Health
Last Updated: 28.06.23
4 Min Read
Understanding Cardiovascular Disease Risk, Cholesterol, and apoB
Attia curates podcast snippets on cardiovascular disease, stressing early intervention and dispelling cholesterol myths. The significance of apoB as a superior risk measure and therapeutic targets for atherosclerotic cardiovascular disease prevention are explored. Attia underscores the potential transformative effect of aggressive apoB reduction on the disease landscape.
Key Takeaways
High level takeaways from the episode.
Source
We recommend using this distillation as a supplemental resource to the source material.
Full Notes
Atherosclerotic Cardiovascular Disease (ASCVD)
- Ubiquitous and inevitable disease of our species
- Most common chronic disease, impacting longevity
- Two biggest risk factors: hypertension and lipid abnormalities
ASCVD and Age
- Over 50% of men and 33% of women will have their first cardiac event before the age of 65
- Disease starts much earlier than symptoms appear
Understanding ASCVD
- Characterized by the buildup of cholesterol in the artery wall
- Starts as a fatty streak, later consolidates into plaques
- Reduction in blood flow leads to ischemia and tissue damage
Cholesterol
- Organic molecule in the lipid family, hydrophobic
- Essential for life, important for various functions in the body
- Presence of cholesterol in the artery wall is the essential condition of atherosclerosis
Why We Need Cholesterol - Essential for two main functions:
- Contributes to the cell membrane of every cell in the body
- Provides fluidity and allows membrane channels for substances to enter and exit cells
- Acts as a substrate for the production of important hormones (cortisol, estrogen, testosterone) and bile acids (necessary for digestion)
- Contributes to the cell membrane of every cell in the body
- “No cholesterol, no life, period.”
Cholesterol in Food vs. Bloodstream
- Cholesterol in food is in a form called “esterified” which is too large for receptors in our gut to absorb
- Most of the cholesterol we eat is excreted, not absorbed into our body
- Most cholesterol measured in the bloodstream is actually made by our body and transported between cells through lipoproteins
Atherosclerosis and Risk Calculation
- Atherosclerosis is a disease in the tissue, not just in plasma
- Current risk calculation methods for heart attacks and strokes are based on 10-year risk, which has limitations
- Doesn’t account for the development of the disease in younger individuals (under 60)
- Starts prevention too late (around 55–60), when the disease is already well advanced in the arteries
- Causal benefit model proposed as an alternative
- Measures non-HDL or apolipoprotein B (ApoB) and projects risk over 20–30 years
- Provides a more meaningful risk assessment for individuals
Understanding Cholesterol
- Cholesterol is a lipid synthesized by every cell in the body
- Essential for cell membrane structure and hormone production
- Referring to cholesterol as “good” or “bad” is imprecise and unhelpful
- Important to understand the specific roles and functions of different types of cholesterol and lipoproteins in the body
Cholesterol and Lipoproteins
- Important to understand the specific roles and functions of different types of cholesterol and lipoproteins in the body
- Cholesterol is essential for life
- Provides fluidity to cell membranes
- Precursor to important hormones (vitamin D, cortisol, estrogen, testosterone, progesterone)
- Essential for bile acids (digestion of food, especially fatty foods)
- Not every cell can make enough cholesterol to meet its needs
- Body needs to transport cholesterol between cells
- Circulatory system is the main transport system
- Cholesterol is a lipid (hydrophobic) and cannot move in water (circulatory system is water-based)
- Solution: lipoproteins (part lipid, part protein)
- Lipid part on the inside, protein part on the outside (water-soluble)
- Allows cholesterol to be transported in the circulatory system
- Solution: lipoproteins (part lipid, part protein)
- Two main types of lipoproteins: ApoB and ApoA
- ApoB 100: VLDL, IDL, LDL, LP (little a)
- ApoA: HDL
- Density of lipoproteins determines their classification (VLDL, IDL, LDL, HDL)
- Higher density objects sink, lower density objects float
- HDL cholesterol (good cholesterol) is associated with metabolic health
- Raising HDL cholesterol pharmacologically has mostly failed in improving outcomes
- LDL cholesterol (bad cholesterol) is associated with atherosclerosis
