The NMR LipoProfile Test

What is the NMR LipoProfile test?

The NMR LipoProfile® test is an advanced cardiovascular diagnostic test that uses nuclear magnetic resonance (NMR) spectroscopy to uniquely provide rapid, simultaneous and direct measurement of LDL particle number and size of LDL particles, as well as direct measurement of HDL and VLDL subclasses.  This detailed lipoprotein particle information allows clinicians to make more effective individualized treatment decisions than previously possible based on standard lipid panel testing. The atherosclerotic culprit is LDL particle number, not LDL cholesterol.

Why should I use the NMR LipoProfile test?

You should use the NMR LipoProfile test in appropriate patients because it provides a more accurate picture of a patient’s cardiovascular (CVD) risk than the standard lipid panel.  

LDL particle number provides a more accurate picture of CVD risk than traditional cholesterol values.

As published in the American Journal of Cardiology (2002;90(suppl):22i-29i.), LDL cholesterol values can be misleading.  The chart below shows how optimal levels of LDL cholesterol can mask increased number of LDL particles. 

In this trial, Distribution of LDL-C values among Framing Offspring Study participants, over 1/3 of the 3,347 patients with "optimal" LDL cholesterol levels have elevated number of LDL particles, which places them at an increased level of CHD risk.

In a separate trial, 32% of the 26,213 patients** had elevated risk based on LDL particle number, rather than LDL cholesterol. 

This finding should be particularly noted when the data are examined by patient clinical category (n=3,812).  Despite LDL cholesterol levels at ATP III goal, elevated LDL particle numbers were found in 64% of CHD risk equivalent patients, such as patients with type II diabetes.   Additionally, 47% of patients with isolated low HDL cholesterol had an elevated LDL particle

number.

Red indicates elevated LDL particle number.

Green indicates goal LDL particle number.

** Data on file, LipoScience Inc.

The clinical value of the NMR LipoProfile test is based on data demonstrating stronger CVD associations compared to the traditional cholesterol-based lipid panel. Data from several clinical trials show significantly stronger associations of NMR LipoProfile test values with:

• “Hard” CVD endpoints (e.g., myocardial infarction or angina, coronary heart disease (CHD), death, stroke);
• Sub-clinical CVD endpoints (e.g., carotid atherosclerosis, coronary lumen diameter, coronary calcification): and
• Microvascular endpoints (e.g., retinopathy, nephropathy) versus the standard lipid panel.
• The NMR LipoProfile test differentiates CHD risk in patients who may have similar cholesterol values, especially when the LDL cholesterol is at or near ATP III treatment goals.

Why is the NMR LipoProfile® test information superior to a standard lipid panel?

The NMR LipoProfile test information is superior to a standard lipid panel because it uses nuclear magnetic resonance spectroscopy to directly measure patients’ lipoprotein particles.  The number and type of particles present cause atherosclerosis, not the amount of cholesterol they carry. The NMR LipoProfile test is the first CHD risk test to give physicians actual numbers of individual lipoprotein particles present, information that has been repeatedly shown to be more predictive of cardiovascular disease than standard lipid testing.

According to Dr. Rader in the Textbook of Cardiovascular Medicine, Edited by Eric Topol, MD. Second Edition: 

‘A given level of LDL cholesterol could be caused by a small number of large LDL particles or a large number of small LDL particles’

LDL cholesterol values can often be misleading; optimal levels of LDL-C can mask increased number of LDL particles and hidden cardiovascular risk.

 

On the left, at the same LDL-C level, varying amounts of particles are present due to the effects of particle size.  When lipoprotein particles are small, there must be more of them to carry equivalent amounts of cholesterol, up to 70% more lipoprotein particles.

 

 

 

 

 

 

 

By the same logic, to the right, when particles carry varying amounts of cholesterol per lipoprotein particle, regardless of particle size, there must be more compositionally abnormal particles to carry equivalent amounts of cholesterol.  This can mean up to a 40% increase in the number of atherogenic lipoprotein particles at the same LDL cholesterol level.

 Although an extensive body of data indicates that plasma lipid levels are useful in defining atherosclerotic risk at a population level, they poorly predict atherosclerotic behavior at an individual patient level. This dichotomy is clinically apparent in patients considered to be at low risk for the development of CHD, who have optimal or near optimal lipid levels and subsequently develop atherosclerosis. It is also apparent in patients with known CHD who manifest recurrent events, despite achieving the desired lipid values with disease modifying therapy.

How Does The NMR LipoProfile® Test Differ From Other Advanced CHD Risk Tests?

Due to lack of a unique method to identify individual particle subclasses, lipoprotein testing has historically taken one of two forms:

1. Time consuming separation technologies designed to determine lipoprotein particle size or density through gradient gel electrophoresis or density gradient ultracentrifugation
2. Estimation of LDL particles via measuring blood levels of apolipoprotein B.  (Apo B)

Apo B is a protein found on every LDL, IDL and VLDL particle.  Since >90% of plasma Apo B is bound to LDL, the assay provides a reasonable approximation of LDL particle number.  Results of many clinical studies have shown that Apo B is a better marker of CHD risk and a better guide to the adequacy of statin drug therapy than is LDL-C.

