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🔑 Key Takeaways

  1. Understanding the complexities of LDL cholesterol and its impact on heart disease is crucial, as different factors like diet can influence cholesterol levels and contribute to atherosclerosis.
  2. The hypothesis that high LDL leads to atherosclerosis may not be accurate due to various factors such as mass balance inconsistency, lack of triglyceride export in insulin-sensitive individuals, and genetic mutations causing similar lipid profiles.
  3. LDL may not be the sole cause of heart disease, highlighting the need for informed decisions in managing dyslipidemia.
  4. Specialized tests, like LDL particle number and APO B, are better predictors of cholesterol-related risk, especially for those on low carbohydrate diets, and can guide their dietary choices.
  5. When analyzing cholesterol levels, it is important to consider factors such as triglyceride levels, cholesterol ester levels, cholesterol synthesis, and phytosterols derived from plants for a better understanding of overall cholesterol profiles.
  6. Understanding how the liver, genes, transporters, and other factors affect cholesterol levels is crucial in managing and monitoring high cholesterol. Diet alone may not always determine cholesterol absorption.
  7. Cholesterol levels may increase in some individuals when consuming high-fat diets, but this response varies. Personalized approaches considering factors like family history and diabetes risk are essential for cholesterol management.
  8. Lipoproteins are lipid carrying proteins that distribute energy throughout the body, and understanding their functions and interactions is important for assessing their impact on health.
  9. Lipoproteins, such as chylomicrons, HDL, and LDL/VLDL, play essential roles in transporting fats and cholesterol. Understanding their functions, such as reverse cholesterol transport and cholesterol transportation, can help determine the nature of lipoprotein remnants.
  10. The lack of clinical assays for measuring APOC3 and LDL triglyceride concentration hinders our understanding of lipid metabolism and its relation to illnesses, emphasizing the need for further research and assays.
  11. LDL levels may appear high in lean mass hyper responders due to increased VLDL secretion, but it is important to consider the individual's metabolic profile when interpreting LDL data.
  12. High LDL cholesterol alone may not indicate trouble with cardiovascular health; considering multiple markers, such as HDL cholesterol, triglycerides, and inflammation levels, is important for a comprehensive assessment. Additional tests, like CIMT and CAC, can provide a more detailed understanding of artery health.
  13. The ox LDL assay is a laboratory test that indirectly measures the likelihood of oxidative damage in arteries, but it only captures a small subset of oxidized LDL particles. The role of vitamin E in combatting oxidative stress is still uncertain. Further research is needed to fully understand oxidation and its implications.
  14. While LDL particles may have some role in immune function, their significance is believed to be much less compared to HDL particles. Further research is needed to understand the trade-offs and long-term effects of LDL particles.
  15. Inhibiting PCSK9 can provide significant benefits in a relatively short time frame, even for patients already on maximum doses of statins. However, driving LDL cholesterol to zero may not be the optimal approach.
  16. Despite the inhibitory effects of statins, cells can still produce sufficient cholesterol for their needs, suggesting that cholesterol synthesis is not solely dependent on transport.
  17. Understanding the role of genes, such as APOC3, in lipid metabolism could lead to potential therapeutic interventions for conditions like atherosclerosis. However, further research is needed to validate these hypotheses.
  18. Dysfunction of endothelial cells can lead to atherosclerosis, while genetic causes like overexpression of PCSK9 can result in higher LDL levels, highlighting the complexity of lipid metabolism and the challenges in targeting specific perturbations.
  19. Evaluating the effectiveness of interventions for cardiovascular risk should consider hard endpoints like mortality, as well as the quality of life and health span. Individual patient decisions and preferences should be respected.
  20. Personalized approaches that consider individual risk factors are essential for optimizing health outcomes, and patients should actively participate in their own healthcare decisions.
  21. Lab results should not be taken at face value. Considering markers like inflammation and triglyceride levels is crucial in assessing overall health risk, even if other lab numbers appear normal.
  22. When evaluating a patient's risk for diseases like cancer and dementia, it is crucial to consider various factors beyond inflammation markers. Individualized assessment and caution are essential for accurate measurements and personalized approaches to managing health issues.
  23. The response to a ketogenic diet on LDL cholesterol levels can vary among individuals, with some experiencing significant increases. The role of exercise and its impact on muscle tissue needs further study for a comprehensive understanding.
  24. Intense exercise may not significantly affect the cholesterol content within LDL particles, challenging previous assumptions. However, more research is needed to fully understand the impact of exercise on cholesterol dynamics.
  25. Measuring remnant cholesterol levels accurately is crucial, and directly measuring VLDL cholesterol is the most reliable method. However, simply knowing the level does not reveal its underlying health implications.
  26. Current assays and markers have limitations in accurately predicting cardiovascular disease risk, highlighting the need for further research and improved testing methods.
  27. Non HDL cholesterol may be a more accurate predictor of all-cause mortality than LDL cholesterol, but it may not be reliable for individuals on a low carb diet due to the influence of triglycerides on LDL particles. Further research is needed to understand the effects of endogenous and exogenous triglycerides on cholesterol levels.
  28. The liver plays a vital role in providing energy to the body by converting fatty acids into fuel and distributing it to different tissues, acting as an engineer and regulator of energy balance.
  29. Understanding the liver's complex functions is essential for overall health, including weight loss and energy utilization. Simplified diagrams do not capture the intricacies of its dual role in energy delivery and vital operations.
  30. Exploring the underlying mechanisms and dynamics of cholesterol distribution is crucial for fully comprehending its impact on health.
  31. The regulation of LDL cholesterol levels involves a complex interplay of cholesterol production, recycling, and demand in different tissues for growth and cellular functions.
  32. Caloric deprivation and fat deprivation can potentially lower LDL cholesterol levels, while eliminating saturated fats from the diet may reverse the increase in LDL cholesterol. However, more research is needed to understand the effects of weight training and resistance training on LDL cholesterol.
  33. By reducing saturated fat intake and increasing monounsaturated fats, it is possible to mitigate the risk of heart disease associated with a ketogenic diet while maintaining its performance and mental well-being benefits.
  34. Continued research and open-mindedness are necessary to deepen our understanding of the relationship between biomarkers and health, as highlighted by the discussion on cholesterol and lipids.
  35. Consistently maintaining a carbohydrate intake of 90 net carbs per day for about 3 days has a significant impact on LDL cholesterol levels, while lowering to 70 net carbs does not yield the same results. Long-term studies are needed to understand the lasting effects on cardiovascular health.
  36. Question mainstream information, but also consider available evidence and avoid dismissing established institutions. Balance is key in understanding the complexities of nutrition.
  37. While LDL particles are important in the development of atherosclerosis, they are not the sole cause. Understanding the distinction between association and causation is crucial in studying this relationship. Careful analysis and understanding are needed for effective analysis.
  38. LDL, along with endothelial dysfunction and inflammation, plays a significant role in the development of atherosclerosis, but it is important to understand that these three factors are all necessary components.
  39. Evaluating the relationship between LDL particles and oxidative stress requires considering individual physiological responses, anti-oxidative defense systems, and being critical in analyzing the existing scientific literature.
  40. Cholesterol production in individuals with insulin resistance is influenced by factors beyond energy considerations, highlighting the need for direct testing to accurately measure LDL and LP little a cholesterol.
  41. While the relationship between high LDL and cardiovascular disease is still being debated, it is important to study the impact of triglyceride content on fat-adapted individuals or those following a ketogenic diet. Further research and understanding are necessary in this complex area.
  42. Further research is needed to study individuals with specific lipid profiles and evaluate the impact of genetic factors and medication use on health outcomes.
  43. Focusing solely on HDL cholesterol and triglycerides may not accurately determine lipid function, as other factors such as LDL C, APO B, and LDLP play a significant role as well.
  44. HDL cholesterol is an imperfect metric for predicting cardiovascular disease risk, and a deeper understanding of lipid metabolism is necessary to accurately assess health.
  45. When examining new research, it is crucial to critically analyze how it fits into existing knowledge and challenge established hypotheses. Comprehensive understanding and consideration of multiple factors are necessary for accurate pathology assessment and improving outcomes.
  46. Collaboration and a thirst for knowledge are crucial in breaking down existing models and progressing forward.

