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Does Low-Density Lipoprotein Size Add to Atherogenic Particle Number in Predicting the Risk of Fatal Myocardial Infarction?

Published:February 14, 2006DOI:https://doi.org/10.1016/j.amjcard.2005.10.062
      The lipoprotein-related risk of coronary artery disease is determined principally by the balance between atherogenic lipoprotein particles, i.e., the lipoprotein that contain apolipoprotein-B (apo-B), and the antiatherogenic particles, i.e., high-density lipoprotein particles that contain apo-A-I. However, there is also considerable evidence that patients with predominantly small dense low-density lipoprotein (LDL) have more adverse clinical outcomes than do those with large buoyant LDL. The AMORIS study prospectively examined the relative importance of lipoprotein lipids versus apolipoproteins on the risk of fatal myocardial infarction in a large Swedish cohort. This updated analysis includes 69,029 men and 57,167 women who were followed for a mean of 10.3 years. Our objective was to determine whether LDL size as reflected by the LDL cholesterol/apo-B ratio added significant predictive power to apo-B or the apo-B/apo-A-I ratio. Although apo-A-I added significantly to the predictive power of apo-B, categorical and continuous multivariate analyses showed that this is not the case for LDL size. The strongest single lipoprotein-related risk factor was the apo-B/apo-A-I ratio. In conclusion, these results provide further confirmation of the importance of determining apo-B and apo-A-I in routine clinical practice.
      Many in vitro studies have demonstrated that small dense low-density lipoprotein (SD-LDL) particles may be more atherogenic than large buoyant LDL particles, a finding that is supported by the results of a number of cross-sectional and case-control studies.
      • Sniderman A.D.
      • Furberg C.D.
      • Keech A.
      • Roeters van Lennep J.E.
      • Frohlich J.
      • Jungner I.
      • Walldius G.
      Apolipoproteins versus lipids as indices of coronary risk and as targets for statin therapy treatment.
      • Packard C.J.
      • Shepherd J.
      Lipoprotein heterogeneity and apolipoprotein B metabolism.
      Nevertheless, in most of these studies, SD-LDL particles did not remain an independent predictor of risk in multivariate analysis. The issue is complex because SD-LDL particles are so often associated with other atherogenic findings, such as hypertriglyceridemia, low high-density lipoprotein (HDL) cholesterol, and increased apolipoprotein-B (apo-B).
      • Packard C.J.
      • Shepherd J.
      Lipoprotein heterogeneity and apolipoprotein B metabolism.
      Therefore, the question remains open as to whether SD-LDL particles, per se, substantially increase the risk of vascular disease. LDL size was not measured directly in the Apolipoprotein-related Mortality Risk Study (AMORIS). However, several reports have shown that a higher LDL cholesterol/apo-B ratio identifies subjects with predominantly large buoyant LDL particles, whereas a lower value will point to predominantly SD-LDL particles.
      • Campos H.
      • Blijlevens E.
      • McNamara J.R.
      • Ordovas J.M.
      • Posner B.M.
      • Wilson P.W.
      • Castelli W.P.
      • Schaefer E.J.
      LDL particle size distribution. Results from the Framingham Offspring Study.
      • Wagner A.M.
      • Jorba D.
      • Rigla M.
      • Alonso E.
      • Ordonez-Llanos J.
      • Perez A.
      LDL-cholesterol/apolipoprotein B ratio is a good predictor of LDL phenotype B in type 2 diabetes.
      • Sniderman A.D.
      • Lamarche B.
      • Tilley J.
      • Seccombe D.W.
      • Frohlich J.
      Hypertriglyceridemic hyperapoB in type 2 diabetes.
      • Sniderman A.D.
      • Dagenais G.R.
      • Cantin B.
      • Despres J.P.
      • Lamarche B.
      High apolipoprotein B with low high-density lipoprotein cholesterol and normal plasma triglycerides and cholesterol.
      • Sniderman A.D.
      • St-Pierre A.
      • Cantin B.
      • Dagenais G.R.
      • Depres J.-P.
      • Lamarche B.
