Triglycerides and Cardiovascular Disease

HomeCirculationVol. 123, No. 20Triglycerides and Cardiovascular Disease Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBTriglycerides and Cardiovascular DiseaseA Scientific Statement From the American Heart Association Michael Miller, MD, FAHA, Neil J. Stone, MD, FAHA, Christie Ballantyne, MD, FAHA, Vera Bittner, MD, FAHA, Michael H. Criqui, MD, MPH, FAHA, Henry N. Ginsberg, MD, FAHA, Anne Carol Goldberg, MD, FAHA, William James Howard, MD, Marc S. Jacobson, MD, FAHA, Penny M. Kris-Etherton, PhD, RD, FAHA, Terry A. Lennie, PhD, RN, FAHA, Moshe Levi, MD, FAHA, Theodore Mazzone, MD, FAHA and Subramanian Pennathur, MD, FAHA Michael MillerMichael Miller Search for more papers by this author , Neil J. StoneNeil J. Stone Search for more papers by this author , Christie BallantyneChristie Ballantyne Search for more papers by this author , Vera BittnerVera Bittner Search for more papers by this author , Michael H. CriquiMichael H. Criqui Search for more papers by this author , Henry N. GinsbergHenry N. Ginsberg Search for more papers by this author , Anne Carol GoldbergAnne Carol Goldberg Search for more papers by this author , William James HowardWilliam James Howard Search for more papers by this author , Marc S. JacobsonMarc S. Jacobson Search for more papers by this author , Penny M. Kris-EthertonPenny M. Kris-Etherton Search for more papers by this author , Terry A. LennieTerry A. Lennie Search for more papers by this author , Moshe LeviMoshe Levi Search for more papers by this author , Theodore MazzoneTheodore Mazzone Search for more papers by this author and Subramanian PennathurSubramanian Pennathur Search for more papers by this author and on behalf of the American Heart Association Clinical Lipidology, Thrombosis, and Prevention Committee of the Council on Nutrition, Physical Activity, and Metabolism, Council on Arteriosclerosis, Thrombosis and Vascular Biology, Council on Cardiovascular Nursing, and Council on the Kidney in Cardiovascular Disease Originally published18 Apr 2011https://doi.org/10.1161/CIR.0b013e3182160726Circulation. 2011;123:2292–2333Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2011: Previous Version 1 1. IntroductionA long-standing association exists between elevated triglyceride levels and cardiovascular disease* (CVD).1,2 However, the extent to which triglycerides directly promote CVD or represent a biomarker of risk has been debated for 3 decades.3 To this end, 2 National Institutes of Health consensus conferences evaluated the evidentiary role of triglycerides in cardiovascular risk assessment and provided therapeutic recommendations for hypertriglyceridemic states.4,5 Since 1993, additional insights have been made vis-à-vis the atherogenicity of triglyceride-rich lipoproteins (TRLs; ie, chylomicrons and very low-density lipoproteins), genetic and metabolic regulators of triglyceride metabolism, and classification and treatment of hypertriglyceridemia. It is especially disconcerting that in the United States, mean triglyceride levels have risen since 1976, in concert with the growing epidemic of obesity, insulin resistance (IR), and type 2 diabetes mellitus (T2DM).6,7 In contrast, mean low-density lipoprotein cholesterol (LDL-C) levels have receded.7 Therefore, the purpose of this scientific statement is to update clinicians on the increasingly crucial role of triglycerides in the evaluation and management of CVD risk and highlight approaches aimed at minimizing the adverse public health–related consequences associated with hypertriglyceridemic states. This statement will complement recent American Heart Association scientific statements on childhood and adolescent obesity8 and dietary sugar intake9 by emphasizing effective lifestyle strategies designed to lower triglyceride levels and improve overall cardiometabolic health. It is not intended to serve as a specific guideline but will be of value to the Adult Treatment Panel IV (ATP IV) of the National Cholesterol Education Program, from which evidence-based guidelines will ensue. Topics to be addressed include epidemiology and CVD risk, ethnic and racial differences, metabolic determinants, genetic and family