Lipoprotein Subfractionation: HDL Size (NMR)

Optimal Takeaways  

High-density lipoproteins (HDLs) serve several functions in the body. A primary role is the scavenging of cholesterol from peripheral tissues and returning it to the liver for elimination or delivering it as a hormone precursor to the adrenals, ovaries, or testes. Early research suggests that larger HDL particles are more protective against cardiovascular disease and diabetes. However, more recent research suggests that smaller HDL particles may have some health benefits as well.

Standard Range: 8.3 – 10.50 nm

The ODX Range: 9.00 – 10.50 nm

Low or small-sized HDL particles may be associated with increased abdominal fat (Beekman 2020), increased cardiovascular risk under certain conditions, and may be associated with decreased risk of dementia (Martinez 2023).

High or large HDL particles may be associated with decreased risk of cardiovascular disease (Parra 2014) and decreased risk of type 2 diabetes (Sokooti 2021).

Overview

The size of HDL particles in circulation can vary from small dense HDL particles 7.3-8.2 nanometers (nm) to large HDL particles ranging from 9.4 to 14 nm. Early research into HDL subfractionation suggests that a larger HDL particle size is associated with a lower risk of CVD, while smaller HDL particles may be associated with increased CVD risk (Parra 2014).

However, more current research suggests that the functionality of HDL at different stages (and sizes) determines its health effects. Some research indicates that small HDL particles carry more antioxidants and have the capacity to pick up more cholesterol, while larger particles may be too full to take on more cholesterol. Additional research notes that larger HDL particles may contain more ApoA-1, which itself confers antioxidant benefits and facilitates reverse cholesterol transport (RCT) (DiMarco 2017).

The size of HDL particles will increase as the amount of cholesterol and lipids they scavenge and carry increases. The size of HDL will then decrease as it drops off cholesterol and lipids to the liver, as well as to steroidogenic tissue, including the adrenals, ovaries, and testes. An HDL particle may circulate for 4-5 days before being broken down by the liver or kidneys. Larger HDL particles are cholesterol and lipid rich and fall into the HDL2 subclass, which accounts for approximately 40% of total HDL. Smaller HDLs are protein-rich and lipid-poor, falling into the HDL3 subclass, which accounts for 60% of total HDLs. Lipoprotein subfractionation by NMR categorizes HDL as large (8.8–13 nm), medium (8.2–8.8 nm), and small (7.3–8.2 nm) particles. Other methods may further break down HDL into HDL2b (largest), HDL2a, HDL3a, HDL3b, and HDL3c (smallest). Results using one method of subfractionation may not be comparable to results using a different method. Researchers point out that the association of cardiovascular disease with HDL follows a U-shaped curve, with extremely low or high levels being associated with increased risk (Lappegad 2021).

Medium and large HDL particles are primarily formed in the periphery from small dense HDLs during the process of reverse cholesterol transport. However, current research suggests that medium and large HDL particles may be synthesized de novo in the liver as well. Individual variations in the production and metabolism of small, medium, and large HDL particles complicate the association between the size and concentration of HDL particles and actual cardiovascular risk. For example, an increased level of small HDL particles may indicate increased production or decreased maturation of small particles, factors that can affect HDL functionality (Wilkins 2019). During reverse cholesterol transport, smaller HDL particles may be more efficient at picking up cholesterol in the periphery, including from arterial wall macrophage foam cells, while larger HDL particles appear to be more effective at dropping cholesterol off at the liver (Bardagiy 2019).

Research suggests that HDL size may not affect CVD risk as much as HDL particle number. The observed association between smaller HDL size and CVD risk was abolished following adjustment for triglycerides and apoB in the EPIC-Norfolk study. In this study, exceptionally high mean HDL size maintained an association with increased cardiovascular risk despite multiple adjustments (Kontush 2015). Also, atherogenic dyslipidemia can compromise the benefits, functions, and interpretation of HDL’s role in cardiovascular protection (Camont 2011). At present, clinical laboratories such as Cleveland Heart Lab maintain that larger HDL particles are the most cardioprotective.

Larger HDL size was associated with lower risk of type 2 diabetes in a prospective general population study of 4,828 subjects without T2DM and 308 subjects with preexisting T2DM. A small HDL diameter of 7.8 nm was inversely associated with developing new-onset T2DM, while an HDL diameter of 9.5 nm was protective. Further analysis found an HDL diameter of 10.8 nm was protective in non-obese subjects but not those who were obese (Sokooti 2021). Abdominal obesity is generally associated with a smaller HDL diameter, and supervised weight loss may increase HDL particle diameter and decrease cardiovascular risk (Beekman 2020).

