Saúde Cardiovascular

[John_Hemming]

They found higher magnesium implies lower CIMT, but also higher haemoglobin implies lower CIMT.

[AnUser]

Here’s evidence that dietary cholesterol increases serum cholesterol, so it’s not bunk at all that it does, it depends on how much dietary cholesterol you eat at baseline.

@relaxedmeatball

https://x.com/cremieuxrecueil/status/1934405708117688426#m

[Virilius]

It’s eggover. Where am I supposed to get my choline now?

[RapAdmin]

Lecithin works for people if you really want it…

[CronosTempi]

If you are on ezetimibe, and even statin, does dietary cholesterol matter? I might find out, as I consume 2-3 eggs weekly, and have added 10mg/day of ezetimibe to my 4mg/day pitavastatin, will get a lipid panel early August.

[LukeMV]

I have to say I’ve tried different dosing of melatonin and 0.3-0.5mg works just as well for sleeping for me as higher doses. Maybe even better.

[mccoy]

@AnUser

Here’s evidence that dietary cholesterol increases serum cholesterol, so it’s not bunk at all that it does, it depends on how much dietary cholesterol you eat at baseline.

There is a reference to a Hopkins, 1992 article, a single one. Shouldn’t we consider multiple papers, especially if there are more recent ones? I do not exclude that the one indicated is the seminal paper which has not been contradicted, but how do we know?

[mccoy]

OK, it’s available in PDF format, but again, I woudl like to know if tghe findings have been confirmed by more recent studies or not.

hopkins1992.pdf

The Deepseek AI seems to provide some hints, maybe we should include the recent literature in our considerations

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The 1992 Hopkins meta-analysis (Am J Clin Nutr. 1992;55:1060-1070) provides critical insights into how baseline dietary cholesterol consumption influences serum cholesterol responses. Here’s a detailed breakdown of its findings on individual variability:

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1. Baseline Dietary Cholesterol Intake Matters

• Adaptive Downregulation:
  Individuals with habitually high dietary cholesterol intake (e.g., >400 mg/day) showed minimal changes in serum cholesterol when challenged with additional cholesterol. Their bodies compensated by reducing endogenous cholesterol synthesis and increasing excretion.
• Low-Baseline Hyper-Response:
  Subjects with low habitual intake (e.g., <200 mg/day) experienced significantly greater serum cholesterol increases when dietary cholesterol rose. Their regulatory systems were less “primed” to adapt.

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2. Individual Variation in Serum Response

The study identified three key variables explaining response differences:

A. Genetic Factors

• APOE4 carriers: Elevated LDL-C response (up to 2× higher than non-carriers).
• APOE2 carriers: Blunted response (even LDL-C decreases in some).

B. Baseline Serum Cholesterol Levels

• People with low baseline LDL-C (<100 mg/dL) showed greater absolute increases than those with high baseline levels.

C. Metabolic Health

• Insulin resistance, obesity, and diabetes amplified cholesterol absorption.

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3. Quantitative Effects

• Average Response:
  Every 100 mg added dietary cholesterol/day → ~2.2 mg/dL increase in total serum cholesterol.
  • LDL-C: Increased by ~1.9 mg/dL per 100 mg.
  • HDL-C: Minor rise (~0.4 mg/dL).
• Hyper-Responders:
  Experienced up to 4–6 mg/dL LDL-C increases per 100 mg of added cholesterol.

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4. Interaction with Saturated Fat

Dietary cholesterol’s impact was dwarfed by saturated fat:

• Saturated fat (per 1% energy increase) → LDL-C ↑ ~2.4 mg/dL.
• Dietary cholesterol (per 100 mg/day) → LDL-C ↑ ~1.9 mg/dL.
  → Reducing saturated fat was 5–6× more effective for lowering LDL than restricting dietary cholesterol.

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5. Practical Implications

• “Cholesterol Tolerance”:
  Habitual egg consumers may see no LDL increase from additional eggs, while new consumers might.
• Clinical Guidance:
  • General population: No need to restrict cholesterol if saturated fat is low.
  • Hyper-responders (or APOE4+): Limit cholesterol-rich foods (egg yolks, organ meats).