📝 Podcast Summary

The Complex Relationship Between LDL Cholesterol and Atherosclerosis

Peter Attia and Dave Feldman discuss the relationship between LDL cholesterol and atherosclerosis. While Dave is skeptical of the LDL is causal paradigm, Peter remains unconvinced by Dave's model. One major point of contention is the mass balance of cholesterol and LDL particles in individuals following a ketogenic or low carbohydrate diet. Peter highlights three possible explanations for the increased levels: making more cholesterol, clearing less cholesterol, or transferring cholesterol from other pools. However, Peter finds that the data supports the likelihood of making more cholesterol as the primary reason. This discussion emphasizes the importance of understanding the complexities surrounding LDL cholesterol and its impact on heart disease.

Challenging the Validity of the LDL-Atherosclerosis Hypothesis

There are several factors that question the validity of the hypothesis that individuals with high LDL are at increased risk for atherosclerosis. The first point is that the model used to support this hypothesis does not respect mass balance, which is a crucial aspect of any physical model. Additionally, the argument that VLDL production drives LDL concentration does not hold up, as insulin-sensitive individuals actually have fewer triglycerides being exported from the liver. Furthermore, ignoring the known genetic mutations that produce similar lipid profiles in lean mass hyperresponders is not justified, as they provide valuable insights into the physiology of the disease. Overall, while certainty is elusive in science, the evidence and probability suggest that the hypothesis in question may not be correct, and that atherosclerosis is a complex condition influenced by various factors beyond just lipoproteins. Ultimately, individuals should make informed decisions based on their own circumstances and understanding.

