Journal of the American College of Cardiology © 2007 by the American College of Cardiology Foundation Published by Elsevier Inc.
Vol. 50, No. 18, 2007 ISSN 0735-1097/07/$32.00 doi:10.1016/j.jacc.2007.07.045
Beyond Low-Density Lipoprotein Cholesterol
Deﬁning the Role of Low-Density Lipoprotein Heterogeneity in Coronary Artery Disease
James O. Mudd, MD,* Barry A. Borlaug, MD,* Peter V. Johnston, MD,* Brian G. Kral, MD, MPH,* Rosanne Rouf, MD,* Roger S. Blumenthal, MD,* Peter O. Kwiterovich, JR, MD† Baltimore, Maryland
Recent clinical trials in patients with coronary artery disease (CAD) provide evidence that low-density lipoprotein cholesterol (LDL-C) levels should be lowered even further to prevent recurrent CAD. However, despite more aggressive interventions for lowering LDL-C levels, the majority of CAD events go undeterred, perhaps related to the fact that intervention was not started earlier in life or that LDL-C levels represent an incomplete picture of atherogenic potential. Nevertheless, LDL-C remains the contemporary standard as the primary goal for aggressive LDL reduction. If triglycerides are 200 mg/dl, the measurement of non–high-density lipoprotein cholesterol (HDL-C) is recommended. Measurement of apolipoprotein (apo)B has been shown in nearly all studies to outperform LDL-C and non–HDL-C as a predictor of CAD events and as an index of residual CAD risk. This is because apoB reﬂects the total number of atherogenic apoB-containing lipoproteins and is a superior predictor of the number of low-density lipoprotein particles (LDL-P). Estimates of LDL-P and size can also be made by nuclear magnetic resonance spectroscopy, density gradient ultracentrifugation, and gradient gel electrophoresis. Although a number of studies show that such estimates predict CAD, LDL-P, and size often accompany low HDL-C and high triglyceride levels, and therefore such additional lipoprotein testing has not been recommended for routine screening and follow-up. Because apoB is a superior predictor of LDL-P, we recommend that apoB and the apoB/apoA-I ratio be determined after measurement of LDL-C, non–HDL-C, and the ratio of total cholesterol/HDL-C to better predict CAD and assess efﬁcacy of treatment. (J Am Coll Cardiol 2007;50: 1735–41) © 2007 by the American College of Cardiology Foundation
Elevated low-density lipoprotein cholesterol (LDL-C) is a well-established independent risk factor for coronary artery disease (CAD). A number of primary and secondary trials have demonstrated that lowering of LDL-C decreases the incidence of CAD. These trials have been reviewed in detail elsewhere (1– 4) and include treatment with a fat-modiﬁed diet and therapeutic agents such as inhibitors of 3-hydroxy3-methylglutaryl coenzyme A reductase (statins), ﬁbrates, niacin, and bile acid sequestrants. These studies, in aggregate, are the basis for the recommendations of the National Cholesterol Education Program (NCEP) that LDL-C be lowered to 100 mg/dl in patients with CAD or CAD risk equivalents, such as diabetes or peripheral arterial disease. The HPS (Heart Protection Study) (5), the PROVE-IT (Pravastatin or Atorvastatin Evaluation and Infection Therapy) study (6), and the REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering) study (7) all indicated a signiﬁcant beneﬁt to lowering LDL-C well below 100 mg/dl. The NCEP-Adult Treatment Panel
From the *Johns Hopkins Ciccarone Preventive Cardiology Center and the †Johns Hopkins University Lipid Clinic, Baltimore, Maryland. Manuscript received April 30, 2007; revised manuscript received July 16, 2007, accepted July 17, 2007.