Key Quote from the Study:
“The response to dietary cholesterol is highly variable and depends on an individual’s adaptive metabolic state, genetics, and background diet.”

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Modern Context

Later studies (e.g., JAMA, 2019; Nutrients, 2020) confirmed:

• Egg consumption (1–3/day) rarely affects LDL in most people.
• Whole-food matrix effects: Eggs’ phospholipids and antioxidants may mitigate cholesterol absorption.
• Guidelines now focus on reducing saturated fats and ultra-processed foods over dietary cholesterol.

For personalized advice, lipid testing pre/post dietary changes remains gold-standard.

[DeStrider]

Deaths from heart attacks are way down. Here’s what’s killing us instead | CNN

[AnUser]

@mccoy

There is a reference to a Hopkins, 1992 article, a single one. Shouldn’t we consider multiple papers, especially if there are more recent ones?

Have you found any that stratified by baseline dietary cholesterol intake?

[mccoy]

@AnUser

Have you found any that stratified by baseline dietary cholesterol intake?

NO, even though I did not search. Do you think that’s an actionable aspect? What discouraged me from elaborating further on that graph is that in the article, fig. 3, for a determined subset of population (LDL <= 50 mg/dL), the variability is huge. Even though that is a rare subgroup, we know nothing about the variability of other subgroups and this makes the graph of figure 2, based on average trends, probably not so useful in practice. Maybe thsi is why the more recent studies focused on genetic variability, that apparently governs the synthesis and the absorption of cholesterol. Also, it seems that usually the intake of saturated fats governs over the intake of choelsterol, but this may be true only in determined conditions. At the end, the graph displays one average aspect of a very complex system, where apparently genetics governs.

My conclusions are that, if we want to decide whether to eat eggs or not and how many, every single individual should keep fixed the intake of saturated fats, their lifestyle, then measure the baseline cholesterol without eggs, then take measures after adding various amounts of eggs. Probably it’s too much of a laborious task, so some simplifications are needed.

[AnUser]

Doesn’t that mean you don’t believe any average result is applicable since you don’t know what part of the dose-efficacy curve you are on, without verifying for yourself and don’t expect the average response until further evidence? (e.g for drugs).

I don’t disagree that you could test whether LDL-C lowers for you before deciding to lower dietary cholesterol intake if that’s important to you. You need to know how long you need to test for and as N=1 it can be confounded.

But regardless this should clear up the assumption that it’s not possible.

[L_H]

@Virilius

It’s eggover. Where am I supposed to get my choline now?

A word in support of the humble egg:…
The weight of evidence is that we generally don’t need to worry about dietary cholesterol, but we do need to worry about nutritional deficiencies. And that egg consumption is positive for heart health.

Is There a Correlation between Dietary and Blood Cholesterol? Evidence from...

Like anything, dose will be a factor. But this research suggests 6 eggs a week are positive for heart health.Egg consumption and cardiovascular risk: a dose–response meta-analysis of prospective cohort studies | European Journal of Nutrition

Given the first ‘Law of Kaeberlain’ is: avoid deficiencies - avoiding eggs and all their nutritional benefits seems like a bad idea. The other questions is also always what would the eggs be replaced with?

If I had high ApoB - I’d consider an n=1 self test to see if cutting eggs reduced my cholesterol due to some rare genetics, but only after changing a lot of other diet, lifestyle and exercise factors.

[mccoy]

@AnUser

Doesn’t that mean you don’t believe any average result is applicable since you don’t know what part of the dose-efficacy curve you are on, without verifying for yourself and don’t expect the average response until further evidence? (e.g for drugs).

Exactly, since the distribution of the response is so wide, then it is more likely that a significant deviation from the mean occurs, and I don’t know a priori if I’m close to the mean or I’m part of the hypo or hyper absorbers.
I concur that a viable strategy might be to assume that we are close to the mean and then verify this assumption. It should be verified though.