Dave Feldman: The Unconventional Lipid Expert

Dave Feldman is recognized in the low carb community as a lipid expert, despite not having formal training in biochemistry or medicine. This reputation stems from his in-depth understanding of lipoproteins and their role in the body. Dave's journey began when he adopted a low carb diet, which sparked his curiosity and led him to delve into the complexities of lipidology. His self-experimentation and exchanges with Peter Attia have shed light on the notion that LDL may not necessarily be the sole cause of heart disease. While this discussion may not provide definitive answers, it underscores the importance of making informed decisions about managing dyslipidemia with incomplete information.

Going beyond the standard lipid panel: Understanding cholesterol levels and risk factors for a comprehensive health assessment.

Understanding and monitoring cholesterol levels goes beyond the standard lipid panel. While total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides are commonly measured, they do not provide a comprehensive picture of an individual's risk. Factors such as LDL particle number and APO B are better predictors of risk and can only be obtained through specialized tests. This is particularly important for individuals considering a low carbohydrate diet, as it may affect cholesterol levels. Therefore, it is recommended for those embarking on such a diet to get a particle count test before starting, as it can provide valuable insights into their cholesterol profile and help guide their dietary choices.

Factors Affecting LDL Particle Count and Cholesterol Levels

When analyzing LDL particle count and cholesterol levels, it is important to consider the various factors that influence them. There are three cargo-related factors that affect LDL particle count: triglyceride levels, cholesterol ester levels, and cholesterol synthesis. An increase in triglyceride levels indicates a greater need for particles to transport them. Cholesterol synthesis can vary among individuals, with some being hypersynthesizers and others synthesizing lower amounts. Additionally, phytosterols, which are derived from plants, provide insight into how cholesterol is recirculated in the body. It is crucial to understand that dietary cholesterol has only a minor impact on circulating cholesterol levels. Considering these factors and obtaining advanced lipid panels can provide a more comprehensive understanding of cholesterol profiles.

Factors and Regulation of Cholesterol Levels

Understanding the factors that regulate cholesterol levels is crucial. It involves the liver, biliary means, transporters like Neiman pick C1 like 1, and genes like LXR and ATP binding cassette G5 8. People with deficiencies in these factors may experience high cholesterol levels. Triglyceride burden, cholesterol synthesis, cholesterol reabsorption, and LDL clearance are also important in determining cholesterol levels. LDL clearance, in particular, is highly regulated by the liver and can be influenced by factors like statin drugs and changes in cholesterol concentration. Monitoring these factors can help determine if LDL clearance has decreased, leading to an increase in LDL levels. Additionally, dietary cholesterol intake may not necessarily result in increased cholesterol absorption.

Individualized Response to High-Fat Diets and Cholesterol Levels

The increase in cholesterol levels, specifically LDL cholesterol, when consuming a diet high in cholesterol and fats is not always a cause for concern. High-fat diets, such as the ketogenic diet, can trigger a hyper synthetic pathway for cholesterol in certain individuals, leading to a significant rise in LDL cholesterol. However, this response is not universal, as not everyone experiences this increase. Additionally, it is important to consider other factors, such as family history and risk of type 2 diabetes, when evaluating cholesterol levels. The conversation highlights the individualized nature of cholesterol response and the need for personalized approaches to managing cholesterol and overall health.

The Role and Interactions of Lipoproteins in the Body

Lipoproteins, which are lipid carrying proteins, play a vital role in the body as an energy distribution network. These lipoproteins, such as Kylomicrons, VLDLs, IDLs, and LDLs, are responsible for delivering fat-based energy to tissues. They contain different types of lipids, including triglycerides, cholesterol, and fat soluble vitamins. The lipoproteins function as complex, interconnected objects, similar to a cloud network in software development. They constantly interact with each other and undergo various interactions as they move through the bloodstream. Understanding the functions and interactions of lipoproteins is crucial in interpreting data and drawing conclusions about their impact on health. While the exact purpose of LDL is not fully understood, the prevailing evidence suggests that it is involved in reverse cholesterol transport.

Understanding the Role of Lipoproteins in Our Bodies

Lipoproteins play a vital role in the transportation of fats and cholesterol in our bodies. There are three main lineages of lipoproteins: chylomicrons, HDL, and LDL/VLDL. Chylomicrons quickly hydrolyze fats from the gut and release them through the interaction of APOC2 and lipoprotein lipase. HDL particles have a longer lifespan and are responsible for reverse cholesterol transport, bringing cholesterol back to the liver from other tissues. LDL/VLDL particles, characterized by APO B100, are involved in the transportation of cholesterol. A small percentage of APO B100 carries APOE, which leads to faster clearance. APOC3 is the worst actor, increasing the residence time of lipoproteins. Measuring APOC3 is crucial in determining the nature of a remnant, whether it is physiological or pathological.

Understanding the Dynamics of Lipoproteins and the Need for Clinical Assays

There is a lack of clinical assays to accurately measure APOC3 and LDL triglyceride concentration. However, it is important to understand the dynamics of these factors in relation to existing illnesses and energy distribution. The residence time of particles like VLDL and LDL is longer in individuals with higher insulin levels, which may explain the greater burden of lipoprotein in people with type 2 diabetes. It is difficult to differentiate whether LDL particles originated from VLDL or directly from the liver without conducting a kinetics study. This lack of knowledge makes it challenging to determine the proportion of LDL particles that are truly used for energy delivery. In summary, the conversation highlights the need for further research and clinical assays to understand the complexities of lipid metabolism.

