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The science behind Boston Heart HDL Map®

The association between cardiovascular risk and HDL subparticle distribution has been well established.

Our research on balanced HDL subpopulation profiles indicates:

    • Increased amounts of large α-mobility HDL particles are associated with healthy HDL maturation and decreased cardiovascular disease risk. High levels of α-1 HDL are a marker of protection from heart disease.
    • Increased amounts of small HDL particles are associated with a deficiency in HDL maturation and increased CVD risk. High levels of the very small preβ-1 and small α-3 and α-4 HDL particles are markers of high risk for the presence of clinical or subclinical cardiovascular disease.

HDL subpopulations are significantly better predictors of CHD than HDL-C values. Every 1 mg/dL apoA-I increase in very large α-1 HDL was associated with a 26% (p<0.0001) decrease in CHD risk.
- Framingham Offspring Study (2004)

Low levels of α-1 HDL and α-2 HDL and high levels of preβ-1 HDL predicted recurrent CVD events versus no recurrence in men selected for low HDL-C (<40 mg/dL) and CHD. Low α-1 HDL levels have been shown to be the most significant parameter predicting CVD recurrence (p<0.001).
- Veterans Affairs HDL Intervention Trial (2005)

In a comparison of postmenopausal women with established CAD as assessed by angiography versus control subjects women with CAD had significantly higher levels of apoA-I in very small preβ-1 HDL (+41%, p<0.0001) and significantly lower levels of apoA-I in very large α-1 HDL (-51%, p<0.0001) and large α-2 HDL (-25%, p<0.0001). Moreover in an analysis predicting severity of CAD the most significant predictor of all lipid variables tested was the level of apoA-I in preβ-1 HDL.
- Estrogen Replacement and Atherosclerosis Trial (2008)

Significant increases in apoA-I in very large α-1 HDL observed with niacin/simvastatin therapy have been linked to regression of the amount of clogging or atherosclerosis in human coronary arteries.
- High-density Lipoprotein Atherosclerosis Treatment Study (2003)

HDL Subfraction Analysis Using the Boston Heart HDL Map

The Boston Heart HDL Map test analyzes the distribution of HDL subpopulations in plasma using a next generation proprietary electrophoresis technique that enables precise differentiation and quantification of HDL subparticles.

Subsequent immunoblotting quantifies the amount of apoA-I, the main protein of HDL, in each of the five most important HDL subpopulations (very small preβ-1, small α-4, medium α-3, large α-2, and very large α-1), providing markedly more accurate risk assessment than HDL-C alone.

In particular, the HDL Map identifies the atherogenic preβ-1 HDL (precursor HDL), as part of the subpopulation profile, providing insight into the interplay/remodeling of HDL. The method’s precise separation allows calculation of the α-1/preβ-1 ratio, a powerful marker of CVD risk. It has been shown that the α-1/preβ-1 ratio is most effective for estimating the efficacy of specific lipid-lowering interventions (diet, exercise, weight loss, and drugs, especially statins).

Optimize Treatment Strategies and Patient Monitoring

The measurement of HDL subpopulations provides useful information about residual risk beyond that obtained by traditional risk factor testing, especially in subjects with normal LDL-C and triglyceride levels.

An optimal HDL subpopulation profile is marked with high α-1 and low small and very small particles (α-3 and preβ-1 levels). Other profiles are suboptimal and should be a target for lifestyle and drug interventions.

The benefits of the HDL Map are:

    • Specific measurement of the concentrations of apoA-I (the major protein of HDL) in the five major HDL subclasses, from very small preβ-1, small α-4, medium α-3, large α-2, and very large α-1 HDL;
    • More accurate prediction of CVD risk than one can achieve with HDL cholesterol measurement alone;
    • Determination of whether optimal levels of apoA-I in the large and very large HDL particles have been achieved with lifestyle and/or pharmacologic therapy. This is important along with optimal LDL-C levels for the prevention of progression or achieving regression of existing coronary artery disease (CAD);
    • Diagnosis of marked HDL deficiency disorders (HDL-C <10) associated with a lack of apoA-I (apoA-I deficiency), a lack of cellular cholesterol efflux (Tangier disease), or a lack of cholesterol esterification (lecithin cholesterol acyltransferase deficiency).
    • A schematic representation of apoA-I containing HDL subpopulations. High concentrations of particles highlighted in green are associated with less risk for CVD and high concentrations of particles highlighted in red are associated with increased risk for CVD.

