, it can be inferred that TG itself is not a causal risk factor for 
CAD, but it's shown as a risk factor due to pleiotropic effects associated with 
LDL-c and HDL-c SNPs
. Large-scale simulation experiments without pleiotropic 
effects also corroborated these results.

DOI: 10.1038/s41598-020-66027-4
PMCID: PMC7280530
PMID: 32514076 [Indexed for MEDLINE]

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2 hours ago, Dean Pomerleau said:

The average person in this study's [1] cohort may not have had quite as favorable markers of metabolic health (besides LDL) as you do, but they were categorized as "low risk" for CVD based on such markers (their median estimated 10-year risk of developing (let alone dying from) CVD was only 1.3%) and they didn't have nearly as high LDL as you do (median LDL-C of 205 in the highest quintile).

Here's a table of baseline characteristics of people in the study:

LDL_CVD_baseline.jpg.735f8e63e0d964c33bcff002fb9673dc.jpg

This cohort has metabolic syndrome/insulin resistance which is no surprise as the majority of adults are prediabetic.  This cohort is merely borderline prediabetic so perhaps low risk by those with low standards.  The higher quintiles of LDL are older with higher rates of hypertension, higher BMI and slightly worse ranges on other markers and lower percentages of women all probably contributing to their increased mortality risk. So this doesn't well isolate the risk of elevated LDL in the unhealthy let alone speak to the risk of LDL in a healthy population.

 

Edited by Todd Allen
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  • 2 weeks later...

For men, [an HDL-c of] 50 - 59 seems to be optimal in terms of maximally reduced risk of death for all causes, with significantly increased mortality risk above 60. That data is in ~19 million subjects, see:
 

 

Edited by Dean Pomerleau
Added paranthetical clarification that Mike's video refers to optimal HDL-c, and not LDL-c.
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  • 5 months later...

Yet another study identifying a large subset of those with extremely high LDL-C who are at low risk with respect to CVD.

Association of Coronary Plaque With Low-Density Lipoprotein Cholesterol Levels and Rates of Cardiovascular Disease Events Among Symptomatic Adults

Quote

Key Points

Question  What is the prevalence of coronary plaque, and is it associated with rates of cardiovascular events in patients with severely elevated low-density lipoprotein cholesterol (LDL-C) levels (≥190 mg/dL) who are universally considered to be at high risk?

Findings  In this cohort study of 23 143 symptomatic patients, absence of coronary artery calcium (CAC) and noncalcified plaque was a prevalent finding among those with severely elevated LDL-C levels. Across the LDL-C spectrum, absence of CAC was associated with low rates of atherosclerotic cardiovascular disease and death, with increasing rates in patients with greater CAC burden.

Meaning  These findings suggest that atherosclerosis burden, including assessment of CAC, can be used to individualize treatment intensity by identifying patients who are at low risk despite having severely elevated LDL-C levels.

 

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There is a study enrolling people who like myself have seen their LDL rise from typical levels to over 200 mg/dL while following a keto diet to find out their burden of CVD and the rate of progression.  Here is a video discussing some very preliminary results 

Here is an older video with more info on the study design, goals and cohort eligibility criteria. 

 

My highest LDL so far has been 391 with a dip back into the 200s on my last test.  But I have refocused my efforts and expect I will break through 400 next time and with perseverance I still believe 600+ is achievable.

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Although the results are interesting, that's one single study, as correctly underlined in the video. A confirmatory study would be needed but I'd say a collection of studies is in order before drawing conclusions on this basic point.

Also, is CAC the single most important factor in assessing the risk of hi LDL ? Why unbiased, non-vegan, non-keto longevity experts in the field, like Peter Attia, who has in the past undertaken a keto regime and is friends with people like Gary Tubbs, affirm that the lower the LDL, the better, down to values of 20-30 mg/dL? Those are the values he advises to his clients who want to reach 100+ years of age.

Peter Attia has a team of analysts who examine the most recent literature available on the specific subject and summarize the relevant results. They examine hundreds of studies on a specific subject. He's presently hiring and expanding his team. 

Bottom line, when he says LDL: the lower the better, that's the analytic inference drawn from just about all the relevant literature known to mankind at present.

Now, I don't know what's his comment on the above study, in a podcast I remember he told there are a few keto followers with a very high LDL who have a zero CAC score. Maybe it was not known they were so many. Maybe that's not the factor which governs a high HR increase in those with hi LDL. It may even be the increased mortality risk is different in the subset of people who follow a strict keto diet, but I'd like to see at the mortality data in addition to the CAC score data.

