To help evaluate your risk of developing cardiovascular disease (CVD)
When you have a personal and/or family history of CVD at an early age; when the result of your low-density lipoprotein (LDL) cholesterol test is within a healthy range, but your healthcare provider thinks that you may have an increased risk of developing heart disease; sometimes to help monitor the effectiveness of lipid-lowering treatment and/or lifestyle changes
A blood sample drawn from a vein in your arm
You may need to fast for 9-12 hours before this test; only water is permitted. Follow any instructions you are given.
Lipoproteins are particles that transport fats throughout the body. These particles are essential and carry a combination of proteins, vitamins, cholesterol, triglyceride, and phospholipid molecules. The composition of a lipoprotein particle changes as it circulates in the blood. Some molecules are removed and others are added, resulting in lipoprotein particles with variable amounts of cholesterol.
Low-density lipoprotein particles (LDL-P) are bi-products of fat transport that remain in circulation for an extended time. While in circulation, LDL-P can penetrate the artery wall and get stuck, forming a fatty plaque. These plaques can build over time and lead to blockages, resulting in heart attacks and strokes. The likelihood of an LDL-P getting trapped in the artery wall increases when more LDL-P are in the blood.
Traditional lipid testing measures the amount of LDL cholesterol (LDL-C) present in the blood, but it does not evaluate the number of LDL particles (LDL-P). LDL-P is often used to get a more accurate measure of LDL due to the variability of cholesterol content within a given LDL. Studies have shown that LDL-P more accurately predicts risk of cardiovascular disease than LDL-C. Researchers think that increased LDL-P could be one of the reasons that some people have heart attacks even though their total cholesterol and LDL cholesterol levels are not particularly high.
Low-density lipoprotein particle (LDL particle or LDL-P) testing evaluates LDL particles according to their concentration in the blood. It may provide useful information for assessing your cardiac risk if you have a personal or family history of heart disease at a young age, especially if your total cholesterol and LDL cholesterol (LDL-C) values are not significantly elevated.
While for many people, the standard LDL-C test is a good indicator of risk of cardiovascular disease (CVD), research has found that some people with healthy levels of LDL-C still have increased risk of CVD. Similarly, individuals with some chronic conditions such as diabetes may have increased risk even though their LDL-C is at a healthy level. For these populations, it has been suggested that the number of LDL particles might be an additional factor to consider when determining their CVD risk. In these cases, LDL-P testing may be used to further evaluate an individual's CVD risk.
LDL-P may also be occasionally ordered to monitor the effectiveness of treatment.
LDL subfraction testing is typically done along with LDL-P, however, subfraction information should not guide decision-making. Laboratories use a variety of methods to determine lipoprotein subfractions, including ultracentrifugation, polyacrylamide gradient gel electrophoresis, and NMR spectroscopy. None of these methods are harmonized, nor do they agree on the definitions of large versus small subfractions. None of the LDL subfraction methods in clinical use have sought Food and Drug Administration (FDA) clearance for subfractionation of LDL.
The National Lipid Association (NLA) has specifically called out the terms "large and fluffy LDL" as potentially misleading as it should be emphasized that all LDL is able to form arterial plaques. Importantly, patients with Familial Hypercholesterolemia, who develop heart attacks at an extremely young age, have "large and fluffy" LDL.
Data do not support routine testing for lipoprotein subfractions. Nevertheless, LDL subfraction testing has been used in clinical settings. No medical society has endorsed the use of lipoprotein subfractions. The National Lipid Association, the National Academic of Clinical Biochemistry, the American College of Cardiology, and the American Heart Association have all published guidelines specifically recommending against the use of LDL subfractions. The guidelines cite a lack of sufficient evidence to support LDL subfraction measurement for initial clinical assessment or on-treatment management decisions.
This testing may be ordered as part of an overall evaluation of cardiac risk when you have a personal or family history of early cardiovascular disease (CVD), especially when you don't have typical cardiac risk factors, such as high cholesterol, high LDL cholesterol, high triglyceride, low HDL cholesterol, smoking, obesity, inactivity, diabetes, and/or hypertension.
Your healthcare practitioner may order LDL-P testing, along with other lipid tests, after you have made lifestyle changes and/or been treated with lipid-lowering medications to determine whether treatment is working.
