Low-Density Lipoprotein Size and Cardiovascular Disease: A Reappraisal

Frank M. Sacks and Hannia Campos

Harvard School of Public Health, Department of Nutrition, Boston, Massachusetts 02115

Address all correspondence and requests for reprints to: Dr. F. M. Sacks, Harvard School of Public Health, Department of Nutrition, 665 Huntington Avenue, Boston, Massachusetts 02115. E-mail: fsacks{at}hsph.harvard.edu.


    Introduction
 Top
 Introduction
 The small dense LDL...
 What is small, dense...
 Measurement of small, dense...
 Mechanisms of atherogenicity for...
 LDL subfractions to predict...
 Effect of LDL size...
 Effect of lipid drugs...
 Conclusions
 References
 
The major lipoprotein types, very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL), are composed of many subgroups (1, 2, 3). Classifications are based on size (1), density, or apolipoprotein (apo) content (2), or a combination of these (3), and the subfractions that are isolated have distinct metabolic and other functional properties. Thus, it is entirely reasonable to think that subfractions of the major lipoproteins have diverse relationships to coronary heart disease (CHD). Because the classical lipid risk factors by no means perfectly predict CHD in patients, lipoprotein subfractionation has the potential to improve risk prediction.


    The small dense LDL hypothesis
 Top
 Introduction
 The small dense LDL...
 What is small, dense...
 Measurement of small, dense...
 Mechanisms of atherogenicity for...
 LDL subfractions to predict...
 Effect of LDL size...
 Effect of lipid drugs...
 Conclusions
 References
 
Among the various lipoprotein subfractionation systems, LDL size and density by far have attracted the most basic, clinical, and population research. Several companies offer LDL size measurements to physicians as a diagnostic test for CHD risk. Several lines of evidence implicate small, dense LDL in the etiology of CHD. Small, dense LDL is often increased in relative proportion or concentration in patients with CHD. Small, dense LDL has several characteristics that are linked to atherogenesis: long residence time in plasma, and enhanced oxidizability, arterial proteoglycan binding, and permeability through the endothelial barrier (4). Together, these findings have led to the hypothesis that small, dense LDL is a potent atherogenic lipoprotein that can be used to improve risk prediction, and evaluate response to lipid therapy (5, 6, 7). Furthermore, small, dense LDL is often part of a group of high-risk characteristics including high triglycerides, low HDL, diabetes, insulin resistance, obesity, and the metabolic syndrome (8, 9, 10). This has led logically to the concept that it contributes to the high rate of CHD in these groups. Yet, the very association between small, dense LDL and these other high-risk conditions challenges proponents of the hypothesis to show a direct, independent relationship between small, dense LDL and CHD. In this article, we evaluate evidence on LDL subclasses in risk assessment and therapy, reaching the conclusion that LDL subclass measurement does not add independent information to that conferred generically by the LDL concentration along with the other standard risk factors.


    What is small, dense LDL and how is it formed?
 Top
 Introduction
 The small dense LDL...
 What is small, dense...
 Measurement of small, dense...
 Mechanisms of atherogenicity for...
 LDL subfractions to predict...
 Effect of LDL size...
 Effect of lipid drugs...
 Conclusions
 References
 
LDL are spherical particles, 22–29 nm in diameter, composed of a core of esterified cholesterol and triglyceride, a surface lipid coat of unesterified cholesterol and phospholipid, an essential structural protein, apo B, and sometimes small apos, such as apo CIII and apo E that modulate LDL metabolism. Each LDL particle has one apo B molecule, which is recognized by LDL receptors that clear LDL from plasma. Thus, the LDL apo B concentration is the plasma concentration of LDL particles. The size of an LDL particle depends on how much lipid is in the core, and the lipid content naturally determines its density. Thus, smaller LDL is denser, larger LDL is lighter, and the two qualities are largely equivalent. Early studies using analytical ultracentrifugation revealed that distinct LDL subpopulations are present in each individual (11). Seven distinct LDL subpopulations were resolved by density-gradient ultracentrifugation and polyacrylamide-gradient gel electrophoresis (1, 12, 13). All people have LDL that is in a range of sizes that correspond to specific densities (8, 14). The size of the predominant LDL particles determines the classification: 22–25.5 nm is small, 25.6–26.5 nm intermediate, and 26.6–28.5 large (13, 14). Using mathematical modeling techniques that separated LDL size tracings on gradient-gel electrophoresis into Gaussian curves, Austin et al. (15) identified two subclass patterns: the classical category, Pattern A, is more than 25.5 nm, and Pattern B is 25.5 nm or less.

