Lipoprotein Subfractionation: LDL Particle Number (ION)

Optimal Takeaways

Measuring low-density lipoprotein (LDL) particle number provides a better assessment of cardiovascular risk and subclinical disease than measuring LDL cholesterol. Even if LDL cholesterol is decreased, the depleted LDL particles can still be atherogenic. Increased circulating LDL particles can also be associated with additional CVD risk factors, including inflammation, insulin resistance, hypertriglyceridemia, and increased coronary artery calcium score. A low LDL particle number may not be clinically relevant.

Standard Range: 0.00 – 1137.99 nmol/L      

The ODX Range: 0.00 – 1137.99 nmol/L

Low LDL particle number may not be clinically relevant unless associated with malnutrition or another disease state.

High LDL particle number is associated with increased cardiovascular disease risk, inflammation, insulin resistance, small LDL particle size (Feingold 2023), an unhealthy diet, and increased trans-fat intake (Garshick 2014).

Overview    

Low-density lipoprotein particle number directly reflects how many LDL particles are in circulation at a given time. An increasing number of particles is a sign of increased cardiovascular risk, even if the amount of cholesterol carried on LDL is low. Research suggests that atherosclerotic cardiovascular disease (ASCVD), carotid intima-media thickness, and coronary artery calcium may be more closely associated with LDL particle number than LDL cholesterol or non-HDL-C (Feingold 2023).    

Higher LDL particle numbers are also associated with other cardiovascular risk factors, including systemic inflammation, insulin resistance, and small LDL particle size. An elevated LDL particle number may identify CVD risk better than LDL-C, HDL-C, or apoB. An increased LDL particle number detected CVD risk even when apoB was optimal, i.e., below 69 mg/dL. However, when the LDL particle number was favorable, apoB was a better indicator of residual CVD risk. A high LDL particle number may also identify “hidden” CVD risk in those with low LDL-C, including those on statin drugs. In such cases, LDL may be depleted of cholesterol but still atherogenic. Researchers note that reducing LDL-C by statins reduces the risk of a cardiovascular event by less than 30% (Varvel 2015), and a relative risk reduction of 25% translates into an absolute risk reduction of only 3.4% (Superko 2022).

Denser LDL particles carrying less cholesterol are cleared less efficiently, leading to an increase in LDL particle number and an increase in CVD risk (Langlois 2018). Guidelines of the Association of Clinical Endocrinologists note that LDL particle number is superior to LDL particle size and sdLDL for predicting adverse cardiovascular events (Talebi 2020).

Data from 3,066 individuals enrolled in the Framingham Offspring Study revealed that LDL particle number was the strongest predictor of future CVD events. The risk of a CVD event was lowest when both LDL particle number and LDL-C were low. However, if LDL-C was low, but the LDL particle number was elevated, the CVD event rate increased. It is possible that lowering LDL-C alone may mask CVD risk that can be picked up by measuring LDL particle number and that a low particle number is a better indicator of low CVD risk than a low LDL-C (Cromwell 2007).

Increased LDL particle number identified residual cardiac risk in type 2 diabetics despite having very low LDL-C below 50 mg/dL (1.29 mmol/L) and a non-HDL-C below 80 mg/dL (2.07 mmol/L). The phenomenon is considered “discordance” when LDL particle number and LDL cholesterol are not in agreement. Researchers also note that triglyceride levels increased as LDL particle size increased, further indicating cardiometabolic dysfunction (Malave 2012).

A healthy diet low in trans-fats and saturated fats, maintaining a healthy weight, and regular exercise can help reduce LDL particles. In fact, LDL particle number decreases as the trans-fat content of the diet decreases (Garshick 2014). Natural products and foods, including avocadoes, phytosterols, plant stanols, and omega-3 DHA, were also associated with a significant reduction in LDL particle number (Talebi 2020).

References  

Cromwell, William C et al. “LDL Particle Number and Risk of Future Cardiovascular Disease in the Framingham Offspring Study - Implications for LDL Management.” Journal of clinical lipidology vol. 1,6 (2007): 583-92. doi:10.1016/j.jacl.2007.10.001

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.

Garshick, M et al. “Reduction in dietary trans fat intake is associated with decreased LDL particle number in a primary prevention population.” Nutrition, metabolism, and cardiovascular diseases : NMCD vol. 24,1 (2014): 100-6. doi:10.1016/j.numecd.2013.06.003

Langlois, Michel R et al. “Quantifying Atherogenic Lipoproteins: Current and Future Challenges in the Era of Personalized Medicine and Very Low Concentrations of LDL Cholesterol. A Consensus Statement from EAS and EFLM.” Clinical chemistry vol. 64,7 (2018): 1006-1033. doi:10.1373/clinchem.2018.287037

Malave, Hector et al. “Evaluation of low-density lipoprotein particle number distribution in patients with type 2 diabetes mellitus with low-density lipoprotein cholesterol <50 mg/dl and non-high-density lipoprotein cholesterol <80 mg/dl.” The American journal of cardiology vol. 110,5 (2012): 662-5. doi:10.1016/j.amjcard.2012.04.046

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

Varvel, Stephen A et al. “Discordance between apolipoprotein B and low-density lipoprotein particle number is associated with insulin resistance in clinical practice.” Journal of clinical lipidology vol. 9,2 (2015): 247-55. doi:10.1016/j.jacl.2014.11.005