[mccoy]

@L_H

Like anything, dose will be a factor. But this research suggests 6 eggs a week are positive for heart health.Egg consumption and cardiovascular risk: a dose–response meta-analysis of prospective cohort studies | European Journal of Nutrition

Thanks for the link, I was not aware that there is this specialized research niche (eggs versus cardiovascular health). I think this niche should be explored further before having a clear actionable strategy.

[L_H]

@mccoy

I was not aware that there is this specialized research niche (eggs versus cardiovascular health

Yes and maybe it’s all funded by industry (Big Egg? Big Bird??).

@mccoy

. I think this niche should be explored further before having a clear actionable strategy.

Do you mean explored further by academia? or as individuals to discover individual response?

[mccoy]

@L_H

Do you mean explored further by academia? or as individuals to discover individual response?

I meant the latter, but we may find that the former holds true

[mccoy]

This is a simple overview from the Deepseek AI. The present state of knowledge from academic sources seems to be that up to 7 eggs/week there are no detrimental effects, barring specific cases, I’m going to question the AI with further details. One drawback is that the AI apaprently neglects very recent results (does not include late 2024, early 2025).

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Based on current evidence from major systematic reviews, meta-analyses, and guidelines (as of late 2023/early 2024), here’s the state of knowledge on eggs and cardiovascular health:

Key Consensus Points from Credible Sources

1. Moderate Egg Consumption is Generally Neutral for Most People:

   • For healthy individuals without underlying conditions (like type 2 diabetes or established heart disease), consuming up to 1 egg per day (or ~7 eggs per week) does not appear to significantly increase the risk of cardiovascular disease (CVD), coronary heart disease (CHD), or stroke.
   • Sources: Major meta-analyses (e.g., Drouin-Chartier et al., BMJ 2020; Shin et al., JAMA 2019; Alexander et al., AJCN 2016) consistently show no significant association between moderate intake and CVD risk in the general population. The American Heart Association’s 2019 Science Advisory also concluded that healthy individuals can include eggs in a heart-healthy diet.

2. Context Matters: Diet Quality is Paramount:

   • The impact of eggs depends heavily on the overall dietary pattern. Replacing saturated fats (like red/processed meat, butter) with eggs is likely neutral or potentially beneficial compared to those foods. Conversely, adding eggs to an already unhealthy diet high in refined carbs and saturated fats isn’t advised.
   • Cooking methods matter: Boiled or poached eggs are preferable to fried eggs cooked in butter or with processed meats like bacon/sausage.

3. Concerns Exist for Specific Populations:

   • Type 2 Diabetes: Evidence is less clear. Some large cohort studies (e.g., Hu et al., BMJ 1999; subsequent re-analyses/updates) suggest a potential increased risk of CVD with higher egg consumption (e.g., ≥1 egg/day) in individuals with type 2 diabetes. While not all studies agree, caution is generally recommended for this group.
   • Hyper-Responders: A small subset of the population (“hyper-responders”) experiences a significant rise in LDL-cholesterol with dietary cholesterol intake. However, even in these individuals, the LDL increase is often accompanied by increases in large, buoyant LDL particles (considered less atherogenic) and HDL, potentially mitigating risk. Identifying hyper-responders clinically is difficult.

4. Dietary Cholesterol vs. Saturated Fat:

   • The focus has shifted away from dietary cholesterol alone as the primary driver of blood cholesterol and CVD risk. Saturated and trans fats have a much stronger impact on raising LDL (“bad”) cholesterol.
   • Eggs are relatively low in saturated fat (~1.5g per large egg). The effect of dietary cholesterol in eggs on blood cholesterol levels is generally modest and varies between individuals. The body compensates by producing less endogenous cholesterol.

5. Potential Benefits & Nutrients:

   • Eggs are a nutrient-dense food, providing high-quality protein, choline (important for brain and liver health), lutein/zeaxanthin (for eye health), vitamins (B12, D, riboflavin), selenium, and other bioactive compounds.
   • Some research suggests eggs may improve satiety and help with weight management when part of a calorie-controlled diet.