determinants, risk factor correlates, and effects related to nutrition, physical activity, and lipid medications.2. Scope of the Problem: Prevalence of Hypertriglyceridemia in the United StatesIn the United States, the National Health and Nutrition Examination Survey (NHANES) has monitored biomarkers of CVD risk for >3 decades. Accordingly, increases in fasting serum triglyceride levels observed between surveys conducted in 1976–1980 and 1999–20026 coincided with adjustments in the classification of hypertriglyceridemia4,10 (Table 1). Current designations are as follows: 150 to 199 mg/dL, borderline high; 200 to 499 mg/dL, high; and ≥500 mg/dL, very high. The prevalence of hypertriglyceridemia by ethnicity in NHANES 1988–1994 and 1999–2008 according to these cut points is shown in Figure 1. Overall, 31% of the adult US population has a triglyceride level ≥150 mg/dL, with no appreciable change between NHANES 1988–1994 and 1999–2008. Among ethnicities, Mexican Americans have the highest rates (34.9%), followed by non-Hispanic whites (33%) and blacks (15.6%) in NHANES 1999–2008 (Table 2). High (≥200 mg/dL) and very high (≥500 mg/dL) fasting triglyceride levels were observed in 16.2% and 1.1% of adults, respectively, with Mexican Americans being overrepresented at both cut points (19.5% and 1.4%, respectively). Figure 2 illustrates the sex- and age-related prevalence of triglyceride levels ≥150 mg/dL in NHANES 1999–2008. Within each group, the highest prevalence rates were observed in Mexican American men (50 to 59 years old, 58.8%) and Mexican American women (≥70 years old, 50.5%), followed by non-Hispanic white men and women (60 to 69 years old, 43.6% and 42.2%, respectively) and non-Hispanic black men (40 to 49 years old, 30.4%) and women (60 to 69 years old, 25.3%). The prevalence of triglyceride levels ≥200 mg/dL was also highest in Mexican American men (≥30 years old) and women (≥40 years old; 21% to 36%), followed by non-Hispanic white men (30 to 69 years old, 20% to 25%). Although the prevalence of triglyceride levels ≥500 mg/dL was relatively low (1% to 2%), Mexican American men 50 to 59 years of age exhibited the highest rate (9%) in NHANES 1999–2008.Table 1. Triglyceride Classification Revisions Between 1984 and 2001TG Designate1984 NIH Consensus Panel1993 NCEP Guidelines2001 NCEP GuidelinesDesirable<250<200<150Borderline-high250–499200–399150–199High500–999400–999200–499Very high>1000>1000≥500TG indicates triglyceride; NIH, National Institutes of Health; and NCEP, National Cholesterol Education Program.Values are milligrams per deciliter.Download figureDownload PowerPointFigure 1. Prevalence of fasting triglyceride levels (≥150, 200, and 500 mg/dL) in males and (non-pregnant) females ≥18 years of age by ethnicity in the National Health and Nutrition Examination Survey (1988–1994 and 1999–2008). TG indicates triglycerides; Non-H, non-Hispanic.Table 2. Overall Prevalence (%) of Hypertriglyceridemia Based on 150, 200, and 500 mg/dL Cut Points by Age, Sex, and Ethnicity in US Adults, NHANES 1999–2008DemographicTriglyceride Cut Points, mg/dL≥150≥200≥500Overall (age ≥20 y)31.016.21.1Age, y 20–2920.79.50.8 30–3925.814.10.7 40–4932.816.71.6 50–5936.720.11.8 60–6941.622.61.0 ≥7034.517.20.5Sex Men35.419.81.8 Women*26.812.70.5Ethnicity Mexican American34.919.51.4 Non-Hispanic, black15.67.60.4 Non-Hispanic, white33.017.61.1NHANES indicates National Health and Nutrition Examination Survey.Data provided by the Epidemiology Branch, National Heart, Lung, and Blood Institute.*Excludes pregnant women.Source: NHANES 1999–2008.Download figureDownload PowerPointFigure 2. Prevalence of hypertriglyceridemia in males and non-pregnant females ≥18 years of age in NHANES 1999–2008. NHANES indicates National Health and Nutrition Examination Survey; TG, triglycerides; Non H, non-Hispanic; Mexican-Am, Mexican-American.Serum triglyceride levels by selected percentiles and geometric means are shown in Table 3. Because triglyceride levels are not normally distributed in the population (Section 3.1), the geometric mean, as derived by log transformation, is favored over the arithmetic mean to reduce the potential impact of outliers that might otherwise overestimate triglyceride