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    #22 - Tom Dayspring, M.D., FACP, FNLA – Part III of V: HDL, reverse cholesterol transport, CETP inhibitors, and apolipoproteins

    enOctober 17, 2018

    Podcast Summary

    • The Complex Process of Reverse Cholesterol Transport (RCT)Understanding Reverse Cholesterol Transport (RCT) is essential for maintaining a healthy cholesterol balance and preventing complications, as LDL and HDL cholesterol levels alone do not provide a complete picture.

      Understanding cholesterol homeostasis is more complex than just looking at LDL and HDL cholesterol levels. Reverse cholesterol transport (RCT) plays a crucial role in removing excess cholesterol from the body. It involves the process of cells effluxing cholesterol, which can then be transported by HDL particles back to the liver. The liver can utilize the cholesterol or excrete it through bile. However, the reabsorption of bile salts by the ileum can limit the effectiveness of RCT. It is important to recognize that LDL and HDL cholesterol measurements do not provide a complete picture of the intricate movement and trafficking of cholesterol. A deeper understanding of RCT is necessary to maintain proper cholesterol balance and prevent complications.

    • The Complexities of Cholesterol Transport in the BodyHigh levels of HDL cholesterol do not necessarily indicate efficient reverse cholesterol transport, as there are multiple pathways for cholesterol to be transported back to the liver, including the use of receptors and free diffusion. Further research is needed to understand the implications for conditions like familial hypercholesterolemia.

      The understanding of cholesterol transport in the body is more complex than previously thought. It was commonly believed that high levels of HDL cholesterol indicated efficient reverse cholesterol transport, as HDL would take cholesterol back to the liver. However, further research has revealed multiple pathways for cholesterol to be transported back to the liver, including the use of receptors and free diffusion. Additionally, it has been found that red blood cells and albumin can also accept free cholesterol through diffusion, providing another pathway for LDL particles to acquire cholesterol. This newfound complexity challenges the traditional view of cholesterol transport and suggests the need for further investigation into its implications for conditions like familial hypercholesterolemia.

    • The Complexity of HDLs in Lipidology: A Challenging Task for ExpertsThe theory of forward cholesterol transport is an oversimplification as multiple particles, including VLDL and chylomicrons, play a role in this process, emphasizing the need for further exploration and understanding.

      Understanding the complexity of high-density lipoproteins (HDLs) in lipidology is a challenging task. Even experts like Peter Attia and Thomas Dayspring admit their limitations in comprehending HDLs fully. It is particularly crucial to note that the early theory of forward cholesterol transport, with APO B family carrying cholesterol to tissues and HDL family bringing it back, is an oversimplification. For instance, VLDL and chylomicrons released by the liver or intestine play a role in the forward cholesterol transportation system. But when these particles lose core triglycerides and phospholipids, they become remnants and are swiftly cleared by receptors primarily found in the liver. This process involves APOE receptors, which contribute to the rapid clearance of VLDLs, chylomicrons, and intermediate-density lipoproteins (IDLs). Ultimately, this conversation highlights the intricate mechanisms involved in lipoprotein transportation and emphasizes the need for further exploration and understanding.

    • APOE and APOC3: Key Factors in Cardiovascular HealthAPOE enhances clearance of LDL particles, reducing the risk of heart disease, while APOC3 increases atherogenicity. Measuring APOC3 levels could identify remnant lipoproteins and inform cardiovascular management.

      APOE is an important ligand that greatly affects the efficacy and clearance of LDL particles. If someone has the genetic gift of expressing APOE on their LDL particles, their clearance rate is enhanced, resulting in lower levels of APOB and LDL particles, which reduces the risk of heart disease. Additionally, APO lipoprotein C3 plays a role in increasing the atherogenicity of LDL particles. Therefore, measuring APOC3 levels through an assay or genetic testing could be a valuable tool in identifying remnant lipoproteins that may contribute to arterial wall issues. Furthermore, higher APOC3 levels indicate a higher risk, independent of lipid profiles, making it an important factor to consider. Pharmaceutical companies are even developing APOC3 inhibitors to address this concern. Overall, this conversation highlights the significance of APOE and APOC3 in understanding and potentially managing cardiovascular health.