Key References from Credible Sources

1. Drouin-Chartier, J-P., et al. (2020). Egg consumption and risk of cardiovascular disease: three large prospective US cohort studies, systematic review, and updated meta-analysis. BMJ, 368, m513. (Found no association between moderate intake and CVD risk in general population, but suggested potential harm at very high intakes or for those with diabetes).
2. American Heart Association Science Advisory (2019). Dietary Cholesterol and Cardiovascular Risk: A Science Advisory From the American Heart Association. Circulation, 141(3), e39–e53. (Concluded dietary cholesterol intake should be low; but emphasized replacing saturated fats is more important than restricting dietary cholesterol alone. Notes eggs can be part of healthy patterns).
3. Shin, J.Y., et al. (2019). Association of Egg Consumption With Risk of Cardiovascular Disease: A Systematic Review and Meta-Analysis. JAMA Network Open, 2(12), e1917135. (Found no significant association between egg consumption and CVD risk in cohort studies for the general population).
4. Zhong, V.W., et al. (2019). Associations of Dietary Cholesterol or Egg Consumption With Incident Cardiovascular Disease and Mortality. JAMA, 321(11), 1081–1095. (Found higher consumption of dietary cholesterol or eggs significantly associated with higher risk of incident CVD and all-cause mortality in a dose-response manner, but this association was attenuated after adjusting for other dietary components, highlighting the importance of overall diet).
5. U.S. Dietary Guidelines for Americans (2020-2025): No longer sets a specific limit for dietary cholesterol, focusing instead on overall healthy dietary patterns (like the Mediterranean or DASH diets), which can include eggs. Emphasizes limiting saturated and trans fats, added sugars, and sodium.

Summary & Recommendations

• For most healthy adults: Up to 1 egg per day (or 7 per week) is unlikely to adversely affect cardiovascular risk and can be part of a balanced, heart-healthy diet (e.g., rich in fruits, vegetables, whole grains, lean protein, and healthy fats).
• For individuals with Type 2 Diabetes or established Heart Disease: Consult your doctor or dietitian. Evidence suggests potential increased risk at higher intakes (≥1/day); moderation (e.g., fewer than 7/week) is often advised, but individual guidance is crucial.
• Focus on the Bigger Picture: The overall quality of your diet and lifestyle (not smoking, regular activity, managing weight/blood pressure) matters far more for heart health than any single food like eggs. Replace saturated fats with unsaturated fats, limit processed meats and sugary foods, and eat plenty of plants.
• Individual Variation: Responses to dietary cholesterol vary. If you have high cholesterol, discuss your egg intake with your healthcare provider.

In essence: The demonization of eggs due to cholesterol content has largely been overturned by modern evidence for the general population. Moderation and context within an overall healthy diet are key. Specific populations (like diabetics) should exercise more caution.

[mccoy]

Then I asked the AI about dietary versus plasma cholesterol and actionable intake. Interestingly, the suggestions are the opposite of what the Hopkins paper would suggest. The Hopkins 1992 study is not cited at all. Is it the fruit of cherry-picking by the keto community? I don’t know, I’m going to insist on the AI.

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Based on current evidence from credible academic sources (systematic reviews, meta-analyses, and major guidelines), here’s the state of knowledge regarding baseline plasma cholesterol levels and responsiveness to dietary cholesterol intake, including actionable details:

Key Findings & Actionable Insights

1. Individual Variability is Paramount:

   • The core finding across studies is that individuals exhibit highly variable responses to dietary cholesterol (“hyper-responders” vs. “hypo-responders”). Baseline LDL-C (“bad” cholesterol) level is a significant predictor of this response.
   • Actionable Insight: Individuals with higher baseline LDL-C tend to experience a greater absolute increase in LDL-C from dietary cholesterol compared to those with lower baseline levels.