(ATP) III guidelines were therefore amended in 2004 by adding an optional goal of LDL-C 70 mg/dl in patients with recent acute coronary syndromes or those otherwise felt to be at “very high risk” for adverse cardiovascular events (2). Subsequently, the TNT (Treating to New Targets) study (8), with atorvastatin 80 mg/day versus 10 mg/day, and ASTEROID (A Study to Evaluate the Effect of Rosuvastatin [40 mg/day] on Intravascular UltrasoundDerived Coronary Atheroma Burden) (9) both supported the more aggressive treatment of LDL-C to 70 mg/dl. O’Keefe et al. (3) proposed that the threshold for atherosclerotic progression may be at an LDL-C level of 70 mg/dl. Still, despite aggressive use of statins, the majority of CAD events are not prevented (1– 8). In the IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering) study, the use of atorvastatin 80 mg/day compared with simvastatin 20 mg/day did not result in a signiﬁcant reduction in the primary outcome of major coronary events (10). This may be due to the fact that these studies were of relatively short duration and in older adults. The beneﬁt is likely to be greater if intervention is started earlier in life and continued for a longer time period (11). The presence of traditional risk factors such as hypertension, diabetes, obesity, elevated triglycerides (TG), and low high-
Mudd et al. LDL Heterogeneity in CAD
JACC Vol. 50, No. 18, 2007 October 30, 2007:1735–41
density lipoprotein cholesterol (HDL-C) may also render the LDL-C intervention less effecapo apolipoprotein tive. The inﬂuence of nontradiCAD coronary artery tional risk factors such as small, disease dense LDL particles, elevated levCE cholesteryl esters els of high-sensitivity C-reactive DGU density-gradient protein (hs-CRP), lipoprotein ultracentrifugation (a) [Lp(a)], homocysteine, and GGE gradient gel unknown genetic and environelectrophoresis mental risk factors on recurrent HDL-C high-density CAD events is not completely lipoprotein cholesterol understood (1,2). LDL-C low-density Another possible contributory lipoprotein cholesterol factor is that LDL-C does not LDL-P total number of reﬂect the atherogenicity of all low-density lipoprotein particles of the apolipoprotein (apo)BLp(a) lipoprotein (a) containing lipoproteins nor does it necessarily represent the total NMR nuclear magnetic resonance number of low-density lipoprotein particles (LDL-P) or the TC total cholesterol distribution of size within those TG triglycerides particles. This is particularly true if small, dense LDL-P is elevated, leading to an underestimate of LDL-P by LDL-C. Low HDL-C with a normal LDL-C is often accompanied by increased small, dense LDL-P (12). Patients with hyper-TG may also have increased small, dense LDL-P, placing them at higher CAD risk than those hyper-TG patients with a normal LDL-P (13). Here we review the epidemiologic and clinical evidence that determination of LDL-P supplements the LDL-C measurement and has both diagnostic and therapeutic implications.
Abbreviations and Acronyms
Biochemical Basis of LDL Heterogeneity Low-density lipoprotein is a heterogeneous group of particles that vary in their core content of cholesterol (12–14). A greater amount of cholesterol in LDL creates larger, more buoyant particles (sometimes referred to as LDL subclass A). A lower amount of cholesterol in LDL generates smaller, denser particles (sometimes referred to as LDL subclass B). Each LDL particle, regardless of its cholesterol content, has 1 molecule of apoB for each LDL molecule (13). For 2 patients with the same LDL-C, the one with a preponderance of small LDL particles will have a greater LDL-P, carry a signiﬁcantly greater risk of CAD, and may therefore beneﬁt from more aggressive therapy (12–16). VLDL–IDL–LDL pathway. Alterations in the very-lowdensity lipoprotein (VLDL)–intermediate-density lipoprotein (IDL)–LDL pathway, whether owing to genetic mutations, acquired disorders, diet, or other factors, result in variation in particle composition, size, and abundance (12–16) (Fig. 1). For example, the metabolic syndrome, diabetes, familial combined hyperlipidemia, and hyperapobetalipoproteinemia (hyperapoB) are conditions in which increased synthesis and secretion of VLDL leads to the overproduction of small, dense LDL and HDL particles, a combination that increases cardiovascular risk (13–17) (Fig. 1). Insulin resistance or a defect in the normal activity of the acylation stimulatory protein can cause higher plasma free fatty acid levels, leading to greater hepatic free fatty acid uptake, increased TG production, decreased hydrolysis of apoB, and increased production and secretion of larger TG-rich VLDL particles (13–17) (Fig. 1). An increased exchange of TG from VLDL for cholesteryl ester (CE) in LDL and HDL occurs via the CE transfer protein, resulting in cholesterol-depleted TG-enriched li-
Mechanisms of the Production of the “Dyslipidemic Triad”
An increased ﬂux of free fatty acids (FFA) from adipose tissue can result from insulin resistance or a defect in the acylation stimulatory protein (ASP) pathway. Enhanced hepatic uptake of FFA leads to increased triglyceride (TG), apolipoprotein (apo) B, and very-low-density lipoprotein (VLDL) production. The TG in VLDL is exchanged for cholesteryl esters (CE) from low-density lipoproteins (LDL) and high-density lipoproteins (HDL) by the cholesteryl ester transport protein (CETP), producing CE-depleted LDL and HDL. The TG in the core of LDL and HDL is then hydrolyzed by lipases, producing both small, dense LDL and HDL. Such HDL is more likely to be excreted by the kidney, resulting in low HDL-C levels. HL hepatic lipase; IDL intermediate-density lipoprotein; IR insulin resistance; LCAT lecithin-cholesterol acyltransferase; LPL lipoprotein lipase.
