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Circulation. Author manuscript; available in PMC Feb 24, 2010.
Published in final edited form as:
PMCID: PMC2663974
NIHMSID: NIHMS90841

Lipoprotein Particle Profiles by Nuclear Magnetic Resonance Compared with Standard Lipids and Apolipoproteins in Predicting Incident Cardiovascular Disease in Women

Abstract

Background

Nuclear magnetic resonance (NMR) spectroscopy measures the number and size of lipoprotein particles, instead of their cholesterol or triglyceride content, but its clinical utility is uncertain.

Methods and Results

Baseline lipoproteins were measured by NMR in 27,673 initially healthy women followed for incident cardiovascular disease (CVD, N=1,015) over 11 years. Adjusting for non-lipid risk factors, hazard ratios (HRs) and 95% confidence intervals (CIs) for top vs bottom quintile of NMR-measured lipoprotein particle concentration (particles/L) were, for low-density lipoprotein (LDLNMR) 2.51 (1.91−3.30), high-density lipoprotein (HDLNMR) 0.91 (0.75−1.12), very-low-density lipoprotein (VLDLNMR) 1.71 (1.38−2.12), and LDLNMR/HDLNMR ratio 2.25 (1.80−2.81). Similarly-adjusted results for NMR-measured lipoprotein particle size (nanometers) were, for LDLNMR size 0.64 (0.52−0.79), HDLNMR size 0.65 (0.51−0.81), and VLDLNMR size 1.37 (1.10−1.70). Hazard ratios for NMR measures were comparable but not superior to standard lipids: total cholesterol 2.08 (1.63−2.67), LDL cholesterol 1.74 (1.40−2.16), HDL cholesterol 0.52 (0.42−0.64), triglycerides 2.58 (1.95−3.41), non-HDL cholesterol 2.52 (1.95−3.25), total/HDL cholesterol ratio 2.82 (2.23−3.58); and apolipoproteins: B100 2.57 (1.98−3.33), A-1 0.63 (0.52−0.77), B100/A-1 ratio 2.79 (2.21−3.54). There was essentially no reclassification improvement with adding LDLNMR particle concentration or apolipoprotein B100 to a model that already included the total/HDL cholesterol ratio and non-lipid risk factors (net reclassification index [NRI], 0% and 1.9%, respectively), nor did the addition of either variable result in a statistically significant improvement in the c-index.

Conclusions

In this prospective study of healthy women, CVD risk prediction associated with lipoprotein profiles evaluated by NMR was comparable but not superior to standard lipids or apolipoproteins.

Keywords: Lipoproteins, lipids, apolipoproteins

While current prevention guidelines recommend measurement of standard lipids to assess risk of cardiovascular disease (CVD),1-3 it has been suggested that alternative lipoprotein measures may improve risk prediction. However, it remains uncertain how well such measures predict CVD when compared with the standard lipids that are routinely obtained in clinical practice.

One method of alternative lipid testing is proton nuclear magnetic resonance (NMR) spectroscopy. This technique simultaneously quantifies the number and size of very low-density lipoprotein (VLDLNMR), low-density lipoprotein (LDLNMR), and high-density lipoprotein (HDLNMR) particles, expressed each as a lipoprotein particle concentration (particles/L), or as an average particle size (nanometers).4 By contrast, standard lipid tests quantify the cholesterol or triglyceride content of lipoproteins, expressed as mg/dL of cholesterol or triglyceride. The cholesterol content of lipoprotein particles varies between individuals because of heterogeneity in particle size and in the relative content of cholesterol ester and triglycerides contained in the particle core.5 6

Whether information about lipoprotein particle concentration or size obtained from NMR predicts CVD risk in asymptomatic individuals is uncertain. In addition, direct comparison data with apolipoproteins are scant. Each particle of LDL and VLDL carries 1 molecule of apolipoprotein B100 on its surface regardless of its cholesterol or triglyceride content,7 hence apolipoprotein B100 is another measure of atherogenic lipoprotein particle number, obtained by immunoassay, and high levels have been associated with higher CVD risk.8 Apolipoprotein A-1 is the major molecule that is carried on HDL particles, but because it is not carried in a 1-to-1 fashion, it is not a measure of HDL particle number, although low levels have been associated with higher CVD risk.9 We conducted this study to evaluate prospectively whether NMR lipoprotein particles predict CVD in initially healthy women, and how they compare with directly-measured standard lipids and immunoassay-measured apolipoproteins.

