CardioNerds Academy Chief Fellows Dr. Rick Ferraro (FIT, Johns Hopkins) and Dr. Tommy Das (FIT, Cleveland Clinic) join Academy fellow Dr. Jessie Holtzman (soon, chief resident at UCSF internal medicine residency) to learn all about LDL physiology and function from Dr. Peter Toth! Low-density lipoprotein cholesterol (LDL-C) has been well established as a risk factor for atherosclerotic cardiovascular disease with an ever growing armamentarium of medications to lower LDL-C plasma levels. Yet, LDL-C also plays a number of key physiologic roles across mammalian species, such as cell membrane formation, bile acid synthesis, and steroid hormone production. In this episode, we discuss the definitions of high, normal, low, and ultra-low LDL-C, what functional assays are used to measure LDL-C, and what is considered the safe lower-limit of LDL-C, if there is one at all. Drawing upon experience from rare genetic conditions including abetalipoproteinemia and loss-of-function variants of the PCSK9 gene, we glean pearls that clarify the risks and benefits of low LDL-C. Relevant disclosure: Dr. Toth has served as a consultant to Amarin, Amgen, Kowa, Resverlogix, and Theravance; and has served on the Speakers Bureau for Amarin, Amgen, Esperion, and Novo Nordisk. Pearls • Quotables • Notes • References • Guest Profiles • Production Team CardioNerds Lipid Series PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Pearls 1. Lipoproteins are processed via two major pathways in mammals: 1) exogenous fat metabolism that digests ingested lipids and 2) endogenous fat metabolism that synthesizes lipids in the liver and small intestine. High density lipoprotein (HDL)-mediated reverse transport also brings lipids from the periphery back to the liver. 2. LDL-C comprises ~70% of plasma cholesterol due to its long half-life of 2-3 days. It is one of 5 major lipid particles in plasma including chylomicrons, very low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), LDL, and HDL. The liver degrades 40-60% of LDL, while no other tissues in the body make up more than 10% of LDL. LDL-C is energy-poor and cholesterol rich, such that peripheral tissues may not utilize these particles as a fuel source. 3. Preserved functions of LDL-C across mammalian species include cell membrane formation, bile acid synthesis, and steroid hormone production. In other mammalian species, LDL-C levels are found in the 35-50 mg/dL range (Way lower than found in the general human population, and likely more representative of baseline human physiology!). 4. Large, randomized control trials do not consistently demonstrate major adverse effects associated with lower serum LDL-C levels, including risks of cognitive decline, hemorrhagic stroke, reduced bone density, or impaired immune function. 5. Initiation of, and education on LDL-lowering therapy remains insufficient, both in terms of long-term adherence to therapy and achieving current guideline directed goals of LDL-C 150mg/dL).All measurement equations are measured against the gold standard of direct measurement via preparative ultracentrifugation, though this method is far more costly and time intensive. This method is preferred with triglycerides 400 mg/dL, where estimates become less accurate.Non-fasting cholesterol measurements may be more reflective of the “real-world” state as patients are most often post-prandial throughout the day, and are generally recommended as reliable lipoprotein measurement per recent guidelines (the two major exceptions being those undergoing evaluation with a family history of premature cardiovascular disease, and those having eaten a very high-fat meal in the previous 8 hours). 4. How low of an LDL-C is still considered safe? What adverse effects are associated with lower LDL-C levels? As above, recent evidence supports lowering LDL-C to

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