Understanding cardiovascular disease risk, cholesterol, and apoB - Dr Peter Attia

Understanding cardiovascular disease risk, cholesterol, and apoB - Peter Attia:

Cardiovascular disease in women: prevention, risk factors, lipids, and more with Erin Michos:

Measuring cardiovascular disease risk and the importance of apoB - Peter Attia

1. Understanding Atherosclerotic Cardiovascular Disease (ASCVD)

• Definition: ASCVD is a disease state characterised by the deposition or build-up of cholesterol (or more rigorously, sterols including cholesterol and phytosterol) in the artery wall.
• Ubiquity and Inevitability: Atherosclerosis is considered the only inevitable disease of the human species if people live long enough, unlike cancer or dementia, which are prevalent but not inevitable. Most people die with atherosclerosis, even if not from it.
• Leading Cause of Death: ASCVD is the leading cause of death globally, in the United States, and specifically for both men and women.
• Timeline of Disease: The disease process begins very early, even in childhood, with fatty streaks observed in aortas of young children (4-8 years old) and subclinical atherosclerosis in military personnel in their 20s. Plaque development can even start in fetuses of mothers with familial hypercholesterolemia (FH). It takes decades for this cholesterol deposition to lead to noticeable plaque or symptoms.
• Clinical Presentation: The most common presentation for a first heart attack is sudden death, historically over 50%, now slightly below 50% but still staggering (around 40%). Over 50% of men and one-third of women will experience their first major adverse cardiac event (heart attack, stroke, or sudden death) before the age of 65.
• Mechanism of Harm: Cholesterol deposition initially forms fatty streaks, which consolidate into plaques. These plaques can reduce blood flow (ischemia) leading to tissue damage, such as a heart attack. More catastrophically, inflamed plaques can rupture or erode, triggering the body's clotting system, which leads to sudden occlusion of the artery and potentially fatal events. The small size of coronary and cerebral arteries makes them particularly vulnerable to obstruction.

2. Cholesterol: Essential Molecule, Misunderstood Role

• Definition: Cholesterol is an organic, hydrophobic molecule (a lipid) that is not soluble in water.
• Essential for Life: It is one of the most important molecules in the body. Every cell in the body synthesises it, and without it, life would cease to exist. Rare genetic conditions impairing cholesterol synthesis are uniformly fatal.
• Key Functions:
  • Cell Membranes: Contributes heavily to the fluidity and structure of virtually every cell membrane, allowing for flexibility and function of membrane channels.
  • Hormone Precursor: Essential substrate for producing vital hormones like cortisol, estrogen, testosterone, and vitamin D.
  • Bile Acid Production: Necessary for the creation of bile acids, which are essential for food digestion, especially fatty foods.
• Dietary vs. Endogenous Cholesterol: The cholesterol consumed in food has very little relationship to the cholesterol measured in the bloodstream because most dietary cholesterol is esterified, too large for gut absorption, and excreted. Most circulating cholesterol is made by the body itself.
• "Good" vs. "Bad" Cholesterol Misconception: It is erroneous to refer to HDL as "good cholesterol" and LDL as "bad cholesterol". Cholesterol itself is a single molecule; it's the lipoproteins (vehicles) that carry it that are either "bad actors" or protective. This imprecise language is unhelpful and reflects a misunderstanding of basic lipid and lipoprotein biology.

3. Lipoproteins: Cholesterol Transport Vehicles

• Necessity: Since cholesterol is not water-soluble, the body developed lipoproteins as vehicles to transport it through the aqueous circulatory system. Lipoproteins are part lipid, part protein, with the hydrophobic lipid cargo inside and a hydrophilic protein coating outside, allowing them to move effortlessly through blood plasma.
• Families of Lipoproteins: Broadly, lipoproteins traffic in two main families, defined by their apoproteins:
  • APO B family: These are atherogenic particles. They include very low-density lipoproteins (VLDLs), intermediate-density lipoproteins (IDLs), low-density lipoproteins (LDLs), and lipoprotein(a) [Lp(a)]. Each APO B-containing lipoprotein has one molecule of APO B.
  • APO A family: These are high-density lipoproteins (HDLs). HDLs have APO A1 as their structural protein, but there can be 1 to 5 copies of APO A1 per HDL particle, making APO A1 less useful as a biomarker for particle concentration than APO B. HDLs are generally not considered atherogenic.
• Density Classification: VLDL, IDL, LDL, and HDL names also refer to their density, with HDL being the highest density.