Although it is not generally recommended as a screening test, a few healthcare providers are ordering LDL-P along with a battery of other cardiac risk tests when they are attempting to determine someone's overall risk of developing CVD.
LDL-P test results are typically reported according to the testing method the laboratory uses. The report will usually include results for your total cholesterol, LDL-C and LDL-P. Additional values might include very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), LDL-C and/or HDL cholesterol, particle and size. Since different lab methods separate the subclasses based on different physical properties (particle number, size, density, and/or electrical charge), results cannot be directly compared between methods or laboratories.
In general, the result is interpreted within the framework of a lipid profile and its associated risk. If you have an increased LDL-P, this finding will add to your risk of developing cardiovascular disease above and beyond the risk associated with LDL cholesterol.
It is important to remember that LDL subfraction testing is not diagnostic, not endorsed by any medical societies, and not approved by the FDA. It attempts to evaluate your risk of developing CVD, but it cannot predict the development or severity of disease in a particular person. For this reason, LDL subfraction results should not be considered when making decisions about treatment or lifestyle changes.
LDL-P can be altered by adopting a reduced-calorie diet, losing excess weight, and exercising regularly. The use of lipid-lowering drugs such as statins and PCSK9-inhibitors will significantly reduce LDL-P.
It depends on the laboratory performing the test. Not every lab performs LDL-P testing as it requires specialized instruments. Your sample may be sent to a reference laboratory for testing, so it may take several days before results are available.
Sources Used in Current Review
(2015 March) "Advanced" Cholesterol Testing: Is It For You? Harvard Medical School. Available online at https://www.health.harvard.edu/diseases-and-conditions/advanced-cholesterol-testing-is-it-for-you. Accessed September 2019.
Harada, P., Akinkuolie, A., Mora S. (2014 August 20) Advanced Lipoprotein Testing: Strengths and Limitations. American College of Cardiology. Available online at https://www.acc.org/latest-in-cardiology/articles/2014/08/25/15/07/advanced-lipoprotein-testing-strengths-and-limitations. Accessed September 2019.
Look Beyond Traditional Cholesterol and Give Your Patients More Than a 50/50 Chance. Mayo Medical Laboratories. Available online at https://news.mayocliniclabs.com/n1/96e99366cea7b0de/uploads/2013/07/ldlp-nmr-reference.pdf. Accessed September 2019.
Wolska, A., Remaley A. (2017 January 3). Lipoprotein Subfractionation Analysis. AACC. Available online at https://www.aacc.org/publications/cln/articles/2017/january/lipoprotein-subfractionation-analysis. Accessed September 2019.
Shiffman, D., Louie, J., Caulfield, M., et al (2017 August). LDL Subfractions Are Associated with Incident Cardiovascular Disease in the Malmo Prevention Project Study. Atherosclerosis. Available online at https://www.sciencedirect.com/science/article/pii/S0021915017311784. Accessed in September 2019.
Bays, H., Jones, P., Orringer C., et al. (2016 January-February) National Lipid Association Annual Summary of Clinical Lipidology 2016. Journal of Clinical Lipidology. Available online at https://www.lipidjournal.com/article/S1933-2874(15)00363-3/fulltext. Accessed September 2019.
Chung M, Lichtenstein AH, Ip S, Lau J and Balk EM. Comparability of methods for LDL subfraction determination: A systematic review. Atherosclerosis. 2009;205:342-8. Otvos JD, Mora S, Shalaurova I, Greenland P, Mackey RH and Goff DC, Jr. Clinical implications of discordance between low-density lipoprotein cholesterol and particle number. J Clin Lipidol. 2011;5:105-13.
Ai M, Otokozawa S, Asztalos BF, Ito Y, Nakajima K, White CC, Cupples LA, Wilson PW and Schaefer EJ. Small dense LDL cholesterol and coronary heart disease: results from the Framingham Offspring Study. Clin Chem. 2010;56:967-76.
Duran EK, Aday AW, Cook NR, Buring JE, Ridker PM and Pradhan AD. Triglyceride-Rich Lipoprotein Cholesterol, Small Dense LDL Cholesterol, and Incident Cardiovascular Disease. J Am Coll Cardiol. 2020;75:2122-2135.