levels.11 Over the past 20 years, there were small increases in median triglyceride levels in both men (122 versus 119 mg/dL) and women (106 versus 101 mg/dL). However, the increases in triglycerides primarily were observed in younger age groups (20 to 49 years old), and overall, triglyceride levels continue to be higher than in less industrialized societies (Section 12.1). We now address the epidemiological and putative pathophysiological consequences of high triglyceride levels.Table 3. Serum Triglyceride Levels of US Adults ≥20 Years of Age, 1988–1994 and 1999–20081988–19941999–2008Geometric MeanSelected PercentileGeometric MeanSelected PercentileAge-SpecificAge-Adjusted5th25th50th75th95thAge-SpecificAge-Adjusted5th25th50th75th95thMen ≥20 y127.95383119176321128.35285122182361 20–2995.1456588126237106.24570100150305 30–39118.85279113169298122.15080119175324 40–49138.45891133190349143.85794134201473 50–59146.66195137223394140.66193133197388 60–69146.764101140200378138.25996133196372 ≥70134.36495131179306121.55487120168266Women* ≥20 y109.74772101150274110.04874106155270 20–2983.842608411118288.7396383123205 30–3991.343628312126795.8426491138243 40–49103.04870102139251105.54973102146249 50–59129.25584126186325124.75584120176305 60–69143.96197137203380135.96396137192299 ≥70137.27097134182284133.06395129180293Race/ethnicity Mexican-American Men138.65383120185387140.85389126196392 Women131.85585118167291126.64881113164277 Non-Hispanic black Men102.544659214025999.7446794129248 Women88.840587911520888.1386283116209 Non-Hispanic white Men131.35585123182323130.35387126188368 Women110.94874102154276112.15077109161275Percentile and geometric mean distribution of serum triglyceride (mg/dL).*Excludes pregnant women.Data provided by the Epidemiology Branch, National Heart, Lung, and Blood Institute.Source: National Health and Nutrition Examination Survey III (1988–1994) and Concurrent National Health and Nutrition Examination Survey (1999–2008).3. Epidemiology of Triglycerides in CVD Risk AssessmentThe independent relationship of triglycerides to the risk of future CVD events has long been controversial. An article published in The New England Journal of Medicine in 1980 concluded that the evidence for an independent effect of triglycerides was “meager,”3 yet despite several decades of additional research, the controversy persists. This may in part reflect conflicting results in the quality of studies performed in the general population and in clinical samples. Second, in studies demonstrating a significant independent relationship of triglycerides to CVD events, the effect size has typically been modest compared with standard CVD risk factors, including other lipid and lipoprotein parameters. Summarized below are methodological considerations and results from representative studies that evaluated triglycerides in CVD risk assessment.3.1. Methodological Considerations and Effect ModificationTriglyceride has long been the most problematic lipid measure in the evaluation of cardiovascular risk. First, the distribution is markedly skewed, which necessitates categorical definitions or log transformations. Second, variability is high (Section 10) and increases with the level of triglyceride.12 Third, the strong inverse association with high-density lipoprotein cholesterol (HDL-C) and apolipoprotein (apo) AI, suggests an intricate biological relationship that may not be most suitably represented by the results of multivariate analysis. Finally, evidence from prospective studies of the triglyceride association supports a stronger link with CVD risk in people with lower levels of HDL-C13,14 and LDL-C13,14 and with T2DM.15,16 Such an effect modification could obscure a modest but significant effect, as demonstrated recently.17In addition to the inverse association with HDL-C, triglyceride levels are closely aligned with T2DM, even though T2DM is not always examined as a confounding factor, and when it is, the diagnosis is commonly based on history. Yet at least 25% of subjects with T2DM are undiagnosed,18 and they are often concentrated within a hypertriglyceridemic population. Similarly, many subjects with high triglyceride levels and impaired fasting glucose