LDL Particle Kinetics and Factors Affecting LDL Levels

The half-life of LDL particles is about a day under nonpathologic states. There can be a longer half-life in a pathologic state, but the kinetic studies conducted by Brown and Goldstein provide a clear understanding of the LDL kinetics. It is important to note that the LDL levels in lean mass hyper responders, who are athletic, thin, and on a very low-carb diet, may appear high due to a higher proportion of VLDL secretion. These individuals may have higher LDLC and LDLP levels, but they also have high levels of HDLC and low levels of triglycerides. While more research is needed to fully understand this phenomenon, it is essential to consider the characteristics and metabolic flexibility of individuals when interpreting LDL data.

Evaluating Cardiovascular Health Beyond LDL Cholesterol Levels

When it comes to assessing cardiovascular health, it's important to consider a range of markers rather than just focusing on LDL cholesterol levels. A specific group of individuals known as lean mass hyperresponders have been found to have higher LDL cholesterol, but their other markers, such as HDL cholesterol and triglycerides, are within a healthy range. These individuals tend to be fit and thin, and their overall inflammation levels are low. This suggests that having high LDL cholesterol alone may not necessarily indicate trouble with cardiovascular health. To get a more comprehensive understanding, tests like CIMT and CAC can be used to assess advanced disease progression and calcification in the arteries. It's important to remember that atherosclerosis can develop over time without any visible signs until later stages, highlighting the need for a thorough evaluation of multiple markers.

Measuring the Burden of Oxidation in LDL Particles

There is a way to measure the burden of oxidation in LDL particles through a laboratory test called the ox LDL assay. This test indirectly determines the likelihood of oxidative damage occurring in the arteries. However, it's important to note that the test only captures a small subset of oxidized LDL particles that have escaped the intima. While some believe that LDL particles with alpha tocopherol (vitamin E) act as antioxidants to combat oxidative stress, there is not enough evidence to support this claim. The detection of oxidized LDLs in the test does not necessarily mean that they have never entered the intima. Further research and understanding is needed to determine the extent of oxidation and its implications.

The Role of LDL Particles and their Impact on Immune Function and Mortality

The main purpose of LDL particles is to carry cholesterol back to the liver. However, there is still ongoing debate regarding the additional functions and roles of LDL particles, particularly in relation to immunological function. While LDL particles may play a role in immune function, it is believed to be much less significant compared to HDL particles. The proteins carried by HDL, such as immunoglobulins, seem to have a more important role in immune function. When it comes to studying the effects of LDL particles on overall mortality, it is challenging due to the complex nature of the studies. Detecting changes in all-cause mortality is difficult, and it is important to consider the power and duration of the study. Ultimately, the trade-offs and long-term exposure to LDL particles need to be further explored and understood.

The benefits of inhibiting PCSK9 in reducing cardiovascular events and revascularizations.

Inhibiting PCSK9 can make a difference in reducing events and revascularizations, even in patients who are already on maximum doses of statins. The trials Fourier and Odyssey showed significant benefits in a relatively short time frame, which contradicts the belief that such trials would require much longer durations to show any effect. It is important to note that the focus here is on the conceptual tool of inhibiting PCSK9 and not the economic discussion or individual decisions regarding its cost and value. The lower the LDL cholesterol, the lower the risk of cardiovascular disease, but driving it to zero may not necessarily be the best approach as it could come with other potential costs.

The body's ability to produce cholesterol and its implications on health and homeostasis.

The body has the ability to produce sufficient cholesterol for its own use in most cells. While statins may inhibit cholesterol synthesis, every cell can still produce enough cholesterol. This is supported by natural experiments, such as individuals with a beta hyperlipoproteinemia who cannot transport cholesterol but still remain healthy. Moreover, there are variations in cholesterol levels during periods of stress or illness, indicating that cholesterol transport is not always in a homeostatic balance. Although there is still ongoing research to prove this hypothesis, the evidence suggests that most cells are capable of synthesizing the cholesterol they need, even in scenarios like muscle repair and growth.

Exploring Genes for Longevity Benefits and Therapeutic Targets

There are a few genes, including hypo-functioning APOC3, that have been identified as having a potential longevity benefit. Researchers are studying these genes and exploring therapeutic targets, such as antisense oligonucleotides, to impair APOC3. However, it is suggested that the benefits of these drugs may not be significant in insulin-sensitive individuals who already have lower insulin levels. Additionally, the conversation highlights the importance of considering genetic studies in understanding lipid metabolism and its relation to conditions like atherosclerosis. Limiting the focus to non-genetic studies may exclude valuable data, as most of the genes associated with lipid alterations are still unidentified. Further research is needed to fully test these hypotheses and explore the potential of lipid cellular malabsorption.

