Lipoprotein Subfractionation: Small LDLs (ION)

Optimal Takeaways

Small low-density lipoprotein (LDL) particles are associated with an increased risk of cardiovascular disease and events. They are a better indicator of CVD risk than measuring LDL-cholesterol. The smaller, denser LDL particles are more prone to oxidation and other modifications that make them more atherogenic. Small LDLs are also associated with elevated triglycerides, metabolic syndrome, diabetes, and arthritis. A healthy diet and various nutrition supplements can help lower small LDLs, and a low level of small LDLs is considered healthy.

Standard Range: 0.00 – 141.99 nmol/L   

The ODX Range: 0.00 – 141.99 nmol/L  

Low levels of small LDLs suggest a decreased risk of cardiometabolic disease, CVD, and metabolic syndrome.

High levels of small LDLs are associated with increased CVD risk (Sæther 2023), progression of coronary artery calcium and plaque progression (Ceponiene 2021), metabolic syndrome, diabetes (Wolska 2020), inflammation, immune activation (Vekic 2022), hypertriglyceridemia (Superko 2022), obesity (Feingold 2023), lower HDL-C (Froyen 2021), phenotype B pattern (Ivanova 2017), rheumatoid arthritis, psoriatic arthritis, hypothyroidism, type 2 diabetes, and cardiac autonomic neuropathy (Gerber 2017).

Overview    

Small low-density lipoprotein (LDL) particles are considered independent risk factors for atherosclerosis and CVD due to their increased susceptibility to oxidation and ability to infiltrate the arterial endothelial layer. Research indicates smaller LDLs may initiate and promote ischemic and coronary heart disease. An increase in small LDLs is a more reliable indicator of CVD, and metabolic syndrome risk than LDL-cholesterol (Talebi 2020).

Several reproducible studies have confirmed the clinical utility of using small LDLs to identify cardiovascular risk, including The Boston Area Heart study, the Harvard Physician’s Health Study, the Women’s Health Study, the Quebec Cardiovascular study, and the Stanford Five City Project (Superko 2022).

Reevaluation of data from the prospective Multi-Ethnic Study of Atherosclerosis (MESA) demonstrated a significant association between smaller LDL particles measured by ion mobility and the progression of carotid artery plaque and coronary artery calcification. Researchers note that the smaller cholesterol-depleted LDLs, ranging from 18-21.41 nm in size, are more apt to infiltrate and accumulate in the endothelial layer of the artery. Post-hoc analysis of the JUPITER trial data confirmed an association between smaller LDL particles (measured by ion mobility) and increased risk of cardiovascular events, an association not observed with baseline LDL cholesterol (Ceponiene 2021).

These small LDLs represent phenotype pattern B, an unfavorable pattern for CVD risk. Smaller LDLs contain more triglycerides and less cholesterol and antioxidant nutrients; are more prone to atherogenic modification via oxidation, glycation, and desialylation; have longer circulation time; induce CVD-associated inflammatory processes; and are more apt to promote atherosclerosis, especially when modified (Ivanova 2017). Oxidized LDL also promotes the differentiation of monocytes into macrophages, immune cells that then secrete pro-inflammatory mediators and contribute to the growth and instability of atherosclerotic lesions (Vekic 2022).

The presence of small LDLs and a pattern B phenotype identifies individuals with a 3-fold greater risk of coronary heart disease and a 2-fold increased rate of arteriographic progression of atherosclerosis. The relevance of small LDLs to cardiovascular risk is further magnified when apoB is elevated. Reducing small LDL predominance provides arteriographic benefits independent of blood pressure, smoking, weight, and age factors and beyond the benefits observed with changes in apoB or LDL-cholesterol (Superko 2009).