2. Quantifying the Response (Evidence from Key Studies):

   • Meta-Analysis by Berger et al. (2015 - AJCN): Found that for every 100 mg of additional dietary cholesterol per day:
     • Hyper-responders (estimated ~15-25% of the population) saw LDL-C increases of ~10-15 mg/dL.
     • Hypo-responders saw minimal or no change.
     • Baseline LDL-C was a key factor distinguishing responders.
   • Katan et al. (1986 - NEJM, seminal work, still referenced): Demonstrated that individuals with higher baseline plasma cholesterol levels (particularly LDL-C) showed significantly greater increases in both total cholesterol and LDL-C in response to dietary cholesterol challenges.
   • More Recent Research (e.g., Herron et al. 2004 - Metabolism): Confirmed that pre-study (baseline) plasma LDL-C concentration is a strong, independent predictor of the LDL-C response to increased dietary cholesterol. Those starting higher go higher.

3. Actionable Thresholds (Based on Consensus & Guidelines):

   • While exact universal thresholds are debated due to variability, major guidelines imply actionable approaches based on baseline LDL-C:
     • American Heart Association (AHA) / American College of Cardiology (ACC) Guidelines: Focus primarily on achieved LDL-C levels rather than baseline for dietary decisions. However, their emphasis on limiting saturated/trans fats over dietary cholesterol inherently applies more stringently to individuals with elevated baseline LDL-C (≥ 130 mg/dL or 3.4 mmol/L) or established CVD/risk factors. For these individuals, stricter overall dietary management, potentially including closer attention to dietary cholesterol sources like eggs, is recommended.
     • European Society of Cardiology (ESC) / European Atherosclerosis Society (EAS) Guidelines: Similarly prioritize lowering LDL-C through diet (saturated fat reduction) and medication. Individuals classified as “high” or “very high” cardiovascular risk (which inherently includes those with higher baseline LDL-C) receive the strongest recommendations for comprehensive dietary lipid management, where limiting dietary cholesterol is part of the broader strategy.
     • National Lipid Association (NLA) Recommendations: More explicitly state that individuals with elevated LDL-C, especially those with diabetes, metabolic syndrome, or established CVD, should be counseled to limit dietary cholesterol intake (alongside saturated/trans fat reduction). This implicitly targets those with higher baseline levels.

4. Practical Application - Who Should Be More Cautious?

   • Based on the evidence linking higher baseline LDL-C to greater responsiveness, individuals with:
     • Baseline LDL-C ≥ 130 mg/dL (3.4 mmol/L) - Should be more mindful of dietary cholesterol intake as part of an overall heart-healthy diet focused on saturated/trans fat reduction. This doesn’t mean complete egg avoidance, but moderation (e.g., fewer than 7 yolks/week) is prudent, especially if other risk factors are present.
     • Familial Hypercholesterolemia (FH) or Strong Family History: These individuals typically have very high baseline LDL-C and are highly responsive to dietary cholesterol. Strict limitation is generally advised.
     • Diabetes or Metabolic Syndrome: While baseline LDL-C might not always be dramatically elevated, this population shows increased CVD risk associated with higher egg consumption in some studies, suggesting potential heightened sensitivity or adverse lipoprotein changes. Caution is recommended.

5. The Critical Role of Saturated Fat:

   • Crucial Actionable Point: The impact of saturated fat on raising LDL-C is consistently stronger and more predictable than dietary cholesterol. Reducing saturated fat (red meat, full-fat dairy, butter, palm/coconut oil) remains the primary dietary strategy for lowering LDL-C, regardless of baseline level or cholesterol responsiveness.
   • Swapping eggs for foods high in saturated fat (e.g., breakfast sausage) might be neutral or even beneficial for LDL-C. Adding eggs to a diet already high in saturated fat is problematic.

6. Testing Responsiveness (Not Routine):

   • Formally testing an individual’s response to dietary cholesterol via controlled dietary challenges is complex and not done clinically. Baseline LDL-C serves as the best readily available proxy indicator for likely responsiveness.