 

Edited by mccoy
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One should always ask questions if unsatisfied with the supporting information underlying a currently accepted practice. The Covid-triggered mass idiocy showed us what happens when "The Science" becomes a religion.

I read with interest findings like this, and actually enjoy the debate, as it forces me learn, and sometimes to reevaluate my positions. I also believe that each adult should be able to ultimately control what they do and how they treat their own body, and accept the consequences.

Having said that, I tend to agree with Dean on this, based on what I know about the topic. Thus I successfully dropped my LDL-C significantly below 100, largely by eliminating my daily consumption of fat, primarily as EVOO. Time will tell, maybe.

Mccoy makes a valid point about CAC.

Here is a larger and longer food for thought:

The association of 14-year dietary cholesterol trajectories with the risk of cardio-metabolic diseases, all-cause mortality and serum lipids

Results

Compared to the participants with persistently low dietary cholesterol intake, participants with gradually increasing cholesterol intake throughout adulthood were more likely to have hypertension (HR = 1.14, 95% CI: 1.03, 1.28) and to die due to all causes (HR = 2.19, 95% CI: 1.57, 3.05). Moreover, participants with persistently high cholesterol intake were more likely to die due to all causes (HR = 2.26, 95% CI 1.47, 3.47). The total cholesterol (TC):HDL-cholesterol (HDL-C) ratio and apolipoprotein B (ApoB) in these two groups were also significantly elevated compared to the group with persistently low dietary cholesterol intake (all P < 0.05). An association between trajectories of cholesterol and the incidence of diabetes was also observed; however, such an association became non significant after additional adjustment for other nutrients, food consumption and social environment.

Edited by Ron Put
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Posted (edited)

Coronary Artery Calcium Scoring for Risk Assessment in Patients With Severe Hypercholesterolemia

Quote

Age, male gender, smoking, diabetes, systolic blood pressure, and obesity (ps ≤0.001) were associated with CAC >0.

...

In patients with severe hypercholesterolemia, 45% had CAC = 0, which was associated with a significantly lower ASCVD risk.

I want to read the full paper but SciHub doesn't have it.   I'd like to know CAC=0 percents of otherwise matched cohorts with low or normal cholesterol but I doubt it is in the full paper.   But whether or not hypercholesterolemia correlates with increased risk of developing calcification I see this as yet more evidence that hypercholesterolemia is insufficient by itself to cause calcification as a large percent of those with hypercholesterolemia do not develop calcification.  There are identified risk factors for those who develop calcification and the only ones I have are age and gender.

Edited by Todd Allen
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10 hours ago, Todd Allen said:

want to read the full paper but SciHub doesn't have it.   I'd like to know CAC=0 percents of otherwise matched cohorts with low or normal cholesterol but I doubt it is in the full paper.   But whether or not hypercholesterolemia correlates with increased risk of developing calcification I see this as yet more evidence that hypercholesterolemia is insufficient by itself to cause calcification as a large percent of those with hypercholesterolemia do not develop calcification.  There are identified risk factors for those who develop calcification and the only ones I have are age and gender.

In the Rhonda PAtrick-Peter Diamandis-Tony Robbins podcast Diamandis says that the serious risk factor is not exactly calcification but soft plaque formation (because of mobilization potential) and goes on explaining the protocol to pinpoint soft plaques. I cannot judge about the reliability or validity of such affirmations.

https://www.foundmyfitness.com/episodes/robbins-diamandis

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It is true, that ASCVD is a multi-step process - starting with LDL-invasion of the arterial walls, a consequent inflammatory response, foam cell formation etc. etc.

But it still remains the fact, that it all starts with LDL (and other APOB bearing particles - Lp(a) etc. ).

Can you control your inflammation so consistently, that ASCVD will not develop? That may be possible in theory. But I would'nt bet my life on it unless I have some proof for, that I'm in that particular cohort.

 

Tha'ts the distribution of causes of death by age group in the US (from the cdc):

02.03_Iriza_large.jpg

The ASCVD share among centenarians is even larger. Because most people have a baseline LDL/APOB-risk that accumulates over decades (exceptions are genetic outliers). Cancer is much more driven by genetics and very specific lifestyle factors/environmental exposure (most prominently smoking). The same applies for diabetes. But in the long run almost everyone is at high risk for ASCVD.