Dysfunction of Endothelial Cells and the Role of PCSK9 in Atherosclerosis and Hypercholesterolemia

The dysfunction of endothelial cells can potentially be problematic for atherosclerosis. While LDL receptors do not exist on endothelial cells, a lack of lipids or lipoprotein uptake by these cells can lead to dysfunction and higher levels of atherosclerosis. However, it is important to note that not all cases of familial hypercholesterolemia (FH) are caused by receptor deficiencies. There are various genetic causes of FH, including overexpression of PCSK9. Patients with hyper-functioning PCSK9 have fewer LDL receptors on their livers, resulting in less LDL particle uptake and higher LDL levels. This perturbation in lipid metabolism does not directly involve the endothelium or atherosclerosis. Therefore, it is challenging to find a perturbation that solely impacts LDL levels without affecting other aspects of the system. The PCSK9 example provides a clear understanding of the gene's function and its effect on lipid metabolism. Hypo-functioning PCSK9 can result in enhanced hepatic clearance and lower LDL cholesterol levels without apparent side effects.

Perspectives on Cholesterol Levels and Cardiovascular Risk

There is a difference in perspective between Dave Feldman and Peter Attia regarding the importance of cholesterol levels in assessing cardiovascular risk. Feldman emphasizes the need for hard endpoints, such as mortality, to determine the effectiveness of interventions. On the other hand, Attia argues that while mortality is important, the quality of life and health span should also be considered. He believes that delaying the onset of death is crucial, but it should not come at the cost of decreased quality of life or increased risks. Both agree that individual patient decisions and preferences should be respected. Ultimately, a comprehensive approach is needed to identify patients who may experience adverse effects from LDL lowering interventions.

The importance of personalized medicine and the role of diverse sources of information in healthcare decision-making.

Individualized and precision medicine is crucial for making informed decisions about healthcare. Population-level data can provide valuable insights, but it must be coupled with genetic, pharmacologic, and mechanistic data to increase certainty and guide treatment choices. The conversation highlights the importance of considering diverse sources of information and challenging one's own beliefs to make well-informed decisions. It also emphasizes the need for patients to actively participate in their own healthcare decisions and not rely solely on their doctors' recommendations. Each person has a unique genetic makeup and medical history, so personalized approaches that take into account individual risk factors are essential for optimizing health outcomes and preventing diseases like cardiovascular disease.

Holistic Assessment of Lab Results for Better Health Risk Management

Even though a patient may have generally good lab results and appear healthy on the surface, certain markers can still indicate potential health risks. In this case, the patient's total cholesterol, LDLC, and APO B levels were high, suggesting a higher risk for cardiovascular disease. Additionally, the presence of inflammatory markers and elevated triglycerides further raised concerns. The conversation highlights the importance of looking beyond just basic lab numbers and considering other factors such as inflammation and triglyceride levels. It emphasizes that even if a patient's calcium score is low, the lipid panel and other markers should not be ignored when assessing overall risk. Patients should work closely with their doctors to make informed decisions about their health based on all available information.

Assessing Disease Risk: The Importance of Multiple Factors and Individualized Assessment

Peter Attia emphasizes the importance of considering multiple factors when assessing a patient's risk for diseases like cancer and dementia. While some inflammation markers may be low, there are other aspects, such as lipoprotein burden and endothelial function, that contribute to overall risk. Attia acknowledges that measuring these factors accurately can be challenging and highlights the need for caution and individualized assessment. In examining a specific patient's case, he observes that the individual's asymmetric and symmetric dimethal arginine levels are surprisingly low, indicating good endothelial health. Additionally, Attia suggests that dietary modifications may be beneficial, based on patterns he has observed in similar cases. This highlights the significance of personalized approaches in managing health issues.

Hyperresponders and the Impact of Exercise on LDL Cholesterol in a Ketogenic Diet

There may be a subset of individuals, referred to as hyperresponders, who experience a significant increase in LDL cholesterol when following a ketogenic diet. This response is not seen in all individuals, even those who exercise intensely. One theory suggests that the difference in response could be due to the varying demands of different types of exercise on muscle tissue. Some believe that certain individuals rely on LDL cholesterol for delivery of raw materials, such as phospholipids, to repair and grow muscle tissue. However, there is currently limited evidence to support this theory. Further research and experimentation are needed to better understand the relationship between exercise, LDL cholesterol, and muscle tissue.

Exercise and Cholesterol: Limited Impact on LDL Particle Cholesterol Content

Intense exercise, such as high-intensity interval training or intense swimming and biking workouts, can cause minimal changes in cholesterol content within the LDL (low-density lipoprotein) particle. While VLDL (very-low-density lipoprotein) and HDL (high-density lipoprotein) particles may experience some movement of triglycerides, the movement of cholesterol within the LDL particle remains relatively stagnant. This finding challenges previous assumptions and suggests that exercise may have a limited impact on the overall cholesterol content within LDL particles. However, it is important to note that this conclusion is specific to the individual in the conversation and may not be universally applicable. Further research is needed to understand the broader implications of exercise on cholesterol dynamics.