Several metabolic pathways are involved in forming small dense LDL, as recently reviewed in detail by Berneis and Krauss (6). Small LDL may be formed by metabolic channeling of large VLDL (16), lipolysis of intermediate-density lipoprotein, and large LDL by hepatic lipase (17, 18), remodeling of LDL by cholesterol ester transfer protein (CETP) (19, 20, 21), secretion into plasma by the liver (22, 23), or a combination of these processes. Small, dense LDL has a low content of esterified and unesterified cholesterol, and phospholipid; the triglyceride content is either similar to (24) or greater than (25) large LDL. This reduced cholesterol content may be an effect of CETP (19, 20). CETP exchanges cholesterol ester and triglyceride among HDL, LDL, and VLDL. During this process, VLDL serves as an acceptor of cholesterol ester from HDL and LDL. LDL and HDL become enriched in triglyceride and depleted of cholesterol ester. Hydrolysis of the triglyceride in LDL by lipases further reduces the size of LDL (21, 26). LDL can be an acceptor as well as a donor of cholesterol ester, but in hypertriglyceridemia, CETP preferentially uses VLDL rather than LDL as an acceptor (20). This process may contribute to the relationship between hypertriglyceridemia and small LDL. Another proposed mechanism for the formation of small LDL is increased hepatic lipase that progressively lipolyzes intermediate-density lipoprotein to large and finally small LDL (17, 18). Increased hepatic lipase also lowers plasma HDL levels, perhaps explaining the relationship between small LDL particles and low HDL concentration.


    Measurement of small, dense LDL
 Top
 Introduction
 The small dense LDL...
 What is small, dense...
 Measurement of small, dense...
 Mechanisms of atherogenicity for...
 LDL subfractions to predict...
 Effect of LDL size...
 Effect of lipid drugs...
 Conclusions
 References
 
Analytical ultracentrifugation is the original gold standard to which subsequent methods have been calibrated and validated (27). Analytical ultracentrifugation measures the flotation velocity of LDL in a gravitational field; the faster the flotation velocity, the more lipid rich the LDL. This method is currently available only in a few research laboratories worldwide. Preparative ultracentrifugation separates discrete LDL subfractions that can be quantified and studied for chemical composition and function. The classic method separates seven LDL density fractions (1), and although it is time consuming, any laboratory that has an ultracentrifuge can do it. Preparative ultracentrifugation is the method that defines the LDL subclasses, and it is the de facto gold standard in the field. Nonequilibrium density gradient ultracentrifugation uses the same principles as analytical ultracentrifugation, and is simpler and less labor intensive. The vertical autoprofiling system is a well-validated example of this technique (28). Gradient gel electrophoresis is a simple, readily available method to determine LDL size (13). It uses a drop of whole plasma or serum, and multiple samples can be processed together (8, 29). It has been extensively validated using ultracentrifugation. Its limitation is that, in contrast to ultracentrifugation, it does not quantify the concentration of LDL particles of specific sizes, just the size of the predominant LDL species or the average size of LDL. Thus, changes in the predominant or average LDL size do not necessarily indicate changes in concentration of a particular species of LDL. For example, a selective reduction in large LDL concentration with no change in small LDL concentration would reduce the average size of LDL; this is often misinterpreted to mean an increase in the plasma concentration of small LDL particles. Nuclear magnetic resonance (NMR) measures the diameter and lipid concentration of LDL (30). Diameter is determined by a signal from the phospholipid surface coat of LDL, and concentration by the number of methyl groups on the cholesterol ester and triglyceride molecules within each of the four LDL subfractions resolved. Average LDL size is then calculated by the weighted average of the LDL subfractions. NMR computes the concentration of LDL subfractions using typical lipid contents of LDL subfractions in the published literature. NMR is the most rapid and convenient method for determining LDL size and subfraction concentration. However, it is limited by lack of published data on detailed procedures, calibration, and validation, which are expected when novel methods are established. The assumptions and calibration method that NMR uses to convert lipid signal intensity and size to LDL concentration have not been revealed, nor is it known whether these assumptions hold equally across diverse populations and during diet or drug therapy that affects the composition of LDL. For example, when LDL becomes cholesterol-ester poor and triglyceride rich, as in the generation of small LDL described above, the algorithms used may be incorrect as there is not likely to be a single triglyceride for cholesterol exchange in the final particle. Validation studies in large populations have not been published on LDL subfraction concentration by NMR and ultracentrifugation on the same samples, as have been long available for gradient gel electrophoresis.