4. APO B: The Superior Metric

• What it is: APO B (specifically APO B100) is a structural apoprotein that defines the lineage of atherogenic lipoproteins.
• Why it's Superior:
  • Particle Count: Because there is one molecule of APO B per atherogenic lipoprotein particle (VLDL, IDL, LDL, Lp(a)), measuring APO B directly counts the total number of these particles. This is critical because atherosclerosis is caused by APO B-containing particles getting into the artery wall and getting stuck.
  • Captures All Atherogenic Particles: APO B captures the total atherogenic burden, including LDLs, Lp(a), IDLs, and VLDLs, which can be problematic in metabolic syndrome and high triglycerides.
  • Discordance with LDL-C: LDL cholesterol (LDL-C) measures the amount of cholesterol within LDL particles, not the number of particles. In some cases, LDL-C can be normal while APO B (particle number) is high, indicating increased risk. This discordance is common in people with metabolic syndrome, insulin resistance, and type 2 diabetes.
  • Causality: Mendelian randomisation studies (which link genetic variations fixed at birth to outcomes, reducing confounding) have shown that APO B is causally related to ASCVD. It incorporates all information from triglycerides, LDL-C, and even HDL-C, making it a more accurate predictor of risk.
  • Cost-Effectiveness: The APO B assay is well-standardised, accurate, and inexpensive (e.g., $2.50 cash price in some labs).
• Limitations: While APO B is generally sufficient, in specific cases like Type 3 dyslipoproteinemia (a highly atherogenic condition with high triglycerides, high cholesterol, but low APO B), or high Lp(a) levels, additional metrics or considerations are needed.
• Non-HDL Cholesterol as a Surrogate: Non-HDL cholesterol (total cholesterol minus HDL cholesterol) is a better surrogate for APO B than LDL-C because it includes cholesterol from all APO B-containing particles. However, APO B is still considered superior.

5. Pathophysiology of ASCVD: A Detailed Process

The deposition of cholesterol in the artery wall is a multi-step process:

1. Particle Entry: APO B-containing lipoproteins (e.g., LDL) traverse the endothelium (the single-cell lining of arteries) into the subendothelial space. This can happen even with a normal endothelium but is accelerated by a damaged/more permeable endothelium due to factors like smoking and high blood pressure.
2. Retention and Aggregation: Once in the artery wall, APO B particles bind to proteoglycans, trapping them. They then aggregate, sticking to one another, forming a mass of lipids.
3. Oxidation: The cholesterol and phospholipids within these trapped, aggregated particles are highly susceptible to oxidation.
4. Immune Response and Foam Cell Formation: Oxidation signals the immune system. Monocytes enter the subendothelial space, transform into macrophages, and ingest the oxidised cholesterol. These lipid-laden macrophages become foam cells, which are characteristic of early atherosclerotic lesions.
5. Plaque Formation and Stabilisation: Smooth muscle cells are recruited from the outer layers of the artery wall, migrating to cover the mass of cholesterol and lipids, forming a fibrous cap. This cap, initially smooth muscle cells, transforms into more complex cells that secrete calcium, giving the plaque structural integrity and making it less likely to rupture.
6. Calcification: Calcium deposition in the plaque occurs later in the disease process, making it visible on imaging studies like a coronary artery calcium (CAC) score, which is a marker of advanced atherosclerosis.

This entire process is slow, taking decades to develop.

6. Risk Factors for ASCVD

Risk factors are classified as causal (proven to cause the disease) or risk markers (associated with risk but not necessarily causal).

