#334 - Cardiovascular disease, the number one killer: development, biomarkers, apoB, cholesterol, brain health, and more | Tom Dayspring, M.D.
This episode features Dr. Tom Dayspring, a clinical lipidology expert, discussing atherosclerosis, its development, and key risk factors like insulin resistance and chronic kidney disease. They delve into cholesterol and lipoproteins, emphasizing apolipoprotein B (apoB)'s critical role in atherosclerosis and the importance of early detection and comprehensive lipid management.
Deep Dive Analysis
18 Topic Outline
Defining Atherosclerotic Cardiovascular Disease (ASCVD)
Timeline and Early Development of Atherosclerosis
Causal Risk Factors vs. Risk Markers for ASCVD
The Role of Insulin Resistance and Chronic Kidney Disease
Apolipoprotein B (ApoB): Structure, Function, and Measurement
Detailed Pathophysiology of Plaque Formation
Challenges in Detecting Early Atherosclerosis and Inflammatory Markers
Understanding Lipoprotein(a) [Lp(a)] and its Genetic Risk
Impact of Aging and Lifestyle on Lipoprotein Clearance
Dietary Strategies to Lower ApoB: Saturated Fat and Triglycerides
The Significance of Non-HDL Cholesterol as a Biomarker
Limitations of HDL Cholesterol as a Heart Health Indicator
Cholesterol Metabolism and Essential Role in Brain Function
ApoE Genotype and its Influence on Brain Health
Brain Cholesterol Clearance Pathways and Biomarkers
Statins, Brain Cholesterol Synthesis, and Cognitive Function
Future Advancements in Lipid Diagnostics and Therapeutics
Recent National Lipid Association Consensus Statements
10 Key Concepts
Atherosclerotic Cardiovascular Disease (ASCVD)
ASCVD is the deposition of cholesterol in artery walls, leading to plaque formation. This pathology can narrow arteries or cause plaque rupture, which triggers clotting and can lead to catastrophic events like heart attacks or strokes, especially in small, vital arteries.
Lipoproteins
Lipoproteins are protein-wrapped lipid particles that enable hydrophobic lipids like cholesterol and triglycerides to be transported through the aqueous solution of blood plasma. They are essential for circulating lipids throughout the body to various tissues.
Apolipoprotein B (ApoB)
ApoB is a structural protein found on all atherogenic lipoproteins (LDL, VLDL, IDL, Lp(a)). Since each of these particles contains exactly one ApoB molecule, measuring ApoB concentration directly counts the number of atherogenic particles in the blood, making it a superior risk indicator.
Plaque Formation (Atherogenesis)
This multi-step process begins when ApoB-containing particles enter the artery wall and bind to proteoglycans. They then aggregate and become oxidized, triggering an immune response where macrophages ingest the oxidized lipids, forming foam cells, which eventually contribute to the development of a fibrous, calcified plaque.
Lipoprotein(a) [Lp(a)]
Lp(a) is a genetically determined, highly atherogenic lipoprotein particle that is essentially an LDL particle with an additional protein, apoprotein(a), bound to its ApoB. It significantly accelerates the atherosclerotic process, making it a major, often overlooked, risk factor.
Remnant Lipoproteins
These are partially metabolized, triglyceride-rich VLDL or chylomicron particles that remain in circulation longer than they should, particularly in insulin-resistant states. They are highly cholesterol-rich per particle and are very atherogenic, contributing significantly to ASCVD risk.
HDL Functionality
This refers to the diverse biological roles of High-Density Lipoproteins, which can be protective or detrimental, depending on their specific protein and phospholipid composition. HDL cholesterol levels in the blood do not reliably indicate this functionality, making HDL-C a poor marker for individual cardiovascular risk.
Brain Cholesterol Homeostasis
The brain is the most cholesterol-rich organ and synthesizes all its own cholesterol (de novo), independent of peripheral cholesterol. Astrocytes produce ApoE-containing lipoproteins to transport cholesterol to neurons, with brain cholesterol having a very slow turnover rate.
