Summary of Podcast Episode #334: Cardiovascular Disease with Tom Dayspring, M.D.

Introduction

In Episode #334 of The Peter Attia Drive, Dr. Peter Attia hosts Dr. Tom Dayspring, a renowned Fellow of the American College of Physicians and the National Lipid Association. The discussion delves deep into the intricacies of cardiovascular disease (CVD), emphasizing its status as the leading cause of death globally. The episode navigates through the pathophysiology of atherosclerosis, key biomarkers like APOB and cholesterol, the role of triglycerides and insulin resistance, the complexities surrounding HDL cholesterol, and the interplay between cholesterol and brain health.

1. Understanding Atherosclerosis

Atherosclerosis is defined as the deposition of cholesterol within the arterial walls, leading to the formation of plaques that can restrict blood flow or rupture, causing acute cardiovascular events.

• Definition and Mechanism: Dr. Dayspring explains, “[04:32] Atherosclerosis is the deposition of cholesterol in the arterial wall... It can build up and cause narrowing or, more catastrophically, plaque rupture leading to clot formation.”

• Vulnerable Arteries: Smaller arteries supplying the heart and brain are more susceptible due to their limited lumen size, making them prone to ischemia even with minor obstructions.

• Plaque Formation: Over time, cholesterol deposition leads to plaque formation, which can become inflamed and rupture, triggering the body's coagulation system and potentially causing heart attacks or strokes.

2. Risk Factors for Cardiovascular Disease

CVD risk factors are categorized into non-modifiable and modifiable factors, each influencing the progression of atherosclerosis differently.

• Non-Modifiable Risk Factors:

  • Age: "Age is one. Now we can't modify that." [17:49]
  • Genetics: Particularly familial hypercholesterolemia (FH), where genetic mutations lead to elevated APOB levels from birth. Dr. Dayspring highlights that FH can begin plaque development even before birth, as seen in fetal autopsy studies.

• Modifiable Risk Factors:

  • Smoking: Damages the endothelium, increasing permeability and susceptibility to plaque formation.
  • Lipid Disorders: High APOB and LDL cholesterol levels are directly implicated in atherosclerosis.
  • Hypertension: Elevated blood pressure stresses arterial walls, facilitating cholesterol deposition.
  • Insulin Resistance and Chronic Kidney Disease (CKD): These conditions are intertwined with lipid abnormalities and hypertension, exacerbating CVD risk.

Dr. Dayspring emphasizes, “[19:52] The more risk factors and risk markers you have, the higher the overall risk for CVD.”

3. The Role of Lipids and APOB

APOB (Apolipoprotein B) serves as a crucial biomarker in assessing the number of atherogenic particles in the blood.

• APOB vs. LDL Cholesterol: "APOB brings that cholesterol into the artery wall is causal, but it's really the cholesterol that do the dirty work once the APOB is in the artery wall." [36:36]

• Lipoprotein Structure: APOB is integral to LDL, VLDL, and IDL particles, each varying in their triglyceride and cholesterol content. APOB levels correlate directly with the number of atherogenic particles, making it a more accurate measure of CVD risk than LDL cholesterol alone.

• Testing and Clinical Relevance: Despite its importance, APOB is underutilized in clinical settings. Dr. Attia and Dr. Dayspring advocate for routine APOB testing to better stratify CVD risk and guide treatment decisions.

4. Triglycerides, Insulin Resistance, and Lipoprotein Dynamics

Elevated triglycerides are not just markers of insulin resistance but actively contribute to increased APOB levels and atherogenic particle formation.

• Insulin Resistance: Dr. Dayspring challenges the notion that insulin resistance is merely associative, stating, “[24:37] It's impossible to separate insulin resistance and lipoprotein abnormalities.”

• Lipoprotein Remodeling: High triglycerides lead to the formation of smaller, triglyceride-rich LDL particles through CETP-mediated exchange. These smaller LDLs have a higher APOB per cholesterol ratio, increasing their atherogenic potential.

• Clinical Implications: Even modest elevations in triglycerides (above 100 mg/dL) can significantly impact APOB levels and CVD risk, necessitating early intervention through lifestyle modifications or pharmacotherapy.

