lipoproteins

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Dan Rader is a Professor at the Perelman School of Medicine at the University of Pennsylvania, where he conducts translational research on lipoprotein metabolism and atherosclerosis with a particular focus on the function of high-density lipoproteins (HDLs). In this episode, Dan goes in-depth on HDL biology, including the genesis of HDL, its metabolism, function, and how this relates to atherosclerotic cardiovascular disease (ASCVD). He explains why having high HDL-C levels does not directly translate to a low risk of cardiovascular disease and reveals research pointing to a better way to measure the functionality of HDL and predict disease risk. He also goes into detail on the role of HDL in reverse cholesterol transport and the benefits this has for reducing ASCVD. Additionally, Dan discusses the latest thinking around the association between HDL cholesterol and neurodegenerative diseases and ends the conversation with a discussion of how the latest research on HDL provides a promising outlook for ongoing trials and future therapeutic interventions.

We discuss:

• The lipidology of apoB and apoA [4:00];
• A primer on the high-density lipoprotein (HDL): genesis, structure, and more [9:30];
• How the lipoprotein system differs in humans compared to other mammals [20:00];
• Clarifying the terminology around HDL and apoA [25:30];
• HDL metabolism [31:45];
• CETP inhibitors for raising HDL-C: does it reduce CVD risk? [34:45];
• Why it’s so important to have hard outcome trials in the field of cardiovascular medicine [42:30];
• SR-B1: an HDL receptor important for cholesterol efflux [48:00];
• The association between HDL levels and atherosclerosis: are they causally linked? [53:15];
• How insulin resistance is impacting HDL, and how HDL-C provides insights into triglyceride metabolism [58:00];
• Disappointing results from the studies of niacin—a drug that raises HDL-C and lowers apoB [1:08:15];
• HDL lipidation, dilapidation, and reverse cholesterol transport [1:12:00];
• Measuring the cholesterol efflux capacity of HDL: a better predictor of ASCVD risk than HDL-C? [1:22:00];
• A promising new intervention that may promote cholesterol efflux and reverse cholesterol transport [1:32:45];
• The association between HDL cholesterol and neurodegenerative diseases [1:34:00];
• Challenges ahead, a promising outlook, and the next frontier in lipidology [1:44:45]; and
• More.

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In this “Ask Me Anything” (AMA) episode, Peter answers questions related to the leading cause of death in both men and women—atherosclerotic cardiovascular disease (ASCVD). He highlights the most important risk factors for ASCVD, such as apoB, LDL, hyperinsulinemia, and Lp(a), and explains the mechanism by which they confer risk and how these factors are interrelated. Peter also dives deep into the data around apoB to try to answer the question of how much residual risk is conferred for ASCVD through metabolic dysfunction once you correct for apoB. He also looks at the data around lifetime risk reduction of ASCVD in the context of low apoB.

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We discuss:

• A racecar analogy for understanding atherosclerotic cardiovascular disease [2:00];
• Defining and differentiating apoB and LDL-C [10:00];
• The interrelated nature of insulin levels, apoB, triglycerides, and ASCVD parameters [13:00];
• Another way that hyperinsulinemia plays a role in endothelial dysfunction [18:00];
• Why Peter uses the oral glucose tolerance test (OGTT) with all patients [20:15];
• Is there any evidence that hyperinsulinemia is an independent contributor to ASCVD? [23:00];
• Thinking through risk in the context of high-fat diets resulting in improved metabolic metrics but with an elevation of apoB/LDL-C [27:30];
• Thinking through risk in the context of low apoB but higher than normal triglyceride levels [32:15];
• The importance of lowering apoB for reducing ASCVD risk [38:15];
• Data on men and women with familial hypercholesterolemia that demonstrates the direct impact of high apoB and LDL-C on ASCVD risk [47:45];
• Importance of starting prevention early, calcium scores, and explaining causality [52:30];
• Defining Lp(a), its impact on ASCVD risk, and what you should know if you have high Lp(a) [56:30];
• Lp(a) and ethnic differences in risk [1:00:30];
• Why someone with elevated Lp(a) should consider being more aggressive with apoB lowering strategies [1:05:00];
• Addressing the common feeling of hesitancy to taking a pharmacologic approach to lower ASCVD risk [1:07:15];
• Peter’s take on the 2022 Formula 1 season and thoughts on 2023 [1:15:15]; and
• More.

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Today's episode of The Qualys is from podcast #03 – Ron Krauss, M.D.: a deep dive into heart disease.

The Qualys is a subscriber-exclusive podcast, released Tuesday through Friday, and published exclusively on our private, subscriber-only podcast feed. Qualys is short-hand for “qualifying round,” which are typically the fastest laps driven in a race car—done before the race to determine starting position on the grid for race day. The Qualys are short (i.e., “fast”), typically less than ten minutes, and highlight the best questions, topics, and tactics discussed on The Drive.

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In this episode, Dave Feldman, discusses his journey from software engineer to n=1 experimenter, his experience with low-carbohydrate diets, and his hypothesis that cholesterol levels are influenced by energy metabolism.

We discuss:

• Peter’s synthesis of Dave’s energy model [5:00];
• Dave’s journey from software engineer to cholesterol enthusiast [15:00];
• Standard blood panels, sterol panels, and what moves the needle when it comes to particle numbers [18:30];
• Hyper-responders [20:00];
• Lipoprotein transport [33:45];
• The lean mass hyper-responder phenotype [47:30];
• The progression of atherosclerosis, CAC, and CIMT [52:30];
• Testing for oxidized LDL [55:30];
• All-cause mortality and clinical endpoints [1:01:15];
• What does “LDL as causal” mean? [1:05:15];
• Dave’s low carb cholesterol challenge and drug & genetic study qualifications [1:13:15];
• If all other markers are in an healthy range, but LDL-P is high, is the patient at risk? A couple of case studies, and a self-experiment [1:27:30];
• Peter’s three-day exercise and ketosis experiment [1:41:00];
• What are remnant lipoproteins? [1:45:00];
• What might cause lean mass hyper-responders to have higher LDL particle numbers? [1:53:30];
• A case study from Dave of a lean mass hyper-responder [1:56:30];
• Mass balance and cholesterol flux [2:05:30];
• Can a higher degree of cholesterol explain the lean mass hyper-responder phenotype? [2:10:00];
• Peter’s LDL during his keto-fast-keto experiment [2:13:30];
• Does substituting saturated fats with monounsaturated fats lower LDL-P and LDL-C? [2:15:45];
• Dave’s carb-swap experiments [2:22:15];
• Dave’s carotid intima-media thickness tests [2:41:15];
• Looking for studies that stratify for high HDL-C and low TG alongside low and high LDL-C [2:53:00]; and
• More

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Pronounced, el-pee-little-a, this lipoprotein is simply described as a low density lipoprotein (LDL) that has an apoprotein “a” attached to it...but Lp(a) goes far beyond its description in terms of its structure, function, and the role that it plays in cardiovascular health and disease. Affecting about 1-in-5 people, and not on the radar of many doctors, this is a deep dive into a very important subject for people to understand.

• A quick primer on lipoproteins [7:30];
• Intro to Lp(a) [11:00];
• Lab tests for Lp(a) and reference ranges [20:00];
• The physiologic functions of Lp(a) [31:00];
• The problems associated with high Lp(a) [34:15];
• Lipid-lowering therapies of Lp(a) [44:45];
• Lp(a) modification through lifestyle intervention [1:00:45];
• High LDL-P on a ketogenic/low-carb-high-fat diet [1:05:30]; and
• More

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