Balling M, Nordestgaard BG, Langsted A, Varbo A, Kamstrup PR and Afzal S. Small Dense Low-Density Lipoprotein Cholesterol Predicts Atherosclerotic Cardiovascular Disease in the Copenhagen General Population Study. J Am Coll Cardiol. 2020;75:2873-2875.
Mora S. Advanced lipoprotein testing and subfractionation are not (yet) ready for routine clinical use. Circulation. 2009;119:2396-404.
Davidson MH, Ballantyne CM, Jacobson TA, Bittner VA, Braun LT, Brown AS, Brown WV, Cromwell WC, Goldberg RB, McKenney JM, Remaley AT, Sniderman AD, Toth PP, Tsimikas S, Ziajka PE, Maki KC and Dicklin MR. Clinical utility of inflammatory markers and advanced lipoprotein testing: advice from an expert panel of lipid specialists. J Clin Lipidol. 2011;5:338-67.
Greenland P, et al., American College of Cardiology Foundation/American Heart Association Task Force on Practice G. 2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2010;122:e584-636.
Members NLC, Myers GL, Christenson RH, Cushman M, Ballantyne CM, Cooper GR, Pfeiffer CM, Grundy SM, Labarthe DR, Levy D, Rifai N and Wilson PW. National Academy of Clinical Biochemistry Laboratory Medicine Practice guidelines: emerging biomarkers for primary prevention of cardiovascular disease. Clin Chem. 2009;55:378-84.
Sources Used in Previous Reviews
Thomas, Clayton L., Editor (1997). Taber's Cyclopedic Medical Dictionary. F.A. Davis Company, Philadelphia, PA [18th Edition].
Pagana, Kathleen D. & Pagana, Timothy J. (2001). Mosby's Diagnostic and Laboratory Test Reference 5th Edition: Mosby, Inc., Saint Louis, MO.
Landray, M. et. al (2002 January 2). Abnormal low-density lipoprotein subfraction profile in patients with untreated hypertension. Association of Physicians Q J Med 2002; 95: 165-171. Available online at http://qjmed.oupjournals.org/cgi/content/full/95/3/165.
Bioletto, S. et. al. (2000 February). Acute hyperinsulinemia and very-low-density and low-density lipoprotein subfractions in obese subjects. American Journal of Clinical Nutrition, Vol. 71, No. 2, 443-449. Available online at http://www.ajcn.org/cgi/content/full/71/2/443.
(Winter 2004). The Fats of Life, 7 Articles. Lipoproteins and Vascular Diseases Division, AACC, Volume XVIII, Vol 1. PDF available for download at http://www.aacc.org/divisions/lipids/winter04.pdf.
(2002). LDL Subfractions. Specialty Laboratories [On-line test information]. PDF available for download at http://laboratory.specialtylabs.com/education/download_PDF/TN_LDLsub.pdf.
(2004). LDL Subclasses. ARUP's Guide to Clinical Laboratory Testing. Available online at http://www.arup-lab.com/guides/clt/tests/clt_a34b.jsp.
Warnick, G. and Cheung, M. (2000). Measurement and Clinical Significance of High-density Lipoprotein Cholesterol Subclasses. Chapter 15 (Handbook of Lipoprotein of Lipoprotein Testing, AACC Press). Available online at http://www.warnick.biz/dextransulfate/Chapter15.htm.
Muniz, N., et. al. (2000). A New Tool for the Automated Analysis of LDL Subfraction Patterns Generated by the Lipoprint™ LDL System. Paper presented at The Frontiers in Lipoprotein and Vascular Disease, St Louis, MO. PDF available for download at http://www.4qc.com/pdf/frontiers.pdf.
Pagana, Kathleen D. & Pagana, Timothy J. (© 2007). Mosby's Diagnostic and Laboratory Test Reference 8th Edition: Mosby, Inc., Saint Louis, MO. Pp 602-605.
Clarke, W. and Dufour, D. R., Editors (2006). Contemporary Practice in Clinical Chemistry, AACC Press, Washington, DC. 253-258.
Mudd, J. et. al. (2007 October 29). Beyond Low-Density Lipoprotein Cholesterol -- Defining the Role of Low-Density Lipoprotein Heterogeneity in Coronary Artery Disease. Journal of the American College of Cardiology 50(18):1735-1741. Available online through http://www.medscape.com/. Accessed on 3/8/08.
