#334 - Cardiovascular disease, the number one killer: development, biomarkers, apoB, cholesterol, brain health, and more | Tom Dayspring, M.D.

Atherosclerotic Cardiovascular Disease (ASCVD) is a condition characterized by the accumulation of cholesterol in the arterial walls. Tom Dayspring defines ASCVD and Peter Attia further discusses its pathophysiology.

Ascvd: Cholesterol Buildup Forms Artery Plaque

Tom Dayspring clarifies that the formation of plaques in the arteries from cholesterol deposits can obstruct blood flow and may become inflamed or rupture. This is a central aspect of ASCVD's development.

Cholesterol Deposition in Artery Walls Is Essential for Atherosclerosis

Dayspring declares cholesterol deposition within the artery wall to be the crucial condition for the disease. As plaque builds, macrophages consume the cholesterol, transforming into a pool covered by a fibrous cap formed by smooth muscle cells. These cells, migrating from the artery wall, can secrete calcium to reinforce the cap. ApoB carrying lipoproteins (e.g., LDL) that enter the subendothelial space and undergo oxidation contribute to the development of atherosclerosis.

Ascvd Affects Coronary and Cerebral Arteries, Making Heart and Brain Vulnerable to Atherosclerosis

Attia notes the heightened susceptibility of coronary and cerebral arteries to atherosclerosis, explaining that their small size means that even minor obstructions can prompt ischemia. The potenti ...

Understanding the risk factors for atherosclerotic cardiovascular disease (ASCVD), which range from genetic predispositions to lifestyle habits, is vital for both prevention and treatment.

Non-modifiable ASCVD Risk Factors: Age, Genetic Variants (E.G., Lp(a)), Family History

ASCVD Affects Elderly, Begins In Childhood, Progresses Over Decades

Age is a significant non-modifiable risk factor for ASCVD, with the disease typically affecting those who are older. However, atherosclerosis starts in childhood and often progresses silently over decades, not causing symptoms until much later in life.

Genetic Factors Like Familial Hypercholesterolemia and Lp(a) Independently Increase ASCVD Risk

Familial hypercholesterolemia and the genetic variant Lp(a) are crucial factors influencing the risk of developing ASCVD early in life. Cholesterol synthesis begins in the womb and continues vigorously post-birth. Fetal autopsy studies of mothers with familial hypercholesterolemia have shown early plaque development in fetuses. Individuals with the ApoE4 allele are at an increased risk of both Alzheimer's disease and ASCVD.

The form of lipoprotein known as Lp(a), which consists of low-density lipoproteins coupled with an additional apoprotein(a), is particularly atherogenic and known to exacerbate oxidative reactions within the artery walls, hastening atherosclerosis. About 20% of the population carries the gene for apo(a), making Lp(a) a leading lipoprotein disorder linked with atherosclerosis. It's also noted that many primary care physicians (PCPs) and cardiologists may not realize its significance in elevating ASCVD risk. This indicates an urgent need for better education among healthcare providers regarding the role of Lp(a) and other genetic factors in ASCVD.

ASCVD Risk Factors: Smoking, Hypertension, Dyslipidemia, Diabetes, [restricted term] Resistance

Smoking and hypertension directly impact endothelial function, leading to increased permeability of artery walls to atherogenic lipoproteins like ApoB particles. [restricted term] resistance and metabolic issues, meanwhile, contribute to the formation of atherosclerosis-inducing LDL particles, with hyperinsulinemia potentially causing vascular damage even when glucose levels are ...

Understanding atherosclerosis requires a deeper exploration into the role of cholesterol, the contributions of various lipoproteins such as LDL, VLDL, IDL, and their implications on cardiovascular risk. Experts like Attia and Dayspring focus on how lipoproteins influence the development of cardiovascular diseases.

LDL ApoB-Containing Lipoproteins Drive Atherosclerosis By Delivering Cholesterol To Artery Walls

Dayspring and Attia describe the gradual process by which LDL particles, laden with ApoB, contribute to the build-up of atherosclerosis over decades. The liver and small intestine produce ApoB, a vital component that enables cholesterol-rich lipoproteins to enter artery walls by binding to LDL receptors.

ApoB Enables Cholesterol-Rich Lipoproteins' Entry via LDL Receptors Into Artery Walls

ApoB's presence on LDL allows these lipoproteins to infiltrate the subendothelial space, inviting oxidative processes that lead to the formation of foam cells and thus atherogenesis. LDL receptors, predominantly produced by the liver, recognize and bind ApoB on LDL particles, internalizing them for catabolism, which helps manage cholesterol levels.

ApoB or LDL-p More Accurately Predicts ASCVD Risk Than LDL Cholesterol Concentration

ApoB serves as a more accurate indicator of atherosclerotic cardiovascular disease risk compared to LDL cholesterol concentration. Dayspring emphasizes that the number of ApoB particles and their concentration within the plasma are pivotal in understanding risk, suggesting that ApoB and LDL particle count (LDL-p) are more precise metrics for such evaluation.

VLDL and Remnant Lipoproteins Contribute To Atherosclerosis

Triglycerides have a major role in lipoprotein metabolism, affecting the size and density of LDL particles and the formation of remnant lipoproteins, which can enter the endothelium, cause inflammation, and exacerbate atherosclerosis.