Phenotype B is associated with a much higher risk of atherosclerotic cardiovascular disease and an increased risk of metabolic syndrome, diabetes, and hypertriglyceridemia. At least three epidemiological studies have found that evaluating small LDLs is superior to evaluating LDL-C when evaluating cardiovascular risk (Wolska 2020). One small study of 60 subjects suspected of having CAD but no prior diagnosis found that those ultimately diagnosed with severe CAD had 30% more small LDLs compared to those with nonsignificant or intermediate coronary artery atherosclerosis, as determined by Gensini score (Sæther 2023).

Small LDLs are often observed in those with high triglycerides, low HDL-cholesterol, and obesity… characteristics of metabolic syndrome and diabetes (Feingold 2023). In one study of 5,366 coronary heart disease patients, 100% of those with a fasting triglyceride above 250 mg/dL (2.82 mmol/L) had elevated small LDLs (Superko 2022).

Natural substances can reduce the oxidation of LDL and potentially reduce small LDL levels. These include phytosterols (plant sterols and sterol esters); polyphenols; plant-based foods including avocadoes, strawberries, and bergamot; omega-3 fatty acids from flax oil, EPA, and DHA; nuts; cocoa; chocolate; and a Mediterranean-style diet (Talebi 2020). A 4-week, randomized, controlled feeding trial found that the combination of dark chocolate and almonds significantly reduced small LDLs, apoB, and the apoB:apoA1 ratio (Lee 2017).

Supplementation for just eight weeks with Armolipid Plus® (containing red yeast rice monacolin K, berberine, policosanols, folic acid, coenzyme Q10, and astaxanthin) favorably increased LDL particle diameter in subjects with familial hyperlipidemia. Weight loss and exercise training can also increase LDL particle size (Gerber 2017).

Additional measures to reduce small LDLs include avoiding simple carbohydrates/sugars, reducing excess body fat, exercising, and incorporating niacin and omega-3 fish oil into clinical treatment plans (Superko 2022). Healthy dietary fat is essential to cardiovascular health, supports the production of large buoyant LDL particles, and decreases the formation of small atherogenic LDLs (Froyen 2021).

References  

Ceponiene, Indre et al. “Association of Coronary Calcium, Carotid Wall Thickness, and Carotid Plaque Progression With Low-Density Lipoprotein and High-Density Lipoprotein Particle Concentration Measured by Ion Mobility (From Multiethnic Study of Atherosclerosis [MESA]).” The American journal of cardiology vol. 142 (2021): 52-58. doi:10.1016/j.amjcard.2020.11.026

Feingold, Kenneth R. “Utility of Advanced Lipoprotein Testing in Clinical Practice.” Endotext, edited by Kenneth R Feingold et. al., MDText.com, Inc., 3 January 2023.

Froyen, Erik. “The effects of fat consumption on low-density lipoprotein particle size in healthy individuals: a narrative review.” Lipids in health and disease vol. 20,1 86. 6 Aug. 2021, doi:10.1186/s12944-021-01501-0

Gerber, Philipp A et al. “Small, dense LDL: an update.” Current opinion in cardiology vol. 32,4 (2017): 454-459. doi:10.1097/HCO.0000000000000410

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

Lee, Yujin et al. “Effects of Dark Chocolate and Almonds on Cardiovascular Risk Factors in Overweight and Obese Individuals: A Randomized Controlled-Feeding Trial.” Journal of the American Heart Association vol. 6,12 e005162. 29 Nov. 2017, doi:10.1161/JAHA.116.005162

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

Sæther, Julie Caroline et al. “Small LDL subfractions are associated with coronary atherosclerosis despite no differences in conventional lipids.” Physiological genomics vol. 55,1 (2023): 16-26. doi:10.1152/physiolgenomics.00098.2022

Superko HR. Advanced lipoprotein testing and subfractionation are clinically useful. Circulation. 2009;119:2383-2395.

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

Vekic, Jelena et al. “Atherosclerosis Development and Progression: The Role of Atherogenic Small, Dense LDL.” Medicina (Kaunas, Lithuania) vol. 58,2 299. 16 Feb. 2022, doi:10.3390/medicina58020299