JACC Vol. 50, No. 18, 2007 October 30, 2007:1735–41
Mudd et al. LDL Heterogeneity in CAD
poproteins that are subsequently converted into smaller, denser particles by hepatic lipase (Fig. 1). The TG-enriched LDL is hydrolyzed, leading to increased small, dense LDL-P (15). The TG-rich HDL is also modiﬁed by hepatic lipase, producing smaller HDL that is cleared more rapidly by the kidneys, contributing to lower levels of HDL-C and its major apolipoprotein, apoA-I (Fig. 1). Such abnormalities in the VLDL–IDL–LDL pathway are often manifested by the dyslipidemic triad of hyper-TG, increased small, dense LDL-P, and low HDL-C. The Contemporary Standards: LDL-C and Non–HDL-C LDL-C. Aggressive reduction of LDL-C is the current primary goal of lipid-lowering therapy (1–10). The LDL-C reﬂects the cholesterol content of several atherogenic lipoproteins, including LDL, IDL, and Lp(a). The conventional lipid panel measures levels of total cholesterol (TC), HDL-C, and TG and calculates LDL-C using the Friedewald equation (18). To use this formula, the patient must be fasting with a TG level 400 mg/dl. As LDL-C nears goal, the inaccuracies of the Friedewald equation are ampliﬁed (19). For example, calculated LDL-C generally underestimates the true concentration of small, dense LDL particles, especially when the TG level is 200 mg/dl (13). Given these limitations of LDL-C, the NCEP recommended using non–HDL-C (total cholesterol HDL-C) as a secondary target of therapy when the TG level is 200 mg/dl (1). Non–HDL-C. The non–HDL-C estimates the cholesterol concentration of all the apoB-containing lipoproteins, namely VLDL, IDL, LDL, and Lp(a), in contrast to LDL-C, which does not include VLDL-C. The non– HDL-C can be measured nonfasting. If the TG level is elevated to 200 mg/dl, the non–HDL level will reﬂect the increase in VLDL-C. The non–HDL-C appears superior to LDL-C estimation in establishing CAD risk and monitoring treatment (20 –23). However, lipid levels do not necessarily equate to lipoprotein particle levels, and non–HDL-C does not permit a determination of whether there is also an increase in small, dense LDL-P in the hyper-TG patient. Beyond LDL-C and Non–HDL-C ApoB measurement. The apoB level reﬂects the total number of atherogenic apoB-containing lipoproteins, because each chylomicron, chylomicron remnant, VLDL, IDL, LDL, and Lp(a) particle contains 1 molecule of apoB. However, 90% of total plasma apoB is contained within the LDL particles (13). Thus, for a given LDL-C level, a higher apoB level indicates higher LDL-P. Measurement of apoB (as well as apoA-I) does not need to be done in the fasting state, has been standardized by the World Health Organization, and is available in most large commercial laboratories (24). Moreover, apoB has been shown in nearly all studies to outperform LDL-C and non–HDL-C measurements in cardiovascular risk stratiﬁcation (25–30). These include several
large, prospective studies such as AMORIS (ApoproteinRelated Mortality Risk Study) (29), the Health Professionals Follow-Up Study (27), the Quebec Cardiovascular Study (25,26), and the study by Moss et al. (30). Benn et al. (31) recently reported that apoB had a higher predictive ability than LDL-C for ischemic cardiovascular disease in 9,231 asymptomatic Danish men and women. Using receiver-operating characteristic curves, they found that the predictive ability of non–HDL-C was similar to apoB. However, the interindividual biological variation for apoB (coefﬁcient of variation [CV] 6.9%) was superior to non–HDL-C (TC CV 6% plus HDL-C CV 7.1%), indicating that repeated measurements of apoB are more reliable in a single patient. Apolipoprotein B also appears to be a better predictor of subsequent CAD events in patients on treatment with statins (28,32). Ratio of apoB to apoA-I. Results from a number of epidemiologic studies indicated that the ratio of apoB to apoA-I was the strongest predictor of CAD (28). In both the placebo and the treatment groups from the AFCAPS/ TEXCAPS (Air Force/Texas Coronary Atherosclerosis Prevention Study) trial, the apoB/apoA-I ratio was a robust predictor of CAD (32). Similarly, van Lennep et al. (33) reported in patients with CAD on statin therapy that only apoB and the apoB/apoA-I ratio predicted myocardial infarction and all-cause mortality, whereas LDL-C and TG did not. In both men and women from the AMORIS (Apolipoprotein-Related Mortality Risk) study, the superiority of the ratio of apoB to apoA-I, compared with the TC/HDL-C ratio, became more obvious as risk of CAD increased (28). In men, the relative risk of CAD increased at an apoB/apoA-I ratio of 1.0, and the comparative ﬁgure for females was 0.86 (28). These results in aggregate are not surprising, given that increased LDL-P is usually accompanied by low HDL and apoA-I (Fig. 1). The percentile distributions for LDL-C, non–HDL-C, and apoB are available from the Framingham Heart Study (23,34,35) (Table 1). For a particular goal for LDL-C treatment from the NCEP-ATP III (e.g., 100 mg/dl) one can estimate what the equivalent goal (based on percent in the population) for apoB might be (e.g., 80 mg/dl) (Table 1). The percentile distributions for HDL-C and
LDL-C, Non–HDL-C, ApoB, Estimated Percentiles of and LDL-P Estimated Percentiles of Table 1 LDL-C, Non–HDL-C, ApoB, and LDL-P
Percentile 5th LDL-C (mg/dl) Non–HDL-C (mg/dl) ApoB (mg/dl) LDL-P (nmol/l) 80 110 60 800 10th 90 120 70 900 25th 110 140 80 1,100 50th 130 160 100 1,400 75th 160 190 120 1,800 90th 180 210 140 2,000 95th 200 230 150 2,100
Estimates were derived from the Framingham Heart Study (23,34,36). Men and women were combined. ApoB apolipoprotein B; LDL-C low-density lipoprotein cholesterol; LDL-P total number of low-density lipoprotein particles; non–HDL-C total cholesterol high-density lipoprotein cholesterol.