who subsequently develop T2DM are not adjusted for in multivariate analysis. Hence, these limitations restrict conclusions that support triglyceride level as an independent CVD risk factor. Compounding the aforementioned problem is the argument that an elevated triglyceride level is simply an epiphenomenon (ie, a by-product) of IR or the metabolic syndrome (MetS). However, analysis of NHANES data evaluating the association of all 5 MetS components with cardiovascular risk found the strongest association with triglycerides.19A pivotal consideration is how triglycerides may directly impact the atherosclerotic process in view of epidemiological studies that have failed to demonstrate a strong relationship between very high triglyceride levels and increased CVD death.13,20 As will be described in Section 4, hydrolysis of TRLs (eg, chylomicrons, very low-density lipoproteins [VLDL]) results in atherogenic cholesterol-enriched remnant lipoprotein particles (RLPs). Accordingly, recent evidence suggests that nonfasting triglyceride is strongly correlated with RLPs,21 and in 2 recent studies, nonfasting triglyceride was a superior predictor of incident CVD compared with fasting levels.21,223.2. Case-Control Studies, Including Angiographic StudiesTriglyceride has routinely been identified as a “risk factor” in case-control and angiographic studies, even after adjustment for total cholesterol (TC) or LDL-C23–34 and HDL-C.24,27–29,33,34 In another case-control study, case subjects were 3-fold more likely to exhibit small, dense low-density lipoprotein (LDL) particles, referred to as the “pattern B” phenotype.35 However, the triglyceride level explained most of the risk of the pattern B phenotype and was a stronger covariate than LDL-C, intermediate-density lipoprotein (IDL) cholesterol, or HDL-C. Overall, data from case-control studies have supported triglyceride level as an independent CVD risk factor.3.3. Prospective Population-Based Cohort StudiesAlthough many early cohort studies found a univariate association of triglycerides with CVD, this association often became nonsignificant after adjustment for either TC or LDL-C. Most of these earlier studies did not measure HDL-C. Two meta-analyses of the triglycerides-CVD question drew similar conclusions. The first, published in 1996, considered 16 studies in men, 6 from the United States, 6 from Scandinavia, and 4 from elsewhere in Europe.36 In univariate analysis, the relative risk per 1 mmol/L (88.5 mg/dL) of triglyceride for CVD in men was 1.32 (95% confidence interval 1.26 to 1.39) and 1.14 (95% confidence interval 1.05 to 1.28) after adjustment for HDL-C. In women, the association was more robust in both univariate analysis (relative risk 1.76 per mmol/L) and after adjustment for HDL-C (relative risk 1.37, 95% confidence interval 1.13 to 1.66). The second meta-analysis evaluated 262 000 subjects and found a higher relative risk (1.4) at the upper compared with the lower triglyceride tertile; this estimate improved to 1.72 with correction for “regression dilution bias” (intraindividual triglyceride variation).2A recent meta-analysis from the Emerging Risk Factors Collaboration evaluated 302 430 people free of known vascular disease at baseline in 68 prospective studies.17 With adjustment for age and sex, triglycerides showed a strong, stepwise association with both CVD and ischemic stroke; however, after adjustment for standard risk factors and for HDL-C and non–HDL-C, the associations for both CVD and stroke were no longer significant. The attenuation was primarily from the adjustment for HDL-C and non–HDL-C, which led to the conclusion that “…for population-wide assessment of vascular risk, triglyceride measurement provides no additional information about vascular risk given knowledge of HDL-C and total cholesterol levels, although there may be separate reasons to measure triglyceride concentration (eg, prevention of pancreatitis).”17Additional data from studies involving young men have provided new insight into the triglyceride risk status question.37 In 13 953 men 26 to 45 years old who were followed up for 10.5 years, there were significant correlations between adoption of a favorable lifestyle (eg, weight loss, physical activity) and a decrease in triglyceride levels. At baseline, triglyceride levels in the top quintile were associated with a 4-fold increased risk of CVD compared with the lowest triglyceride quintile, even after adjustment for other risk factors, including HDL-C. Evaluation of the change in triglyceride levels over the first 5 years and incident CVD in the next 5 years found a direct correlation between increases in triglyceride levels and CVD risk. These observations add a dynamic element of triglyceride to CVD risk assessment based on lifestyle intervention that will be elaborated on later in this statement.3.4. Insights From Clinical TrialsA related question is the ability of triglyceride levels to predict clinical benefit from lipid therapy in outcome trials. In many of these studies, subjects with elevated triglyceride levels exhibited improvement in CVD risk, irrespective of drug class or targeted lipid fraction,38–40 primarily because elevated triglyceride level at baseline was commonly accompanied by high LDL-C and low HDL-C, and this combination (ie, the atherogenic dyslipidemic triad) was associated with the highest CVD risk. Taken together, the independence of triglyceride level as a causal factor in promoting CVD remains debatable. Rather, triglyceride levels appear to provide unique information as a biomarker of risk, especially when combined with low HDL-C and elevated LDL-C.4. Pathophysiology of Hypertriglyceridemia4.1. Normal Metabolism of TRLs4.1.1. Lipoprotein CompositionLipoproteins are macromolecular complexes that carry various lipids and proteins in plasma.41 Several major classes of lipoproteins have been defined by their physical and chemical characteristics, particularly by their flotation characteristics during ultracentrifugation. However, lipoprotein particles form a continuum, varying in composition, size, density, and function. The lipids are mainly free and esterified cholesterol, triglycerides, and phospholipids. The hydrophobic triglyceride and cholesteryl esters (CEs) compose the core of the lipoproteins, which is covered by a unilamellar surface that contains mainly the amphipathic (both hydrophobic and hydrophilic) phospholipids and smaller amounts of free cholesterol and proteins. Hundreds to thousands of triglyceride and CE molecules are carried in the core of different lipoproteins.Apolipoproteins are the proteins on the surface of the lipoproteins. They not only participate in solubilizing core lipids but also play critical roles in the regulation of plasma lipid and lipoprotein transport. Apo B100 is required for the secretion of hepatic-derived VLDL, IDL, and LDL. Apo B48 is a truncated form of apo B100 that is required for secretion of chylomicrons from the small intestine.4.2. Transport of Dietary Lipids on Apo B48–Containing LipoproteinsFigure 3 provides an overview of triglyceride metabolism. After ingestion of a meal, dietary fat and cholesterol are absorbed into the cells of the small intestine and are incorporated into the core of nascent chylomicrons. Newly formed chylomicrons, representing 80% to 95% triglyceride as a percentage of composition of lipids,41 are secreted into the lymphatic system and then enter the circulation at the junction of the internal jugular and subclavian veins. In the lymph and blood, chylomicrons acquire apo CII, apo CIII, and apo E. In the capillary beds of adipose tissue and muscle, they bind to glycosylphosphatidylinositol-anchored HDL-binding protein 1 (GPIHBP1),42 and core triglyceride is hydrolyzed by the enzyme lipoprotein lipase (LPL) after activation by apo CII.43 The lipolytic products, free fatty acids (FFAs), can be taken up by fat cells and reincorporated into triglyceride or into muscle cells, where they can be used for energy. In addition to apo CII, other activators of LPL include apo AIV,44 apo AV,45 and lipase maturation factor 1 (LMF1),46 whereas apo CIII47 and angiopoietin-like (ANGPTL) proteins 3 and 448 inhibit LPL. Human mutations in LPL, APOC2, GPIHBP1, ANGPTL3, ANGPTL4, and APOA5 have all been implicated in chylomicronemia (Section 5).Download figureDownload PowerPointFigure 3. Overview of triglyceride metabolism. Apo