Lipoprotein Subfractionation: Large HDL Particle Concentration (NMR)

Optimal Takeaways  

Research suggests that measuring large HDL particle concentration is superior to measuring HDL-C when evaluating cardiovascular risk, with a higher level of large HDLs associated with a lower risk of CVD. Large HDL concentrations can be influenced by factors such as inflammation, obesity, and menopause and can differ between individuals with type 1 and type 2 diabetes.

Nutrition interventions such as a high-fiber nutrient-dense snack bar and egg consumption have been found to increase concentrations of large HDLs, along with other positive health effects. Higher concentrations of large HDLs are considered cardioprotective, while low levels are associated with an increased risk of cardiometabolic disorders.

Standard Range: 3.5 – 50.00 (umol/L)

The ODX Range: 7.2 – 50.00 umol/L

Low concentrations of large HDL particles are associated with obesity, insulin resistance, metabolic syndrome, type 2 diabetes (Sokooti 2021), and increased uric acid (Vekic 2009).

High concentrations of large particles are associated with a lower risk of CVD (El Harchaoui 2009), greater HDL efflux (Mutharasan 2017), type 1 diabetes (Ahmed 2021), consumption of a specialized nutrition bar (Mietus-Snyder 2012), and eating 1-3 eggs per day (DiMarco 2017).

Overview

Evaluation of high-density lipoprotein cholesterol (HDL-C) is often utilized when assessing overall cardiovascular risk. However, the same HDL-C between two individuals can be associated with significantly different HDL characteristics and levels of risk. Measuring large HDL particle concentration appears to be superior to measuring HDL-C when evaluating cardiovascular risk. Research suggests that a higher level of large HDLs is associated with a lower risk of CVD. In one nested case-control study of 2,223 participants from the prospective EPIC-Norfolk Study, those who developed coronary artery disease (fatal or nonfatal) had lower levels of large HDLs, defined in this study as 8.8-13 nm. The mean concentration in those with CAD was 5.2 compared to 6.2 umol/L in those who did not develop CAD over the 6-year period (El Harchaoui 2009).

Contemporary clinical research suggests that the ability of HDL to carry out reverse cholesterol transport (RCT) is a more important indicator of cardiovascular risk than the level of cholesterol being carried, i.e., HDL cholesterol. A strong inverse relationship is observed between HDL efflux capacity, a measure of RCT, and actual atherosclerotic cardiovascular disease risk (Wilkins 2019). Results from the Chicago Healthy Aging Study indicate that higher concentrations of large HDL particles were associated with greater HDL efflux. Conversely, significantly lower levels of large HDLs were seen in subjects with lipid-rich necrotic core plaque versus those without, i.e., 5.31 vs. 6.52 umol/L (Mutharasan 2017).

Decreased levels of large HDLs can be associated with inflammation, a factor associated with cardiometabolic risk. Smaller, denser HDL particles were associated with higher uric acid levels in a study of 194 middle-aged asymptomatic subjects. Those with the highest uric acid had higher fibrinogen and hs-CRP as well, suggesting that low-grade inflammation and alterations in lipoprotein metabolism may contribute to an increased risk of atherosclerosis (Vekic 2009).

Data from 4,828 subjects participating in the prospective PREVEND study suggest that decreased concentrations of large HDL particles may increase risk of type 2 diabetes, especially in women. Over the 7.3-year follow-up period, the number of new cases of T2DM was inversely associated with large HDL concentrations in non-obese subjects. The same association was not observed in obese subjects, i.e., those with a BMI of 30 or greater. Researchers note that obesity may impair HDL function and that obesity, insulin resistance, and metabolic syndrome are associated with a lower concentration of large HDL particles in general (Sokooti 2021). Research also suggests that HDL functionality may be affected by the menopausal transition period. In one study of 471 women, HDL cholesterol efflux capacity per large HDL particle declined, suggesting that large HDLs became less efficient during this time (El Khoudary 2021).

While a decrease in large HDLs has been observed with type 2 diabetes, higher concentrations are observed with type 1 diabetes. In one cross-sectional study of 100 type 1 diabetics, the mean concentration of large HDL particles (8.9–13 nm) was significantly higher in those with T1DM, i.e., 9.36 in diabetics versus 6.99 umol/L in nondiabetics. Researchers suggest that the observed increase in large HDLs and HDL efflux may be associated with an attempt to mitigate the advance of atherosclerosis in these high-risk individuals (Ahmed 2021).

Twice daily consumption of a high-fiber, fruit-based, nutrient-dense bar containing vitamins and minerals, fruit polyphenolics, non-alkali processed dark chocolate, beta-glucan, whey protein isolate, glutamine, wheat bran, walnuts, and omega-3 DHA for two weeks resulted in a significant 28% increase in the concentration of large HDLs along with significant increases in glutathione and significant decreases in plasma homocysteine (Mietus-Snyder 2012).

Interestingly, a study of 38 young healthy adults found that eating at least 1-3 eggs per day was associated with increased concentrations of large HDL particles; increased blood levels of the antioxidant nutrients lutein and zeaxanthin; and increased activity of PON1, an HDL antioxidant enzyme usually associated with smaller HDLs. LDL particle number concentration increased favorably with egg consumption as well. Blood pressure decreased significantly with egg consumption in a dose-dependent manner (DiMarco 2017).

References  

Ahmed, Mohamad O et al. “HDL particle size is increased and HDL-cholesterol efflux is enhanced in type 1 diabetes: a cross-sectional study.” Diabetologia vol. 64,3 (2021): 656-667. doi:10.1007/s00125-020-05320-3

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

El Harchaoui, Karim et al. “High-density lipoprotein particle size and concentration and coronary risk.” Annals of internal medicine vol. 150,2 (2009): 84-93. doi:10.7326/0003-4819-150-2-200901200-00006

El Khoudary, Samar R et al. “HDL (High-Density Lipoprotein) Subclasses, Lipid Content, and Function Trajectories Across the Menopause Transition: SWAN-HDL Study.” Arteriosclerosis, thrombosis, and vascular biology vol. 41,2 (2021): 951-961. doi:10.1161/ATVBAHA.120.315355

Mietus-Snyder, Michele L et al. “A nutrient-dense, high-fiber, fruit-based supplement bar increases HDL cholesterol, particularly large HDL, lowers homocysteine, and raises glutathione in a 2-wk trial.” FASEB journal : official publication of the Federation of American Societies for Experimental Biology vol. 26,8 (2012): 3515-27. doi:10.1096/fj.11-201558

Mutharasan, R Kannan et al. “HDL efflux capacity, HDL particle size, and high-risk carotid atherosclerosis in a cohort of asymptomatic older adults: the Chicago Healthy Aging Study.” Journal of lipid research vol. 58,3 (2017): 600-606. doi:10.1194/jlr.P069039

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

Sokooti, Sara et al. “HDL Particle Subspecies and Their Association With Incident Type 2 Diabetes: The PREVEND Study.” The Journal of clinical endocrinology and metabolism vol. 106,6 (2021): 1761-1772. doi:10.1210/clinem/dgab075

Vekic, Jelena et al. “High serum uric acid and low-grade inflammation are associated with smaller LDL and HDL particles.” Atherosclerosis vol. 203,1 (2009): 236-42. doi:10.1016/j.atherosclerosis.2008.05.047          

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