Mudd et al. LDL Heterogeneity in CAD
JACC Vol. 50, No. 18, 2007 October 30, 2007:1735–41
and ApoA-I Levels (mg/dl) in Men Estimated Percentiles of HDL-C and Women Estimated Percentiles of HDL-C Table 2 and ApoA-I Levels (mg/dl) in Men and Women
Percentile 5th HDL-C Men Women ApoA-I Men Women 92 107 99 116 114 132 130 154 153 181 178 206 196 224 28 35 31 39 37 46 43 55 51 66 61 77 67 84 10th 25th 50th 75th 90th 95th
Estimates were derived from the Framingham Heart Study (35). ApoA-I apolipoprotein A-I; HDL-C high-density lipoprotein cholesterol.
apoA-I in men and women from the Framingham Heart Study (35) are also provided in Table 2. We propose that in addition to apoB, the ratio of apoB/apoA-I be included as alternative goals in consensus recommendations for LDL reduction and HDL increase. Other assessments of LDL particle number and size. The LDL-P is determined by the rate at which the LDL particles are produced and cleared from the circulation (13–16) (Figs. 1 and 2). Furthermore, there are documented variations between different ages, genders, and races (36 – 38). For a given LDL-C level, an increase in small, dense LDL-P is associated with increased atherogenesis, which may explain some of the variation in risk between different individuals and populations (36 –38). More direct measures of LDL-P may help to further delineate the risk of CAD attributable to metabolic abnormalities such as diabetes and the metabolic syndrome (14,16,17). The direct measurement of LDL-P number and size is technically difﬁcult, relatively time consuming, and more expensive than apoB measurement. The LDL-P number and size have also been assessed by nuclear magnetic resonance (NMR) spectroscopy, density-gradient ultracentrifugation (DGU), or gradient gel electrophoresis (GGE). A recent report found that an assessment of these methods to determine LDL size agreed poorly (39). The LDL-P however, was not evaluated, but the different tests also reported signiﬁcant variations in LDL-C, which is what our current treatment guidelines are based upon. NMR spectroscopy. Nuclear magnetic resonance spectroscopy rapidly determines the sizes and concentrations of 15 lipoprotein subclasses based on the spectral characteristics of methyl groups within the lipid molecules and the difference in size of the lipoprotein particles (12). The LDL-P by NMR includes IDL and 3 LDL subclasses. Nuclear magnetic resonance has been validated against existing methods of lipoprotein subclass determination (12); however, there is no international standardization program. Nuclear magnetic resonance was only performed by LipoScience (Raleigh, North Carolina). The LDL-P appears to be a particularly strong predictor of CAD in women. In the prospective CHS (Cardiovascular Health Study) (37), NMR-determined LDL-P and small LDL particle size predicted incident CAD, primarily
among elderly women. The LDL-P remained signiﬁcant, even after adjustment for traditional risk factors, whereas LDL particle size did not. Mackey et al. (40) found that LDL-P, small, dense LDL, and large VLDL were positively associated with coronary artery calciﬁcation in healthy postmenopausal women, after adjustment for age, systolic blood pressure, current smoking, LDL-C, HDL-C, and TG. Blake et al. (15) found that LDL-P in healthy women was independently predictive of future myocardial infarction, even after adjustment for the ratio of TC to LDL-C, apoB, and hs-CRP. Rosenson et al. (41) measured LDL and HDL particle size and concentration by NMR spectroscopy in frozen plasma samples of placebo- and pravastatin-treated subjects. Whereas lipid levels did not predict angiographic progression of CAD, LDL-P strongly correlated with progression (41). In the MESA (Multiethnic Study of Atherosclerosis) study, Mora et al. (42) studied the association of LDL-P and particle size by NMR with carotid intima-media thickness (IMT) in over 5,000 apparently healthy individuals. When controlling for traditional CAD risk factors and LDL subclass correlation, both large and small LDL-P, but not LDL size, were signiﬁcantly associated with carotid IMT.
Proposed Biochemical and Cellular Mechanisms of Enhanced Small, Dense LDL
Increased small dense low-density lipoprotein (LDL) production, combined with a lower afﬁnity of small, dense LDL for the low-density lipoprotein receptor (LDL-R) and a longer residence time in plasma, leads to an increased number of small, dense LDL particles. The increased small, dense LDL cross the arterial wall more readily, bind more avidly to proteoglycans in the intimal matrix, and are more easily oxidized, characteristics all conducive to atherogenesis (16). Small, dense LDL promotes endothelial cell dysfunction, inducing greater production of plasminogen activator inhibitor (PAI)-I and thromboxane A2 (TXA2).