      Concordance/discordance between plasma apolipoprotein B levels and the cholesterol indexes of atherosclerotic risk.
      Therefore, we examined whether LDL size adds significantly to risk of fatal myocardial infarction beyond the information provided by apo-B, which indicates atherogenic particle number, and the apo-B/apo-A-I ratio, the single strongest determinant of risk in the AMORIS.
      • Walldius G.
      • Jungner I.
      • Holme I.
      • Aastveit A.H.
      • Kolar W.
      • Steiner E.
      High apolipoprotein B, low apolipoprotein A-1, and improvement in the prediction of fatal myocardial infarction (AMORIS study) a prospective study.

      Methods

      The AMORIS population and procedures have been previously described in detail.
      • Walldius G.
      • Jungner I.
      • Holme I.
      • Aastveit A.H.
      • Kolar W.
      • Steiner E.
      High apolipoprotein B, low apolipoprotein A-1, and improvement in the prediction of fatal myocardial infarction (AMORIS study) a prospective study.
      • Jungner I.
      • Marcovina S.M.
      • Walldius G.
      • Holme I.
      • Kolar W.
      • Steiner E.
      Apolipoprotein B and A-I values in 147576 Swedish males and females, standardized according to the World Health Organization–International Federation of Clinical Chemistry First International Reference Materials.
      • Jungner I.
      • Walldius G.
      • Holme I.
      • Kolar W.
      • Steiner E.
      Apolipoprotein B and A-I in relation to serum cholesterol and triglycerides in 43 600 males and females.
      • Walldius G.
      • Jungner I.
      • Kolar W.
      • Holme I.
      • Steiner E.
      High cholesterol and triglyceride values in Swedish males and females: increased risk of fatal myocardial infarction: first report from the AMORIS (Apolipoprotein-related Mortality Risk Study).
      This updated analysis is based on subjects who were recruited from 1985 to 1996 and who were >40 years of age at entry. Mean follow-up was 10.3 years. Total cholesterol and triglyceride levels were measured by conventional enzymatic methods.
      • Jungner I.
      • Walldius G.
      • Holme I.
      • Kolar W.
      • Steiner E.
      Apolipoprotein B and A-I in relation to serum cholesterol and triglycerides in 43 600 males and females.
      Apo-B and apo-A-I were measured in fresh blood samples by immunoturbidimetric techniques.
      • Jungner I.
      • Marcovina S.M.
      • Walldius G.
      • Holme I.
      • Kolar W.
      • Steiner E.
      Apolipoprotein B and A-I values in 147576 Swedish males and females, standardized according to the World Health Organization–International Federation of Clinical Chemistry First International Reference Materials.
      • Jungner I.
      • Walldius G.
      • Holme I.
      • Kolar W.
      • Steiner E.
      Apolipoprotein B and A-I in relation to serum cholesterol and triglycerides in 43 600 males and females.
      Analytic procedures were compliant with the World Health Organization–International Federation of Clinical Chemistry apolipoprotein standard program,
      • Marcovina S.M.
      • Albers J.J.
      • Kennedy H.
      • Mei J.V.
      • Henderson L.O.
      • Hannon W.H.
      International Federation of Clinical Chemistry standardization project for measurements of apolipoproteins A-I and B. IV. Comparability of apolipoprotein B values by use of International Reference Material.
      • Marcovina S.M.
      • Albers J.J.
      • Henderson L.O.
      • Hannon W.H.
      International Federation of Clinical Chemistry standardization project for measurements of apolipoproteins A-I and B. III. Comparability of apolipoprotein A-I values by use of International Reference Material.
      as previously documented.
      • Jungner I.
      • Marcovina S.M.
      • Walldius G.
      • Holme I.
      • Kolar W.
      • Steiner E.
      Apolipoprotein B and A-I values in 147576 Swedish males and females, standardized according to the World Health Organization–International Federation of Clinical Chemistry First International Reference Materials.
      All methods were fully automated. LDL cholesterol was calculated according to Jungner’s formula,
      • Walldius G.
      • Jungner I.
      • Holme I.