A-V indicates apolipoprotein A-V; CMR, chylomicron remnant; FFAs, free fatty acids; HTGL, hepatic triglyceride lipase; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; LDL-R, low-density lipoprotein receptor; LPL, lipoprotein lipase; LRP, LDL receptor–related protein; VLDL, very low-density lipoprotein; and VLDL-R, very low-density lipoprotein receptor.The consequence of triglyceride hydrolysis in chylomicrons is a relatively CE- and apo E–enriched chylomicron remnant (CMR). Under physiological conditions, essentially all CMRs are removed by the liver by binding to the LDL receptor, the LDL receptor–related protein, hepatic triglyceride lipase (HTGL), and cell-surface proteoglycans.49–51 Apo AV facilitates hepatic clearance of CMRs through direct interaction with SorLA.52 HTGL also plays a role in remnant removal,49 and HTGL deficiency is associated with reduced RLP clearance. However, studies53 have indicated that HTGL is elevated in T2DM (Section 6) and may be an important contributor to low HDL-C levels in this disease.4.3. Transport of Endogenous Lipids on Apo B100–Containing Lipoproteins4.3.1. Very Low-Density LipoproteinsVLDL is assembled in the endoplasmic reticulum of hepatocytes. VLDL triglyceride derives from the combination of glycerol with fatty acids that have been taken up from plasma (either as albumin-bound fatty acids or as triglyceride–fatty acids in RLPs as they return to the liver) or newly synthesized in the liver. VLDL cholesterol is either synthesized in the liver from acetate or delivered to the liver by lipoproteins, mainly CMRs. Apo B100 and phospholipids form the surface of VLDL. Although apos CI, CII, CIII, and E are present on nascent VLDL particles as they are secreted from the hepatocyte, the majority of these molecules are probably added to VLDL after their entry into plasma. Regulation of the assembly and secretion of VLDL by the liver is complex; substrates, hormones, and neural signals all play a role. Studies in cultured liver cells51,54 indicate that a significant proportion of newly synthesized apo B100 may be degraded before secretion and that this degradation is inhibited when hepatic lipids are abundant.54Once in the plasma, VLDL triglyceride is hydrolyzed by LPL, generating smaller and denser VLDL and subsequently IDL. IDL particles are physiologically similar to CMRs, but unlike CMRs, not all are removed by the liver. IDL particles can also undergo further catabolism to become LDL. Some LPL activity appears necessary for normal functioning of the metabolic cascade from VLDL to IDL to LDL. It also appears that apo E, HTGL, and LDL receptors play important roles in this process. Apo B100 is essentially the sole protein on the surface of LDL, and the lifetime of LDL in plasma appears to be determined mainly by the availability of LDL receptors. Overall, ≈70% to 80% of LDL catabolism from plasma occurs via the LDL receptor pathway, whereas the remaining tissue uptake occurs by nonreceptor or alternative-receptor pathways.41,534.4. Metabolic Consequences of HypertriglyceridemiaHypertriglyceridemia that results from either increased production or decreased catabolism of TRL directly influences LDL and HDL composition and metabolism. For example, the hypertriglyceridemia of IR is a consequence of adipocyte lipolysis that results in FFA flux to the liver and increased VLDL secretion. Higher VLDL triglyceride output activates cholesteryl ester transfer protein, which results in triglyceride enrichment of LDL and HDL (Figure 4). The triglyceride content within these particles is hydrolyzed by HTGL, which results in small, dense LDL and HDL particles. Experimental studies suggest that hypertriglyceridemic HDL may be dysfunctional,55,56 that small, dense LDL particles may be more susceptible to oxidative modification,57,58 and that an increased number of atherogenic particles may adversely influence CVD risk59; however, no clinical outcome trials to date have determined whether normalization of particle composition or reduction of particle number optimizes CVD risk reduction beyond that achieved through LDL-C lowering.Download figureDownload PowerPointFigure 4. Metabolic consequences of hypertriglyceridemia. Apo