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

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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 <70mg/dL (And even lower in specific scenarios, such as repeat cardiovascular events).

“It’s pretty clear that this is an area where you can make a profound difference in the lives of people. It’s very clear from the clinical trials that when we initiate therapies, whether it’s lifestyle, through a statin, or an antihypertensive, you impact not only the quality of life, but the quantity of life. You make life better, you make life freer of disability, and you forestall death.”

“The bottom line is that LDL is spent garbage liquid and it is tantamount that the body be well-equipped to remove this LDL from the central circulation, because I will argue today that it is the single most important toxin that we produce.”

“If you ask what should a normal LDL be? Well, I’ll tell you right now…the best estimate is actually around 38 to 40 mg/dL.”

1. How does the body metabolize lipoproteins and where does LDL-C fit into these processing pathways?

• There are two major pathways through which the body metabolizes lipoproteins. The exogenous fat metabolism pathway includes digestion, absorption, and re-packaging of the lipids that we ingest. Dietary fats are disassembled from energy dense lipid macromolecules into chylomicrons. Chylomicrons are the largest, least dense particles followed by VLDL, IDL, LDL, and HDL. Second, there is the endogenous fat metabolism pathway that allows the liver to synthesize and secrete lipids.
• The structure of LDL-C contains apolipoprotein(B) that serves as a scaffold molecule, with the core compromised of triglyceride and cholesteryl esters, interspersed with phospholipids and cholesterol.
• VLDL is secreted into the central circulation and is acted upon by lipoprotein lipase primarily – but also hepatic lipase and endothelial lipase – to release fatty acid which is used as oxidized fuel by peripheral tissues.
• LDL-C is the energy poor product of triglyceride and fatty acid removal from prior less dense lipoprotein molecules. It is a highly concentrated particle, enriched with cholesterol that cannot be used as fuel by the tissues. It is subsequently converted into bile acids and stored in steroid-producing tissues including the adrenal glands, ovaries, testicles, and placenta. Given its small size, however, it can also traverse the arterial intima of vasculature, ultimately leading to atherosclerosis and cardiovascular disease.
• For more on lipid metabolism and management, enjoy episode #42: Lipid Management with Drs. Ann Marie Navar & Nishant Shah.

2. What is the physiology and function of LDL-C?  How does LDL-C physiology compare between humans and other mammalian species?

• LDL-C transports cholesterol to cells for exogenous uptake and use in bile acid formation and steroid production.
• Most cells have the capacity to produce de novo cholesterol and do not have a strict reliance upon the delivery of extracellular cholesterol via lipoproteins. Cholesterol itself provides a number of important functions within the cell, such as modifying the fluidity of cell membranes, regulating ATP, providing transcriptional control within the nucleus regulating gene expression, and modifying protein functionality.
• In most other mammalian species, studies have demonstrated serum LDL-C levels around 35-50 mg/dL, which is likely more representative of baseline levels in humans without the dietary extremes often accompanying modern diets. Indeed, hunter-gatherer populations are generally very resistant to atherosclerotic cardiovascular disease, and exhibit much lower LDL-C levels.
• Similarly, after the National Cholesterol Education Program published ATPIII (Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults s- Adult Treatment Panel III) in 2001, further analyses investigating the correlation between LDL and ischemic heart disease demonstrated excess hazard starting as low as 38 mg/dL.

3. How do we estimate or measure LDL-C? 

• The Friedewald Equation traditionally allowed for estimation of LDL-C as the [total cholesterol – (HDL – triglycerides/5)], with the last term, triglycerides/5 reflecting an estimate for VLDL-C in the serum.
• Subsequently, the Martin/Hopkins Equation was adopted for the estimation of LDL-C, calculated as the [total cholesterol – (HDL – triglycerides/adjustable factor)], given that VLDL can vary significantly between individuals. This equation more accurately estimates LDL-C levels, particularly with low LDL-C (LDL-C <70mg/dL) or high triglycerides (triglycerides >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 <70 mg/dL in those at high cardiovascular risk,  <55 mg/dL in those at very high cardiovascular risk, and even <40 mg/dL in those with a repeat cardiovascular event within two years based on recent U.S. and European  Guidelines.
• The Fourier Trial compared LDL cholesterol reduction with a PCSK9 monoclonal antibody vs placebo and found a 59% reduction from baseline to a median of 30 mg/dL There was no statistically significant difference in adverse events (apart from injection site reactions) in individuals with ultra-low LDL.
• There is no lower limit of LDL cholesterol that is known to be unsafe. Meta-analyses of primary prevention data demonstrate a linear relationship between LDL-C and ischemic coronary event, so the prevailing philosophy currently remains – when it comes to LDL-C, lower is better.
• Modern studies have suggested that lower LDL-C is not associated with risk of increased cognitive impairment or hemorrhagic stroke. The ODYSSEY trial in 2019 demonstrated that for patients with recent ACS and dyslipidemia, PCSK-9 therapy decreased the risk of stroke, regardless of LDL-C levels achieved. The PROSPER trial additionally did not demonstrate any significant difference in cognitive function with statin therapy.
• There is currently no RCT data to suggest impaired immune function or bone density associated with lipid lower therapy. In fact, recent data has suggested that statin therapy may help regulate T-helper cell function and decrease risk of cytokine storm in severe infection.