Smaller, denser HDLs play a role in protecting LDL from oxidation and can inactivate existing oxidized lipids, a cardioprotective measure. Smaller HDLs also have anti-inflammatory effects on the endothelium. In one study of 214 individuals with existing coronary artery disease, the number of small HDL particles (7.3-8.7 nm) measured by NMR was inversely associated with CVD and all-cause mortality. The number of small HDL particles was also lower in subjects who died over the 12.5-year follow-up period. Average HDL size was significantly higher in the deceased group (8.94 versus 8.82 nm in survivors), while HDL particle number and ApoA-1 were significantly lower. Those who were deceased had more severe and more prolonged heart disease. Researchers suggest that excessive large HDLs may reflect defective HDL catabolism, especially decreased hepatic uptake of cholesterol. Anti-inflammatory, antioxidant, and cytoprotective effects may be compromised depending on HDL size and metabolism, though further research is needed to clarify the desirability of large versus small HDL particles (Duparc 2020).

The size and function of HDLs may affect lipid metabolism in the brain and the risk of Alzheimer’s disease. Small HDL particles may play an important role in clearing lipids from brain microglia and astrocyte cells. This action helps prevent local inflammation that may compromise the integrity of the blood-brain barrier (BBB) and contribute to cognitive decline. Researchers suggest that small HDLs may reduce the risk of Alzheimer’s by transporting oxidized lipids out of blood vessels in the brain. One cross-sectional study of 180 subjects aged 60 or older with increased CVD risk due to hypertension and/or low serum HDL-cholesterol found an association between higher levels of smaller HDLs (7.0-10.5 nm vs. 10.4-14.5 nm), better performance on cognitive testing, and lower Alzheimer’s disease risk. However, more research is needed to determine the specific neuroprotective properties of small HDLs in the range of 7.0-10.5 nm (Martinez 2023).

Ultimately, research suggests that larger HDL particles may be more cardioprotective and reduce the risk of type 2 diabetes. However, smaller HDL particles may have antioxidant and neuroprotective roles that must be investigated.

References  

Bardagjy, Allison S, and Francene M Steinberg. “Relationship Between HDL Functional Characteristics and Cardiovascular Health and Potential Impact of Dietary Patterns: A Narrative Review.” Nutrients vol. 11,6 1231. 30 May. 2019, doi:10.3390/nu1106123

Beekman, Marian et al. “Lifestyle-Intervention-Induced Reduction of Abdominal Fat Is Reflected by a Decreased Circulating Glycerol Level and an Increased HDL Diameter.” Molecular nutrition & food research vol. 64,10 (2020): e1900818. doi:10.1002/mnfr.201900818

Camont, Laurent et al. “Biological activities of HDL subpopulations and their relevance to cardiovascular disease.” Trends in molecular medicine vol. 17,10 (2011): 594-603. doi:10.1016/j.molmed.2011.05.013

Cleveland Heart Lab. NMR. https://www.clevelandheartlab.com/tests/lipoprotein-fractionation-nmr-with-lipids/

DiMarco, Diana M et al. “Intake of up to 3 Eggs per Day Is Associated with Changes in HDL Function and Increased Plasma Antioxidants in Healthy, Young Adults.” The Journal of nutrition vol. 147,3 (2017): 323-329. doi:10.3945/jn.116.241877

Duparc, Thibaut et al. “Serum level of HDL particles are independently associated with long-term prognosis in patients with coronary artery disease: The GENES study.” Scientific reports vol. 10,1 8138. 18 May. 2020, doi:10.1038/s41598-020-65100-2

Kontush, Anatol. “HDL particle number and size as predictors of cardiovascular disease.” Frontiers in pharmacology vol. 6 218. 5 Oct. 2015, doi:10.3389/fphar.2015.00218

Lappegard, Knut Tore et al. “High-Density Lipoprotein Subfractions: Much Ado about Nothing or Clinically Important?.” Biomedicines vol. 9,7 836. 18 Jul. 2021, doi:10.3390/biomedicines9070836  

Labcorp. Understanding the NMR Lipoprofile. https://www.labcorp.com/tests/related-documents/L15035

Lappegad, Knut Tore et al. “High-Density Lipoprotein Subfractions: Much Ado about Nothing or Clinically Important?.” Biomedicines vol. 9,7 836. 18 Jul. 2021, doi:10.3390/biomedicines9070836 This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

Martinez, Ashley E et al. “The small HDL particle hypothesis of Alzheimer's disease.” Alzheimer's & dementia : the journal of the Alzheimer's Association vol. 19,2 (2023): 391-404. doi:10.1002/alz.12649

Parra, Eliane Soler et al. “HDL size is more accurate than HDL cholesterol to predict carotid subclinical atherosclerosis in individuals classified as low cardiovascular risk.” PloS one vol. 9,12 e114212. 3 Dec. 2014, doi:10.1371/journal.pone.0114212

Wilkins, John T, and Henrique S Seckler. “HDL modification: recent developments and their relevance to atherosclerotic cardiovascular disease.” Current opinion in lipidology vol. 30,1 (2019): 24-29. doi:10.1097/MOL.0000000000000571