At what age does atherosclerosis typically begin, and can it be prevented early?

Atherosclerosis is a slow, decades-long process that can begin in childhood or even in utero, as evidenced by autopsy studies finding fatty streaks in young individuals. Primordial prevention, focusing on identifying and modifying risk factors at a younger age (e.g., lipid testing in pediatric age groups), is crucial to arrest its development.

What are the key modifiable and non-modifiable risk factors for ASCVD?

Non-modifiable risk factors include age, LP(a) levels (a genetic component), and certain polygenic family histories. Modifiable causal risk factors are smoking, lipid disorders (especially high ApoB), and high blood pressure. Risk markers can include high homocysteine, uric acid, and various inflammatory markers.

How does insulin resistance contribute to atherosclerosis beyond its effects on lipids and blood pressure?

While insulin resistance is strongly associated with dyslipidemia and hypertension, there's a strong argument for its independent causality. Hyperinsulinemia alone may cause vascular damage, potentially by making the endothelium more susceptible to inflammation from substances like uric acid and homocysteine, even in the presence of normal blood glucose.

What is ApoB, and why is it considered the most important biomarker for ASCVD?

ApoB is a structural protein on atherogenic lipoproteins (like LDL, VLDL, Lp(a), and remnants). Each of these particles has one ApoB molecule, making ApoB concentration a direct count of the number of particles that can invade artery walls. This makes it a superior and causal marker for atherosclerosis risk compared to LDL cholesterol alone.

Can early atherosclerosis be detected before calcification or symptoms appear?

Currently, there are no definitive non-invasive tools to detect very early atherosclerosis (e.g., foam cells or fatty streaks) before some plaque development. Advanced imaging techniques and inflammatory markers like high-sensitivity C-reactive protein (hs-CRP) are being explored, but they lack sufficient specificity or sensitivity at the earliest stages.

How can diet and lifestyle changes lower ApoB levels?

Lowering triglycerides and reducing saturated fat intake are two effective nutritional levers. Excess saturated fat can decrease LDL receptor expression in the liver, impairing ApoB clearance. High triglycerides (often due to insulin resistance) cause overproduction of VLDLs, which exchange triglycerides for cholesterol with LDLs, making LDLs smaller, denser, and harder for the liver to clear.

Why is 'good cholesterol' (HDL-C) often a misleading marker of cardiovascular health?

HDL cholesterol levels in the blood have almost no relationship to the functionality of HDL particles a patient has. HDL's protective or harmful properties depend on its protein and phospholipid content, which cannot be measured by standard blood tests. People with low HDL-C often have high ApoB due to high triglycerides, while some with very high HDL-C can still have advanced atherosclerosis due to dysfunctional HDLs.

What is cholesterol's role in the brain, and how is it transported?

Cholesterol is vital for brain function, with the brain being its largest carrier organ, synthesizing all its own cholesterol. Peripheral lipoproteins cannot cross the blood-brain barrier. In the brain, astrocytes produce ApoE-containing lipoproteins that transport cholesterol to neurons. ApoE genotype (e.g., E4 variant) affects the functionality of these brain lipoproteins, influencing Alzheimer's risk.

What new biomarkers for brain cholesterol health like desmosterol and 24S-hydroxycholesterol?

24S-hydroxycholesterol is an oxysterol produced by neurons that is water-soluble, allowing the brain to excrete excess cholesterol into the bloodstream. Desmosterol is a precursor to cholesterol, predominantly used in brain and steroidogenic tissue. Serum desmosterol levels are being investigated as a biomarker for brain cholesterol synthesis and a potential risk factor for cognitive impairment, especially in Statin users.

Do statins cause cognitive impairment or Alzheimer's disease?

Meta-analyses of Statin trials, while not primarily designed for cognitive outcomes, generally show no increase or even a reduction in the risk of dementia. All statins, regardless of their classic hydrophilic or lipophilic classification, appear to cross the blood-brain barrier and can suppress brain cholesterol synthesis. While a tiny minority might experience 'brain fog,' this is not a general population concern.

What new treatment options are available beyond statins for lowering ApoB?

Medical practice in 2024 offers numerous ApoB-lowering agents including ezetimibe, bempedoic acid, and short/long-acting PCSK9 inhibitors. These alternatives allow for flexible treatment strategies, minimizing side effects and enabling personalized approaches to achieve ApoB goals, especially for patients with contraindications or concerns with statins.