    Mechanisms of atherogenicity for LDL subfractions
 Top
 Introduction
 The small dense LDL...
 What is small, dense...
 Measurement of small, dense...
 Mechanisms of atherogenicity for...
 LDL subfractions to predict...
 Effect of LDL size...
 Effect of lipid drugs...
 Conclusions
 References
 
Mechanistic support for small LDL having a special atherogenicity depends on atherogenic actions being greater for small than for intermediate or large LDL. This case has not been proven, however. Both large and small LDL compared with intermediate size LDL have reduced affinity for the LDL receptor which clears LDL from plasma (31, 32). Decreased clearance of these forms of LDL by the liver and steroidogenic tissues is thought to lead to increased uptake by the arterial wall. In vivo, small LDL has a longer residence time in plasma than large LDL (22, 33). This may be caused by reduced exposure on small LDL of the region of apo B that binds to the LDL receptor, an interaction that is necessary to clear LDL from the circulation. The long residence time in plasma for small LDL could foster atherosclerosis if small LDL entered the arterial intima more readily than other LDL. Although this was found in experiments in rabbits (34), a study of transvascular transport of LDL in vivo in humans did not find a correlation with LDL size (35). This finding suggests that for every unit of time, large LDL is just as likely as small LDL to enter the arterial intima. Because large LDL has more cholesterol ester than small LDL, a large LDL particle would deposit more cholesterol into plaque than small LDL. Small LDL binds to arterial proteoglycan (36) in the arterial wall, but so does large cholesterol-rich LDL (37). Proteoglycan exists on the endothelial cell surface as well as inside the intima. Proteoglycan binding on endothelium may facilitate lipoprotein entry into the vascular intima, and binding to arterial intimal proteoglycan activates or accelerates plaque progression. Thus, it appears that both large and small LDL share undesirable characteristics.

Oxidized LDL has atherogenic actions in the vascular wall including stimulation of foam cell formation and activation of inflammation. Circulating oxidized LDL is associated with increased risk of CHD in cross-sectional studies (38, 39). Small, dense LDL is depleted of vitamin E and is more rapidly oxidized in vitro (40), characteristics that could make small LDL more atherogenic. Furthermore, the susceptibility of small LDL to oxidation can be reversed by repletion with vitamin E. However, oxidizability of LDL was not independently associated with carotid intima-media thickness (IMT) in patients with combined hyperlipidemia (41). In a clinical trial in healthy men and women, vitamin E supplements reduced LDL oxidizability but did not reduce the progression of carotid IMT (42). Large trials of vitamin E and other antioxidant supplements definitively showed no reduction in CHD. Thus, a link between LDL oxidizability and human atherosclerosis and CHD remains to be established. Native, unoxidized LDL has direct atherogenic effects, for example to enhance activated monocytes to produce the inflammatory mediators TNF-{alpha} and IL-8 (43). Finally, large cholesterol-rich LDL is the predominant type of LDL in familial hypercholesterolemia (44), and it is firmly established that this LDL is responsible for their premature atherosclerosis. Thus, large and small LDL are atherogenic, and it is not possible to judge which if any is more harmful, overall.