Oxysterols (24-S-hydroxycholesterol)
These are oxidized derivatives of cholesterol, such as 24-S-hydroxycholesterol, produced by neurons. By adding a second hydroxyl group, cholesterol becomes water-soluble, allowing it to cross the blood-brain barrier and be transported to the liver for excretion, serving as a brain cholesterol clearance mechanism.
Desmosterol Pathway
One of two cholesterol synthesis pathways, predominantly utilized by brain astrocytes and steroidogenic tissues. Serum desmosterol levels can serve as a biomarker reflecting brain cholesterol synthesis, and its suppression by certain interventions like statins is of interest in specific patient populations.
10 Questions Answered
ASCVD is a specific type of vascular disease characterized by the deposition of cholesterol in artery walls, forming plaques that can narrow blood vessels or rupture, leading to blood clots and potentially fatal events like heart attacks or strokes.
Atherosclerosis is a slow, decades-long process that can begin in childhood with fatty streaks in arteries, progressing to noticeable plaque development over many years before symptoms appear or diagnostic imaging can detect it.
Risk factors are conditions or traits (like high ApoB, hypertension, smoking) that have been causally linked to the development of ASCVD, whereas risk markers (like high CRP, coronary calcium) are indicators of increased risk but are not necessarily causal themselves.
ApoB is superior because each atherogenic lipoprotein particle (LDL, VLDL, IDL, Lp(a)) contains exactly one ApoB molecule, allowing for a direct count of the particles that can invade artery walls, whereas LDL cholesterol measures the amount of cholesterol within these particles, which can be misleading if particle size or number changes.
Excess saturated fat can trigger nuclear transcription factors in the liver to reduce the expression of LDL receptors, which are responsible for clearing ApoB-containing particles from the plasma. This decreased clearance leads to higher circulating ApoB levels.
High triglycerides lead to the overproduction of large VLDL particles by the liver, which then exchange triglycerides for cholesterol with LDL and HDL particles. This process creates smaller, triglyceride-rich, cholesterol-poor LDL particles that are less efficiently cleared by LDL receptors, thus increasing ApoB particle concentration and promoting their entry into artery walls.
The protective or detrimental functions of HDL (HDL functionality) are determined by its complex protein and phospholipid content, not by the amount of cholesterol it carries (HDL cholesterol level). Therefore, HDL cholesterol levels do not accurately reflect an individual's cardiovascular risk or HDL's actual activity in the body.
Cholesterol is crucial for brain function, being the most cholesterol-carrying organ. The brain synthesizes all its own cholesterol (de novo) locally, primarily in astrocytes, which then package it into ApoE-containing lipoproteins to supply neurons; no cholesterol is delivered from the periphery across the blood-brain barrier.
The ApoE genotype (specifically the E4 allele) affects the shape and functionality of ApoE proteins, which are the main structural proteins of brain lipoproteins. ApoE4 proteins result in dysfunctional brain lipoproteins that are less effective at transferring cholesterol to neurons and clearing amyloid/tau, increasing susceptibility to Alzheimer's disease.
While all statins can cross the blood-brain barrier and suppress brain cholesterol synthesis, large population studies and meta-analyses have shown no signal that statins worsen or cause cognitive impairment or Alzheimer's disease. However, in a small minority of individuals, statins may induce brain fog, and specific biomarkers like desmosterol could potentially identify those at higher risk.
16 Actionable Insights
1. Measure ApoB Concentration
Get your ApoB concentration measured, as it is the best and easiest way to accurately count atherogenic lipoprotein particles, which are causal in atherosclerosis.
2. Test Lp(a) Once
Get your Lp(a) level checked once in your life, as it is a genetic risk factor for atherosclerosis that, if elevated, necessitates aggressive management of all other modifiable risk factors.
3. Early Lipid Testing for Children
Encourage lipid testing for children, ideally around age 8 or 9, to identify atherosclerosis risk factors early and enable primordial prevention by modifying them sooner.
4. Prioritize ApoB Reduction
Understand that lowering ApoB is the primary goal of all lipid-modifying interventions, whether lifestyle or pharmaceutical, to reduce cardiovascular events.