5. What are future directions for research and clinical practice with regard to lipid lowering therapy?

• Though benefits of lipid therapy have been clearly demonstrated, uptake of LDL-lowering therapy remains inadequate. Only 18-40% of very-high risk patients have LDL-C <70mg/dL. Less than 50% of Medicare patients who sustain MI were on statin therapy at the time of cardiac event. Of individuals who start lipid-lower therapy, more than half will stop therapy within five years.
• Reduced adherence to statin therapy among eligible patients has been directly associated with increased risk of death. In particular, women, minorities, younger adults, and older adults have been found to be less likely to adhere to statins, signaling important disparities among patient populations that must be addressed further.

1. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001; 285: 2486–2497.
2. Olsson AG, Angelin B, Assmann G et al. Can LDL cholesterol be too low? Possible risks of extremely low levels. J Intern Med. 2017;281(6):534.
3. Benn M, Nordestgaard BG, Grande P et al. PCSK9 R46L, low‐density lipoprotein cholesterol levels, and risk of ischemic heart disease: 3 independent studies and meta‐analyses. J Am Coll Cardiol 2010; 55: 2833–42.
4. Grundy SM, Stone NJ, Bailey AL et al. 2018 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019 Jun 18;139(25):e1082-e1143.
5. Members ATF, Piepoli MF, Hoes AW et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts) Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur J Prev Cardiol 2016; 23: NP1–96.
6. Cohen JC, Boerwinkle E, Mosley TH et al. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006; 354: 34–42.
7. Michos ED, McEvoy JW, Blumenthal RS. Lipid Management for the Prevention of Atherosclerotic Carciovascular Disease.  N Engl J Med 2019 Oct 17;381(16):1557-1567.
8. Chien KR. Molecular Basis of Cardiovascular Disease: A Companion to Braunwald’s Heart Disesae. 2nd Ed. 2004.
9. Damask A, Steg PG, Schwartz GG et al. Patients With High Genome-Wide Polygenic Risk Scores for Coronary Artery Disease May Receive Greater Clinical Benefit From Alirocumab Treatment in the ODYSSEY OUTCOMES Trial. Circulation. 2020 Feb 25;141(8):624-636.
10. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). European Heart Journal 2020;41:111–188.

Dr. Peter Toth is the Director of Preventive Cardiology at CGH Medical Center in Sterling, IL, and Professor of Clinical Family and Community Medicine at the University of Illinois College of Medicine in Peoria, and adjunct associate professor of medicine, Johns Hopkins University School of Medicine. He received his medical degree from Wayne State University School of Medicine in Detroit, MI, and PhD in Biochemistry from Michigan State University in East Lansing. He has written extensively on the topic of lipids and is Co-Editor of twenty textbooks in preventive cardiology, diabetes, hypertension, and lipidology. Additionally, Dr. Toth is the President of the American Society of Preventive Cardiology, past President of the National Lipid Association, as well as incoming chair of the American Heart Association’s Council on Lipoproteins, Lipid Metabolism, and Thrombosis.

Dr. Jessie Holtzman (@jholtzman3) is an internal medicine resident at the University of California, San Francisco. She received her medical degree from Harvard Medical School, before which she had the time of her life as a Fulbright Scholar doing research in Buenos Aires, Argentina. She ultimately hopes to pursue a career that combines clinical cardiology with an emphasis on women’s cardiovascular health, medical education, and policy making. In her spare time, Jessie loves kayaking on the San Francisco bay, as well as reading about medical device regulation and novel payment models.

• Tommy Das, MD
• Dr. Rick Ferraro
• Amit Goyal, MD
• Daniel Ambinder, MD