• Causal Risk Factors:
  • Age: Non-modifiable, risk increases with age.
  • Smoking: Highly modifiable and a top causal risk factor, damaging the endothelium.
  • Lipid Disorders (Hyper-beta-lipoproteinemia): Specifically, high levels of APO B-containing lipoproteins are causal.
  • High Blood Pressure (Hypertension): Causal, pushing particles into the artery wall and potentially damaging the endothelium. Its pathophysiology is complex, possibly linked to loss of elastance in the proximal aorta.
  • LP(a): A genetic disorder where APO protein (a) binds to primordial LDL particles, making them extremely atherogenic (7-8 times more atherogenic per particle than LDL) due to enhanced oxidation. 20% of the world population has it, making it the most common lipid disorder associated with atherosclerosis. Current treatment focuses on controlling other risk factors while drugs are being developed.
• Associated Conditions/Risk Markers:
  • Insulin Resistance / Hyperinsulinemia: Highly associated with dyslipidemia (specifically, lipoprotein signatures like large VLDLs, small LDLs, small HDLs) and hypertension. While its independent causality beyond lipid and hypertensive components is debated, it's considered a serious abnormality that warrants aggressive management. Hyperinsulinemia itself may cause vascular damage.
  • Chronic Renal Failure (CKD): A major risk factor, primarily through associated lipid disturbances (high APO B) and hypertension. It can also lead to high homocysteine and other metabolites that irritate arteries.
  • Inflammatory Markers (e.g., hsCRP): Subtle elevations can signal inflammation in the artery wall but lack specificity and sensitivity for early atherosclerosis, as they can be elevated for other reasons. They are considered risk markers rather than causal.
  • Family History: Strong family history can indicate other polygenic causes of atherosclerosis, even with normal lipid levels.

7. Flaws in Current Risk Assessment Models

• 10-Year Risk Models: Major guidelines (e.g., American College of Cardiology, AHA) base statin prevention on 10-year risk of disease.
• Age and Sex Driven: These calculations are primarily driven by age and sex, with cholesterol and blood pressure contributing minimally.
• Delayed Prevention: This means that for younger individuals (under 55-60), the calculated 10-year risk is often low, despite the disease process having already begun in their 20s and 30s. This approach makes prevention of premature disease almost impossible.
• High Event Rate Below 60: Almost half of all heart attacks and strokes occur before age 60, yet prevention guidelines don't trigger treatment until 55-60. This is due to a larger absolute number of people under 60, even if the event rate is lower.
• Lack of Individual Precision: A 10-year risk number (e.g., 4.1%) indicates a group's probability, not an individual's definite risk. There's significant variance within that category.
• Poor Incentive: A 7.5% risk means 92.5% of the time nothing will happen, which is not a great incentive for patients to understand and act on their true long-term risk.
• Resistance to Change: The lipid world has been resistant to adopting newer, more accurate metrics like APO B in guidelines, partly due to perceived complexity and cost, and a consensus-driven process that can be slow to incorporate new evidence.

8. Alternative Risk Assessment Tools

• Causal Benefit Model: This model measures APO B or non-HDL cholesterol and projects risk over 20 or 30 years, providing a more meaningful number for younger individuals (e.g., 30% chance of event before age 65 for a 35-year-old). It accounts for the non-linear compounding nature of atherosclerosis.
• Coronary Artery Calcium (CAC) Score:
  • What it is: A non-invasive X-ray technique to detect calcium (bone) in coronary arteries, which is a feature of advanced atherosclerosis.
  • Utility: A positive CAC score in a younger patient (under 50-60) is a "four-alarm fire" regardless of APO B, indicating advanced disease and warranting aggressive treatment.
  • Limitations:
    • Its frequency increases with age, so a positive score in an older patient (e.g., 70-year-old) is less informative.
    • A zero CAC score does NOT rule out early or developing atherosclerosis, especially in younger patients with high APO B, as calcification is a late-stage marker.
    • It doesn't provide information on soft, non-calcified plaque, which can still be present.
• Advanced Imaging (e.g., CT Angiogram with contrast, Intravascular Ultrasound): Can show more anatomic detail of the lumen and soft plaque, but may not detect very early damage. Newer research tools like fat attenuation index are being explored but are not yet ready for prime time.