    • The Role of Insulin Resistance in Lipoprotein PathologiesInsulin resistance leads to an increase in LDL particle numbers and VLDL levels, emphasizing the importance of evaluating absolute changes in lipid markers for insulin-resistant patients.

      Insulin resistance plays a significant role in the increase of LDL particle numbers and VLDL levels. Thomas Dayspring emphasizes that triglyceride-rich lipoprotein pathologies, which are commonly associated with insulin resistance, lead to higher levels of VLDL particles. These VLDL particles, with APOC 3, have a longer plasma residence time and are converted into LDL particles. As a result, LDL particle numbers skyrocket, while VLDL particles only double or triple in quantity. Peter Attia highlights that it's crucial to consider absolute changes rather than just relative changes when evaluating lipid markers. He also questions the accuracy of using VLDL cholesterol as a measurement for VLDL remnants, suggesting it is a crude estimation. Despite this, targeting a VLDL cholesterol level below 15 milligrams per episode is still recommended for insulin-resistant patients.

    • Understanding Lipid Transportation Systems and Particle Numbers in Clinical AssessmentsParticle numbers, specifically APOB or LDL particle number, are crucial in accurately assessing and making clinical decisions regarding cholesterol levels. Understanding the role of different particles in lipid transportation is also important.

      The therapy used to reduce LDL particles also helps in getting rid of remnant lipoproteins. Normalizing APOB or LDL particle number is crucial in making clinical decisions. There is a significant discordance between APOB or LDL particle number and non HDL cholesterol, indicating the need to rely on particle numbers for accurate clinical assessments. Alan Snyderman, who is highly respected in this field, emphasizes the importance of using particle numbers to make appropriate clinical decisions. Furthermore, it is important to understand the role of chylomicrons and VLDLs in delivering triglycerides, not cholesterol, to specific cells in the body. Cholesterol in these particles serves a structural purpose, making them spherical and allowing them to carry more triglycerides. Overall, this conversation highlights the significance of understanding lipid transportation systems and the role of different particles in cholesterol delivery.

    • The Actions of Lipoproteins Determine the Classification of CholesterolThe terms "good" and "bad" cholesterol can be misleading, as it is the actions of lipoproteins that determine whether cholesterol is beneficial or detrimental to the body.

      Cholesterol molecules are not inherently good or bad. What determines their classification is what the lipoprotein carrying the cholesterol does with it. HDL, often referred to as "good cholesterol," acts as a cholesterol acceptor and helps cells get rid of excess cholesterol. When HDL acquires free cholesterol, it transforms it into cholesterol ester and transfers it to other lipoproteins like LDL, commonly known as "bad cholesterol." However, the cholesterol molecule itself remains the same throughout this process. It is the actions of the lipoproteins that determine whether the cholesterol is beneficial or detrimental. Therefore, using terms like "good" and "bad" cholesterol can be misleading and should be avoided when discussing cholesterol with patients.

    • The importance of considering multiple lipid metrics in cardiovascular risk assessmentLDL cholesterol alone is not enough to accurately assess cardiovascular risk; other factors like HDL cholesterol, triglycerides, and APOB should also be considered for a comprehensive assessment.

      LDL cholesterol alone is not the only important factor when assessing cardiovascular risk. Many people argue that LDL cholesterol is irrelevant because it is calculated and not directly measured, introducing variability. However, it is important to consider other factors such as HDL cholesterol, triglycerides, and APOB as they are proxies for APOB, which is a strong indicator of atherosclerotic disease. Adjusting for APOB would significantly impact the role of low HDL cholesterol as an independent risk factor. Studies like the multi-ethnic study of atherosclerosis (MESA) and the Framingham offspring study offer valuable insights into the relationship between lipid metrics and cardiovascular risk. It is important to consider a comprehensive assessment of lipid levels when making recommendations for patient risk assessment.