METHODS

Study Population

Study participants were drawn from the Women's Health Study (WHS), a recently completed randomized, double-blinded, placebo-controlled trial of low-dose aspirin and vitamin E in the primary prevention of CVD and cancer in women.10-12 WHS participants were apparently healthy female health care professionals, ages 45 years or older, who were free of self-reported CVD and cancer at study entry (1992−1995). Women gave written informed consent and completed questionnaires at the time of enrollment on demographics, anthropometrics, medical history, and lifestyle factors. They were also asked to provide a baseline blood sample; 28,345 women did so, and of these, 98.5% (N=27,909) had NMR measurements. For this study, we excluded women with missing data on baseline lipids or apolipoproteins (N=236), leaving 27,673 women for analysis. The study was approved by the institutional review board of the Brigham and Women's Hospital (Boston, Mass). Drs. Mora and Ridker had full access to the data and take full responsibility for its integrity. All authors have read and agree to the manuscript as written.

Laboratory Measurements

EDTA blood samples were obtained at the time of enrollment into the WHS and stored in vapor phase liquid nitrogen (−170° C). Samples for lipoprotein particle analysis by proton NMR spectroscopy were thawed, aliquoted (200 ul), refrozen, and shipped on dry ice to LipoScience, Inc. (Raleigh, NC). Particle concentrations of lipoproteins of different sizes were calculated from the measured amplitudes of their spectroscopically distinct lipid methyl group NMR signals. Weighted-average lipoprotein particle sizes are derived from the sum of the diameter of each subclass multiplied by its relative mass percentage based on the amplitude of its methyl NMR signal.5 Particle diameters and coefficients of variation (CVs) are shown in Supplementary Table 1. The NMR lipoprotein variables that we examined are those that are provided when ordering an NMR lipoprotein profile for clinical use.

In a laboratory (N. Rifai, Children's Hospital, Boston, MA) certified by the National Heart, Lung, and Blood Institute/Centers for Disease Control and Prevention Lipid Standardization program, baseline samples were thawed and analyzed for standard lipids and apolipoproteins. Standard lipids were directly measured using reagents from Roche Diagnostics (Indianapolis, IN), with CVs <3%. Apolipoproteins B100 and A-1 were measured using immunoturbidimetric assays (DiaSorin, Stillwater, Minn), with CVs of 5% and 3%, respectively.

Ascertainment of CVD Events

The primary endpoint of interest was a composite endpoint of incident CVD (nonfatal myocardial infarction, percutaneous coronary intervention, coronary artery bypass grafting, nonfatal ischemic stroke, or cardiovascular death). During the 11 year follow-up period, women reported the endpoints of interest on follow-up questionnaires every 6 or 12 months, and medical records were obtained to confirm events by a blinded end-points committee of physicians as previously described.12

Statistical Analysis

Statistical analyses were performed using STATA version 8.2 (STATA Corporation, College Station, Texas). We calculated Spearman rank correlation coefficients to evaluate the interrelations between the measured lipid biomarkers. Following guidelines from the Department of Health and Human Services,13 lipid biomarkers were divided into quintiles based on the distribution among women not taking hormone replacement. Cox proportional hazard regression models were used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) according to these quintiles. The proportional hazard assumption was satisfied using Schoenfeld residuals and the natural logarithm of follow-up time.