What Outcomes Studies Support Using the NMR LipoProfile® Test?

There are many studies that support the use of the NMR LipoProfile test.  The clinical value of any specific lipoprotein test should be based on data demonstrating stronger cardiovascular disease (CVD) associations than the current standard, the traditional cholesterol-based lipid profile.  To date, NMR LipoProfile analyses have been conducted in a blinded fashion on over 80,000 frozen plasma specimens received from over 350 ongoing or completed clinical trials. Results from these trials have been published or presented at major international scientific meetings.  Click on the title of each study to view the relevant findings:

1. Cardiovascular Health Study Kuller LH, Arnold A, Tracy R, et al. Nuclear Magnetic Resonance (NMR) spectroscopy of lipoproteins and risk of coronary heart disease in the cardiovascular health study. Aterioscler Thromb Vasc Biol. 2002;22:1175-1180.
2. Women’s Health Study Blake GJ, Otvos JD, Rifai N, Ridker PM. Low-density lipoprotein particle concentration and size as determined by nuclear magnetic resonance (NMR) spectroscopy as predictors of cardiovascular disease in women. Circulation. 2002;106:1930-1937.
3. Veteran’s Affairs HDL Intervention Trial (VA-HIT) Otvos JD, Collins D, Freedman DS, et al. LDL and HDL particle subclasses are independent predictors of cardiovascular events in the Veteran Affairs HDL Intervention Trial. American Heart Association 75th Annual Scientific Session; Chicago, Ill. November 2002.
4. PLAC-1 Trial Rosenson RS, Otvos JD, Freedman DS. Relations of lipoprotein subclass levels and low-density lipoprotein size to progression of coronary artery disease in the pravastatin limitation of atherosclerosis in the coronary arteries (PLAC-I Trial). Am J Cardiol. 2002;90:89-94.
5. Healthy Women Study Mackey RH, Kuller LH, Sutton-Tyrrel K, Evans RW, Holubkov R, Matthews KA. Lipoprotein subclasses and coronary artery calcium in postmenopausal women from the Healthy Women Study. Am J Cardiol 2002;90(suppl):71i-76i.
6. Healthy Women Study Mackey RH, Kuller, lH, Matthews KA, Sutton-Tyrrell K, Evans RW.  Does hormone replacement therapy affect associations between carotid atherosclerosis in high-risk patients.  American Heart Association 41st Annual Conference on Cardiovascular Disease Epidemiology and Prevention.  February 2001.  San Antonio, TX.
7. Pittsburgh Epidemiology of Diabetes Complications (EDC) Study Soedamah-Muthu SS, Chang Y-F, Otvos J, Evans RW, Orchard TJ. Lipoprotein subclass measurements by nuclear magnetic resonance (NMR) spectroscopy improve the prediction of coronary artery disease in type 1 diabetes. A prospective report from the Pittsburgh Epidemiology of Diabetes Complications Study. Diabetologia. 2003;46:674-682.
8. DCCT/EDIC Study Lyons TJ, Zheng D, Otvos, JD, et al.  Nuclear Magnetic Resonance NMR) Determined lipoprotein subclass profile in the DCCT/EDIC cohort: associations with retinopathy and nephropathy. American Diabetes Association 60th Annual Scientific Sessions.  June 2000. San Antonio, TX
9. DCCT/EDIC Study Lyons TJ, Klein RL, Zheng, D, Otvos JD, Garvey WT, Jenkins AJ.  Nuclear Magnetic Resonance (NMR) – Determined lipoprotein subclass profile in the DCCT/EDIC cohort: associations with retinopathy.  International Society of Ocular Toxicology 7th Congress.  October 2000.  Kiawah Island, South Carolina.

Other relevant studies include:

1. Plac-1 Trial Rosenson RS, Shalaurova I, Freedman DS, Otvos, JD.  Effects of pravastatin treatment on lipoprotein subclass profiles and particle size in the PLAC-1 Trial.  Atherosclerosis. 2002; 160:41-8.
2. Insulin Resistance Atherosclerosis Study Goff et al.  Insulin resistance and adiposity influence low density lipoprotein size, particle concentration and subclass concentration but not low density lipoprotein cholesterol concentration, IRAS.  American Heart Association Scientific Sessions.  November 2001.  Anaheim, CA
3. Hopkins SIB Study Kral BG, Becker LC, Yook RM, Blumenthal RS, Kwitterovich PO, Otvos JD, Becker DM. Racial differences in low density lipoprotein particle size in families at high risk for premature coronary heart disease. Ethn Dis 2001; 11:325-37.
4. African-American Siblings (SIBS) Study Post et al. LDL Particle Concentration and Insulin Level Predict Carotid Atherosclerosis in High Risk Patients.  American College of Cardiology Scientific Sessions.  March 2002.  Atlanta, GA

In terms of choosing between the available CHD risk tests, collectively these data show significantly stronger associations of NMR LipoProfile® values when compared to standard lipids or apolipoproteins with respect to:

• “Hard” cardiovascular endpoints such as myocardial infarction or angina, CHD death, stroke _1-3
• Subclinical CVD endpoints such as carotid atherosclerosis, coronary lumen diameter, coronary calcification _4-9
• Microvascular endpoints such as retinopathy, nephropathy _10-11

References:

1. Sniderman AD, Furberg CD, Keech A, van Lennep JER, Frohlich J, Jungner I, Walldius G. Apolipoproteins versus lipids as indices of coronary risk and as targets for statin treatment. Lancet 2003;361:777-80.
2. Beisiegel U and St Clair RW. An emerging understanding of the interactions of plasma Lipoproteins and the arterial wall that leads to the development of atherosclerosis.  Curr Opin Lipidiology. 1996;7(5):265-268.
3. Weissberg PL, Rudd, JH. Atherosclerotic Biology and Epidemiology of Disease. Textbook of Cardiovascular Medicine - Second Edition (Topol, EJ editor) 2002, Lippincott Williams & Wilkins, Philadelphia. p 6.
4. Lamarche B, Tchernof A, Moorjani S, Cantin B, Dagenais GR, Lupien PJ, Despres JP.  Small, dense low-density lipoprotein particles as a predictor of the risk of ischemic heart disease in men.  Circulation 1997;95:69-75.
5. Otvos JD, Jeyarajah EJ, Cromwell WC. Measurement issues related to lipoprotein heterogeneity. Am J Cardiol 2002;90 (suppl):22i-29i.
6. Rader, DJ. Lipid Disorders. Textbook of Cardiovascular Medicine - Second Edition (Topol, EJ editor) 2002, Lippincott Williams & Wilkins, Philadelphia. pp 65-66.
7. Otvos J.  Measurement of triglyceride‑rich Lipoproteins by nuclear magnetic resonance (NMR) spectroscopy.  Clin Cardiol 1999;22(6 Suppl):II21‑27.
8. Packard CJ. Understanding coronary heart disease as a consequence of defective regulation of Apolipoprotein B metabolism.  Curr Opin Lipidol 1999;10:237-244.
9. Otvos, JD. Measurement of lipoprotein subclass profiles by nuclear magnetic resonance (NMR) spectroscopy. Handbook of Lipoprotein Testing - Second Edition (Rifai N, Warnick R, Dominiczak M, editors) 2000, AACC Press, Washington DC.
10. Kuller LH, Arnold A, Tracy R, Otvos JD, Burke G, Pstay B, Siscovick D, Freedman DS, Kronmal R.  Nuclear Magnetic Resonance (NMR) Spectroscopy of Lipoproteins and Risk of Coronary Heart Disease in the Cardiovascular Health Study. Aterioscler Thromb Vasc Biol 2002;22:1175-1180.
11. Blake, GJ, Otvos JD, Rifai N, Ridker PM.  Low-density lipoprotein particle concentration and size as determined by nuclear magnetic resonance (NMR) spectroscopy as predictors of cardiovascular disease in women. Circulation 2002;106:1930-1937.
12. Otvos JD, Collins D, Freedman DS, Pegus C, Schaefer EJ, Robins SJ, Rubins HB. LDL and HDL particle subclasses are independent predictors of cardiovascular events in the Veteran Affairs HDL Intervention Trial.  American Heart Association 75th Annual Scientific Session, November 2002, Chicago Illinois.
13. Freedman DS, Otvos JD, Jeyarajah EJ, Barboriak JJ, Anderson AJ, Walker JA.  Relation of Lipoprotein subclasses as measured by proton nuclear magnetic resonance (NMR) spectroscopy to coronary artery disease. Atheroscler Thromb Vasc Biol 1998;18:1046-1053.
14. Rosenson RS, Otvos JD, Freedman DS.  Relations of lipoprotein subclass levels and low-density lipoprotein size to progression of coronary artery disease in the Pravastatin Limitation of Atherosclerosis in the Coronary Arteries (PLAC-1 Trial).  Am J Cardiol 2002;90:89-94.
15. Mackey RH, Kuller LH, Sutton-Tyrrel K, Evans RW, Holubkov R, Matthews KA. Lipoprotein subclasses and coronary artery calcium in postmenopausal women from the Healthy Women Study. Am J Cardiol 2002;90(suppl):71i-76i.
16. Frederickson DS, Levey RI, Lees RS. Fat transport in Lipoproteins—an integrated approach to mechanisms and disorders. N Engl J Med. 1967;276(3):148-56
17. Rader, DJ. Lipid Disorders.  Textbook of Cardiovascular Medicine – Second Edition (Topol, EJ editor) 2002, Lippincott Williams & Wilkins, Philadelphis.  pp 65-66.
18. Otvos, JD, Jeyarajah EJ. Bennett DW. Krauss RM.  Development of a proton NMR spectroscopic method for determining plasma lipoprotein concentrations and subspecies distribution from a single, rapid measurement. Clin Chem 1992;38:1632-1638