    • The Limitations of Cholesterol Levels in Assessing Atherosclerosis RiskCholesterol levels alone may not accurately predict the risk of atherosclerosis, as demonstrated in a case where a woman had elevated atherosclerosis despite normal LDL levels. Other cardiovascular risk factors should be considered for a comprehensive assessment. CTP inhibitors show potential in addressing HDL dysfunction.

      Cholesterol levels alone cannot accurately determine the risk of atherosclerosis. In the case discussed, a woman had elevated atherosclerosis despite having normal levels of LDL ("bad" cholesterol) and high levels of HDL ("good" cholesterol). This was due to a rare genetic condition where the cholesterol trafficking pattern was disrupted, resulting in dysfunctional HDL particles that could not effectively clear cholesterol. Lowering APOB was found to be the only treatment option. It is important to consider other cardiovascular risk factors and not solely rely on cholesterol levels. The CTP inhibitors were mentioned as potential drugs to address HDL dysfunction, pointing to an interesting area of research in the field of cardiovascular health.

    • The Intricacies of Cholesterol Transfer and the Importance of HDL and LDL TeamworkHDL cholesterol levels alone do not provide a complete understanding of its function. More specific biomarkers are needed to accurately assess HDL function and improve treatment and nutrition therapies.

      The process of cholesterol transfer within the body is highly intricate and involves multiple lipoproteins. HDL is responsible for pulling cholesterol out of cells and can transfer it to LDL particles. Surprisingly, 30 to 60 percent of the cholesterol in LDL particles comes from HDL particles. This teamwork between HDL and LDL is essential for proper lipid transportation. However, the measurement of HDL cholesterol levels alone does not provide a complete understanding of its functional status. More specific biomarkers are needed to assess HDL function accurately. The complexity of the lipid transportation system suggests that the term "reverse cholesterol transport" is overly simplistic and lacking in true understanding. Therefore, it is crucial to delve deeper into the intricacies of cholesterol transfer for effective treatment and nutrition therapies.

    • The Role of HDL Subpopulations in Transporting Substances to CellsUnderstanding HDL functionality is still limited and attempts to increase HDL levels through drugs have been unsuccessful. High HDL cholesterol levels may not provide protection against coronary atherosclerosis.

      HDL subpopulations, with their various proteins and phospholipids, play a vital role in transporting necessary substances to specific cells in the body. Similar to how fire departments dispatch different trucks to different types of fires, HDL subpopulations show up where they are needed based on the recognition of proteins or phospholipids on their surface by the cells that need them. However, there is still much we don't understand about HDLs and how to analyze them effectively. Attempts to raise HDL levels through drugs like niacin and CTEP inhibitors have not been successful due to limited knowledge and understanding of HDL functionality. Furthermore, individuals with high HDL cholesterol levels may not necessarily have protection against coronary atherosclerosis, suggesting that other factors like APOE may be involved in the clearance of cholesterol.

    • Reevaluating the Use of CETP Inhibitors for Raising HDL Cholesterol LevelsRaising HDL cholesterol alone does not provide cardiovascular benefits, highlighting the importance of comprehensive research and a nuanced approach to addressing cardiovascular risk factors.

      The use of CETP inhibitors to raise HDL cholesterol levels was a misguided approach in the past. It was believed that raising HDL cholesterol through CETP inhibition would provide cardiovascular benefits. However, subsequent research, such as Mendelian randomization studies, showed that high HDL cholesterol does not necessarily protect against heart disease. The lack of understanding about the complex interplay between different lipid markers and genes led to the development of ineffective drugs. This highlights the importance of comprehensive research before developing medications that target specific markers. Additionally, it emphasizes the need for a nuanced approach in addressing cardiovascular risk factors, rather than solely focusing on one biomarker like HDL cholesterol.

    • Unexpected Challenges and Costly Trials in Drug DevelopmentDrug development can be unpredictable and expensive, with unexpected toxicities leading to the termination of trials. Despite setbacks, companies continue research to find safer and more effective alternatives in lowering APO B levels.