To examine the extent to which each lipid biomarker was associated with incident events, we initially considered each lipid variable in a separate model that adjusted for non-lipid risk factors (age, randomized treatment assignment, smoking status, menopausal status, postmenopausal hormone use, blood pressure, diabetes, and body mass index). Removing body mass index and diabetes from the multivariable analyses did not substantially affect the findings, nor did the addition of physical activity or alcohol use. Excluding the 883 women who were on baseline lipid lowering therapy did not change the results, and hence these women were included in the analyses. Analyses were also stratified according to fasting/nonfasting status based on our prior work in this cohort.14 P value for linear trend was obtained using the median value for each quintile. All P-values were two-tailed. Since lipoprotein particles are metabolically interrelated and their concentrations are not independent,4,15 NMR lipoproteins were also analyzed in a model that included the 9 NMR lipoprotein subclasses (large and small LDLNMR, IDLNMR, 3 HDLNMR and 3 VLDLNMR lipoprotein subclasses). We also analyzed LDLNMR lipoprotein concentration in multivariate Cox models that adjusted for other lipids.

The likelihood ratio χ2 statistic was used to evaluate the goodness-of-fit of predictive models. Model discrimination was examined using the c-index,16a generalization of the area under the receiver operator characteristic curve. Model calibration was assessed using the Hosmer-Lemeshow goodness-of-fit test.17 Risk reclassification was assessed by categorizing the predicted 10-year risk for each model into categories of less than 5%, 5% to less than 10%, 10% to less than 20%, and 20% or higher. We calculated the proportion of participants who were reclassified by the comparison model as compared to the reference model. We computed the Net Reclassification Improvement (NRI),18 which compares the shifts in reclassified categories by observed outcome, and the Integrated Discrimination Improvement (IDI),18 which compares the integrals of sensitivity and specificity under two models.

RESULTS

During a mean follow-up of 11 years (302,399 person-years), a total of 1,015 first CVD events occurred, with “hard” events comprising 74% of these events (155 CVD deaths, 265 myocardial infarctions, and 334 strokes). In comparison to the standard lipid measurements which reflect the cholesterol or triglyceride content of lipoprotein particles, the NMR-measured lipoprotein particle concentrations of total LDLNMR and VLDLNMR were higher in the women who developed CVD (Table 1), but no difference in total HDLNMR was found. Women with CVD had significantly smaller LDLNMR and HDLNMR particle sizes and larger VLDLNMR particle size.

Table 1
Baseline characteristics of participants according to incident cardiovascular disease

Table 2 shows the Spearman correlation coefficients for NMR lipoproteins with each other and with standard lipids and apolipoproteins. Total LDLNMR particle concentration correlated positively with LDL cholesterol (r = 0.62) but correlated more closely with apolipoprotein B100 (r = 0.83), non-HDL cholesterol (r = 0.74), total/HDL cholesterol ratio (r = 0.80), and apolipoprotein B100/A-1 ratio (r = 0.80), all P<0.001.

Table 2
Spearman correlation coefficients for NMR lipoproteins with lipids and apolipoproteins

Association of NMR Lipoproteins, Lipids, and Apolipoproteins with CVD

Table 3 shows the association of each of the NMR lipoproteins, standard lipids, and apolipoproteins with CVD examined in separate Cox regression models that adjusted for non-lipid risk factors. Of the NMR measures, total LDLNMR particle concentration had the largest hazard ratio and best goodness-of-fit likelihood ratio χ2. The concentration of small LDLNMR particles was associated with higher CVD, but large LDLNMR was not. However, when small and large LDLNMR were examined in a model that included all 9 NMR-measured lipoprotein particle concentrations (data not shown), both large and small LDLNMR were significantly associated with CVD to a similar degree.

Table 3
Associations of lipoprotein and lipid measures with incident cardiovascular disease, adjusted for non-lipid risk factors

Of the HDLNMR measures, the total concentration of HDLNMR particles was not significantly associated with CVD. Large HDLNMR particles were significantly and inversely associated with CVD, while medium and small HDLNMR particles had no significant associations. All VLDLNMR particles were associated with higher CVD. Associations of NMR lipoproteins with CVD, analyzed according to self-reported fasting/nonfasting status (< or ≥ 8 hours to last meal) resulted in stronger associations for large and medium VLDLNMR particles with CVD in the nonfasting state.