JACC Vol. 50, No. 18, 2007 October 30, 2007:1735–41
Mudd et al. LDL Heterogeneity in CAD
In the prospective EPIC (European Prospective Investigation Into Cancer and Nutrition)-Norfolk study (22) in 25,663 subjects, both LDL-P, as assessed by NMR, and non–HDL-C were more closely associated with CAD than LDL-C. After HDL-C and TG levels were accounted for, LDL-P lost its discriminative power over LDL-C. Consistent with the MESA study, the EPIC-Norfolk study also found that LDL size was not predictive of CAD after adjustment for LDL-P. These results argue against the routine implementation of determining LDL-P number and size by NMR for CAD risk assessment. However, the fact that patients with low HDL-C and/or higher TG often have elevated numbers of LDL-P, without having high LDL-C, may enable their LDL-related CAD risk to be managed more effectively. Although data from clinical intervention studies (see subsequent text) support LDL-P by NMR as an alternative treatment target (but not superior to apoB), the value of LDL-P monitoring as an additional treatment target beyond LDL-C needs to be assessed in intervention trials. DGU. In DGU, lipoprotein fractions from a density gradient are eluted systematically and the cholesterol content determined. The method allows an estimate of the relative distribution of cholesterol but not particle number within the IDL and LDL subclasses. Evidence from several angiographic trials using DGU indicated that treatment beneﬁt is related to a signiﬁcant decrease in small, dense LDL-C (43– 45), independent of other lipid and nonlipid risk factors. The Vertical Auto Proﬁle II (Atherotech, Birmingham, Alabama) is a DGU-based test that determines the cholesterol content of VLDL, LDL, and HDL subclasses, Lp(a), and patterns of LDL size (LDL subclass A, AB, or B) (46). GGE. The GGE also determines the size and estimates the relative concentration of lipoprotein subclasses. Seven different LDL subclasses are identiﬁed by GGE and their concentration is estimated by densitometry. Such testing is available from the Berkeley HeartLab (Burlingame, California). In the Stanford Study (47) and the Physicians’ Health Study (48), small, dense LDL by GGE predicted CAD but was not independent of the TC/HDL-C ratio and nonfasting TG, respectively. The SCRIPS (Stanford Coronary Risk Intervention Project) (49) trial, a 4-year angiographic trial, found that small, dense LDL by GGE predicted both the progression of stenosis in the control group and the vast majority of angiographic beneﬁt in the group on multifactorial intervention. Those with predominantly large LDL, despite the same LDL-C reduction as those with small, dense LDL, showed angiographic progression at the same rate as the usual care (control) group. Treatment Implications of LDL Heterogeneity Although hyper-TG and reduced HDL-C, commonly observed in diabetes (16) and the metabolic syndrome (17), are
reﬂected in the conventional lipid proﬁle, calculated LDL-C often does not reﬂect small, dense LDL-P in such patients (13). Recognition of this is important, because increased small, dense LDL-P due to enhanced production of TG-rich VLDL appears to be the single most frequent dyslipidemia in patients with premature CAD (13–16). Thus, a low or normal LDL-C level may result in a less aggressive approach than may be clinically indicated, particularly in the patient who may beneﬁt more from combined lipid-altering therapy. Multiple biochemical and cellular mechanisms of atherogenic small, dense LDL particles have been proposed (16) (Fig. 2). It is still incompletely resolved whether risk of CAD is simply related to LDL-P per se, or whether LDL size is also an independent predictor of CAD (see preceding text). Although studies have demonstrated improvement in LDL particle size distribution with pharmacologic intervention, it remains to be established whether risk stratiﬁcation based on LDL size by “advanced” or additional lipoprotein testing is sufﬁciently additive to merit a change in management strategies.