      The development of certain drugs can be unpredictable and costly. The trial for the drug Torsetropip was initially thought to be a sure success but was ultimately terminated due to unforeseen toxicities. Despite this setback, Pfizer and other companies continued their research and developed different CTEP inhibitors. One such inhibitor, Dalsetripib, showed promising results with minimal toxicity. However, due to the expense of conducting trials and the availability of more effective alternatives like PCSK9 inhibitors, further development of Dalsetripib was discontinued. Merck was the only company to successfully complete a trial for a potent CTEP inhibitor, but concerns about its long-term effects and lack of significant benefits led them to choose not to bring it to market. The focus shifted towards finding safer options that could effectively lower APO B levels.

    • Balancing Innovation and Safety in Pharmaceutical DevelopmentThe pharmaceutical industry must carefully consider the potential risks and benefits of new drugs, prioritizing patient safety and adhering to strict regulations to avoid harm and legal repercussions.

      The pharmaceutical industry faces the challenge of balancing the potential benefits and risks of new drugs. In particular, the discussion highlights the case of Merck, who decided not to commercialize a product despite successful trials. This decision was driven by concerns about the long-term consequences and potential harm to other biological systems, as well as the strict regulations imposed by the FDA. The conversation also references the example of Vioxx, a drug that was hailed as a breakthrough but later withdrawn due to safety concerns. These instances illustrate the delicate balance between bringing innovative treatments to market and ensuring patient safety. It underscores the importance of taking a cautious and responsible approach in pharmaceutical development to avoid legal consequences and harm to patients.

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    • Methods of measuring HRV: EKG, wrist-based sensors, and more [11:30];
    • How HRV is calculated from the data [22:30];
    • The role of the autonomic nervous system (ANS) in regulating HRV [25:45];
    • The decline in HRV with age, and the mitigating effects of fitness and other lifestyle factors [33:30];
    • The role of genetics in HRV, the modifiability of HRV, and a comparison of VO2 max and HRV as predictors of mortality [37:00];
    • How aging affects HRV and sympathetic drive, and the importance of spontaneous movement and exercise in maintaining the body's adaptability [43:30];
    • How Morpheus measures HRV using RMSSD and normalizes it to a 100-point scale for easier interpretation [49:45];
    • The Morpheus system: development, integration with various metrics, and personalized daily training recommendations to optimize fitness and recovery [51:30];
    • The benefits of morning HRV readings for assessing daily readiness compared to overnight HRV measurements [1:03:00];
    • Why Morpheus recommends using a chest strap rather than an arm band [1:10:00];
    • The impact of consistent exercise, stress, alcohol, and other lifestyle factors on HRV [1:11:15];
    • Optimizing zone 2 training with Morpheus [1:18:15];
    • Using heart rate recovery (HRR) as an indicator of athletic conditioning and the balance between aerobic and anaerobic systems [1:22:45];
    • The importance of tracking HRV trends over time rather than focusing on data from a given day [1:29:00];
    • Effect of GLP-1 agonists on heart rate and HRV [1:34:45];
    • Where HRV belongs in the hierarchy of health metrics [1:42:00];
    • Parting thoughts [1:46:30]; and
    • More.

    Connect With Peter on TwitterInstagramFacebook and YouTube

    The Peter Attia Drive
    enJune 10, 2024

    #304 – NEW: Introducing quarterly podcast summaries - Peter shares his biggest takeaways on muscle protein synthesis, VO2 max, toe strength, gut health, and more

    #304 – NEW: Introducing quarterly podcast summaries - Peter shares his biggest takeaways on muscle protein synthesis, VO2 max, toe strength, gut health, and more

    View the Show Notes Page for This Episode

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    In this quarterly podcast summary (QPS) episode, Peter introduces a new format aimed at summarizing his biggest takeaways from the last three months of guest interviews on the podcast. Peter shares key insights from each episode, covering diverse topics such as protein and muscle building with Luc van Loon, toe strength with Courtney Conley, VO2 max with Olav Aleksander Bu, liquid biopsies for cancer with Alex Aravanis, gut health and probiotics with Colleen Cutcliffe, and road safety with Mark Rosekind. Additionally, Peter shares any personal behavioral adjustments or modifications to his patient care practices that have arisen from these engaging discussions.