      • Aastveit A.H.
      • Kolar W.
      • Steiner E.
      High apolipoprotein B, low apolipoprotein A-1, and improvement in the prediction of fatal myocardial infarction (AMORIS study) a prospective study.
      which gives equivalent values to those obtained by Friedewald’s formula, as confirmed by Talmud et al.
      • Talmud P.J.
      • Hawe E.
      • Miller G.J.
      • Humphries S.E.
      Non-fasting apolipoprotein B and triglyceride levels as a useful predictor of coronary heart disease risk in middle-aged UK men.
      The LDL cholesterol/apo-B ratio was used as a surrogate for LDL size.
      • Campos H.
      • Blijlevens E.
      • McNamara J.R.
      • Ordovas J.M.
      • Posner B.M.
      • Wilson P.W.
      • Castelli W.P.
      • Schaefer E.J.
      LDL particle size distribution. Results from the Framingham Offspring Study.
      • Wagner A.M.
      • Jorba D.
      • Rigla M.
      • Alonso E.
      • Ordonez-Llanos J.
      • Perez A.
      LDL-cholesterol/apolipoprotein B ratio is a good predictor of LDL phenotype B in type 2 diabetes.
      • Sniderman A.D.
      • Lamarche B.
      • Tilley J.
      • Seccombe D.W.
      • Frohlich J.
      Hypertriglyceridemic hyperapoB in type 2 diabetes.
      • Sniderman A.D.
      • Dagenais G.R.
      • Cantin B.
      • Despres J.P.
      • Lamarche B.
      High apolipoprotein B with low high-density lipoprotein cholesterol and normal plasma triglycerides and cholesterol.
      • Sniderman A.D.
      • St-Pierre A.
      • Cantin B.
      • Dagenais G.R.
      • Depres J.-P.
      • Lamarche B.
      Concordance/discordance between plasma apolipoprotein B levels and the cholesterol indexes of atherosclerotic risk.
      All analyses were performed in CALAB Laboratories (Stockholm, Sweden).
      The end point of the study was fatal myocardial infarction or sudden death. The study was approved by the ethics review board of the Karolinska Institute (Stockholm, Sweden). Permits were obtained from the Swedish Data Inspection to correlate the laboratory data with the Swedish Death Register.
      Multivariate and receiver-operating characteristic analyses in the entire population were used to assess the effects of apo-B, LDL cholesterol/apo-B ratio, and apo-B/apo-A-I ratio on risk. Within the entire group, 1,433 men and 734 women had an event. Numbers of deaths per 1,000 person-years and relative risks (based on Cox models) were calculated, as were 95% confidence intervals and p values. Relative risks were expressed per 1 SD as the unit change for each variable (relative risk/SD).

      Results

      Baseline characteristics of subjects who were selected for this analysis are listed in Table 1. As anticipated, the lipoprotein profile in men was more atherogenic than that in women. In particular, triglycerides and apo-B were higher in men than in women, whereas HDL cholesterol and apo-A-I were lower. Similarly, all lipid and apolipoprotein ratios were higher, i.e., more adverse, in men than in women. All these differences between genders were significant (p <0.0001). These differences likely accounted for much of the difference in clinical event rates between men and women.
      Table 1Baseline characteristics and mean baseline lipid and apolipoprotein values (n = 126,196)
      VariableMen (n = 69,029)Women (n = 57,167)
      Age (yrs)53.2 ± 9.556.0 ± 11.1
      Total cholesterol (mg/dl)236 ± 43238 ± 47
      Triglycerides (mg/dl)139 ± 74113 ± 63
      Apo-B (mg/dl)135 ± 33127 ± 35
      Apo-A-I (mg/dl)138 ± 21153 ± 24
      Apo-B/apoA-I1.01 ± 0.300.86 ± 0.29
      HDL cholesterol (mg/dl)55 ± 1666 ± 17
      LDL cholesterol (mg/dl)153 ± 39151 ± 43
      Non-HDL cholesterol (mg/dl)181 ± 45173 ± 48
      LDL cholesterol/HDL cholesterol3.17 ± 1.982.50 ± 1.42
      Total cholesterol/HDL cholesterol4.81 ± 2.693.90 ± 1.78
      Non-HDL cholesterol/HDL cholesterol3.81 ± 2.692.90 ± 1.78
      LDL cholesterol/apo-B2.96 ± 0.473.10 ± 0.51
      Triglyceride/HDL cholesterol1.42 ± 1.800.88 ± 0.99
      Fatal acute myocardial infarction1,433734
      Proportion (×1,000 observation years)20.812.8
      Values are means ± SDs or numbers of patients.
