Lipoprotein Subfractionation: LDL Peak Size (ION)

Optimal Takeaways

Cholesterol is mainly transported in the blood by low-density lipoprotein (LDL) particles, which vary in size and cardiovascular risk. Smaller, denser LDL particles pose the most significant risk for cardiovascular disease and insulin resistance. They are more prone to oxidation and glycation and can more easily penetrate artery walls and become proatherogenic.

LDL particle size can be improved through lifestyle changes, such as weight loss, exercise, a healthy plant-based diet, and natural products and foods that help reduce LDL particle numbers and increase their size.

Standard Range: 222.91 – 500 Angstrom            

The ODX Range: 257.00 – 500 Angstrom  

Low or smaller LDL size is associated with increased triglycerides, increased coronary artery calcium (Aneni 2019), cardiovascular risk (especially combined with weight gain and an unhealthy lifestyle, genetic factors (Lamarche 1997), insulin resistance (Chiu 2017), oxidation, and glycation, including glycated apoB (Ivanova 2017).

High or optimal LDL size is associated with reduced coronary artery calcium, lower triglycerides (Aneni 2019), and decreased risk of cardiovascular disease. Large LDL size correlates with HDL and may be considered cardioprotective (Afanasieva 2016).

Overview    

Most cholesterol in the blood is transported on low-density lipoprotein (LDL). The amount of cholesterol each LDL particle carries can vary, creating a range of LDL particle sizes and a range of susceptibility to oxidative damage and cardiovascular risk. The smaller the LDL size, the greater the risk of CVD. Having many small LDL particles poses the most significant risk for CVD and insulin resistance, even though they have less cholesterol than larger particles.

There are various methods for measuring lipoprotein size and concentration, and their results are not interchangeable. Ion mobility and nuclear magnetic resonance (NMR) are the most commonly used for lipoprotein subfractionation. Ion mobility measures LDL size in Angstroms (0.1 nm), while NMR measures LDL size in nanometers (nm). A separate measurement of small dense LDL cholesterol (sdLDL-C) can be performed to assess cardiometabolic risk further.

LDL size ranges from large and buoyant (pattern A) to small and dense (pattern B) (Pagana 2021). Small dense LDL particles have less cholesterol but more triglyceride content than larger particles and carry fewer protective antioxidant nutrients. The smaller LDL particles can penetrate the artery wall more easily and become oxidized, glycated, and proatherogenic (Ivanova 2017, Langlois 2018). Smaller LDL particles were also associated with increased coronary artery calcium (CAC) in a study of 170 individuals with a high risk of cardiometabolic disease (Aneni 2019).

Smaller LDLs are associated with increased serum triglyceride levels and related cardiometabolic risk. In one study of 5,366 coronary heart disease patients, only 4.2% of subjects expressed small LDL particles when fasting triglycerides were below 70 mg/dL (0.79 mmol/L). However, 27% had small LDLs when using a cut-off of 150 mg/dL (1.69 mmol/L) or below for fasting triglycerides. In those with fasting triglycerides between 150-250 mg/dL (1.69-2.82 mmol/L), 79.1% had elevated small LDLs, and when fasting triglycerides were above 250 mg/dL, 100% of subjects expressed small LDLs. The LDL peak particle diameter in the study was defined as 263 angstroms or above for large LDLs, and 257 angstroms or below for small LDLs (Superko 2022).

Smaller LDL particles are associated with an increased risk of cardiovascular disease, insulin resistance, and diabetes. Evaluating LDL particle size may help identify cardiometabolic risk even in individuals with LDL cholesterol, non-HDL cholesterol, and triglyceride levels considered “low risk” (Bowden 2011).

More than half of heart attack victims have smaller LDLs, tripling the risk of coronary plaque and myocardial infarction. The tendency toward producing smaller, denser LDLs may be a genetic predisposition triggered by weight gain and unhealthy lifestyle habits. However, it can also occur in those who are not overweight (Lamarche 1997). These small cholesterol-depleted LDL particles are associated with insulin resistance (Chiu 2017) and are considered a more sensitive biomarker for metabolic syndrome than LDL cholesterol (Liou 2020).