    If you’re not a subscriber and are listening on a podcast player, you’ll only be able to hear a preview of the AMA. If you’re a subscriber, you can now listen to this full episode on your private RSS feed or our website at the episode #304 show notes page. If you are not a subscriber, you can learn more about the subscriber benefits here.

    We discuss:

    • How Peter keeps track of his takeaways from each podcast episode [5:15];
    • Luc van Loon episode: fat utilization, muscle protein synthesis, dietary protein, aging and inactivity, and more [8:45];
    • Behavioral changes that have come about from the conversation with Luc van Loon [23:45];
    • Courtney Conley episode: importance of toe strength and the impact of dedicated foot training [26:45];
    • Olav Aleksander Bu episode: the importance of VO2 max for lifespan, and the practicalities of measuring and improving VO2 max [36:45];
    • Behavioral changes that have come about from the conversation with Olav [56:00];
    • Alex Aravanis episode: liquid biopsies for cancer detection [1:01:30];
    • Colleen Cutcliffe episode: the importance of gut bacteria balance, and the potential therapeutic uses of probiotics, particularly Akkermansia [1:16:45];
    • Mark Rosekind: the significant issue of road fatalities and injuries, their causes, and practical safety measures to reduce risks [1:27:00]; and
    • More.

    Connect With Peter on TwitterInstagramFacebook and YouTube

    The Peter Attia Drive
    enJune 03, 2024

    #303 - A breakthrough in Alzheimer’s disease: the promising potential of klotho for brain health, cognitive decline, and as a therapeutic tool for Alzheimer's disease | Dena Dubal, M.D., Ph.D.

    #303 - A breakthrough in Alzheimer’s disease: the promising potential of klotho for brain health, cognitive decline, and as a therapeutic tool for Alzheimer's disease | Dena Dubal, M.D., Ph.D.

    View the Show Notes Page for This Episode

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    Dena Dubal is a physician-scientist and professor of neurology at UCSF whose work focuses on mechanisms of longevity and brain resilience. In this episode, Dena delves into the intricacies of the longevity factor klotho: its formation and distribution in the body, the factors such as stress and exercise that impact its levels, and its profound impact on cognitive function and overall brain health. Dena shares insights from exciting research in animal models showing the potential of klotho in treating neurodegenerative diseases as well as its broader implications for organ health and disease prevention. She concludes with an optimistic outlook for future research in humans and the potential of klotho for the prevention and treatment of Alzheimer’s disease.

    Disclosure: Peter is an investor in Jocasta Neuroscience, a company working to develop klotho as a therapy for people with Alzheimer’s disease.

    We discuss:

    • Dena’s fascination with aging and how she came to study klotho [3:30];
    • Biological properties of klotho: production, regulation, decline with age, and factors influencing its levels [11:45];
    • Potential benefits of klotho on brain health [22:00];
    • The relationship between soluble klotho protein, platelet factors, and cognitive enhancement [33:45];
    • The role of platelet factor 4 (PF4) and it’s interaction with GluN2B in mediating cognitive enhancement [46:45];
    • Benefits of klotho observed in a mouse model of Parkinson’s disease [55:45];
    • Benefits of klotho observed in a mouse model of Alzheimer’s disease [1:03:00];
    • Promising results of klotho in primate models, and the importance of finding an appropriate therapeutic dose before moving to human trials [1:08:00];
    • Speculating why a single klotho injection has such long-lasting effects [1:25:30];
    • Potential cognitive benefits of klotho in humans, the impact of the KL-VS genetic variant on klotho levels, and the need for human trials to confirm these effects [1:27:45];
    • The interaction between the KL-VS genetic variant and APOE4 and how it impacts risk of Alzheimer’s disease [1:34:45];
    • The significance of klotho levels: studies linking lower levels to increased mortality and the broader implications for organ health and disease prevention [1:47:15];
    • Measuring klotho levels and determining an individual’s KL-VS status [1:52:15];
    • The promising potential of klotho for Alzheimer’s disease treatment, and the importance of philanthropy for funding research [1:58:00]; and
    • More.