Altering LDL Particle Number and Size Statins are the most potent class of drugs to reduce LDL-P, including small, dense LDL-P. Higher doses of the more powerful statins may also decrease VLDL production, leading to a small shift from small, dense to larger LDL particles. Both niacin and ﬁbrates convert small, dense LDL into larger, more buoyant LDL. Although LDL-P clearly predicts CAD events, it is unclear if altering LDL size decreases CAD events independent of any effect on lowering LDL-P. In the VA-HIT (Veterans Affairs High-Density Lipoprotein Intervention Trial) study (50) subjects with low HDL-C and average LDL-C treated with gemﬁbrozil had a signiﬁcant decrease in CAD events compared with placebo, an effect proportional to the increase in HDL-C, because LDL-C was not decreased with gemﬁbrozil. Using NMR, Otvos et al. (51) reported that gemﬁbrozil lowered small, dense LDL-P, thereby increasing total LDL size. Total HDL-P, particularly HDL-3, increased with gemﬁbrozil. These changes in particle composition independently decreased risk of new CAD events and explained a signiﬁcant amount of the beneﬁt of gemﬁbrozil in the VA-HIT study. Additionally, the DAIS (Diabetes Atherosclerosis Intervention Study) trial (52) showed that patients with type 2 diabetes treated with fenoﬁbrate had a signiﬁcantly decreased rate of angiographic CAD progression and a greater increase in LDL size compared with placebo controls. In a substudy, Vakkilainen et al. (53) found that small LDL size was associated with greater CAD progression, regardless of treatment group, and that fenoﬁbrate produced a greater increase in LDL particle size compared with placebo. In contrast, the FIELD (Feno-
Mudd et al. LDL Heterogeneity in CAD
JACC Vol. 50, No. 18, 2007 October 30, 2007:1735–41
ﬁbrate Intervention and Event Lowering in Diabetes) study (54) was associated with a nonsigniﬁcant 11% reduction in the primary end point (coronary heart disease death and nonfatal myocardial infarction); however, changes in LDL-P and LDL particle size were not reported.
Reprint requests and correspondence: Dr. Peter O. Kwiterovich, Jr., University Lipid Clinic, Suite 310, 550 North Broadway Building, Baltimore, Maryland 21205. E-mail: pkwitero@ jhmi.edu.
Perspectives and Future Directions The evidence supporting the incremental value of measuring apoB is strong and internally consistent. The ThirtyPerson/Ten-Country Panel has proposed that evidencedbased guidelines endorse alternatives such as apoB in both men and women (28), a recommendation further supported by the results of the large Copenhagen City Heart Study (31). Statin-treated patients may have a proportionally higher apoB than LDL-C, indicating that too many LDL-P are still present. Those patients will require further intervention, often in the form of combined lipid-altering drugs. For patients with CAD, CAD risk equivalents, or a high risk of CAD, a more aggressive LDL-C goal of 70 mg/dl should be considered. This goal is in fact less than the ﬁfth percentile for LDL-C. The recently proposed goal of 80 mg/dl for apoB in such high-risk patients is about the 25th percentile. Although it is not certain what the equivalent goal of apoB should be when the LDL-C goal is 70 mg/dl, the equivalent percentile for apoB is 60 mg/dl. Recent evidence indicates that non–HDL-C and LDL-P also provide additional prognostic information over LDL-C. Population-based percentiles for LDL-C, non– HDL-C, apoB, and LDL-P are available from the Framingham Heart Study (36). Alternative goals for LDL-P as well as apoB related to current NCEP treatment goals for LDL-C and non–HDL-C should be considered in future recommendations. Further study is needed to deﬁne the incremental value of LDL-P and LDL size in the setting of LDL-C targets 70 mg/dl. The preponderance of small, dense LDL-P may provide independent information that predicts risk beyond the traditional lipid proﬁle, particularly in the presence of the dyslipidemic triad. With regard to high LDL-P and low HDL, there is evidence that the ratio of apoB/apoA-I may be the strongest predictor of CAD and that such measurement could be incorporated into clinical practice. Population-based percentiles for men and women for apoA-I and HDL-C also are available from the Framingham Heart Study (36). Only through well-designed prospective clinical trials will we be able to determine when lipoprotein heterogeneity analysis is justiﬁed and how best to use the information. For now, selective measurement of apoB might be incorporated into clinical practice (when the TG level is above normal), with the addition of the apoB/apoA-I ratio and LDL-P only when it is likely to change clinical management.
