Understanding Cardiovascular Disease Risk, Cholesterol, and apoB

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)
• “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
• 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
• 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 5^th percentile (around 60 mg/​​dL)