Navab, M. et. al. (2006 October 20). Mechanisms of Disease: Proatherogenic HDL-An Evolving Field. Nat Clin Pract Endocrinol Metab. 2006;2(9):504-511. Available online through http://www.medscape.com/. Accessed on 3/8/08.
CCMDweb.org. Clinical Insights. Available online through http://www.ccmdweb.org/clinicalinsights. Accessed May 2008.
The National Academy of Clinical Biochemistry. Laboratory Medicine Practice Guidelines, Emerging Biomarkers of Cardiovascular Disease and Stroke, Draft Guidelines, Version 0906, summary.
Mackey, R. et. al. (2012 August). High-density lipoprotein cholesterol and particle concentrations, carotid atherosclerosis, and coronary events: MESA (multi-ethnic study of atherosclerosis). J Am Coll Cardiol. 2012 Aug 7;60(6):508-16. [On-line information]. Available online at http://www.ncbi.nlm.nih.gov/pubmed/22796256. Accessed September 2013.
Otvos, J. et. al. (2011 March-April). Clinical Implications of Discordance Between LDL Cholesterol and LDL Particle Number. J Clin Lipidol. 2011 Mar–Apr; 5(2): 105–113. [On-line information]. Available online at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3070150/. Accessed September 2013.
Rosenson RS, and Underberg JA. (2013 July 28). Systematic Review: Evaluating the Effect of Lipid-Lowering Therapy on Lipoprotein and Lipid Values. Cardiovasc Drugs Ther. 2013 Jul 28. Abstract [Epub ahead of print] [On-line information]. Available online at http://www.ncbi.nlm.nih.gov/pubmed/23893306. Accessed September 2013.
Cole, T. et. al. (2013 ). Association of Apolipoprotein B and Nuclear Magnetic Resonance Spectroscopy–Derived LDL Particle Number with Outcomes in 25 Clinical Studies: Assessment by the AACC Lipoprotein and Vascular Diseases Division Working Group on Best Practices. Clinical Chemistry May 2013 vol. 59 no. 5 752-770 Abstract [On-line information]. Available online at http://www.clinchem.org/content/59/5/752.abstract. Accessed September 2013.
Master, S. and Rader, D. (2013 March 13). Beyond LDL Cholesterol in Assessing Cardiovascular Risk: apo B or LDL-P? Clinical Chemistry 2013; v. 59, p.723-725 Extract. [On-line information]. Available online at http://www.clinchem.org/content/59/5/723.extract. Accessed September 2013.
Sniderman, A. and Kwiterovich, PO. (2013 April). Update on the detection and treatment of atherogenic low-density lipoproteins. Curr Opin Endocrinol Diabetes Obes. 2013 Apr;20(2):140-7 Abstract. [On-line information]. Available online at http://www.ncbi.nlm.nih.gov/pubmed/23422241. Accessed September 2013.
Mietus-Snyder, M. et. al. (2013 August). Low-Density Lipoprotein Cholesterol versus Particle Number in Middle School Children. J Pediatr. 2013 Aug;163(2):355-362 Abstract. [On-line information]. Available online at http://www.ncbi.nlm.nih.gov/pubmed/23415622. Accessed September 2013.
DeGoma, E. and Rader, D. (2012) High-Density Lipoprotein Particle Number. A Better Measure to Quantify High-Density Lipoprotein? Medscape Multispecialty from J Am Coll Cardiol. 2012;60(6) [On-line information]. Available online at http://www.medscape.com/viewarticle/768499. Accessed September 2013.
(2013 July 19). A Test in Focus: LDL Particle Concentration NMR, Plasma. Mayo Clinic Mayo Medical Laboratories [On-line information]. Available online at http://news.mayomedicallaboratories.com/2013/07/19/a-test-in-focus-ldl-particle-concentration-nmr-plasma-2/. Accessed September 2013.
(© 1995–2013). LDL Particle Concentration NMR, Plasma. Mayo Clinic Mayo Medical Laboratories [On-line information]. Available online at http://www.mayomedicallaboratories.com/test-catalog/Overview/62186. Accessed September 2013.
Ghassab, R. et. al. (March 2010). Determination of Low Density Lipoprotein Particle Size by Polyacrylamide Gradient Gel Electrophoresis in Patients with Coronary Artery Stenosis. LabMedicine v 41 (3) [On-line information]. Available online at http://labmed.ascpjournals.org/content/41/3/164.full. Accessed September 2013.
