#229 ‒ Understanding cardiovascular disease risk, cholesterol, and apoB
This episode compiles clips on atherosclerotic cardiovascular disease (ASCVD), cholesterol, and ApoB. Peter Attia, Allan Sniderman, and Tom Dayspring discuss why early intervention is critical, the limitations of standard lipid panels, and why ApoB is a superior metric for risk prediction.
Deep Dive Analysis
14 Topic Outline
Why Atherosclerotic Cardiovascular Disease (ASCVD) Matters
ASCVD is Not Just a Disease of Old Age
Understanding Atherosclerotic Cardiovascular Disease (ASCVD)
Defining Cholesterol and Its Essential Biological Roles
How Atherosclerosis Develops and Its Early Onset
Fatal Flaws of the 10-Year Risk Approach for Prevention
Introducing Lipoproteins: Why 'Good' and 'Bad' Cholesterol are Misleading
The Essential Role of Cholesterol and Lipoprotein Transport
Limitations of Standard Blood Panels for Lipid Assessment
ApoB as a Superior Metric for Cardiovascular Risk Prediction
Mendelian Randomization: A Tool for Causal Inference
Hypertension and Atherosclerosis: Pathophysiology and Relationship with ApoB
Optimal ApoB Levels and the Timing of Intervention
Total Body Cholesterol vs. Circulating Cholesterol
6 Key Concepts
Atherosclerotic Cardiovascular Disease (ASCVD)
ASCVD is a disease state characterized by the deposition of cholesterol (sterols) in the artery wall, initially as fatty streaks, which then consolidate into plaques. This buildup can reduce blood flow, leading to ischemia, heart attacks, or strokes.
Cholesterol
Cholesterol is an essential organic molecule from the lipid family that is hydrophobic and synthesized by every cell in the body. It is crucial for cell membrane fluidity, and serves as a precursor for vital hormones (like vitamin D, cortisol, estrogen, testosterone) and bile acids necessary for digestion.
Lipoprotein
A lipoprotein is a vehicle composed of lipids (on the inside) and proteins (on the outside) designed to transport hydrophobic cholesterol through the water-soluble circulatory system. This structure allows cholesterol to be moved effortlessly through the blood to meet the body's needs.
ApoB (Apolipoprotein B)
ApoB is an apolipoprotein that defines a lineage of atherogenic lipoproteins, including VLDL, IDL, LDL, and Lp(a). It is considered a superior metric for assessing cardiometabolic risk because its concentration directly reflects the total number of these 'bad actor' particles.
10-Year Risk Approach
This approach is a guideline-based method for selecting individuals for statin prevention based on their calculated risk of a cardiovascular event over a decade. It is flawed because the calculation is heavily driven by age and sex, making it difficult to identify and prevent premature disease in younger individuals where the disease is already developing.
Mendelian Randomization
Mendelian randomization is a research tool that uses genetic variations, which are randomly assigned at conception, to infer causal relationships between a modifiable risk factor (like ApoB levels) and disease outcomes. By leveraging these fixed genetic differences, it helps overcome confounding factors common in observational studies.
7 Questions Answered
ASCVD is a ubiquitous and inevitable disease that significantly impacts human longevity, but understanding it is crucial because we possess effective tools to mitigate its effects and delay its onset, thereby extending both healthspan and lifespan.
No, atherosclerosis begins to take hold in the arteries during the first three decades of life, and over 50% of men and one-third of women will experience their first major cardiac event (heart attack, stroke, or sudden death) before the age of 65, making early prevention critical.
There is very little relationship; most cholesterol consumed in food is in an esterified form that is too large for the gut to absorb and is excreted, meaning the majority of cholesterol in circulation is actually synthesized by the body itself.
This language is imprecise because cholesterol itself is a single molecule; the terms actually refer to the lipoproteins (HDL and LDL) that transport cholesterol, and while LDL lipoproteins are 'bad actors' due to their role in depositing cholesterol in artery walls, the cholesterol they carry is chemically identical to that carried by HDL.
ApoB measures the total number of all atherogenic particles (LDL, VLDL, IDL, Lp(a)), providing a more accurate and comprehensive assessment of the overall atherogenic burden than LDL cholesterol, especially in conditions like metabolic syndrome where discordance can lead to underestimation of risk.