 

 

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Maybe I understand it wrong but calcification is a rather a consequence of CVD development that could happen in some cases and is not happening in others. Maybe it makes the plaques more prone to be destructed and because of this there is a statistical correlation based on which it was selected to be used as an additional diagnostic marker. (Or it is a advertised-promoted factor that is not of such high use in reality, hard to say w/o analyzing tonnes of data)

IMHO, it depends on how well calcium-vitD-PTH carousel, osteoclasts/osteoblasts activity, renal capacities, calcium-bounding anions availability and other known and unknown factors of calcium homeostasis work, for some people who

1. have increased plaques formation chances

and

2. have high Ca circulating for long timeframes (area under the square)

this will lead to calcifications but for those who do not have factor 2 this will not seriously lower CVD risks.

I do not remember in details what was on it on Attia's drives but I have a feeling that he also came to conclusions that the risc factor is just related to 1, Ca-related checks are useful in medical practice (because of protocols and practices only?)

 

Br,

Igor

Edited by IgorF
small text fixes
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16 hours ago, mccoy said:

In the Rhonda PAtrick-Peter Diamandis-Tony Robbins podcast Diamandis says that the serious risk factor is not exactly calcification but soft plaque formation

Here's a case study of an individual expressing the Lean Mass Hyper Responder phenotype in response to a keto diet showing it is possible to sustain high LDL without developing any soft plaque.

https://www.frontiersin.org/articles/10.3389/fendo.2022.830325/full

Quote

After two and a half years of persistently elevated LDL-C levels, and a prior CAC of 0, LM was again counseled to initiate statin therapy. He considered, and a compromise was reached whereby he agreed to initiate pharmacotherapy if “it was first proven” that he was developing measurable atherosclerotic plaque. Given consideration of data available at the time in young people at elevated risk for ASCVD (6), and LM’s significant exposure (LDL-C ~400–550 for ~2.5 years), a CCTA was ordered for calcified and non-calcified plaques. No plaque or stenosis was observed in any vessels CAD-RADS = 0 (Figure 2).

The LMHR study currently underway is doing these CT scans on 100 such individuals upon enrollment and after 1 year of sustained hypercholesterolemia to yield a rate of plaque progression which will allow comparison to rates of progression observed in those with normal cholesterol levels.  Some initial data has been released suggesting the cohort will be starting with significantly lower than expected levels of plaque.

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4 hours ago, Todd Allen said:

Here's a case study of an individual expressing the Lean Mass Hyper Responder phenotype

There are outliers on both sides, probably, it would be interesting to know the incidence (% of such outliers) in the general population.

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Posted (edited)
6 hours ago, mccoy said:

interesting to know the incidence (% of such outliers) in the general population

My guess is the rate is low in the general pop because most people are fat and extreme cholesterol elevation is very tightly linked to having small adipocytes.  But in the video I posted up thread on the LMHR study over 60% had zero plaque hard or soft and nobody had a lot despite years of being in the top tenth of a percent of cholesterol levels.

Edited by Todd Allen
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On 1/2/2023 at 7:10 PM, Todd Allen said:

I want to read the full paper but SciHub doesn't have it. 

Here's the full paper Coronary Artery Calcium Scoring for Risk Assessment in Patients With Severe Hypercholesterolemia

Quote

Discussion

To the best of our knowledge, this is the largest study investigating the role of CAC in a real world cohort of patients with severe dyslipidemia. Our study demonstrates that CAC provides value in risk stratification for patients with severe hypercholesterolemia (LDL-C ≥190 mg/ 100 ml). CAC was linked with dose-response relation with statin prescription and cholesterol lowering in this cohort.

It was previously demonstrated that approximately 600,000 patients in the United States and between 14 and 35 million people worldwide manifest the severe hypercholesterolemia phenotype.2,9 More recent studies suggest that the population prevalence of severe hypercholesterolemia may have been underestimated.10 Patients with severe hyper- cholesterolemia are considered a high risk group per the American College of Cardiology and the American Heart Association guidelines, and high intensity statin therapy is recommended.4 These patients typically do not undergo further ASCVD risk stratification in the clinical setting because of the high CV risk of lifelong exposure to hypercholesterolemia. However, although severe hypercholesterolemia undoubtedly imparts significant CV risk, this risk is highly heterogenous and not all patients with severe dyslipidemia are at increased risk. For instance, many studies on heterozygous FH have now shown a highly heterogenous presentation, with many having much lower ASCVD event rates than expected.11 Conversely, some patients with degrees of LDL-C elevation in the heterozygous FH range may have recurrent events. It has been suggested that such patients may have additional risk factors, such as smoking, hypertension, diabetes, and elevated lipoprotein (a) levels, which all tend to be more common in FH. Given the highly heterogenous presentation, common CV risk equations are imprecise in the risk stratification of the severe hypercholesterolemia phenotype. Specific risk equations, such as the SAFEHEART (Spanish Familial Hypercholesterolemia Cohort Study), have been developed for heterozygous FH.12 A recent analysis by Gallo et al13 found that the addition of CAC score improved ASCVD risk stratification compared with the SAFEHEART risk equation.