334 - Cardiovascular disease, the number one killer: development, biomarkers, apoB, and more

Peter Attia MD

Science & Technology3 min read145 min video

Feb 3, 2025|97,594 views|2,003|302

Peter Attia MD Dr. Peter Attia Early Medical The Drive Podcast The Drive Longevity Zone 2

Save to Pod

Key Moments

TL;DR

Understanding atherosclerosis: its development, risk factors (apoB, cholesterol, insulin resistance), and the crucial role of lipids in brain health.

Key Insights

Atherosclerotic cardiovascular disease (ASCVD) is the leading global cause of death and develops over decades through cholesterol deposition in artery walls.

Key risk factors include age, smoking, hypertension, insulin resistance, and chronic kidney disease, with apolipoprotein B (apoB) being a critical marker of atherogenic particle number.

Cholesterol is essential for brain function, but the brain synthesizes its own; lipoproteins within the brain, primarily apoE-containing, play a vital role in cholesterol transport.

HDL functionality, not just cholesterol levels, is crucial for cardiovascular health; dysfunctional HDLs and LDL particle size can still pose risks, even with seemingly good lipid profiles.

Controlling lifestyle factors like diet (reducing saturated fat and triglycerides) and managing insulin resistance are key to lowering apoB and mitigating ASCVD risk.

Emerging research focuses on the brain's cholesterol homeostasis, the role of apoE genotype in Alzheimer's risk, and the potential of biomarkers like desmosterol and 24S-hydroxycholesterol.

THE PATHOLOGY OF ATHEROSCLEROSIS

Atherosclerotic cardiovascular disease (ASCVD) is the primary cause of death worldwide, developing over decades. It involves the deposition of cholesterol within artery walls, forming plaques. These plaques can lead to luminal narrowing, obstructing blood flow, or rupture, triggering the body's clotting response and causing acute events like heart attacks. This process begins early in life, often with fatty streaks observed in autopsies of young individuals, highlighting the long-term nature of the disease.

IDENTIFYING AND MANAGING RISK FACTORS

Key risk factors for ASCVD are categorized into non-modifiable (age, genetics like Lp(a)) and modifiable (smoking, hypertension, dyslipidemia). While age is unchangeable, risk can be significantly reduced by addressing other factors. Insulin resistance and chronic kidney disease are significant contributors, often indirectly by exacerbating lipid disorders and hypertension. A crucial distinction is made between causal risk factors and risk markers; apoB is highlighted as a central causal risk factor representing the number of atherogenic particles.

THE CENTRAL ROLE OF APOLIPOPROTEIN B (APOB)

Apolipoprotein B (apoB) is the structural protein on all atherogenic lipoproteins, making it a direct measure of the number of particles capable of entering artery walls and initiating atherosclerosis. Unlike LDL cholesterol, which measures the cholesterol content within those particles, apoB provides a particle count. The apoB family includes LDL, VLDL, and IDL. A key principle is that one apoB molecule exists per particle, making apoB measurement a reliable quantification of atherogenic particle concentration.

LIPID METABOLISM AND ITS COMPLEXITIES

Lipids, due to their insolubility in water, require lipoprotein carriers for transport in the bloodstream. Triglycerides, often elevated in insulin resistance, play a significant role. High triglycerides can lead to larger VLDL particles and smaller, more atherogenic LDL particles due to lipid exchange mediated by CETP. This process can result in increased apoB levels even if LDL cholesterol appears stable. Non-HDL cholesterol, calculated as total cholesterol minus HDL cholesterol, serves as a surrogate for apoB-containing cholesterol and is a valuable metric.

UNDERSTANDING HDL AND BRAIN LIPID FUNCTION

While HDL is often termed 'good cholesterol,' its functionality, not just its cholesterol content, determines its protective or detrimental effects. Dysfunctional HDLs, which can occur even with high HDL-cholesterol levels, are linked to increased cardiovascular risk and other diseases. In the brain, cholesterol is synthesized de novo and is essential for neuronal function, myelin sheath formation, and repair. Brain lipoproteins, primarily apoE-containing, are distinct from peripheral ones, and apoE genotype influences Alzheimer's disease risk.