Elevated Triglycerides Form Small, Dense LDL Less Efficiently Cleared by the Liver, Increasing ApoB Concentration

High triglyceride levels are associated with an elevated number of small, dense LDL particles that are not efficiently cleared by the liver. These particles carry less cholesterol per particle due to an exchange of triglycerides with VLDL or chylomicrons, leading to an increase in the number of LDL particles and a consequent rise in ApoB concentration.

Triglyceride Remnants Enter Arteries, Promote Inflammation, Contribute To Atherosclerosis

Triglyceride rich-remnants and their passage into the arterial walls ...

Tom Dayspring and Peter Attia delve into the role of various biomarkers in assessing the risk for atherosclerotic cardiovascular disease (ASCVD), focusing primarily on ApoB, non-HDL cholesterol, and inflammatory markers.

Apob: Primary Biomarker For Ascvd Risk, Measures Atherogenic Lipoprotein Particles

Apob Better Assesses Ascvd Risk Than Ldl, Capturing all Apob-Lipoproteins

ApoB is deemed essential in assessing ASCVD risk due to its ability to measure the concentration of atherogenic lipoprotein particles, like LDLs, VLDLs, LP little As, and remnant VLDLs. Tom Dayspring points out ApoB's role in transporting cholesterol into the artery wall, directly linked to the onset of ASCVD. He suggests that if triglycerides are high—often due to [restricted term] resistance—this is related to the production of triglycerides and VLDLs in the liver. Dayspring emphasizes the necessity of therapies aimed at normalizing ApoB to reduce atherosclerotic disease risk. Peter Attia echoes Dayspring, noting that lowering ApoB is the primary biomarker for ASCVD risk and lifestyle changes, such as caloric reduction, can significantly affect its levels.

The significance of ApoB as a biomarker is underscored; it encompasses various particles, which differ in atherogenic potential, hence the need to analyze various atherogenic particles beyond ApoB concentration. Moreover, statins can affect cognitive functions, indicating a consideration of other biomarkers for heart disease risk.

Non-hdl Cholesterol, a Proxy For Apob, Includes all Apob-Containing Lipoproteins

Non-HDL cholesterol reflects all cholesterol not in HDL particles, which can be indicative of elevated ApoB levels. Dayspring notes that when low HDL cholesterol is paired with atherosclerosis, high ApoB concentrations are always present, thereby validating ApoB as a more reliable biomarker over LDL. He asserts that even with high HDL cholesterol, it’s essential to treat high ApoB concentrations independently. Dayspring also discusses the ApoE genotype's role in brain cholesterol transport and its relationship with ApoE-containing lipoproteins, connected to ApoB in assessing ASCVD risk. Furthermore, desmosterol is introduced as a biomarker for Alzheimer's disease risk assessment and as a cautionary marker when using statins.

Inflammatory Markers Like Hscrp Offer Ascvd Risk Insight, but Lack Specificity/Sensitivity Compared To Apob or Non-hdl Cholesterol

Inflammatory Markers' Utility as an Ascvd Risk Tool Limited by Infection and Non-cardiovascular Diseases

Dayspring critiques the use of inflammatory markers like high sensitivit ...

The discussions among medical experts emphasize the importance of early detection and preventive strategies for the progression of atherosclerotic cardiovascular disease (ASCVD).

Early Risk Factor Modification Crucial for Atherosclerosis Prevention

Experts agree on the necessity of addressing risk factors early in life as a critical component of atherosclerosis prevention.

Early Lipid Assessments Identify Elevated Atherogenic Profiles For Intervention

Pediatric guidelines have encouraged lipid testing in young age groups, typically around age eight or nine. The process of cholesterol deposition in arteries takes a long time, and early intervention is key. Dayspring mentions the increasing use of "baby dose" statins and other ApoB-lowering drugs to upregulate LDL receptors and manage ASCVD risk early on.

Lifestyle Changes, Including Diet, Exercise, and Targeted Pharmacotherapy, Can Help Prevent Cholesterol Buildup In Arteries

The impact of saturated fat on lipid levels underscores the importance of diet in preventing cholesterol buildup. Additionally, Attia emphasizes dietary changes to reduce APOB levels, such as decreasing triglycerides and saturated fat intake, substituting fat calories with monounsaturated and polyunsaturated fats, and reducing total calorie and carbohydrate intake for better lipid management. Adverse lifestyle factors affect transcription factors that regulate ApoB particle clearance, indicating that lifestyle adjustments can influence lipid balance.

Pharmacotherapy, when necessary, often begins with low-dose statins due to the presence of alternative medications such as bempedoic acid, [restricted term], and PCSK9 inhibitors, which do not significantly affect brain cholesterol synthesis.

Imaging, Like Coronary Artery Calcium Scoring, Reveals Subclinical Atherosclerosis for Personalized Risk Assessment and Prevention Strategies

Imaging is critical for early detection and prevention. Peter Attia discusses the use of calcium scanning for detecting calcium in the artery wall, an indicator of atherosclerosis and an advanced risk assessment tool. Such calcification comes from cholesterol deposits and reveals that the process has been ongoing for decades ...