1. Adult Treatment Panel III. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486 –97. 2. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110:227–39. 3. O’Keefe JH Jr., Cordain L, Harris WH, Moe RH, Vogel R. Optimal low-density lipoprotein is 50 to 70 mg/dl. Lower is better and physiologically normal. J Am Coll Cardiol 2004;43:2142– 46. 4. Robinson JG, Smith B, Maheshwari N, Schrott H. Pleiotrophic effects of statins: beneﬁt beyond cholesterol reduction? A meta-regression analysis. J Am Coll Cardiol 2005;46:1855– 62. 5. Heart Protection Study Collaborative Group. MRC/BHF heart protection study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomized placebo-controlled trial. Lancet 2002;360:7–22. 6. PROVE-IT Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495– 504. 7. REVERSAL Investigators. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized control study. JAMA 2004;291:1071– 80. 8. LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary artery disease. N Engl J Med 2005;352:1425–35. 9. Nissen SE, Nicholls SJ, Sipahi I, et al., ASTEROID Investigators. Effect of very-high intensity statin therapy on regression of coronary atherosclerosis. The ASTEROID trial. JAMA 2006;295: 1556 – 65. 10. Pedersen TR, Faergeman O, Kastelein JJ, et al. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction. The IDEAL study: a randomized controlled trial. JAMA 2005;294:2437– 45. 11. Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke; systematic review and meta-analysis. BMJ 2003;326:1–7. 12. Otvos JD, Jeyarajah EJ, Cromwell WC. Measurement issues related to lipoprotein heterogeneity. Am J Cardiol 2002;90 Suppl:22i–9i. 13. Sniderman AD. How, when, and why to use apolipoprotein B in clinical practice. Am J Cardiol 2002;90 Suppl:48i–54i. 14. Kwiterovich PO. Clinical relevance of the biochemical, metabolic and genetic factors that inﬂuence low-density lipoprotein heterogeneity. Am J Cardiol 2002;90 Suppl:30i– 45i. 15. Blake GJ, Otvos JD, Rifai N, Ridker PJ. Low-density lipoprotein particle concentration and size as determined by NMR spectroscopy as predictors of cardiovascular disease in women. Circulation 2002;106: 1930 –7. 16. Sniderman AD, Scantlebury T, Cianﬂone K. Hypertriglyceridemic hyperapoB: the unappreciated atherogenic dyslipoproteinemia in type 2 diabetes. Ann Intern Med 2001;135:447–59. 17. Kathiresan S, Otvos JD, Sullivan ML, et al. Increased small lowdensity lipoprotein particle number: a prominent feature of the metabolic syndrome in the Framingham Heart Study. Circulation 2006;113:20 –9. 18. Friedewald WT, Levy RI, Fredrickson DS. Estimation of low-density lipoprotein in plasma without use of preparative ultracentrifuge. Clin Chem 1972;18:499 –502. 19. Scharnagl H, Nauck M, Wieland H, Marz W. The Friedewald formula underestimates LDL-C cholesterol at low concentrations. Clin Chem Lab Med 2001;39:426 –31. 20. Frost PH, Havel RJ. Rationale for use of nonhigh-density lipoprotein cholesterol rather than low-density lipoprotein cholesterol as a tool for
JACC Vol. 50, No. 18, 2007 October 30, 2007:1735–41 lipoprotein cholesterol screening and assessment of risk and therapy. Circulation 1998;97:1837– 47. Cui Y, Blumenthal RS, Flaws JA, et al. Non-high-density lipoprotein cholesterol level as a predictor of cardiovascular disease mortality. Arch Intern Med 2001;161:1413–9. Harchaoui KE, van der Steeg WA, Stroes ESG, et al. Value of low-density lipoprotein particle number and size as predictors of coronary artery disease in apparently healthy men and women. The EPIC-Norfolk prospective population study. J Am Coll Cardiol 2007;49:547–53. Liu J, Sempos CT, Donahue RP, Dorn J, Trevisan M, Grundy SM. Non-high-density lipoprotein and very-low-density lipoprotein cholesterol and their risk predictive values in coronary heart disease. Am J Cardiol 2006;98:1363– 8. Marcovina SM, Albers JJ, Kennedy H, Mei JV, Henderson LO, Hannon WH. 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. Clin Chem 1994;40:586 –92. Lamarche B, Tchernof A, Moorjani S, et al. Small, dense low-density lipoprotein particles as a predictor of the risk of ischemic heart disease in men. Prospective results from the Quebec Cardiovascular Study. Circulation 1997;95:69 –75. St-Pierre A, Cantin B, Dagenais GR, et al. Low-density lipoprotein subfractions and the long-term risk of ischemic heart disease in men. 13-year follow-up data from the Quebec Cardiovascular Study. Arterioscler Thromb Vasc Biol 2005;25:553–9. Pischon T, Girman CJ, Sacks FM, et al. Non-high-density lipoprotein cholesterol and apolipoprotein B in the prediction of coronary heart disease in men. Circulation 2005;112:3375– 83. Barter PJ, Ballantyne CM, Carmena R, et al. Apo B versus cholesterol in estimating cardiovascular risk and in guiding therapy: report of the Thirty-Person/Ten-Country Panel. J Intern Med 2006;259:247–58. Walldius G, Jungner I, Holme I, et al. High apolipoprotein B, low apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS study): a prospective study. Lancet 2001;358:2026 –33. Moss AJ, Goldstein RE, Marder VJ, et al. Thrombogenic factors and recurrent coronary events. Circulation 1999;99:2517–22. Benn M, Nordestgaard BG, Jensen GB, Tybjaerg-Hansen A. Improving prediction of ischemic cardiovascular disease in the general population using apolipoprotein B. The Copenhagen City Heart Study. Arterioscler Thromb Vasc Biol 2007;27:661–70. Gotto AM Jr., Whitney E, Stein EA, et al. Relation between baseline and on-treatment lipid parameters and ﬁrst acute major coronary events in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TEXCAPS). Circulation 2000;101:477– 84. van Lennep JE, Westerveld HT, van Roeters Lennep HWO, et al. Apolipoprotein concentrations during treatment and recurrent coronary artery disease events. Arterioscler Thromb Vasc Biol 2000;20: 2408 –13. Schaefer EJ, Lamon-Fava S, Cohn SD, et al. Effects of age, gender, and menopausal status on plasma low density lipoprotein cholesterol and apolipoprotein B levels in the Framingham Offspring Study. J Lipid Res 1994;35:779 –92. Schaefer EJ, Lamon-Fava S, Ordovas JM, et al. Factors associated with low and elevated plasma high density lipoprotein cholesterol and apolipoprotein A-I levels in the Framingham Offspring Study. J Lipid Res 1994;35:871– 82. Freedman DS, Otvos JD, Jeyarajah EJ, et al. Sex and age differences in lipoprotein subclasses measured by nuclear magnetic resonance spectroscopy: the Framingham Study. Clin Chem 2004;50:1189 –200. Kuller L, Arnold A, Tracy R, et al. Nuclear magnetic resonance spectroscopy of lipoproteins and risk of coronary heart disease in the
Mudd et al. LDL Heterogeneity in CAD
38. 39. 40. 41.