The Challenge of Determining Remnant Cholesterol Levels

Determining remnant cholesterol levels is not a straightforward process. Remnant cholesterol refers to cholesterol that is not found in LDL or HDL particles. One way to estimate remnant cholesterol is by subtracting HDL cholesterol from total cholesterol. However, according to Peter Attia, this method is considered an abomination and should never be used. He explains that remnant cholesterol levels are generally low and track closely with triglyceride levels. The most accurate way to measure remnant cholesterol is by directly measuring VLDL cholesterol, with a desirable level being below 15 milligrams per deciliter. However, the absolute value of remnant cholesterol does not provide information about its pathology.

The complexity of measuring and predicting cardiovascular disease risk

The measurement and prediction of cardiovascular disease risk is complex and still not fully understood. While there are different cholesterol markers like LDL cholesterol, non-HDL cholesterol, and remnant cholesterol, their individual predictive value is questionable. The discussion highlights the limitations of current commercial assays in accurately measuring important markers like VLDL and APO B. The focus on insulin sensitivity and the relationship between insulin resistance and lipid profiles adds another layer of complexity. Furthermore, the conversation suggests that individuals on a ketogenic diet may have different lipid profiles that require further exploration. Overall, this conversation emphasizes the need for more research and better assays to accurately predict and understand cardiovascular disease risk factors.

The Correlation between Non HDL Cholesterol and Remnant Cholesterol and its Impact on Cholesterol Assessment.

There is a strong correlation between non HDL cholesterol and remnant cholesterol, and non HDL cholesterol may be more predictive than LDL cholesterol in terms of all-cause mortality. However, for individuals on a low carb diet, there is a potential issue with using non HDL cholesterol as a marker. This is because the body may be powered more by triglycerides found in VLDLs, which could result in higher LDL particles. The higher degree of synthesis of cholesterol, rather than absorption, is believed to be the primary factor influencing LDL levels. To further test this hypothesis, it is suggested to separate endogenous triglycerides from exogenous triglycerides and study their effects on cholesterol levels. Understanding the movement of energy and triglycerides within the body is crucial for accurate cholesterol assessment.

The Liver: A Key Player in Energy Supply and Balance

The liver plays a crucial role in supplying energy to the body. When someone is fasted and engaging in physical activity, their adipose tissue releases free fatty acids. These fatty acids are transported to the muscles through albumin, where they undergo beta oxidation. Additionally, the liver converts a portion of these fatty acids into beta hydroxybuterate, which is then used as fuel by different tissues. The liver also produces VLDLs and IDLs that carry lipid payloads to various tissues. It is important to note that the liver's main purpose is to replenish energy stores throughout the body, including both muscle and adipose tissue. This view, although not widely accepted, suggests that the liver acts as an engineer and regulator of energy balance in the body.

The Crucial Role of the Liver in Maintaining Health and Functioning

The liver plays a crucial role in maintaining our overall health and functioning. It is capable of detecting and responding to changes in circulating energy and metabolites, primarily ATP. The liver is a remarkable organ that can support our body's various functions, such as removing toxins and processing nutrients, but it does not have extracorporeal support like other organs. When it comes to weight loss, the liver is involved in lipolysis, where the amount of fat leaving fat cells needs to exceed what is reentering them. Remnant cholesterol levels may not provide meaningful information, and the focus should be on understanding why triglycerides are not being efficiently utilized by the body. The liver, being an APO B100-containing lipoprotein, plays a dual role in energy delivery and other important operations. So, it is important to consider the complexity and intricacies of the liver's functions beyond simplified diagrams.

Understanding the Complexity of Cholesterol Levels and Distribution

The hypothesis suggests that the secretion of VLDLs (very low-density lipoproteins) can lead to an increase in LDL (low-density lipoprotein) particles. However, the conversation also highlights the complexity of understanding cholesterol levels and their distribution in the body. Peter questions why there is excess cholesterol in LDL particles if the VLDL particles are shedding their triglyceride content. Dave suggests that the drop-off rate of LDL cholesterol remains relatively standard on a per-particle basis in a healthy subject. They discuss the variability and source of cholesterol in LDL particles and acknowledge the need for further research and understanding in this area. Overall, the conversation emphasizes the need to explore the underlying mechanisms and dynamics of cholesterol distribution to fully comprehend its impact on health.

Understanding the Complexity of LDL Cholesterol Regulation.

The regulation of LDL cholesterol levels in the body is a complex process. The discussion revolves around understanding where the excess LDL cholesterol in a patient is coming from. While the idea of recycling cholesterol is presented, the consensus is that the patient is likely producing more cholesterol rather than solely relying on recycling. The liver plays a crucial role in both the synthesis and degradation of cholesterol. However, the demand for cholesterol, especially for cell membranes, is a determining factor in the overall cholesterol levels. It is clear that there are various factors at play in the regulation of cholesterol, including the demand for cholesterol in different tissues for growth and cellular functions.