9. Prevention and Treatment Strategies

• Early and Aggressive APO B Reduction:
  • The evidence strongly suggests that infantile levels of APO B (30-40 mg/dL) are not deleterious in adults, even pharmacologically reduced.
  • Treat early and aggressively: For individuals in their late 30s or early 40s with APO B levels even slightly above the 20th percentile (around 80 mg/dL), the goal should be to lower it significantly, with a suggested APO B ceiling of 60 mg/dL (around the 5th percentile).
  • Thought Experiment: Pharmacologically lowering APO B to 20-30 mg/dL for everyone in their 20s could potentially eliminate deaths from atherosclerotic causes. This is already done in patients with severe genetic abnormalities like familial hypercholesterolemia, often starting in teenage years.
• Lifestyle Interventions:
  • Diet: Lowering triglycerides and saturated fat intake are key nutritional levers to reduce APO B. Saturated fat can reduce LDL receptor expression in the liver, leading to higher APO B. High triglycerides, often a marker of insulin resistance, lead to an overproduction of large VLDLs and a cascade of lipid exchange (via CETP) that results in more numerous, smaller, triglyceride-rich, cholesterol-poor LDL particles that are poorly cleared by the liver, thus increasing APO B.
  • Caloric Reduction: Often the key to lowering high triglycerides.
  • Exercise, Weight Management: Though not explicitly detailed in these excerpts, these are implied as part of lifestyle.
• Pharmacological Options:
  • Statins: Work by lowering APO B particle number, reducing the number of particles that get into the arterial wall.
    • Low-dose statins are highly effective, achieving most of the LDL receptor upregulation and significant APO B lowering. High-dose statins are often unnecessary given other available drugs.
    • Side Effects: Concerns about cognitive side effects ("brain fog") are an extreme minority, and there's no overall signal from large trials that statins worsen cognitive function.
  • Ezetimibe, Bempedoic Acid, PCSK9 inhibitors: These newer drugs provide additional options for lowering APO B, especially when statins are not tolerated or insufficient. PCSK9 inhibitors can routinely get APO B into the 20-40 mg/dL range.
  • Future Drugs: Oral PCSK9 inhibitors and drugs targeting other apoproteins are in development.
• Holistic Approach: ASCVD is multifactorial; treatment involves not just APO B reduction but also addressing other factors injuring the endothelium or arterial wall (e.g., hypertension).

10. Cholesterol and Brain Health

• Brain's Unique Cholesterol Metabolism:
  • The brain is the most cholesterol-carrying organ and synthesises more cholesterol than any other organ, including the liver.
  • Brain cholesterol is a separate system from peripheral cholesterol: No cholesterol-carrying particles from the plasma cross the blood-brain barrier to enter the brain. All brain cholesterol is synthesized de novo within the brain.
  • Slow Turnover: Cholesterol in the brain has a very long half-life (5 years, up to 30 years residence time), compared to 2-3 days in plasma.
  • Astrocytes as Suppliers: In adulthood, astrocytes are the primary suppliers of cholesterol to neurons, packaging it into APO E-containing lipoproteins.
• Brain Lipoprotein System: The brain has its own lipoprotein delivery system, where APO E is the main structural protein. These are often called "brain HDLs" but are distinct from peripheral HDLs (which primarily use APO A1).
• APOE4 Gene and Dysfunction:
  • Individuals with APO E4 genotype (e.g., 2/4, 3/4, 4/4) produce an APO E4 protein that gives brain lipoproteins less affinity for transferring cholesterol, leading to "dysfunctional HDLs" in the brain.
  • This is why APO E4 carriers have a greater susceptibility to Alzheimer's disease, although it's not a deterministic gene.
• Statin Impact on Brain Cholesterol:
  • All statins, regardless of their hydrophilic or lipophilic nature, eventually cross the blood-brain barrier and can suppress cholesterol synthesis in the brain.
  • Brain fog: A small minority of patients on statins report brain fog, potentially linked to a significant drop in brain cholesterol synthesis (measurable by biomarkers like desmosterol).
  • Overall Safety: Large observational and randomized trials have found no signal that statins worsen cognitive impairment or Alzheimer's disease in the general population; some even suggest a reduction in risk.
  • Personalised Approach: For patients concerned about dementia, especially APO E4 carriers, monitoring brain cholesterol synthesis markers (e.g., desmosterol) may be beneficial, allowing for the use of lower-dose statins or non-brain-penetrating lipid-lowering drugs (e.g., ezetimibe, bempedoic acid, PCSK9 inhibitors).

11. Future Outlook and Challenges

• Advancement of Knowledge: Peter Attia and his guests express excitement about advancements in understanding lipids and the brain, but acknowledge that much is still unknown and current understandings may evolve.
• Educational Gap: A significant challenge remains in educating practitioners (GPs, cardiologists) about APO B and Lp(a), as many are unfamiliar with these metrics despite their proven importance.
• Guidelines Lag: Current guidelines are seen as slow to incorporate cutting-edge evidence, hindering the widespread adoption of superior metrics like APO B.
• Humility in Medicine: The importance of acknowledging uncertainty in medical decisions and fostering open debate among experts, rather than enforcing unanimous consensus, is highlighted as crucial for scientific progress and better patient care.