    LDL subfractions to predict CHD: small or large?
 Top
 Introduction
 The small dense LDL...
 What is small, dense...
 Measurement of small, dense...
 Mechanisms of atherogenicity for...
 LDL subfractions to predict...
 Effect of LDL size...
 Effect of lipid drugs...
 Conclusions
 References
 
If LDL size is to be used to quantify risk of CHD, it first must be shown that it adds information on risk or is superior to the standard lipid risk factors used in national guidelines. Many studies found that small dense LDL is increased in concentration or relative proportion in CHD (5, 6, 7). However, small LDL size is substantially correlated with high triglycerides and low HDL, and mildly related to obesity and perhaps insulin resistance (4, 8, 9, 10). These metabolic connections complicate efforts to determine whether small LDL particles have an especially strong relationship to CHD, beyond their being simply LDL. In contrast, LDL cholesterol concentration has a very low correlation with other lipid risk factors and most nonlipid risk factors, and its establishment as the principal lipid risk factor for prevention and treatment has been straightforward (45).

All established CHD risk factors have passed the test of multiple regression analysis that investigates the etiological relationship of potential risk factors to the disease. We have often encountered misunderstanding among colleagues about what multiple regression analysis can accomplish. It is a powerful technique that disentangles related variables, ideal when correlations are mild to moderate (i.e. r <= 0.7), but with a large population, it can be effective even when the correlation coefficients are higher. An instructive example is the case of LDL size and plasma triglycerides that are moderately inversely correlated (for example, r = -0.71) in a large prospective study of U.S. male physicians (46). In crude analysis, small LDL size and high triglycerides both were associated with myocardial infarction (MI). Multiple regression analysis tested the effect of LDL size across the concentration range of triglycerides, and the effect of triglycerides across the range of LDL sizes. If small LDL size is truly related to CHD, then it will be so whether triglyceride is high or low. Because the correlation between triglycerides and LDL size, -0.71, explains only 50% of the variance of each, there would be a wide range of LDL sizes among people with high triglyceride concentrations, and a wide range of triglyceride concentrations among people with small LDL to disentangle these two lipid variables. Figure 1Go shows that the relative risk of MI is similar across tertiles of LDL size within each triglyceride tertile. In contrast, high triglyceride is strongly related to MI regardless of LDL size. For example, the relative risk is the same, 2.7, for high triglycerides with either small or large LDL size. Thus, LDL size does not give information beyond that given by triglycerides on risk of MI. This study demonstrates that triglycerides but not LDL size independently predicted first MI in U.S. male physicians. As we show subsequently, this is a typical result for LDL size in epidemiological studies.



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FIG. 1. Relationship between triglycerides, LDL size, and MI in a prospective study of U.S. physicians. This figure demonstrates that the association between small LDL size and MI arises only from the association between small LDL size and high triglyceride concentration. High triglyceride concentration is independently related to MI regardless of LDL size. Analysis provided by Jing Ma, Ph.D., Physicians Health Study (46 ), Channing Laboratory, Brigham & Women’s Hospital (Boston, MA).

