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Cardio IQ Lipoprotein Fractionation, Ion Mobility

Test code(s) 91604

Question 1. What is ion mobility lipoprotein fractionation?

Ion mobility lipoprotein fractionation is a technology that uses gas-phase (laminar flow) electrophoresis to separate unmodified lipoproteins on the basis of size. Following the separation, each lipoprotein particle is directly detected and counted as it exits the separation chamber.

Ion mobility fractionation is the latest technology in the evolution of advanced lipid subclass measurement. It has evolved from the analytical ultracentrifugation (AnUC) and segmented gradient gel electrophoresis (SGGE) technologies developed at the University of California, Berkeley. Ion mobility incorporates and improves on the best features of advanced lipoprotein measurement methods. It combines high resolution separation of the full spectrum of lipoprotein particles along with direct quantitation of particles in each lipoprotein subclass. The high resolution of ion mobility’s lipoprotein subfractionation is comparable to that seen with AnUC and SGGE methods. Thus, the extensive literature supporting the clinical use of lipoprotein subclasses derived from these 2 methods can be applied to ion mobility-derived subclasses as well.

The size of the lipoprotein particles detected and counted are not affected by particle modifications. The particles are unaltered by stains or ultracentrifugation forces. Ionized lipoprotein particles are electrophoretically separated in a gas phase, and lipoprotein particles are distinguished on the basis of size. Size-separated particles are detected and counted by light scattering.

Figure. Ion mobility separation of lipoproteins

 

Ionized lipoproteins migrate across a laminar gas-phase flow, based on size and electrical field. Only a single size of lipoprotein will exit the field and be isolated (green line) at any point across the voltage gradient; larger and smaller lipoproteins (dotted black) are not collected. As the voltage ramps across the gradient, all of the lipoproteins are captured.

Question 2. Which lipoprotein fractions are reported and why?

Ion mobility technology precisely quantifies lipoprotein fractions across the entire lipoprotein spectrum; this comprises VLDL, IDL, LDL, and HDL particles.1 However, to facilitate risk assessment, Quest Diagnostics reports only those measurements that were significantly correlated with CVD events in a cohort of men and women from the prospective Malmo Diet and Cancer Study2:

  • Small, medium, and total LDL particle numbers (P ≤0.004)
  • LDL peak size (P = 0.009) and the associated LDL pattern
  • Large HDL particle number (P <0.001)

The focus on these measurements is consistent with identification of the “atherogenic lipoprotein phenotype” first proposed 2 decades ago.3,4

An elevated total LDL particle number is associated with a 1.4-fold increase in CVD risk.5 Similarly, elevated small and medium LDL particle numbers have been associated with a 1.3- to 1.4-fold increase.5

Ion mobility identifies 2 main subclasses of HDL: large HDL and small HDL. Large HDL may help protect the arterial wall due to its antioxidant properties. A decreased large HDL subclass suggests increased CVD risk.

Question 3. How do ion mobility- and NMR-derived LDL particles compare?

The NMR-derived LDL particle number (LDL-P, nmol/L) includes the 3 LDL subclasses and IDL. The concentration is measured indirectly from NMR signals emanating from terminal methyl groups in the lipoprotein particle shell and core.

In contrast, the ion mobility-derived total LDL particle concentrations (nmol/L), ie, LDL small and medium subclasses, are a direct detection and quantitation of the total number of LDL particles.1

Question 4. How does the ion mobility-derived total LDL particle measurement compare to an apolipoprotein B measurement?

The ion mobility-derived total LDL particle concentration (nmol/L) is a direct detection and quantitation of the total number of LDL particles.1

Apolipoprotein B (apo B) measurements represent the number of LDL particles and the overall number of atherogenic particles. Commercially available apo B assays measure lipoproteins containing apo B-100 and apo B-48. This includes the apo B component of LDL, IDL, VLDL, lipoprotein(a), and chylomicrons. Results are reported as mg/dL.

Question 5. How should discrepant apolipoprotein B and ion mobility-derived total LDL particles be interpreted?

When assessing a person’s risk for CVD, and especially when assessing residual risk, both markers may be considered even when they place the person in different risk categories. This is because the apo B test measures total apo B (apo B attached to VLDL, IDL, and LDL), while the ion mobility-derived LDL particle number is specific to LDL particles.

In the same way that an elevated apo B can be considered more revealing than LDL cholesterol when characterizing residual risk, the ion mobility-derived total LDL particle number correlates better with risk associated with LDL particle number. The apo B may correlate better with the risk attributed to all apo B-containing particles (LDL, IDL, and VLDL).

Question 6. How should discrepant LDL phenotype, LDL particle size, total LDL particle number, and LDL subclass results be interpreted?

When assessing a person’s risk for CVD, all results from risk markers should be considered even when they place the person in different risk categories. This is especially important when assessing residual risk.

That being said, it is reasonable that the finer the measuring tool and the more specific the data being generated, the more insightful are the conclusions that can be made. Historically LDL subclass patterns (ie, phenotype) have been characterized as predominantly small and dense (LDL pattern B) or predominantly large and buoyant (LDL pattern A) in order to characterize populations for analysis in research studies. However, some patients classified as LDL pattern A can have an unhealthy amount of small LDL.

The LDL particle size is the mean LDL particle diameter; it reflects the average size and is a good general measure. However, it does not always accurately reflect particle distribution.

A high total LDL particle number may be the result of a high number of large LDL particles or a high number of small LDL particles. The former is not associated with increased CVD risk, but the latter would indicate a higher risk. Thus, knowledge of the individual LDL subclass contribution to the total LDL particle number helps the clinician interpret the total LDL particle number result.