In our patient population, only 1.8% experienced an ASCVD event over a mean follow-up time of 1.9 years, which is in line with recent studies suggesting a low <1% yearly ASCVD risk in this population.7 In addition, we found that a large proportion of patients (45%) had a CAC of 0, which is consistent with a recent review of 1,176 patients with FH, in whom 45% (95% CI 34% to 55%) had a CAC of 0.11 In addition, women were much more likely than men to have a CAC of 0 despite being 5 years older in our cohort, which is consistent with previous studies dem- onstrating a delayed rate of ASCVD in women by about a decade.14 The presence of CAC in patients with severe hypercholesterolemia was associated with a threefold higher risk for ASCVD events. The detection of CAC lead to the initiation of statin therapy, as would be predicted with the degree of statin use and subsequent decrease in LDL-C related to the treatment and presumed treatment intensification after CAC scoring. Before CAC scoring, only 46% of patients were already on a statin medication. After CAC scoring, a higher CAC was associated with increased cumulative statin prescriptions compared with a lower CAC category. This was also reflected in greater LDL-C reductions in patients with high CAC. These findings suggest that precision CV risk assessment may lead to a more personalized approach to primary prevention. The patients with the highest baseline risk (CAC >400) experienced the highest reduction in LDL-C levels.

Several studies have examined the role of CAC in FH.15−17 The early detection of CAC may preempt more aggressive management early on and pave a personalized approach in all patients with this disorder. Our findings underscore the high percentage of patients with severe hypercholesterolemia with a CAC of 0. Evidence from recent studies suggests that roughly half of patients with heterozygous FH may have a CAC of 0. 11 The corresponding event rates are low in this population; although, it must be emphasized that a CAC of 0 does not equate to no risk of ASCVD. The CAC score does not allow the detection of soft, vulnerable plaque, and in specific cases, it is not a predictor of non coronary vascular disease. In contrast, patients with very high CAC are at an extreme risk of future ASCVD events and may be likely to benefit from intensive lipid lowering therapy, such as proprotein convertase subtilisin/kexin type 9 inhibitors or novel small interfering RNA. Thus, our results add to the body of data supporting a potential additional role for CAC in risk assessment to further stratify ASCVD risk; although, well designed prospective studies in the contemporary era are needed to further confirm a definitive role for CAC in this patient population.

Our study has several limitations. The first is the single center analysis with possible biases in terms of the referral for CAC scoring and the fact that the no cost nature of the CAC screening may have resulted in a very specific population of patients. Secondly, our short follow-up period reduced the number of events and hence the statistical power to discriminate across gradations of CAC and events. In addition, we did not have data on extracardiac imaging and thus could not determine if atherosclerosis was present beyond the coronary arteries (e.g., cerebrovascular disease). We also did not have coronary CT angiography data, which could more accurately define the presence and extent of coronary atherosclerosis. Finally, we did not have information regarding family history or genetic testing, which could help further identify FH-related hypercholesterolemia in this population.

In conclusion, patients with severe hypercholesterolemia have heterogeneous ASCVD risk and a wide range of CAC burden, with a sizable proportion having a CAC of 0. For these patients, higher CAC was associated with greater ASCVD risk. CAC scoring may be used to refine ASCVD risk and guide primary prevention in this asymptomatic population with severe hypercholesterolemia.  

 

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7174731/#!po=18.7500

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There are distinct and constant differences in the electrical charge of
LDL subfractions at neutral pH of 7.4 arising as a result of either
dissimilarities in the relative proportions of charged phospholipids or
of sialytion of associated proteins [[11](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2014286/#b11), [20](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2014286/#b20)].
 Negative charge increases with increasing density of LDL particles.
Small LDL particles have significantly lower neutral carbohydrate and
sialic acid content [[20](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2014286/#b20), [21](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2014286/#b21)].
 LDL particles with lower sialic acid content have greater affinity for
proteoglycans in the arterial wall and could be preferentially involved
in the development of atherosclerosis [[21](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2014286/#b21), [22](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2014286/#b22)].

https://www.ketogenicforums.com/t/what-type-of-ldl-distinction-tests/116377/13

Edited by InquilineKea
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