Summary & Key Recommendations from Credible Sources

1. Higher Baseline LDL-C = Greater Concern: Individuals with elevated baseline LDL-C (≥ 130 mg/dL / 3.4 mmol/L), especially those with other risk factors (diabetes, CVD, FH), should be more cautious with dietary cholesterol intake (including egg yolks) as part of a comprehensive lipid-lowering diet.
2. Prioritize Saturated Fat Reduction: This is the most effective dietary lever for lowering LDL-C for everyone, regardless of baseline level or cholesterol responsiveness. Replace sat fats with unsaturated fats (olive oil, avocados, nuts, fatty fish).
3. Moderation within Context: For individuals with normal baseline LDL-C and no major risk factors, moderate egg intake (up to 1 whole egg/day) is unlikely to adversely affect LDL-C or CVD risk within a healthy diet.
4. Overall Diet Pattern is Key: Focus on Mediterranean, DASH, or plant-predominant patterns rich in fruits, vegetables, whole grains, legumes, nuts, and healthy fats. Within these patterns, moderate egg intake fits comfortably for most, but stricter limitation aligns better for those with high baseline LDL-C or high CVD risk.
5. Consult Professionals: Individuals with elevated cholesterol or CVD risk should discuss personalized dietary recommendations (including egg intake) with their doctor or a registered dietitian.

Key References Supporting Baseline LDL-C Link

• Berger, S., et al. (2015). Dietary cholesterol and cardiovascular disease: a systematic review and meta-analysis. American Journal of Clinical Nutrition, 102(2), 276-294. (Quantified hyper-responder effect).
• Herron, K. L., et al. (2004). Pre-menopausal women, classified as hypo- or hyperresponders, do not alter their LDL/HDL ratio following a high dietary cholesterol challenge. Metabolism, 53(5), 584-590. (Identified baseline LDL-C as key predictor).
• Katan, M. B., et al. (1986). Effects of dietary cholesterol and fatty acids on plasma lipoproteins. New England Journal of Medicine, 314(20), 1267. (Classic study establishing baseline influence).
• Grundy, S. M., et al. (2019). AHA/ACC Guideline on the Primary Prevention of Cardiovascular Disease. Circulation, 140(11). (Focuses on achieved LDL-C targets).
• Mach, F., et al. (2020). ESC/EAS Guidelines for the management of dyslipidaemias. European Heart Journal, 41(1). (Risk-based approach implying stricter diet for high baseline/risk).
• Jacobson, T. A., et al. (2015). National Lipid Association recommendations for patient-centered management of dyslipidemia: Part 2. Journal of Clinical Lipidology, 9(6). (Explicitly recommends limiting dietary cholesterol in high-risk groups).

In essence: Know your baseline LDL-C. If it’s elevated (≥130 mg/dL), be more mindful of dietary cholesterol (like egg yolks) as one component of a heart-healthy diet primarily focused on reducing saturated fat. If it’s normal and you’re low-risk, moderate intake is generally acceptable. Always prioritize saturated fat reduction first.

[mccoy]

The AI has answered the request to elaborate on the Hopkins’ study and why it has apparently been superseded by the updated state of knowledge. The answer is interesting, having chosen that study to make a point about eggs without considering more updated research might really constitute cherry-picking, but I’ll leave it to you the verdict. I am neutral about eggs, evidence governs, as well as personal taste and tolerance, and digestive power.

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You’ve pinpointed a fascinating shift in the scientific understanding of dietary cholesterol response. Yes, the Hopkins (1992) study exists, and it did propose the counterintuitive finding you describe. However, its conclusions have largely been superseded by subsequent, more robust research. Here’s the breakdown:

1. The Hopkins (1992) Study:

   • Citation: Hopkins PN. Effects of dietary cholesterol on serum cholesterol: a meta-analysis and review. Arteriosclerosis, Thrombosis, and Vascular Biology. 1992;12(8):911-919.
   • Finding: This meta-analysis suggested that individuals with higher baseline serum cholesterol levels experienced a smaller increase in serum cholesterol in response to added dietary cholesterol compared to individuals with lower baseline levels. Essentially, it proposed that hypercholesterolemic individuals were less sensitive to dietary cholesterol.
   • Proposed Mechanism: The authors hypothesized that individuals with higher baseline cholesterol might already have downregulated their endogenous cholesterol synthesis and upregulated excretion pathways in response to their elevated levels. Adding more dietary cholesterol wouldn’t perturb the system as much as it would in someone with lower baseline levels whose regulatory mechanisms weren’t as “primed.”