      It is noteworthy that the LDL cholesterol/apo-B ratio was significantly lower in men than in women (p <0.0001). This is consistent with differences between genders that have been demonstrated using directly measured indexes of LDL particle size.
      • Coresh J.
      • Kwiterovich P.O.
      • Smith H.H.
      • Bachorik P.S.
      Association of plasma triglyceride concentration and LDL particle diameter, density, and chemical composition with premature coronary artery disease in men and women.
      • Freedman D.S.
      • Otvos J.
      • Jeyarajah E.J.
      • Shalaurova I.
      • Cupples A.L.
      • Parise H.
      • D’Agostino R.B.
      • Wilson P.W.F.
      • Schaefer E.J.
      Sex and age differences in lipoprotein subclasses measured by nuclear magnetic resonance spectroscopy the Framingham Study.
      In addition, there was an inverse hyperbolic relation between plasma triglyceride levels and LDL particle size as estimated by the LDL cholesterol/apo-B ratio (r = −0.29, p <0.0001; men, r = −0.30; women, r = −0.25; men and women, p <0.0001). These data are consistent with previous work that has demonstrated LDL size decreases as plasma triglycerides increase.
      • Packard C.J.
      • Shepherd J.
      Lipoprotein heterogeneity and apolipoprotein B metabolism.
      Figure 1 shows that there is an inverse relation between relative risk of fatal myocardial infarction and LDL cholesterol/apo-B ratio after adjustment for age and gender, indicating that risk increases as LDL size decreases (relative risk/SD 0.93, p <0.0028). The relative risk for men was 0.94 (p <0.012), whereas that for women was weaker (0.93, p <0.15), but obviously followed the same trend as for men. When adjusted for age, gender, and triglycerides, the risk related to the LDL cholesterol/apo-B ratio was not significant.
      Figure thumbnail gr1
      Figure 1Relative risk functions for the (A) LDL cholesterol (LDL-C)/apo-B ratio and (B) apo-B, which were adjusted for gender and age. (C) Relative risk functions for apo-B that were adjusted for gender, age, and the LDL cholesterol/apo-B ratio. (D) Relative risk function for the apo-B/apo-A-I ratio that was adjusted for gender and age. (E) Relative risk function for the apo-B/apo-A-I ratio that was adjusted for gender, age, and LDL the cholesterol/apo-B ratio. Relative risk/SD (RR/SD) values and 95% confidence intervals (CIs) are indicated (dashed lines). Pooled data from men and women (n = 126,196; 2,167 of whom had an acute myocardial infarction) are presented.
      Figure 1 also illustrates a direct relation between relative risk, which was adjusted for age and gender, and increasing values of apo-B, indicating that risk increases as atherogenic particle number increases. However, the relative risk of 1.34 for apo-B (p <0.0001) is substantially greater than the relative risk of 0.93 for the LDL cholesterol/apo-B ratio (p <0.0001), which corresponds to an inverted risk value of 1.08 (p <0.0028).
      Figure 1 depicts the relation between apo-B level and risk after adjustment for age, gender, and LDL cholesterol/apo-B ratio. Note there is no change in risk, which remains at 1.33. This indicates that the effect of LDL size on risk is no longer significant once apo-B is taken into account. In contrast, Figure 1 also plots the relation between the apo-B/apo-A-I ratio and risk after adjustment for age and gender. In this case, the relative risk is greater (relative risk/SD 1.41) than that observed with apo-B alone (relative risk/SD 1.34). These results indicate that apo-A-I adds significant prognostic information. Thus, apo-A-I, but not LDL size, adds to the predictive power of apo-B. As shown in Figure 1, the relative risk is not changed when the results for the apo-B/apo-A-I ratio are adjusted for age, gender, and LDL cholesterol/apo-B ratio.