LDLNMR and HDLNMR particle size were inversely associated, and VLDLNMR particle size directly associated, with CVD. After adjusting for LDLNMR particle concentration, there was no additional contribution of LDLNMR size to CVD risk (P for trend=0.25), while HDLNMR and VLDLNMR particle size remained significantly associated with CVD after adjustment for the respective concentrations.

When we removed body mass index and diabetes from the adjusted models, the adjusted HRs for top vs bottom quintiles were: total LDLNMR particle concentration 2.92 (2.24−3.81), apolipoprotein B100 2.89 (2.24−3.72), non-HDL cholesterol 2.61 (2.04−3.35), and the total/HDL cholesterol ratio 3.19 (2.54−3.99).

As shown in Table 3 and summarized in the Figure, hazard ratios for NMR measures were of approximately similar magnitude as those for standard lipids and apolipoproteins, although the total/HDL cholesterol ratio had the largest hazard ratio for any lipid or lipoprotein measure with CVD and the best goodness-of-fit likelihood ratio χ2.

figure nihms-90841-f0001
Hazard ratios and 95% CIs for the top vs bottom quintile, unless otherwise noted, adjusted for non-lipid risk factors (age, randomized treatment assignment, smoking status, menopausal status, postmenopausal hormone use, blood pressure, diabetes, and body ...

Multivariate Lipid Models

In models that included non-lipid risk factors plus other lipids, the association of LDLNMR particle concentration with CVD was attenuated (Supplementary Table 2). In particular, after adjustment for the total/HDL cholesterol ratio, the association of LDLNMR examined as quintiles was attenuated but remained significant (top quintile HR 1.63; 95% CI 1.18−2.25). However, when LDLNMR was examined as a continuous variable there was no significant association after including the total/HDL cholesterol ratio.

Model Discrimination, Calibration, and Reclassification

Finally, we compared measures of model discrimination, calibration, and reclassification (Table 4). The referent model was comprised of the total/HDL cholesterol ratio and non-lipid risk factors, and compared to two other models: one that additionally incorporated LDLNMR particle concentration, and the other additionally incorporated apolipoprotein B100. All three models were well-calibrated.19 There was no statistically significant difference in the c-index for the models that added LDLNMR or apolipoprotein B100 to the referent model. There was essentially no reclassification improvement with adding LDLNMR particle concentration or apolipoprotein B100 to the referent model (NRI 0% and 1.9%, respectively).

Table 4
Comparison of models based on discrimination, calibration, and reclassification measures

DISCUSSION

In this prospective cohort of 27,673 initially healthy women, we found that NMR-measured lipoproteins were significantly associated with incident CVD after adjusting for non-lipid risk factors, with a magnitude of risk comparable but not superior to standard lipids or immunoassay-measured apolipoproteins. Even though NMR-measured LDLNMR particle concentration performed well for CVD risk prediction in this study, and was similar in risk to apolipoprotein B100, neither measurement was better than the total/HDL cholesterol ratio which is readily obtained from a standard lipid panel. These data support current guidelines that recommend the use of a standard lipid panel, in particular the total/HDL cholesterol ratio, for CVD risk assessment in clinical practice.

Our findings have direct clinical relevance on several fronts. First, major European and North American guidelines have endorsed the use of standard lipids for CVD risk prediction in asymptomatic individuals.1-3 By contrast, a recent statement involving an international panel of lipid experts proposed that CVD risk may be more closely related to atherogenic lipoprotein particle number than to LDL cholesterol.8 Atherogenic particle concentration may be measured by NMR, which provides the number per unit volume of lipoprotein particles of varying size, or by immunoassay measurement of apolipoprotein B100, since each VLDL, IDL, and LDL particle carries on its surface only one molecule of apolipoprotein B100.8

Previous studies, predominantly cross-sectional or case-control studies found that NMR-measured LDLNMR particle concentration may predict atherosclerotic diseases better than LDL cholesterol levels.15 20-24 Data from INTERHEART25 and other studies26-29 have found that apolipoprotein B100 or the apolipoprotein B100/A-1 ratio predict CVD. However, direct prospective comparison data for NMR measurements with apolipoproteins and standard lipid ratios are scarce.