A-I indicates apolipoprotein A-I; Apo B-100, apolipoprotein B-100; CE, cholesteryl ester; CETP, cholesteryl ester transfer protein; DGAT, diacylglycerol acyltransferase; FFA, free fatty acid; HDL, high-density lipoprotein; HTGL, hepatic triglyceride lipase; LDL, low-density lipoprotein; TG, triglyceride; and VLDL, very low-density lipoprotein.An additional complication in hypertriglyceridemic states is accurate quantification of atherogenic particles in the circulation. That is, a high concentration of circulating atherogenic particles is not reliably assessed simply by measurement of TC and/or LDL-C. Moreover, as triglyceride levels increase, the proportion of triglyceride/CE in VLDL increases (ie, >5:1), which results in an underestimation of LDL-C based on the Friedewald formula.60 Although this scientific statement will address other variables to consider in the hypertriglyceridemic patient (eg, apo B levels), it supports the quantification of non–HDL-C.60,614.5. Atherogenicity of TRLsIn human observational studies, TRLs have been associated with measures of coronary atherosclerosis.62 To provide a pathophysiological underpinning for observations that relate specific lipoprotein particles to human atherosclerosis or CVD, experimental models have been developed to investigate the impact of specific lipoprotein fractions on isolated vessel wall cells. For example, in macrophage-based studies, lipoprotein particles that increase sterol delivery or reduce sterol efflux or that promote an inflammatory response are considered atherogenic. In endothelial cell models, lipoprotein particles that promote inflammation, increase the expression of coagulation factors or leukocyte adhesion molecules, or impair responses that produce vasodilation are also considered atherogenic. These experimental systems have been used to understand the mechanisms by which modified LDL particles are associated with atherosclerosis in humans and in animals.When one evaluates the usefulness of these systems, it is important to recognize that triglyceride overload is not a classic pathological feature of human atherosclerotic lesions, because the end product, FFA, serves as an active energy source for myocytes or as an inactive fuel reserve in adipocytes. However, the by-product of TRLs (ie, RLPs) may lead to foam cell formation63 in a manner analogous to modified LDL. In addition, TRLs share a number of constituents with classic atherogenic LDL particles. They include the presence of apo B and CE. Although TRLs contain much less CE than LDL particles on a per particle basis, there are pathophysiological states (eg, poorly controlled diabetes mellitus [DM]) in which CEs can become enriched in this fraction. TRLs also possess unique constituents that may contribute to atherogenicity. For example, the action of LPL on the triglycerides contained in these particles releases fatty acid, which in microcapillary beds could be associated with pathophysiological responses in macrophages and endothelial cells. Apo CIII contained in TRLs has also been shown to promote proatherogenic responses in macrophages and endothelial cells. In the following paragraphs, we will consider selected aspects of the atherogenicity of TRL using in vitro macrophage and endothelial cell models and associated in vivo correlates.4.5.1. Remnant Lipoprotein ParticlesA number of experimental systems have demonstrated that TRLs can produce proatherogenic responses in isolated endothelial cells. RLPs are a by-product of TRL that can be isolated from the postprandial plasma of hypertriglyceridemic subjects; they are intestinal (ie, CMRs) or liver-derived (eg, VLDL remnants) TRLs that have undergone partial hydrolysis by LPL. Liu et al64 have shown that these particles can accelerate senescence and interfere with the function of endothelial progenitor cells; these cells play an important role in the organismal reparative response to in vivo vessel wall injury. Postprandial TRL (ppTG) has also been shown to increase the expression of proinflammatory genes (eg, interleukin-6, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and monocyte chemotactic protein-1),65 induce apoptosis,66 and accentuate the infla