46. 47. 48. 49. 50. 51.
Cardiovascular Health Study. Arterioscler Thromb Vasc Biol 2002; 22:1175– 80. Benton JL, Blumenthal RS, Becker DM, Yanek LR, Moy TF, Post W. Predictors of low-density lipoprotein particle size in a high-risk African American population. Am J Cardiol 2005;95:1320 –32. Ensign W, Hill N, Heward CB. Disparate LDL phenotypic classiﬁcation among 4 different methods assessing LDL particle characteristics. Clin Chem 2006;52:1722–7. Mackey RH, Kuller LH, Sutton-Tyrell K, et al. Lipoprotein subclasses and coronary artery calcium in postmenopausal women from the Healthy Women Study. Am J Cardiol 2002;90:71i– 6i. Rosenson RS, Otvos JD, Freedman DS. Relations of lipoprotein subclass levels and low-density lipoprotein size to progression of coronary artery disease in the Pravastatin Limitation of Atherosclerosis in the Coronary Arteries (PLAC-1) trial. Am J Cardiol 2002;90: 89 –94. Mora SA, Szklo M, Otvos JD, et al. LDL particle subclasses, LDL particle size, and carotid atherosclerosis in the Multi-Ethnic Study of Atherosclerosis (MESA). Atherosclerosis 2006;192:211–7. Watts GF, Mandalia S, Brunt JN, Slavin BM, Coltart DJ, Lewis B. Independent associations between plasma lipoprotein subfraction levels and the course of coronary artery disease in the St. Thomas’ Atherosclerosis Regression Study (STARS). Metabolism 1993;42: 1461–7. Mack WJ, Krauss RM, Hodis HN. Lipoprotein subclasses in the Monitored Atherosclerosis Regression Study (MARS). Treatment effects and relation to coronary angiographic progression. Arterioscler Thromb Vasc Biol 1996;16:697–704. Zambon A, Hokanson JE, Brown BG, Brunzell JD. Evidence for a new pathophysiological mechanism for coronary artery disease regression: hepatic lipase-mediated changes in LDL-C density. Circulation 1999;99:1959 – 64. Kulkami KR, Garber DW, Marcovina SM, Segrest JP. Quantiﬁcation of cholesterol in all lipoprotein classes by the VAP-II method. J Lipid Res 1994;35:159 – 68. Gardner CD, Fortmann SP, Krauss RM. Association of small lowdensity lipoprotein particles with the incidence of coronary artery disease in men and women. JAMA 1996;276:875– 81. Stampfer MJ, Krauss RM, Ma J, et al. A prospective study of TG level, low-density lipoprotein particle diameter, and risk of myocardial infarction. JAMA 1996;76:882– 8. Williams PT, Superko HR, Haskell WL, et al. Smallest LDL particles are most strongly related to coronary disease progression in men. Arterioscler Thromb Vasc Biol 2003;23:314 –21. Robins SJ, Collins D, Wittes JT, et al. Relation of gemﬁbrozil treatment and lipid levels with major coronary events: VA-HIT: a randomized control trial. JAMA 2001;285:1585–91. Otvos JD, Collins D, Freedman DS, et al. Low-density lipoprotein and high-density lipoprotein particle subclasses predict coronary events and are favorably changed by gemﬁbrozil therapy in the Veterans Affairs High-Density Lipoprotein Intervention. Circulation 2006;113: 1556 – 63. Diabetes Atherosclerosis Intervention Study Investigators. Effect of fenoﬁbrate on progression of coronary-artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomized study. Lancet 2001;357:905–10. Vakkilainen J, Steiner G, Ansquer J-C, et al. Relationships between low-density lipoprotein particle size, plasma lipoproteins, and progression of coronary artery disease. The Diabetes Atherosclerosis Intervention Study (DAIS). Circulation 2003;107:1733–7. Keech A, Simes RJ, Barter P, et al., FIELD Study Investigators. Effects of long-term fenoﬁbrate therapy on cardiovascular events in 9795 people with type 2 diabetes (the FIELD study): randomized placebo-controlled trial. Lancet 2003;361:2005–16.