To our knowledge, this study is the first large prospective comparison of associations of NMR-measured lipoproteins with both standard lipids and immunoassay-measured apolipoproteins for predicting incident CVD. We found that NMR-measured total LDLNMR particle concentration was similar in CVD risk prediction to apolipoprotein B100 and both measurements performed better than LDL cholesterol. However, the differences compared with triglycerides, non-HDL cholesterol and the total/HDL cholesterol ratio were small and do not support the routine measurement of NMR lipoproteins or immunoassay apolipoproteins when a standard lipid panel is available. The data from this study, along with our prior findings14,29 and recent data from the Framingham Study,30 provide evidence-based confirmation for guidelines that are based on the use of standard lipid measurements, particularly the total/HDL cholesterol ratio.

Second, our study provides new data regarding the potential atherogenicity of the various HDL particles, which are heterogeneous in size and composition, carrying variable amounts of cholesterol and apolipoprotein A-1 molecules.31 In this population of women, only large HDLNMR particles were associated with lower CVD risk. The magnitude of the inverse association of large HDLNMR particles with CVD was similar to that of apolipoprotein A-1 or HDL cholesterol, suggesting that the potentially protective effects of HDL cholesterol may be due to the large HDLNMR particles. Prior studies have demonstrated strong inverse relationships between insulin resistance and the large HDLNMR subclass as measured by NMR,32 or the corresponding HDL2 (sometimes referred to as “buoyant” HDL) as measured by ultracentrifugation.33 This observation of the potential cardioprotective role of large HDLNMR but not smaller HDLNMR particles may have clinical implications for developing therapeutic agents that target HDL metabolism, such as CETP inhibitor drugs.31 CETP inhibitors, such as torcetrapib, increase HDL cholesterol, predominantly altering the large HDL subclass, but there is controversy as to whether this results in reduced or enhanced cholesterol efflux from macrophages.34,35

While our study addresses primary prediction of CVD with NMR-based lipoprotein testing, our data should not be construed to exclude possible utility in this setting for alternative lipid or lipoprotein testing assessed by other measurement methods. Since our study is largely limited to Caucasian women, these data may not be generalizable to men or other patient groups. In particular, since we studied an apparently healthy cohort at low overall risk for CVD, our data do not address the question of whether or not lipoprotein testing with NMR has clinical utility for risk assessment and treatment strategies for higher risk patients, such as those with known cardiovascular disease, diabetes/insulin resistance, dyslipidemia, or for the monitoring of patients taking lipid altering therapy. Such studies need to be performed in the appropriate patient settings, preferably within the context of randomized trials of primary or secondary prevention.

In sum, CVD risk prediction associated with NMR lipoprotein profiles in this large prospective cohort of women was comparable but not superior to standard lipids or immunoassay-measured apolipoproteins. Thus, our data support the use of standard lipids, in particular the total/HDL cholesterol ratio, which are highly effective and readily available, for routine CVD risk assessment.

Supplementary Material

Suppl

Sources of Funding

The research for this article was supported by a grant to Dr. Mora from the American Heart Association (0670007N). Dr. Mora is also supported by the National Heart, Lung, and Blood Institute (K08 HL094375), the Sandra A. Daugherty Foundation and the Lerner Research Young Investigator Award. The Women's Health Study is supported by grants HL 43851, HL 080467 and CA 47988 from the National Heart, Lung, and Blood Institute and the National Cancer Insitute, the Donald W. Reynolds Foundation (Las Vegas, NV), and Leducq Foundation (Paris, France). The funding agencies played no role in the design, conduct, data management, analysis, or manuscript preparation related to this manuscript.

Footnotes

Disclosures

Dr Otvos is employed by, is a stockholder of, and serves on the board of directors of LipoScience, Inc., a diagnostic laboratory company that performed the lipoprotein subclass analyses described in the manuscript. Dr Rosenson is a stockholder of LipoScience, Inc., and he serves as a member of its Scientific Advisory Board.

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