The Impact of Dietary Fat on LDL Cholesterol Levels

Dietary fat can have a significant impact on LDL cholesterol levels. Both Peter Attia and Dave Feldman discuss their personal experiences with high-fat diets and fasting, noting that caloric deprivation and fat deprivation can lead to a decrease in LDL cholesterol. They also mention that eliminating saturated fats from the diet may help reverse the increase in LDL cholesterol seen in some individuals. However, they acknowledge that more research is needed, particularly examining the effects of weight training and resistance training on LDL cholesterol levels. Overall, this conversation highlights the complexity of lipid metabolism and the need for further investigation into the relationship between diet, fasting, and LDL cholesterol.

Improving Cardiovascular Health on a Ketogenic Diet by Focusing on Fat Quality

A young man on a ketogenic diet experienced exceptional performance and mental well-being. However, his lab results showed alarming levels of LDLP, indicating a potential risk for heart disease. Despite the risks, the man was unwilling to give up the ketogenic diet and prioritize his long-term health. To address this, they hypothesized that it was the saturated fat, rather than the ketones, that was causing the issue. By reducing saturated fat intake to 25 grams per day and increasing monounsaturated fats through olive oil and macadamia nuts, the man's lab results improved significantly. This approach was tested on six more patients, who also showed positive results. This suggests that by focusing on the quality of fats consumed, it is possible to mitigate any negative effects of a ketogenic diet on cardiovascular health. However, it is important to consider the potential risks of increasing peroxidation levels when adding more polyunsaturated fats.

Exploring the Complexity of Biomarkers and Health Outcomes

There is still much uncertainty and ongoing research when it comes to understanding the relationship between various biomarkers and health outcomes. Peter Attia and Dave Feldman discuss their different perspectives and theories on cholesterol and lipids, highlighting the complexity of the human body and the need for further investigation. While they discuss factors like arachidonic acid levels, APOE gene, and glycogen stores, they both acknowledge that their sample sizes and understanding are limited. However, they emphasize the importance of thought experiments and considering different hypotheses to deepen our understanding of how the body functions. This conversation highlights the need for continued research and open-mindedness in the field of health and nutrition.

The impact of carbohydrate intake on LDL cholesterol levels

Carbohydrate intake, particularly around the threshold of 90 net carbs per day, seems to have a significant impact on LDL cholesterol levels in individuals. This effect is observed when the person consistently maintains this carbohydrate level for about 3 days. Lowering carbohydrate intake to 70 net carbs per day does not yield the same results. Additionally, the conversation highlights the need for long-term studies to determine if these effects are transient or lasting. It also emphasizes the importance of understanding if high LDL particle count (LDL P) due to a ketogenic diet increases the risk of cardiovascular disease. While the role of remnant lipoproteins is debatable, the evidence pointing to the causal relationship between LDL P and APO B is substantial.

The importance of balanced skepticism and evidence in the low carb community.

Dismissiveness and rejection of mainstream information can be dangerous in the low carb community. While it is important to question the quality of evidence and be critical of established institutions, it is equally crucial to consider the body of literature and evidence available. The conversation highlights that the food pyramid and previous nutritional guidelines may have been flawed, but it does not necessarily imply a grand conspiracy. It is essential to differentiate between strong personalities and lousy science. On one hand, there is evidence pointing towards the causal role of LDL in atherosclerosis, and on the other hand, there are concerns regarding the improper use of statins without considering the pathophysiology of the disease. The key lies in a measured approach that carefully considers the literature and evidence available.

The Complexity of LDL Particles and Atherosclerosis

While LDL particles are important in the development of atherosclerosis, they are not the sole cause. LDL is necessary but not sufficient for the condition. Just as ambulances are necessary for ambulance-related deaths but not the direct cause, LDL particles play a crucial role in atherosclerosis but are not the sole culprit. It is important to distinguish between association and causation when studying the relationship between LDL particles and atherosclerosis. Additionally, not all individuals with familial hypercholesterolemia (FH) have completely defective LDL receptors, indicating that the metabolism of lipoproteins is not always impeded in these individuals. The conversation highlights the complexity of these issues and the need for careful analysis and understanding.

The Role of LDL in Atherosclerosis

LDL, or low-density lipoprotein, plays a significant role in the development of atherosclerosis, along with endothelial dysfunction and inflammation. While there may be other factors and genetic variations involved in lipid metabolism, it is crucial to acknowledge the strong evidence linking LDL to the formation of atherosclerotic plaques. Skepticism is an essential aspect of scientific inquiry, but at some point, the probability becomes disproportionately evident. LDL's involvement in atherosclerosis is nearly 100% when considering its contribution to plaque development. However, it is important to note that nobody reasonable claims LDL to be the sole factor, as endothelial dysfunction and inflammation are also necessary components. These three factors form a metaphorical "three-legged stool" in understanding atherosclerosis.

Evaluating the Impact of Oxidative Stress on LDL Particles: Perspectives and Limitations

The nature of complicated biology means that no single factor is sufficient to determine the impact of oxidative stress on LDL particles. The discussion revolves around whether it is preferable to have 1000 or 2000 LDL particles when faced with the same level of oxidative stress. One of the speakers initially believed that having 1000 LDL particles was better, but his viewpoint changed based on new knowledge and personal data. They also touch upon the importance of anti-oxidative defense systems and measurements like CIMT. The conversation highlights the need to consider various perspectives and individual physiological responses when evaluating the relationship between LDL particles and cholesterol. It emphasizes the limitations of existing scientific literature and the importance of critically analyzing the data.