Shortcomings in Other Methods

The Boston Heart HDL Map is the only test presently available for quantifying large and small α-, preα-, and preβ-mobility HDL particles in the same assay. Many other technologies measure only one aspect of HDL particles and none of them is able to detect and separate preβ-mobility HDL from α- and preα-mobility HDL particles. The HDL Map directly measures apoA-I containing HDL subpopulations, unlocking knowledge that provides the most advanced insight in identifying abnormalities that increase an individual’s cardiovascular risk. Other lipoprotein assays have significant shortcomings:

    • Nuclear magnetic resonance (NMR) estimates the fatty acid content (not cholesterol) of various lipoprotein particles, with numerous assumptions made about the composition of lipoprotein particles.
    • The vertical rotor ultracentrifugation (VAP) test has very low resolution in the HDL size range and produces artifacts due to the high salt concentration and the high G-force.

The figure above compares the various HDL subpopulations separated by different methods.

Scientific Milestones in HDL Subpopulation Analysis

1993

Apolipoprotein A-I containing HDL subpopulation analysis became quantifiable by the introduction of image analysis.1

2000

It was reported that the apoA-I containing HDL subpopulation profile differs significantly between subjects with and without CHD independent of HDL-C and apoA-I concentrations. CHD patients not only have HDL deficiency but also a major rearrangement in HDL subpopulations with significantly lower α-1 and significantly higher α-3 particles.2

2000

Dr. Asztalos was awarded a 5-year NIH grant (HL-64738) to investigate the relationship between HDL subpopulations and CHD (2000–2005).

2004

The effects of five different statins at common therapeutic doses on HDL-C, apoA-I, and HDL subpopulations were investigated. Atorvastatin was shown to be the most effective agent to treat lipid disorders and to beneficially modify the HDL subpopulation profile by increasing the concentration of the large, cholesterol-rich α-1 and decreasing the small triglyceride-rich α-3 HDL subpopulations. It is followed in effectiveness by simvastatin, pravastatin, and lovastatin.3,4

2004

In the HDL Atherosclerosis Treatment Study (HATS), a significant negative correlation between changes in α-1 HDL particle concentration and coronary stenosis was noted.5

2004 – 2007

HDL subpopulations quantified by 2-D electrophoresis, immunoblotting and image analysis, were shown to be significantly better predictors of CHD than HDL-C:

  • In the Framingham Offspring Study (FOS), in men, every 1 mg/dL increase in the large α-1 HDL subpopulation level decreased odds of CHD by 26% (p<0.0001) whereas each mg/dL increase in HDL-C decreased odds of CHD by 2% in a model including all established CHD risk factors.6
  • In the Veterans’ Affairs HDL Intervention Trial (VA-HIT), an altered HDL subpopulation profile, marked with low levels of α-1 and α-2 and high levels of preβ-1 predicted recurrent CVD events compared with no recurrence in men with low HDL-C and CHD. Low α-1 HDL level was the most significant parameter predicting CVD recurrence.7
  • The mechanisms whereby statins, including rosuvastatin, alter HDL-C and HDL subpopulations were further investigated concluding that statins decrease triglyceride-rich lipoproteins as well as cholesteryl ester transfer protein (CETP) activity.8,9

2008

In the Estrogen Replacement and Aging Study, postmenopausal women with established coronary artery disease as assessed by angiography had significantly higher levels of apoA-I in very small prebeta-1 HDL (+41%, p<0.0001) and significantly lower levels of apoA-I in very large alpha-1 HDL (-51%, p<0.0001) and large alpha-2 HDL (-25%, p<0.0001) than control women. Moreover in an analysis predicting severity of coronary artery disease the most significant predictor of all lipid variables tested was the level of apoA-I in prebeta-1 HDL.10

2008 – 2010

The HDL Map allowed healthcare providers to monitor the effects of HDL-modifying therapies (statins, fibrates, niacin, CETP inhibitors, hormone-replacement therapy, and weight loss) so that progress and change of CVD risk can be followed.11,12,13,14,15

2015

Next generation HDL Map advancements provide further optimized resolution of the individual HDL particles as well as increased reproducibility and throughput. Newly developed proprietary imaging technology that improves precision of the HDL Map also deployed.