 
The first epidemiological studies that investigated LDL size and CHD had a cross-sectional (retrospective case:control) design. Although this design is not the ideal epidemiological approach because of confounding by indication (samples collected after the clinical disease manifests), the findings from these original studies are consistent with the more recent prospective studies described subsequently. LDL size was measured in patients who had clinical CHD and in healthy controls. In 6 of 12 studies, the average LDL size was significantly smaller in the cases than controls (47, 48, 49, 50, 51, 52) (Table 1Go). However, with consideration of lipid and other risk factors in multiple regression analysis, the difference in LDL size lost significance in all but one (51). Three studies showed no difference in LDL size with univariate (crude) or multivariate analysis (53, 54, 55), and in two studies large LDL was associated with CHD (56, 57). Campos et al. (56) studied LDL size in men who had CHD with average lipid levels [mean total cholesterol 180 mg/dl (4.66 mmol/liter), mean triglycerides 105 mg/dl [1.19 mmol/liter)] and no CHD risk factors to determine whether small LDL size could identify the cases better than traditional risk factors. Contrary to expectation, the cases had larger LDL than the healthy controls, and this finding remained significant in multiple regression analysis. Large LDL was associated with CHD in another study but data on multivariate analysis are not available (57). Tornvall et al. (58) found that the concentration of triglyceride in both light and dense LDL was related to coronary atherosclerosis. Among Native American communities, large LDL is more common where the CHD prevalence is high (53). Large LDL is more common in countries with high prevalence of CHD, for example in Scotland compared with Korea (59), and in the United States compared with Costa Rica (60). Of course, cross-cultural comparisons are limited by many factors that could cause confounding.


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TABLE 1. Cross-sectional studies of LDL size and cardiovascular disease (CVD)

 
Prospective studies are more informative than cross-sectional studies because LDL size and other lipid risk factors are measured before the manifestation of CHD, so the disease and its treatment do not affect the lipids. In five of eight prospective studies, small LDL predicted coronary death, MI, or other serious CHD in univariate analyses (46, 61, 62, 63, 64) (Table 2Go). However, after adjustment for the effects of standard lipid risk factors or apo B, small LDL was not significant whereas one or more other lipids were independently predictive. For example, in the Physicians’ Health Study previously discussed, the relative risk for MI for small LDL diminished from 1.38 (P < 0.001) to 1.09 (P = 0.46) after adjusting for lipid and nonlipid risk factors. In the adjusted model, plasma triglyceride, and the total to HDL cholesterol ratio were significant predictors (46). A recent study in women (64) found similar results regarding LDL size. In this study, a relative risk of 2.04 (P = 0.03) for small LDL in univariate analysis was reduced to 1.20 (P = 0.7) after adjusting for the total to HDL cholesterol ratio and triglyceride level. The independent predictors were LDL concentration, cholesterol to HDL ratio, and C-reactive protein.


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TABLE 2. Prospective studies of LDL size and cardiovascular disease

 
The Stanford Five Cities Project found that mean LDL size was 0.52 nm smaller in cases than in controls (P < 0.001). This difference was reduced to 0.24 nm and no longer statistically significant (P = 0.23) after adjusting for the total to HDL cholesterol ratio, which itself remained a significant predictor. In the Quebec Cardiovascular Study, the authors concluded "the risk attributed to small LDL particles may be partly independent of the concomitant variation in plasma lipoprotein lipid concentrations." Such ambiguous wording regarding independence was necessitated by the results of multivariate analysis that small LDL size was not a statistically significant predictor of CHD (62), whereas apo B was the only significant independent lipoprotein predictor. Likewise, no independent association between LDL size and CHD was found among men and women participants in the Cardiovascular Health Study (65). In Finnish elderly men and women, LDL size did not predict CHD in either univariate or multivariate analyses (66), whereas the total to HDL cholesterol ratio was the independent predictor. In Japanese-American men, small LDL size was a predictor of CHD only in the univariate model (63). Interestingly, after adjusting for plasma triglyceride and HDL cholesterol levels, large not small LDL size trended toward predicting CHD along with low HDL levels. This observation in the Japanese cohort agrees with results in U.S. and Canadian patients who had had a MI. Large, not small LDL, was a strong predictor of CHD death and recurrent MI, significant in both multivariate and univariate analyses [relative risk = 4.00; 95% confidence interval (CI), 1.81–8.82] (67).

