Lipoprotein Subfractionation: Small Dense LDL Particles (NMR)

Optimal Takeaways  

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

Standard Range: 0.00 – 1408.00 nmol/L

The ODX Range: 0.00 – 467.00 nmol/L

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

High levels of sdLDLs are associated with increased CVD risk (Sæther 2023), phenotype pattern B (Ivanova 2017), metabolic syndrome, diabetes (Wolska 2020), atherosclerosis, increased Lp-PLA2, obesity, central adiposity, insulin resistance, “atherogenic lipid triad” of increased sdLDLs and triglycerides with decreased HDL-C (Nikolic 2013), inflammation, immune activation (Vekic 2022), rheumatoid arthritis, psoriatic arthritis, hypothyroidism, type 2 diabetes, and cardiac autonomic neuropathy (Gerber 2017).

Overview    

Small dense low-density lipoprotein particles (sdLDLs) 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 that sdLDLs may initiate and promote ischemic heart disease and coronary heart disease. In fact, elevated sdLDLs are more reliable indicators than LDL-cholesterol for detecting CVD and metabolic syndrome (Talebi 2020). Multiple reproducible studies have confirmed the clinical utility of using sdLDLs 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).

With a size of 18-20.5 nm, sdLDLs represent phenotype pattern B, an unfavorable pattern for CVD risk. Small dense LDLs contain more triglycerides and less cholesterol; contain fewer 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 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 dense 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 sdLDL to cardiovascular risk is further magnified when apoB is elevated. A reduction in sdLDL 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).

The atherogenic phenotype associated with sdLDLs reflects a much higher risk of atherosclerotic cardiovascular disease and an association with metabolic syndrome, diabetes, and hypertriglyceridemia. At least three epidemiological studies have found sdLDL superior to LDL-C in accurately 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).

Elevations in sdLDL are often observed in those with obesity, high triglycerides, and low HDL-cholesterol, 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 sdLDLs (Superko 2022). Increased sdLDLs are associated with an increase in central obesity and a reduction in insulin sensitivity, contributing to metabolic syndrome and cardiovascular risk. Small dense LDL, along with elevated triglycerides and decreased HDL cholesterol, make up the “atherogenic lipid triad,” a phenomenon often associated with central obesity. Lifestyle changes, including increased physical activity and personalized nutrition intervention, can reduce sdLDL levels (Nikolic 2013).

Natural substances can reduce the oxidation of LDL and reduce sdLDL levels as well. 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 sdLDLs, apoB, and the apoB:apoA1 ratio (Lee 2017).

Nutrition intervention, including the use of flaxseed oil, marine-based omega-3s, and avocadoes, can help reduce sdLDLs by increasing particle size. 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 also have the beneficial effect of increasing LDL particle size (Gerber 2017).

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

Natural substances can reduce the oxidation of LDL and reduce sdLDL 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 sdLDLs, apoB, and the apoB:apoA1 ratio (Lee 2017).

References  

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

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

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