1. Asztalos et al. Asztalos, BF, Sloop, CH, Wong,L, Roheim, PS. Two-dimensional electrophoresis of plasma lipoproteins: recognition of new apo A-I-containing subpopulations. Biochimica et Biophysica Acta. 1993;1169:291-300.
2. Asztalos BF, Roheim PS, Milani RL, et al. Distribution of ApoA-I-containing HDL subpopulations in patients with coronary heart disease. Arterioscler, Thromb Vascular Biol. 2000;20:2670-2676.
3. Asztalos BF, Horvath KV, McNamara JR, Roheim PS, Rubinstein JJ, Schaefer EJ. Comparing the effects of five different statins on the HDL subpopulation profiles of coronary heart disease patients. Atherosclerosis. 2002; 164:361-369.
4. Asztalos BF, Horvath KV, McNamara JR, Roheim PS, Rubinstein JJ, Schaefer EJ. Effects of atorvastatin on the HDL subpopulation profile of coronary heart disease patients. Journal of Lipid Research. 2002;43:1701-1707.
5. Asztalos BF, Batista M, Horvath KV, et al. Change in α-1 HDL concentration predicts progression in coronary artery stenosis. Arterioscler Thromb Vasc Biol. 2003;23:847–852.
6. Asztalos BF, Cupples LA, Demissie S, et al. High-density lipoprotein subpopulation profile and coronary heart disease prevalence in male participants of the Framingham Offspring Study. Arterioscler Thromb Vasc Biol. 2004;24:2181–2187.
7. Asztalos BF, Collins D, Cupples LA, et al. Value of high-density lipoprotein (HDL) subpopulations in predicting recurrent cardiovascular events in the Veterans Affairs HDL Intervention Trial. Arterioscler Thromb Vasc Biol. 2005;25:2185–2191.
8. Schaefer EJ, Asztalos BF. The effects of statins on high-density lipoproteins. Curr Atheroscler Rep. 2006;8(1):41–49.
9. Asztalos BF, LeMaulf F, Dallal GE, et al. Comparison of the effects of high doses of rosuvastatin versus atorvastatin on the subpopulations of high-density lipoproteins. Am J Cardiol. 2007;99:681–685.
10. Lamon-Fava S, Herrington DM, Reboussin DM, et al. Plasma levels of HDL subpopulations and remnant lipoproteins predict the extent of angiographically-defined coronary artery disease in post-menopausal women. Arterioscler Thromb Vasc Biol. 2008;28:575–579.
11. Asztalos BF, Collins D, Horvath KV, Bloomfield HE, Robins SJ, Schaefer EJ. Relation of gemfibrozil treatment and high-density lipoprotein (HDL) subpopulation profile with cardiovascular events in the Veterans Affairs HDL Intervention Trial (VA-HIT). Metabolism. 2008;57(1):77–83.
12. Lamon-Fava S, Diffenderfer MR, Barrett HR, et al. Extended-release niacin alters the metabolism of apolipoprotein (apo) A-I and apoB-containing lipoproteins. Arterioscler Thromb Vasc Biol. 2008;28:1672–1678.
13. Lamon-Fava S, Herrington DM, Reboussin DM, et al. Changes in remnant and high-density lipoproteins associated with hormone therapy and progression of coronary artery disease in postmenopausal women. Atherosclerosis. 2009;205:325–330.
14. Asztalos BF, Swarbrick MM, Schaefer EJ, et al. Effects of weight loss, induced by gastric bypass surgery, on HDL remodeling in obese women. J Lipid Res. 2010;51:2405–2412.
15. Asztalos, BF. High-density lipoprotein particles, coronary heart disease, and niacin. J Clin Lipidol. 2010;4(5):405–410.

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