Other studies evaluated atherosclerosis with ultrasound measurements of carotid or femoral artery intima-media thickness (IMT) or with coronary arteriography. Two cross-sectional studies found that small LDL was independently associated with carotid IMT in healthy men (68) and in patients with familial combined hyperlipidemia and family members (41). Another study found the opposite, that large LDL was associated with carotid artery IMT in patients with hypercholesterolemia and or normal cholesterol levels; there was no relationship with femoral artery IMT (69). Prospective studies reported that LDL size did not predict worsening of coronary atherosclerosis (70, 71, 72), although a high concentration of small LDL was weakly but significantly correlated (r = -0.17) with stenosis progression (70).

In summary, the picture that is emerging from epidemiology is that small LDL does not have a special relationship to CHD beyond its contribution to LDL concentration. This could be more quantitatively studied by meta-analysis or pooled analysis of the individual studies; however, a definite conclusion may well require additional studies in representative populations, highly powered with large numbers of cardiovascular events. We think that it is likely that confounding by triglycerides and other lipid risk factors is severe since most studies reported that the risk initially associated with small LDL becomes null or inverse after adjustment. Technical factors such as measurement or biological variability are not explanations for this phenomenon because LDL size is a particularly stable and reproducible measurement among the plasma lipids and lipoproteins.


    Effect of LDL size on clinical response to lipid therapy
 Top
 Introduction
 The small dense LDL...
 What is small, dense...
 Measurement of small, dense...
 Mechanisms of atherogenicity for...
 LDL subfractions to predict...
 Effect of LDL size...
 Effect of lipid drugs...
 Conclusions
 References
 
Another potential use for LDL subtyping is to evaluate response to lipid therapy. Diet and drug therapy for hyperlipidemia improved coronary artery stenosis in patients who had dense LDL before treatment but not in those who had buoyant LDL (71). Zambon et al. (17) found that increases in LDL buoyancy (indicating larger size) and decreases in hapatic lipase activity were correlated with improvement in coronary artery stenosis after treatment with lovastatin and colestipol or niacin and colestipol. LDL buoyancy increased and hepatic lipase decreased in patients with small LDL and high hepatic lipase at baseline. This group had a wild-type promoter polymorphism in the hepatic lipase gene (73). However, it is also interesting that patients with the promoter variant allele associated with low hepatic lipase activity had buoyant LDL at baseline and during treatment, and this group showed the most worsening of coronary stenosis. The Copenhagen City Heart Study also found that this hepatic lipase promoter variant conferred increased risk of CHD (74). These results (73, 74) suggest an atherogenic role for buoyant LDL. In two additional trials, neither LDL size nor the plasma concentration of small LDL during lovastatin or pravastatin treatment was associated with progression of coronary artery stenosis (70, 72). In contrast, small LDL size during fenofibrate treatment was independently associated with worsening of coronary artery stenosis (75). Overall, these varying results do not establish the usefulness of LDL size during lipid treatment in predicting clinical response. This topic is best investigated in large clinical trials with clinical cardiovascular endpoints. In this regard, LDL size at baseline was not a predictor of CHD death or recurrent MI in patients treated with pravastatin in the CARE trial (67).


    Effect of lipid drugs and diet on LDL subtypes
 Top
 Introduction
 The small dense LDL...
 What is small, dense...
 Measurement of small, dense...
 Mechanisms of atherogenicity for...
 LDL subfractions to predict...
 Effect of LDL size...
 Effect of lipid drugs...
 Conclusions
 References
 
Winkler et al. (76) found that fluvastatin decreased dense LDL in patients with type 2 diabetes. This is an important finding because diabetic patients have a preponderance of dense LDL, and it likely explains some of the reduction in CHD by statin therapy in patients with diabetes. Previous studies showed that statins reduce dense LDL in nondiabetic patients who have a preponderance of this LDL subtype (77), and in patients with familial combined hyperlipidemia (78). Do statins have a selective effect on any particular LDL subtype? Winkler et al. (76) and other groups clearly show that statins decrease whatever LDL type predominates in a patient (72, 79, 80, 81). The mechanism is stimulation of receptor-mediated catabolism across the spectrum of LDL and other apo B lipoproteins (82). This indeed may explain the finding that large LDL did not predict coronary events in patients who were treated with pravastatin, although it did in those taking placebo (67).