The Complexity of Cholesterol Production in Insulin Resistance

There is a discrepancy between the expected cholesterol levels and the actual cholesterol production in individuals with insulin resistance. The discussion revolves around the idea that if someone is solely focused on energy, they should not be producing any additional cholesterol. However, in cases of insulin resistance, patients do produce more cholesterol, particularly in the form of VLDLs. This suggests that there are factors beyond energy considerations that influence cholesterol production and composition. The conversation highlights the complexity of assessing remnant cholesterol and emphasizes the need for direct testing to accurately measure LDL and LP little a cholesterol. Ultimately, the differences in cholesterol levels are primarily driven by the LDL particle rather than the VLDL particle.

Considering All Perspectives and the Need for Further Research in the Relationship Between High LDL and Cardiovascular Disease

While there is ongoing debate and uncertainty regarding the relationship between high LDL (low-density lipoprotein) and cardiovascular disease, it is important to consider all perspectives. Dave Feldman and Peter Attia discuss the need for kinetic studies on people who are fat adapted or follow a ketogenic diet in order to better understand the impact of triglyceride content. Peter emphasizes that there may be no good reason, from a cardiovascular standpoint, to have high LDL cholesterol levels, while there could be other reasons for elevated LDL in certain medical conditions. It is also highlighted that biology is complex, and factors like bilirubin levels can have a U-shaped curve in terms of cardiovascular disease risk. Ultimately, the conversation emphasizes the need for further research and comprehensive understanding in this area.

Challenging the Conventional Understanding of Lipid Profiles and Health Risks

Dave Feldman is advocating for a broad-based study of individuals with specific lipid profiles (high HDL, low triglycerides, and high LDL) to determine if they have high rates of cardiovascular disease and all-cause mortality. He believes that studying this population, without considering genetic factors or medication use, could yield significant data that challenges the conventional understanding of the relationship between high LDL levels and health risks. While Peter Attia acknowledges the importance of genetic factors and patient-specific variables in understanding phenotypes, he raises concerns about the feasibility and validity of such a study. Ultimately, this conversation highlights the need for further research to better understand the complexities of lipid profiles and their impact on health outcomes.

Challenges in accessing data hinder medical research in lipid function analysis, as highlighted by Dave Feldman's frustration and Peter Attia's cautionary advice.

Dave Feldman is frustrated by the cultural difference between medicine and software in terms of accessing data. He has been trying to obtain a large dataset that allows him to stratify on three axes - triglycerides, HDL, and preferably LDL p - to determine the validity of the energy model. However, he has faced challenges in accessing the data and getting the necessary information. Peter Attia emphasizes that focusing solely on HDL cholesterol and triglycerides may not provide a comprehensive understanding of lipid function. He suggests that if Dave were to hang his hat on those markers against LDL C or APO B or LDLP, it would likely fail.

The limitations of relying solely on HDL cholesterol for assessing lipid metabolism.

Relying solely on HDL cholesterol (HDLC) as a metric for assessing lipid metabolism is flawed. Peter Attia emphasizes that HDLC is a crude and simplistic marker that lacks utility in predicting cardiovascular disease risk accurately. He dismisses the idea that high HDLC and low triglyceride levels can overshadow the importance of LDL cholesterol (LDLC). Peter stresses the need for a deeper understanding of lipid metabolism, urging Dave Feldman to engage with lipid experts to broaden his knowledge. Furthermore, he emphasizes that in science, nothing can be completely proven, only supported by probability. Therefore, Peter advises against ignoring LDLC based on anecdotes or incomplete datasets. The conversation highlights the complexity of lipid metabolism and the need for comprehensive assessments beyond HDLC.

Evaluating Research and Challenging Beliefs: Peter Attia on the Importance of Critical Analysis and Comprehensive Understanding.

When evaluating new research or data, it is essential to consider how it fits into the existing body of literature and challenge the null hypothesis. In this case, Peter Attia emphasizes the importance of looking at the lipid hypothesis and how it is supported or contradicted by new findings. He also highlights the need for comprehensive understanding by considering multiple factors that contribute to pathology, such as lipoprotein, endothelial damage, and inflammatory changes. Additionally, he discusses the significance of reducing risk factors like blood pressure and smoking to improve outcomes. It is crucial to approach research with an open mind, seeking truth rather than simply confirming existing beliefs, and engaging with experts in the field to gain deeper insights.

Collaboration, Knowledge, and Progress

Both Dave Feldman and Peter Attia are willing to collaborate and challenge the existing model. Despite their tangents and limited knowledge, they appreciate each other's time and expertise. Dave Feldman acknowledges his limited experience and eagerness to fill the gaps in his knowledge, while Peter Attia expresses his willingness to help. They discuss the timing of the release and understand that their conversation may spark curiosity and inquiries from their audience. Overall, the key takeaway is that collaboration and a thirst for knowledge are crucial in breaking down existing models and progressing forward.