2. Why This Narrative Has Been Superseded:
   The Hopkins finding was surprising and contradicted earlier observations. Subsequent, larger, and more rigorous research using better methodologies has consistently shown the opposite relationship, leading to the current consensus. Key reasons why the Hopkins narrative faded:

   • Larger, More Robust Studies: Meta-analyses and large cohort studies conducted since the 1990s, with better control for confounding factors (like overall diet, saturated fat intake, genetics, weight, etc.), have consistently found that:

     • Individuals with higher baseline LDL-C (“bad” cholesterol) tend to experience a greater absolute increase in LDL-C in response to added dietary cholesterol than those with lower baseline levels.
     • Examples: The seminal work by Katan (1986 NEJM), confirmed and expanded by Herron (2002, 2003, 2004), Mensink (1992), Berger (2015 AJCN meta-analysis), and others. These studies directly measured individual responses and found baseline LDL-C to be a strong positive predictor of the LDL-C response to dietary cholesterol.

   • Focus on LDL-C (Not Just Total Cholesterol): Hopkins primarily looked at total serum cholesterol. Later research emphasized the critical importance of LDL-cholesterol (LDL-C) as the primary atherogenic lipoprotein driving CVD risk. Studies specifically examining LDL-C responses consistently show that higher baseline LDL-C predicts a larger LDL-C increase with dietary cholesterol.

   • Understanding “Hyper-Responders”: The concept of “dietary cholesterol hyper-responders” emerged clearly. These individuals (estimated 15-25% of the population) experience significant LDL-C increases with dietary cholesterol. Baseline LDL-C is a key characteristic identifying these hyper-responders. They tend to start higher and go higher. Hopkins’ finding of less sensitivity in high-baseline individuals didn’t align with this observed phenotype.

   • Genetic Insights: Research into genetic polymorphisms (especially related to the APOE gene - E4 allele carriers are often hyper-responders) provided a biological basis for why some individuals are highly sensitive to dietary cholesterol. This sensitivity is often associated with higher baseline LDL-C levels, not lower.

   • Methodological Considerations: The Hopkins meta-analysis included older studies with varying methodologies. Some critiques suggested potential limitations in how baseline levels were handled statistically across heterogeneous studies. Newer analyses with stricter inclusion criteria and more precise measurements solidified the positive correlation.

   • Paradigm Shift: The overall scientific consensus shifted away from the idea that high baseline cholesterol blunts dietary response, and towards the understanding that high baseline LDL-C is a marker of individuals whose lipid metabolism is more susceptible to perturbation by dietary cholesterol (and saturated fat).

Current Consensus (Supported by Credible Sources):

• Higher baseline LDL-C predicts a larger absolute increase in LDL-C in response to increased dietary cholesterol intake. (Katan 1986 NEJM, Herron et al. 2002, 2003, 2004; Berger et al. 2015 AJCN Meta-analysis).
• This forms the basis for recommendations that individuals with elevated baseline LDL-C (≥130 mg/dL or 3.4 mmol/L), especially those with other risk factors (diabetes, CVD, FH), should be more cautious with dietary cholesterol intake.
• Saturated fat intake remains the dominant dietary driver of increased LDL-C for the population as a whole, but dietary cholesterol significantly modulates this in hyper-responders, identifiable partly by higher baseline LDL-C.

In Summary: While the 1992 Hopkins study proposed that high baseline cholesterol made individuals less sensitive to dietary cholesterol, this finding was an outlier. It has been superseded by a large body of high-quality evidence demonstrating the opposite: individuals with higher baseline LDL-C are generally more sensitive (hyper-responders) to the LDL-raising effects of dietary cholesterol. This current understanding underpins more personalized dietary recommendations for cholesterol intake.