Fibrates, fenofibrate, and gemfibrozil, lowered the concentration of large and small LDL in patients with combined hyperlipidemia or dyslipidemia of type 2 diabetes; the concentration of intermediate size LDL increased (80, 83). Because fibrates decrease small LDL more than large LDL, the distribution of LDL shifts toward larger size particles (75, 80, 83, 84, 85). Niacin lowers dense LDL concentration (86), shifting the distribution of LDL to larger particles (87, 88). In one study (86), niacin increased the concentration of large LDL measured by NMR by about the same amount that it decreased small LDL. Such divergent effects of niacin on LDL subfractions are inconsistent with its action to decrease the plasma total concentration of LDL particles raising concern about the quantification by NMR of the individual LDL size subfractions. Hormone replacement therapy with oral estrogens decreases plasma concentration of large LDL with no change in small LDL; this is due to an increase in clearance rate of large LDL from plasma (22).

Low-fat, high-carbohydrate diets compared with high saturated fat decrease mean LDL size (89); the largest and smallest subfractions decreased in concentration, whereas the intermediate-small fraction increased. The net effect was a decrease in LDL concentration, as expected. Unsaturated fats, both mono- and polyunsaturated, slightly reduce LDL size compared with saturated fat (90). Overall, it is difficult to provide a clinical interpretation to infer benefit or harm from such changes in LDL sizes during these interventions.

In some patients with small dense LDL or high triglycerides, the plasma concentration of VLDL remains high even when therapy has lowered LDL cholesterol to the recommended goal. NCEP ATP III has approached this situation by using high triglyceride levels rather than the presence of small dense LDL as an indicator of an elevated VLDL concentration (45). ATP III recommends that patients with high triglyceride who have reached their LDL-C goal should be treated more intensively to reach the secondary goal of a low non-HDL cholesterol, the term used for VLDL plus LDL cholesterol.


    Conclusions
 Top
 Introduction
 The small dense LDL...
 What is small, dense...
 Measurement of small, dense...
 Mechanisms of atherogenicity for...
 LDL subfractions to predict...
 Effect of LDL size...
 Effect of lipid drugs...
 Conclusions
 References
 
The burden of proof for any newly proposed risk factor is that it must add significantly to risk assessment by existing measurements, or that it is equivalent but more economical. LDL subtyping does not meet either of these expectations. Metabolic studies demonstrate that large and small LDL subtypes are atherogenic. In as much as any type of LDL is contained in the plasma total LDL concentration, the standard clinical measurement of risk, all LDL types should be viewed as harmful. The best indicator of response to lipid therapy is a reduction in the plasma concentration of atherogenic lipoproteins, as conventionally measured by LDL and triglycerides, but alternatively by non-HDL cholesterol or apo B (91).


    Footnotes
 
Abbreviations: apo, Apolipoprotein; CETP, cholesterol ester transfer protein; CHD, coronary heart disease; CI, 95% confidence interval; HDL, high-density lipoprotein; IMT, intima-media thickness; LDL, low-density lipoprotein; MI, myocardial infarction; NMR, nuclear magnetic resonance; VLDL, very low-density lipoprotein.

Received April 14, 2003.

Accepted July 14, 2003.


    References
 Top
 Introduction
 The small dense LDL...
 What is small, dense...
 Measurement of small, dense...
 Mechanisms of atherogenicity for...
 LDL subfractions to predict...
 Effect of LDL size...
 Effect of lipid drugs...
 Conclusions
 References
 

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