No, reducing plasma cholesterol levels (e.g., through lifestyle or medication) primarily decreases the amount of cholesterol being transported by lipoproteins in the bloodstream, which represents only a tiny fraction of the total body cholesterol, most of which is contained within cell membranes and the brain.
The general principle is 'lower is better,' with evidence suggesting that achieving ApoB levels similar to those found in newborns (30-40 mg/dL) or even lower, through pharmacological means, offers the most significant risk reduction without signals of harm.
13 Actionable Insights
1. Aggressive ApoB Reduction
Adopt an aggressive and early approach to ApoB reduction, aiming for levels between 20-40 mg/dL (infantile levels), potentially starting in your 20s. This proactive strategy is suggested to potentially eliminate death from atherosclerotic causes, as evidence shows lower ApoB is better and pharmacologic lowering to these levels has no signal of harm.
2. Early ASCVD Prevention
Prioritize atherosclerotic cardiovascular disease (ASCVD) prevention when you are young (e.g., in your 30s and 40s), as the disease takes hold over decades and current guidelines often delay prevention until it’s well advanced. By your late 30s or early 40s, aim to lower ApoB to below 60 mg/dL (below the 5th percentile).
3. Prioritize ApoB Measurement
Insist on knowing your ApoB concentration as it is the most important biomarker for cardiometabolic risk, capturing the total atherogenic burden of lipoproteins (LDL, VLDL, IDL, Lp(a)). This metric is superior to LDL-C or even non-HDL-C for assessing risk and diagnosing specific conditions like Type 3 dyslipoproteinemia.
4. Understand LDL-C Limitations
Recognize that standard LDL cholesterol (LDL-C) is often an estimation, not a direct measurement, and multiple calculation methods exist, leading to varying results. The number of LDL particles (LDL-P) or ApoB is a more accurate index of risk than LDL-C.
5. Avoid ‘Good/Bad’ Cholesterol Terms
Refrain from using imprecise language like ‘good cholesterol’ or ‘bad cholesterol’ because the cholesterol molecules themselves are identical; the distinction lies in the lipoproteins (HDL and LDL) that transport them. Misusing these terms indicates a fundamental misunderstanding of lipid biology.
6. Don’t Rely on High HDL-C
Do not rely solely on a high HDL cholesterol (HDL-C) level as an indicator of good health, as it doesn’t reflect the functionality of HDL, which is what truly matters. Efforts to pharmacologically raise HDL-C have largely failed to improve cardiovascular outcomes.
7. Address All Risk Factors
Beyond ApoB, actively address other primary modifiable risk factors for ASCVD, which unambiguously include smoking and hypertension, and examine other treatable factors that might injure the endothelium or arterial wall.
8. Understand Dietary Cholesterol Impact
Recognize that the cholesterol consumed in food (e.g., eggs) has very little impact on the cholesterol levels measured in your bloodstream because most dietary cholesterol is in a form too large for gut absorption and is excreted.
9. Don’t Fear Low Plasma Cholesterol
Do not be concerned about very low plasma cholesterol levels resulting from lifestyle or pharmacological interventions, as they do not significantly deplete total body cholesterol. Cells can synthesize their own cholesterol, ensuring they have more than enough for essential functions.
10. Be Critical of Information
Be skeptical of information sources, especially those discussing lipids and lipoproteins, if they use imprecise or incorrect terminology like ‘good’ or ‘bad’ cholesterol, as this indicates a fundamental lack of understanding of the subject.
11. Understand Long-Term Risk
Focus on understanding your long-term (20-30 year) risk projections for ASCVD, especially if you are young, as these numbers provide a more meaningful context for prevention strategies than short-term (10-year) risk calculations.
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5 Key Quotes
Atherosclerosis is really the only inevitable disease of our species.
Peter Attia
Over 50% of people's first heart attack is fatal.
Peter Attia
No cholesterol equals no life, full stop.
Peter Attia
It is totally erroneous to say HDL is good cholesterol and LDL is bad cholesterol. No, instead, what is true is that LDLs themselves as lipoproteins are bad actors because of what they do.
Peter Attia
Lower is better.
Tom Dayspring