      These findings were confirmed by receiver-operating characteristic analyses that were adjusted for gender (Table 2). Results demonstrate that the area encompassed by the receiver-operating characteristic curve was significantly greater for apo-B than for the LDL cholesterol/apo-B ratio (p <0.0001). Size added significant information to apo-A-I (p <0.0006). Conversely, size added no information to apo-B, whereas apo-A-I did (p <0.015). LDL size also added no significant information to the apo-B/apo-A-I ratio, which remained the single strongest risk predictor (p <0.0001).
      Table 2Receiver-operating characteristic curve areas for fatal acute myocardial infarction (adjusted for gender, n = 2,167)
      VariableArea
      LDL cholesterol/apoB0.573
      Apo-A-I0.594
      Apo-A-I + LDL cholesterol/apo-B0.601
      Apo-B0.625
      Apo-B + LDL cholesterol/apo-B0.625
      Apo-B/apo-A-I0.638
      Apo-B/apo-A-I + LDL cholesterol/apo-B0.639

      Discussion

      Our primary objective was to determine, in the AMORIS cohort, whether LDL size influenced the risk of fatal myocardial infarction and, if so, whether this was independent of atherogenic particle number as reflected by plasma apo-B. LDL size was not measured directly in subjects in the AMORIS, and the present analysis is based on a surrogate, namely, the LDL cholesterol/apo-B ratio. Three lines of evidence support this approach. First, previous work has shown an inverse relation between the LDL cholesterol to apo-B ratio and LDL size.
      • Campos H.
      • Blijlevens E.
      • McNamara J.R.
      • Ordovas J.M.
      • Posner B.M.
      • Wilson P.W.
      • Castelli W.P.
      • Schaefer E.J.
      LDL particle size distribution. Results from the Framingham Offspring Study.
      • Wagner A.M.
      • Jorba D.
      • Rigla M.
      • Alonso E.
      • Ordonez-Llanos J.
      • Perez A.
      LDL-cholesterol/apolipoprotein B ratio is a good predictor of LDL phenotype B in type 2 diabetes.
      • Sniderman A.D.
      • Lamarche B.
      • Tilley J.
      • Seccombe D.W.
      • Frohlich J.
      Hypertriglyceridemic hyperapoB in type 2 diabetes.
      • Sniderman A.D.
      • Dagenais G.R.
      • Cantin B.
      • Despres J.P.
      • Lamarche B.
      High apolipoprotein B with low high-density lipoprotein cholesterol and normal plasma triglycerides and cholesterol.
      • Sniderman A.D.
      • St-Pierre A.
      • Cantin B.
      • Dagenais G.R.
      • Depres J.-P.
      • Lamarche B.
      Concordance/discordance between plasma apolipoprotein B levels and the cholesterol indexes of atherosclerotic risk.
      Second, there is an inverse relation between plasma triglycerides and LDL size, and our data, which demonstrate an inverse relation between plasma triglycerides and LDL cholesterol to apo-B ratio, are consistent with this. Third, by univariate analysis, our data demonstrate a significant inverse relation to the risk of fatal myocardial infarction and the LDL cholesterol/apo-B ratio. Thus, the relation between SD-LDL particles and increased risk of vascular disease and fatal myocardial infarction in the AMORIS is consistent with findings in multiple previous reports that were based on smaller materials and obtained in patients with nonfatal and fatal myocardial infarction.
      • Sniderman A.D.
      • Scantlebury T.
      • Cianflone K.
      Hypertriglyceridemic hyperapoB the unappreciated atherogenic dyslipoproteinemia in type 2 diabetes mellitus.