Myers, G. Editor (© 2009). Emerging Biomarkers for Primary Prevention of Cardiovascular Disease and Stroke. The National Academy of Clinical Biochemistry, Laboratory Medicine Practice Guidelines, Emerging Biomarkers for Primary Prevention [On-line information]. Available online through http://www.aacc.org. Accessed September 2013.
Pagana, K. D. & Pagana, T. J. (© 2011). Mosby's Diagnostic and Laboratory Test Reference 10th Edition: Mosby, Inc., Saint Louis, MO. Pp 622-625.
Clarke, W., Editor (© 2011). Contemporary Practice in Clinical Chemistry 2nd Edition: AACC Press, Washington, DC. Pp 285-297.
(June 13, 2009) The New Blood Lipid Tests -- Sizing Up LDL Cholesterol. Heart Health Special Report. Johns Hopkins Medicine. Available online at http://www.johnshopkinshealthalerts.com/reports/heart_health/1886-1.html. Accessed November 2013.
2016 review performed by Rose Romeo, PhD, DABCC, FACB.
Yan Zhang, Sha Li, Rui-Xia Xu, Cheng-Gang Zhu, Yuan-Lin Guo, Na-Quiong Wu, Jing Sun and Jian-Jun Li. System Inflammatory Markers Are Closely Associated with Atherogenic Lipoprotein Subfractions in Patients Undergoing Coronary Angiography. Mediators of Inflammation (2015):2015 Article ID 235742 (9 pages). Available online at http://www.hindawi.com/journals/mi/2015/235742/abs/. Accessed February 7, 2016.
Harold E. Bays, Peter H. Jones, W. Virgil Brown and Terry A. Jacobson. National Lipid Association Annual Summary of Clinical Lipidology 2015. Journal of Clinical Lipidology; 2014 (8) S1-S36. Available online at http://nlaresourcecenter.lipidjournal.com/Content/PDFs/Summary-Revised.pdf as. Accessed February 7, 2016.
Samia Mora, Michael P. Caulfield, Jay Wohlgemuth, Zhizong Chen, Robert Superko, Charles M. Rowland, Robert J. Glynn, Paul M. Ridker, Ronald M. Kraus. Atherogenic Lipoprotein Subfractions Determined by Ion Mobility and First Cardiovascular Events After Random Allocation to High Intensity Statin or Placebo. The Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) Trial. Circulation (2015); 132:2220-2229. Abstract available online at http://circ.ahajournals.org/content/132/23/2220.abstract. Accessed February 7, 2016.
Mark A. Sarzynshi, Jeffrey Burton, Tuomo Rankinen, Steven N. Blair, Timothy S. Church, Jean-Pierre Despres, James M. Hapberg, Rian Landers-Ramos, Arthur S. Leon, Catherine R. Mikus, D.C. Rao, Richard L. Selp, James S. Skinner, Cris A. Sientz, Paul D. Thompson, Kenneth R. Wilund, William E. Kraus, Claude Bouchard. The effects of exercise of the lipoprotein subclass profile: A meta-analysis of 10 interventions. Atherosclerosis (2015) 243: 364-372. Abstract available online at http://www.ncbi.nlm.nih.gov/pubmed/26520888. Accessed February 7, 2016.
Paul T. Williams, Xue-Qiao Zhao, Santica M. Marcovina, James D. Otvos, B. Greg Brown, Ronald M. Krauss. Comparison of four methods of analysis of lipoprotein particle subfractions for their association with angiographic progression of coronary artery disease. Atherosclerosis (2015) 233: 713-720. Abstract available online at http://www.atherosclerosis-journal.com/article/S0021-9150(14)00060-4/abstract. Accessed February 7, 2016.
Heejung Shim, Daniel I. Chasman, Joshua D. Smith, Samia Mora, Paul M. Ridker, Deborah A. Nickerson, Ronald M. Krauss, Matthew Stephens.. A Multivariate Genome-Wide Association Analysis of 10 LDL Subfractions, and Their Response to Statin Treatment, in 1868 Caucasians. PLOS ONE 10(4):1-20. Available online at http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0120758. Accessed February 7, 2016.