IMPLICATIONS FOR THERAPEUTICS AND FUTURE DIRECTIONS

Managing apoB is the primary goal for reducing ASCVD risk, achievable through lifestyle modifications like diet and exercise, and pharmacological interventions. While statins remain a cornerstone, newer therapies like PCSK9 inhibitors offer potent apoB reduction. Awareness of brain lipid metabolism is growing, with implications for understanding cognitive decline, Alzheimer's disease, and the potential impact of lipid-lowering therapies on brain health. Future research aims to refine diagnostic tools and develop targeted therapies for complex lipid disorders and brain health.

Mentioned in This Episode

●Tools

●Companies

●Organizations

●Concepts

●People Referenced

Common Questions

ASCVD is a specific type of vascular disease involving the deposition of cholesterol in artery walls, forming plaques. It primarily affects small arteries supplying the heart and brain, which can lead to narrowing of blood flow or plaque rupture, causing sudden, catastrophic events like heart attacks or strokes due to clotting.

Topics

ASCVD LDL Cholesterol HDL Cholesterol Plaque Formation Cholesterol Metabolism

Mentioned in this video

personRichard Isaacson

A researcher at the Cornell Dementia Clinic whom Peter introduced Tom to, sparking Tom's increased interest in lipids' role in the brain.

conceptDesmosterol

A penultimate sterol in the cholesterol synthesis pathway, primarily used by astrocytes and steroidogenic tissue. Serum desmosterol levels are being investigated as a biomarker for brain cholesterol synthesis and Alzheimer's risk.

conceptASCVD (Atherosclerotic Cardiovascular Disease)

The leading cause of death globally, characterized by the deposition of cholesterol in artery walls, leading to plaque formation and potential rupture.

conceptLDL Receptor

A protein on the surface of liver cells that binds to ApoB-containing lipoproteins (like LDL) to clear them from plasma, crucial for maintaining healthy lipid levels.

toolNuclear Magnetic Resonance (NMR) analysis of lipoproteins

A diagnostic tool used to analyze lipoprotein signatures, revealing distinct patterns associated with insulin resistance, such as the size and characteristics of VLDLs, LDLs, and HDLs.

toolC-reactive protein (CRP)

A readily available inflammatory biomarker, used to assess subtle inflammation in the artery wall related to atherosclerosis. High-sensitivity CRP (hs-CRP) has a different reference range for cardiovascular risk.

organizationNational Lipid Association (NLA)

A professional organization that recently published statements on ApoB and Lp(a), advocating for their wider recognition and testing, despite existing challenges in practitioner knowledge and insurance coverage.

conceptApolipoprotein E (ApoE)

The main structural protein for lipoproteins in the brain, distinct from peripheral ApoB or ApoA1. Different isoforms (E2, E3, E4) have varying affinities for cholesterol transfer, with ApoE4 associated with increased Alzheimer's risk.

concept24S-hydroxycholesterol (24OH)

An oxysterol produced by neurons that is water-soluble and can cross the blood-brain barrier, serving as a marker for brain cholesterol elimination from the central nervous system.

conceptUric acid

Mentioned as another metabolite that could irritate arteries in conditions like chronic kidney disease, potentially contributing to atherosclerosis.

conceptLp(a) (Lipoprotein(a))

An inherited lipoprotein disorder, identified as a strong non-modifiable risk factor for ASCVD, where an additional protein (apoA) binds to an LDL particle, making it highly atherogenic.

conceptFamilial Hypercholesterolemia (FH)

A genetic disorder characterized by very high LDL cholesterol levels, leading to early plaque development; used as an example of early onset atherosclerosis in fetal studies.

drugSimvastatin (Zocor)

An early, potent lipophilic statin that was widely used and contributed to early discussions about the differences in statin properties and potential brain fog side effects.

drugPravastatin (Pravachol)

An early hydrophilic statin, contrasted with simvastatin, and was anecdotally considered safer due to early beliefs about its reduced ability to cross the blood-brain barrier, though later research suggests all statins cross.

conceptLathosterol

A sterol in the cholesterol synthesis pathway, representing the major pathway of peripheral cell cholesterol synthesis, distinct from the desmosterol pathway. Not a reliable biomarker for brain cholesterol.

supplementBempedoic Acid

supplementPCSK9 Inhibitors

supplementEzetimibe (Zetia)