5. Reduce Saturated Fat Intake
Reduce saturated fat intake to improve the liver’s ability to clear ApoB particles from plasma, thereby preventing their deposition in artery walls.
6. Lower Triglycerides if High
Aim to lower triglycerides, especially if they are above 80 mg/dL, as high triglycerides indicate insulin resistance and increase atherogenic ApoB particles due to delayed clearance.
7. Prioritize Smoking Cessation
Stop smoking, as it is a top causal risk factor for atherosclerotic cardiovascular disease and can be modified with patient cooperation.
8. Manage Blood Pressure
Actively manage high blood pressure, as it is a causal risk factor for atherosclerosis.
9. Use Low-Dose Statins, Add Others
If statin therapy is needed, start with low-dose statins and combine them with other ApoB-lowering drugs (e.g., ezetimibe, bempedoic acid, PCSK9 inhibitors) to achieve target ApoB levels without needing high-dose statins.
10. Calculate Non-HDL Cholesterol
Calculate non-HDL cholesterol (Total Cholesterol - HDL Cholesterol) as a useful metric; if it remains high despite normal ApoB, it may indicate excess atherogenic remnant VLDL particles.
11. Do Not Rely on HDL Cholesterol
Do not rely on HDL cholesterol levels as a sole indicator of cardiovascular health or protection, as HDL functionality is not reflected by its cholesterol cargo.
12. Consider ApoE Genotype Testing
Consider getting your ApoE genotype tested, especially if there’s a family history of Alzheimer’s disease, as the ApoE4 allele is associated with dysfunctional brain lipoproteins and increased AD risk.
13. Manage AD Risks if ApoE4 Positive
If you carry one or two copies of the ApoE4 gene, diligently manage all other modifiable risk factors for Alzheimer’s disease due to increased susceptibility.
14. Monitor Desmosterol with Statins
If at risk for Alzheimer’s disease and taking a statin, consider monitoring serum desmosterol levels as a cautionary marker for potential brain cholesterol synthesis suppression.
15. Do Not Stop Statins for Brain
Do not stop statin therapy based on general brain health concerns, as population-level data shows no signal that statins worsen or cause cognitive impairment or Alzheimer’s disease.
16. Consider Inflammatory Markers
If causal risk factors like high ApoB or Lp(a) are present, consider inflammatory markers (like hsCRP) as additional indicators of increased risk, even if they are not causal themselves.
8 Key Quotes
There's like one sine qua non for atherosclerosis. And that says, do you have cholesterol in your artery wall or do you not? If you don't, you don't have atherosclerotic heart disease.
Tom Dayspring
It's not that the arteries of the heart are uniquely susceptible to this process you just described as atherosclerosis. It's just that two things are conspiring against us. The first is that they are very small arteries... And then of course... the second fundamental problem is it happens to afflict an artery that is, let's call it specifically sensitive to the demands of oxygen.
Peter Atiyah
If carriers of cholesterol are invading the artery wall, it takes decades for this plaque to finally get to a point where it's noticeable on some diagnostic image.
Tom Dayspring
ApoB is the ball game nowadays. It's not widely tested like it should be.
Tom Dayspring
Particle for particle, [Lp(a)] is seven to eight times more atherogenic than an LDL particle. So even now you have way, way, way more LDL particles... Not everybody's a criminal in our country, but it doesn't take a lot of criminals to cause a lot of havoc.
Tom Dayspring
Every cholesterol molecule that's in the brain got there by de novo synthesis in the brain. Not a single molecule of cholesterol was delivered from the periphery.
Tom Dayspring
The turnover time for cholesterol in the plasma is two to three days. So if a cholesterol molecule is synthesized in the brain, what is its half-life? Five years.
Tom Dayspring
In today's world, why do you ever have to double, triple, or quadruple the dose of a statin when we have all these other additive drugs that you take a baby statin... and you combine it with a zetamide, benpidoic acid, or PCSK9 inhibitor, you've got a military machine that can destroy ApoB.
Tom Dayspring