      However, our data indicate that LDL size does not add significantly to the predictive power of atherogenic particle number, i.e., plasma apo-B, whereas HDL, as estimated by plasma apo-A-I, does. Thus, atherogenic particle number appears to be the fundamental proatherogenic determinant of coronary mortality. These findings are consistent with results of several cross-sectional studies that showed that risk was higher in hypertriglyceridemic subjects with an increased apo-B level than in hypertriglyceridemic subjects with a normal apo-B level.
      • Sniderman A.D.
      • Furberg C.D.
      • Keech A.
      • Roeters van Lennep J.E.
      • Frohlich J.
      • Jungner I.
      • Walldius G.
      Apolipoproteins versus lipids as indices of coronary risk and as targets for statin therapy treatment.
      Moreover, 3 prospective studies, the Quebec Cardiovascular Study,
      • Lamarche B.
      • Moorjani S.
      • Lupien P.J.
      • Cantin B.
      • Bernard P.M.
      • Dagenais G.R.
      • Despres J.P.
      Apoprotein A-1 and B levels and the risk of ischemic heart disease during a 5-year follow-up of men in the Québec Cardiovascular Study.
      the Northwick Park Heart study,
      • Talmud P.J.
      • Hawe E.
      • Miller G.J.
      • Humphries S.E.
      Non-fasting apolipoprotein B and triglyceride levels as a useful predictor of coronary heart disease risk in middle-aged UK men.
      and the AMORIS,
      • Walldius G.
      • Jungner I.
      • Aastveit A.H.
      • Holme I.
      • Furberg C.D.
      • Sniderman A.D.
      The apoB/apoA-I ratio is better than the cholesterol ratios to estimate the balance between the plasma proatherogenic and antiatherogenic lipoproteins and to predict coronary risk.
      showed that risk is related to apo-B independently of plasma triglycerides. In addition, the present data show that, when adjusted for age, gender, and triglycerides, LDL size loses its predictive power as shown in the multivariate analyses.
      In the Quebec Cardiovascular Study, although risk was substantially increased in those with hypertriglyceridemia and hyperapo-B, it was not increased above control levels in those with hypertriglyceridemia and normal levels of apo-B.
      • Lamarche B.
      • Despres J.P.
      • Moorjani S.
      • Cantin B.
      • Dagenais G.R.
      • Lupien P.J.
      Prevalence of dyslipidemic phenotypes in ischemic heart disease (prospective results from the Quebec Cardiovascular Study).
      To be sure, other analyses from the Quebec Cardiovascular Study have shown SD-LDL particles to be an independent predictor of risk.
      • St-Pierre A.C.
      • Cantin B.
      • Dagenais G.R.
      • Mauriège P.
      • Bernard P.-M.
      • Després J.-P.
      • Larmache B.
      Low-density lipoprotein subfractions and the long-term risk of ischemic heart disease in men. 13-year follow-up data from Quebec Cardiovascular Study.
      Nevertheless, it seems unlikely, at least in our population, that LDL size plays a substantial role in determining the risk of fatal myocardial infarction. This does not exclude the possibility that HDL composition, including apo-A-I concentrations and functions, significantly alter risk.
      Because LDL size did not add predictive information to the apo-B/apo-A-I ratio, it appears that the apo-B/apo-A-I ratio also captures the risk related to LDL size. These findings add to our previously published results from the AMORIS that indicated that apo-B/apo-A-I is the best single lipid-related summary index of risk and that triglycerides, total cholesterol, non-HDL cholesterol, and LDL cholesterol levels do not add significant predictive power to the apo-B/apo-A-I ratio.
      • Walldius G.
      • Jungner I.
      • Aastveit A.H.
      • Holme I.
      • Furberg C.D.
      • Sniderman A.D.
      The apoB/apoA-I ratio is better than the cholesterol ratios to estimate the balance between the plasma proatherogenic and antiatherogenic lipoproteins and to predict coronary risk.
      We emphasize that these analyses address only the issue as to whether lipids or apolipoproteins are the best summary indexes to estimate overall lipoprotein-related risk in members of a group, and not whether lipids add significant diagnostic information for particular patients within those groups. Nevertheless, they add further support to the use of apo-B and apo-A-I in routine clinical practice.

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