5. HDL Cholesterol: Functionality vs. Levels

HDL cholesterol’s role in CVD is complex, with functionality being more critical than mere HDL-C levels.

• HDL Functionality: Dr. Dayspring notes, “[89:59] HDL particles perform a lot of functions that, especially with the heart, may be very cardioprotective... or they can perform bad functions.”

• Misconceptions: High HDL-C is often misconstrued as inherently protective. However, the functionality of HDL particles varies based on their protein and phospholipid composition, rendering HDL-C levels an unreliable standalone metric for CVD risk.

• Clinical Approach: Focus should remain on lowering APOB and non-HDL cholesterol rather than solely attempting to elevate HDL-C levels.

6. Cholesterol in the Brain and APOE

Cholesterol plays a pivotal role in brain health, with distinct regulatory mechanisms separating central and peripheral cholesterol pools.

• Brain Cholesterol Synthesis: The brain synthesizes its own cholesterol, primarily through astrocytes, and transports it to neurons via APOE-containing lipoproteins.

• APOE Genotypes: Different APOE isoforms (E2, E3, E4) influence cholesterol transport in the brain. APOE4 is associated with increased risk of Alzheimer’s disease (AD) due to dysfunctional HDL-like particles that impair cholesterol clearance and amyloid-beta management.

• Biomarkers for Brain Health: Desmosterol, a precursor in cholesterol synthesis, is emerging as a potential biomarker for brain cholesterol homeostasis and AD risk, although it remains primarily in the research domain.

7. Statins and Brain Health

The impact of statins on cognitive function and brain health remains a topic of active investigation.

• Blood-Brain Barrier Penetration: All statins can cross the blood-brain barrier to some extent, potentially affecting central cholesterol synthesis.

• Cognitive Effects: Large-scale trials have not demonstrated a significant association between statin use and increased risk of dementia. Some studies even suggest a protective effect against cognitive decline, likely mediated through improved vascular health.

• Clinical Recommendations: While anecdotal reports of 'brain fog' exist, the consensus from clinical trials supports the safety of statins concerning cognitive function for the vast majority of patients.

8. Future Directions in Cardiovascular Lipidology

Advancements in both therapeutic and diagnostic arenas promise to enhance CVD management and prevention.

• New Therapeutics: Development of more potent and orally bioavailable PCSK9 inhibitors, along with drugs targeting other apolipoproteins, aim to further reduce APOB levels with minimal side effects.

• Enhanced Diagnostics: There is a push towards integrating APOB measurements into routine clinical practice, alongside emerging biomarkers like desmosterol for comprehensive CVD risk assessment.

• Education and Guidelines: Efforts are underway to educate healthcare providers on the importance of APOB and to incorporate it into clinical guidelines for CVD prevention.

Conclusion

Dr. Peter Attia and Dr. Tom Dayspring provide an exhaustive exploration of cardiovascular disease, highlighting the centrality of APOB and lipoprotein dynamics in atherosclerosis. They challenge traditional metrics like HDL-C, advocating for a nuanced understanding of lipidology that prioritizes particle number and functionality over simplistic cholesterol measurements. The conversation underscores the importance of early intervention, personalized medicine, and the continuous evolution of diagnostic and therapeutic strategies in combating the global burden of CVD.

Notable Quotes:

• Tom Dayspring [04:32]: "If you don't have cholesterol in your artery wall, you don't have atherosclerotic heart disease."

• Peter Attia [09:46]: "This is a disease that begins at birth... what might separate the people who never get it has to do with the rate of the accelerator and the rate of the brake application."

• Tom Dayspring [17:49]: "Age is one. Now we can't modify that."

• Peter Attia [75:53]: "It's the APOB that’s 'brought that cholesterol into the artery wall' is causal, but it's really the cholesterol that do the dirty work once the APOB is in the artery wall."

• Tom Dayspring [89:59]: "HDL functionality has zero relationship to their cholesterol cargo."

• Peter Attia [126:43]: "In every one of those trials, regardless of statin used, there has either been no change in the risk of dementia or a reduction in the risk of dementia."

This summary encapsulates the key discussions and insights from the episode, offering a comprehensive overview for those who haven't listened to the full conversation.