    Connect With Peter on TwitterInstagramFacebook and YouTube

    The Peter Attia Drive
    enMay 27, 2024

    #302 - Confronting a metabolic epidemic: understanding liver health and how to prevent, diagnose, and manage liver disease | Julia Wattacheril, M.D., M.P.H.

    #302 - Confronting a metabolic epidemic: understanding liver health and how to prevent, diagnose, and manage liver disease | Julia Wattacheril, M.D., M.P.H.

    View the Show Notes Page for This Episode

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    Julia Wattacheril is a physician scientist and director of the Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) program at Columbia University Irving Medical Center. In this episode, Julia delves deep into the complex world of liver health, beginning with a foundational overview of liver physiology. She provides an in-depth look at how alcohol impacts liver function, breaking down the metabolism of ethanol and its detrimental effects. Julia then shifts the focus to understanding liver function tests and optimal enzyme levels, providing a detailed explanation of AST and ALT and elucidating why fluctuations in these levels may or may not be concerning. She provides a primer on the four major stages of liver disease, discussing risk and emphasizing the importance of early diagnosis. Julia highlights the role of liver disease in increasing the risk of cancer and cardiovascular disease and covers in detail the various strategies for diagnosing, treating, and preventing the progression of liver disease.

    We discuss:

    • Julia’s training, the importance of liver health, and the challenges and innovations of hepatology [3:15];
    • The complex and crucial functionality of the liver, its four most essential functions, and more [8:45];
    • Liver injuries: historical and evolving understanding of causal factors, and the progression to liver diseases and cancer [13:15];
    • How the liver metabolizes nutrients and what happens in the presence of excess calories or alcohol [24:45];
    • Methods of diagnosing liver disease and how insights guide treatment and management strategies [33:30];
    • The poisonous nature of ethanol to the liver [40:30];
    • Varied responses to alcohol, damaging effects of alcohol beyond the liver, and the process of advising patients on their alcohol consumption [47:15];
    • Understanding liver enzymes AST and ALT—interpreting levels, lifestyle factors that affect them, and diagnostic approaches [58:30];
    • Interpreting liver function tests for fatty liver disease, and the challenges of diagnosing liver pathologies, particularly in children versus adults [1:13:15];
    • Comprehensive liver health assessments via imaging and various diagnostic tools to prevent overlooking potential liver pathologies [1:18:45];
    • Potential impact of recreational drugs, statins, and other medications on liver function test results [1:26:45];
    • Shifting nomenclature from NAFLD to MASLD to reflect accuracy in the underlying pathophysiology and understanding of liver diseases [1:30:30];
    • Pathophysiology of MASLD, the need for proactive screening, and the significance of liver fat percentage as an indicator of metabolic health [1:36:30];
    • The importance of screening for rare conditions alongside common metabolic diseases associated with fatty liver accumulation [1:42:45];
    • Practical strategies for managing MAFLD [1:45:30];
    • The impact of fructose consumption on liver health and the challenges of disentangling its effects from other factors like obesity and insulin resistance [1:52:45];
    • The potential of GLP-1 agonists for the treatment of MASLD [1:57:45];
    • How the four stages of liver disease have evolved [2:00:30];
    • Increased cancer and heart disease risk associated with early-stage MAFLD [2:05:15];
    • Emerging drugs and therapies for addressing fat accumulation and fibrosis related to MAFLD [2:12:15];
    • Peter’s major takeaways [2:18:45]; and
    • More.

    Connect With Peter on TwitterInstagramFacebook and YouTube

    The Peter Attia Drive
    enMay 20, 2024

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