LDL particle size can be improved via weight loss, exercise, blood glucose control, and a healthy plant-based diet containing oat bran (Davy 2002), flaxseeds (Dodin 2008), and dark chocolate, almonds, and other nuts (Guasch-Ferré 2023).

Clinical trials indicate that the use of natural products and foods, including psyllium, plant sterols, inositol, strawberries, oolong tea, fish oil; and Armolipid Plus® (containing red yeast rice monacolin K, berberine, policosanols, folic acid, coenzyme Q10, and astaxanthin) can help reduce LDL-particle number and reduce the number of small dense atherogenic LDLs. These natural products can also favorably increase LDL particle size to at least 25 nm, a characteristic of the more desirable phenotype pattern A (Talebi 2020).

References  

Afanasieva, O I et al. Kardiologiia vol. 56,6 (2016): 5-11. doi:10.18565/cardio.2016.6.5-11

Aneni, Ehimen C et al. “Lipoprotein Sub-Fractions by Ion-Mobility Analysis and Its Association with Subclinical Coronary Atherosclerosis in High-Risk Individuals.” Journal of atherosclerosis and thrombosis vol. 26,1 (2019): 50-63. doi:10.5551/jat.40741

Bowden, Rodney G et al. “LDL particle size and number compared with LDL cholesterol and risk categorization in end-stage renal disease patients.” Journal of nephrology vol. 24,6 (2011): 771-7. doi:10.5301/JN.2011.6376

Chiu, Sally et al. “Effects of a very high saturated fat diet on LDL particles in adults with atherogenic dyslipidemia: A randomized controlled trial.” PloS one vol. 12,2 e0170664. 6 Feb. 2017, doi:10.1371/journal.pone.0170664

Davy, Brenda M et al. “High-fiber oat cereal compared with wheat cereal consumption favorably alters LDL-cholesterol subclass and particle numbers in middle-aged and older men.” The American journal of clinical nutrition vol. 76,2 (2002): 351-8. doi:10.1093/ajcn/76.2.351

Dodin, Sylvie et al. “Flaxseed on cardiovascular disease markers in healthy menopausal women: a randomized, double-blind, placebo-controlled trial.” Nutrition (Burbank, Los Angeles County, Calif.) vol. 24,1 (2008): 23-30. doi:10.1016/j.nut.2007.09.003

Ivanova, Ekaterina A et al. “Small Dense Low-Density Lipoprotein as Biomarker for Atherosclerotic Diseases.” Oxidative medicine and cellular longevity vol. 2017 (2017): 1273042. doi:10.1155/2017/1273042

Lamarche B, Tchernof A, Moorjani S, et al. Small, dense low-density lipoprotein particles as a predictor of the risk of ischemic heart disease in men. Prospective results from the Quebec Cardiovascular Study. Circulation. 1997 Jan 7;95(1):69-75.

Liou, Lathan, and Stephen Kaptoge. “Association of small, dense LDL-cholesterol concentration and lipoprotein particle characteristics with coronary heart disease: A systematic review and meta-analysis.” PloS one vol. 15,11 e0241993. 9 Nov. 2020, doi:10.1371/journal.pone.0241993

Nikolic, Dragana et al. “Lipoprotein subfractions in metabolic syndrome and obesity: clinical significance and therapeutic approaches.” Nutrients vol. 5,3 928-48. 18 Mar. 2013, doi:10.3390/nu5030928

Witte, D R et al. “Study of agreement between LDL size as measured by nuclear magnetic resonance and gradient gel electrophoresis.” Journal of lipid research vol. 45,6 (2004): 1069-76. doi:10.1194/jlr.M300395-JLR200

Superko, Harold, and Brenda Garrett. “Small Dense LDL: Scientific Background, Clinical Relevance, and Recent Evidence Still a Risk Even with 'Normal' LDL-C Levels.” Biomedicines vol. 10,4 829. 1 Apr. 2022, doi:10.3390/biomedicines10040829

Talebi, Sepide et al. “The beneficial effects of nutraceuticals and natural products on small dense LDL levels, LDL particle number and LDL particle size: a clinical review.” Lipids in health and disease vol. 19,1 66. 11 Apr. 2020, doi:10.1186/s12944-020-01250-6