- LDL particles can enter artery walls, get oxidized, and cause inflammation and plaque buildup
- ApoB concentration is the most important number for predicting cardiometabolic risk
- Captures all atherogenic particles (LDL, LP (little a), IDL, VLDL)
- Cholesterol in HDL and LDL is the same; it’s the lipoproteins themselves that are different
- No such thing as good or bad cholesterol, just good or bad lipoproteins
Understanding Lab Results
- Doctors receive reports with total cholesterol, triglycerides, non-HDLC, LDLC, HDLC
- Most focus on LDLC for treatment decisions
- Difference between calculated and measured LDL
- Calculated LDL is an estimation based on other lipid measurements
- Measured LDL is a direct measurement of LDL particles in the blood
- Understanding the role of triglycerides in ApoB is important for assessing cardiometabolic risk
LDL Cholesterol and ApoB - LDL cholesterol is often calculated, with at least eight different methods
- Direct measurement of LDL cholesterol has not been validated in disease patients
- ApoB is a more accurate index of risk than LDL cholesterol
VLDL Cholesterol and Triglycerides
- VLDL cholesterol is atherogenic and found in very low-density lipoprotein particles
- High triglycerides are associated with increased risk of heart disease
- High triglycerides are often accompanied by a higher number of LDL and VLDL particles
Mendelian Randomization
- A method to determine causality in observational studies
- Identifies groups of genes associated with specific phenotypes
- Allows for a closer examination of causality by eliminating confounding factors
- Mendelian randomization studies have shown that ApoB incorporates information from triglycerides, LDL cholesterol, and HDL cholesterol
HDL Cholesterol
- Low HDL cholesterol was once thought to be a strong predictor of cardiac events
- Mendelian randomization studies have shown that HDL cholesterol is not causal in heart disease, while ApoB and cholesterol are
Hypertension and Smoking
- Both hypertension and smoking are widely accepted to exacerbate the risk of atherosclerosis
- The pathophysiology of hypertension is not well understood, and basic science research has not produced clinically useful information in recent years
Hypertension and Atherosclerosis - Hypertension and smoking are major risk factors for cardiovascular disease
- Both weaken or injure the endothelium
- ApoB-bearing particles in the presence of injured endothelium may initiate a destructive trajectory
- Cholesterol enters the subendothelial space, undergoes chemical oxidation, and triggers an inflammatory response
- This response can result in a fatal injury
Exceptions and Individualized Treatment
- Not all individuals with high ApoB or cholesterol levels develop atherosclerosis
- Some people may have protective factors or different particle qualities
- Treatment should be individualized, considering multiple risk factors and potential causes of atherogenesis
- Particle concentration and particle quality are important factors to consider
- Other components of lipoproteins, such as proteins and lipids, may also play a role in atherogenicity
Limits of Reduction and J‑Curve
- There may be a limit to the benefit of reducing ApoB or cholesterol levels
- Diminishing returns or even a J‑curve effect, where further reduction becomes harmful
- More research is needed to determine the optimal balance of treatment for each individual
Re-examining ApoB and Atherosclerosis - ApoB and atherosclerosis have a strong causal relationship
- Unclear what the dose response looks like for risk reduction
- Lowering ApoB levels is generally better for reducing risk
Cholesterol Pools in the Body
- Three pools of cholesterol: brain, peripheral cells, and plasma
- Brain cholesterol is separate and not affected by plasma cholesterol
- Plasma cholesterol does not correlate with cellular cholesterol
ApoB Reduction
- Leading modifiable causes of ASCVD: smoking, hypertension, and hyper beta lipoproteinemia (too many lipoproteins with ApoB)
- ApoB is a better measure than non-HDL cholesterol or LDL cholesterol
- Infantile levels of ApoB (30–40 mg/dL) are not harmful and may be beneficial for adults
Treating Early and Aggressively
- Treating early and aggressively can potentially eliminate ASCVD
- Starting ApoB reduction in the 20s may be necessary for maximum benefit
- Aim for ApoB levels below the 5th percentile (around 60 mg/dL)
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