Question 7. How are the optimal (O), moderate (M), and high (H) risk categories shown on the Cardio IQreport determined?

The cut-points are based on analysis of data from the Malmo Diet and Cancer Study cardiovascular cohort. The cohort included  4,594 individuals who were followed for 12 years. Data showed that significantly higher risk was associated with values in the upper (or lower) tertile of population values. For example, a small LDL particle number in the upper third was associated with a significantly increased risk. Thus, the O, M, and H risk categories shown on the report are based on the tertile distribution of values in this cohort.2

Question 8. How are ion mobility-derived results incorporated into an overall risk assessment?

When assessing a person’s risk for CVD, all results from risk markers should be considered even when they place the person in different risk categories. This is especially important when assessing residual risk. Below is an example that demonstrates the importance of considering multiple ion mobility-derived risk markers.

Pattern A is classified as optimal, and pattern B is classified as high risk. This is based on large population studies showing that people without coronary heart disease tend to have an abundance of large, buoyant LDL particles (pattern A), and people with coronary heart disease tend to have an abundance of smaller, dense LDL particles (pattern B).7

However, the literature suggests that CVD risk is conferred by a trio of factors that define the atherogenic lipoprotein profile (ALP).8 The ALP includes elevated small LDL particles (pattern B), low levels of high density lipoprotein (HDL) cholesterol, and often, but not always, an elevated fasting triglyceride concentration. So the LDL pattern phenotype is only one aspect of the ALP. Additionally, neither the LDL pattern phenotype nor the ALP reflect risk associated with HDL subclasses or the number of small LDL particles.

Here is an example on how LDL particle number can contribute to the overall CVD risk. Consider a patient with an optimal pattern A LDL phenotype and a high total LDL mass. If the number of small LDL particles is also high, the patient may be at increased risk despite the favorable pattern A result. Thus, quantitating lipoprotein subclasses (eg, small, medium, large) can provide important information when assessing overall CVD risk. Interpreting the favorable pattern A result as indicative of low CVD risk could mistakenly rule out treatment in a patient who could benefit from it.

Question 9. Why do you use ångström units in the Cardio IQ report?

The ångström (Å) (0.1 nm) is a unit of measure denoting the diameter (size) of a particle. This diameter is used to determine the pattern A vs pattern B LDL phenotype.

The Cardio IQ report shows the particle diameter on the horizontal axis of the lipoprotein fractionation graphical display. The ångström measurement at the apex of the major LDL lipoprotein peak is reported in both the summary results table and the ion mobility detail table, labeled as LDL Peak Size.

LDL Peak Size and CVD Risk

Question 10. How much risk is associated with various lipoprotein subclasses?

The following CVD risk associations were observed in the Malmo Diet and Cancer Study cardiovascular cohort2:

  • High number of small LDL particles: 1.3 times increased risk
  • High number of medium LDL particles: 1.4 times increased risk
  • Low number of large HDL particles: 1.8 times increased risk

Question 11. What do the various HDL results mean?

Protection from CVD is associated with:

  • High HDL-C concentration
  • High number of large HDL particles
  • Large, buoyant HDL phenotype

Conversely, values in the lower tertile are associated with increased risk for CVD.2

Question 12. Which therapeutic agents have an impact on lipoprotein subclasses?

Image of Table

Statins tend to reduce the entire LDL spectrum, large and small alike.

 

References
 
  1. Caulfield MP, Li S, Lee G, et al. Direct determination of lipoprotein particle sizes and concentrations by ion mobility analysis. Clin Chem. 2008;54:1307-1316.
  2. Musunuru K, Orho-Melander M, Caulfield M, et al. Ion mobility analysis of lipoprotein subfractions identifies three independent axes of cardiovascular risk. Arterioscler Thromb Vasc Biol. 2009;29:1975-1980.
  3. Austin MA, King MC, Vranizan KM, Krauss RM. Atherogenic lipoprotein phenotype. A proposed genetic marker for coronary heart disease risk. Circulation. 1990;82:495-506.
  4. Superko HR. Advanced lipoprotein testing and subfractionation are clinically useful. Circulation 2009;119:2383-2395.
  5. Musunuru K,  Orho-Melander M, Caulfield MP, et al. Ion mobility analysis of lipoprotein subfractions identifies three independent axes of cardiovascular risk. Arterioscler Thromb Vasc Biol. 2009;29:1975-1980.
  6. Mudd JO, Borlaug BA, Johnston PV, et al. Beyond low-density lipoprotein cholesterol: defining the role of low-density lipoprotein heterogeneity in coronary artery disease. J Am Coll Cardiol. 2007;50:1735-1741.
  7. Superko HR. Advanced lipoprotein testing and subfractionation are clinically useful. Circulation 2009;119;2383-2395.
  8. Krauss RM. Lipoprotein subfractions and cardiovascular disease risk. Curr Opin Lipidol. 2010;21:305–311.
  9. Superko HR, Garrett BC, King SB 3rd, et al. Effect of combination nicotinic acid and gemfibrozil treatment on intermediate density lipoprotein, and subclasses of low density lipoprotein and high density lipoprotein in patients with combined hyperlipidemia. Am J Cardiol. 2009;103:387-392.
  10. Superko HR, Berneis KK, Williams PT, et al. Gemfibrozil reduces small low-density lipoprotein more in normolipemic subjects classified as low-density lipoprotein pattern B compared with pattern A. Am J Cardiol. 2005;96:1266-1272.
This FAQ is provided for informational purposes only and is not intended as medical advice. A physician’s test selection and interpretation, diagnosis, and patient management decisions should be based on his/her education, clinical expertise, and assessment of the patient.
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