Postprandial hypertriglyceridemia as a coronary risk factor.

Clinica Chimica Acta 431 (2014) 131–142

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Invited critical review

Postprandial hypertriglyceridemia as a coronary risk factor Jan Borén a,⁎, Niina Matikainen b,c, Martin Adiels a, Marja-Riitta Taskinen b a b c

Department of Molecular and Clinical Medicine/Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden HUCH Heart and Lung Centre, Research Programs Unit Diabetes and Obesity, Cardiovascular Research Group, Finland Department of Endocrinology, Helsinki University Central Hospital, Diabetes & Obesity, University of Helsinki, Helsinki, Finland

a r t i c l e

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Article history: Received 13 November 2013 Received in revised form 10 January 2014 Accepted 11 January 2014 Available online 6 February 2014 Keywords: Postprandial hypertriglyceridemia Cardiovascular risk factor Triglyceride-rich lipoproteins

a b s t r a c t Postprandial hypertriglyceridemia is now established as an important risk factor for cardiovascular disease (CVD). This metabolic abnormality is principally initiated by overproduction and/or decreased catabolism of triglyceride-rich lipoproteins (TRLs) and is a consequence of predisposing genetic variations and medical conditions such as obesity and insulin resistance. Accumulation of TRLs in the postprandial state promotes the retention of remnant particles in the artery wall. Because of their size, most remnant particles cannot cross the endothelium as efficiently as smaller low-density lipoprotein (LDL) particles. However, since each remnant particle contains approximately 40 times more cholesterol compared with LDL, elevated levels of remnants may lead to accelerated atherosclerosis and CVD. The recognition of postprandial hypertriglyceridemia in the clinical setting has been severely hampered by technical difficulties and the lack of established clinical protocols for investigating postprandial lipemia. In addition, there are currently no internationally agreed management guidelines for this type of dyslipidemia. Here we review the mechanism for and consequences of excessive postprandial hypertriglyceridemia, epidemiological evidence in support of high triglycerides and remnant particles as risk factors for CVD, the definition of hypertriglyceridemia, methods to measure postprandial hypertriglyceridemia and apolipoproteins and, finally, current and future treatment opportunities. © 2014 Elsevier B.V. All rights reserved.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . Chylomicrons and VLDL particles . . . . . . . . . . . . . . Uptake of dietary fat and formation of CMs . . . . . . . . . . Regulation of the secretion of apoB-containing lipoproteins . . Metabolism of TRLs in the plasma and hepatic uptake . . . . . 5.1. Intravascular lipolysis of TRLs . . . . . . . . . . . . 5.2. ApoCIII: a key regulator of TRL metabolism . . . . . . 5.3. Hepatic removal of remnant lipoproteins . . . . . . . Definition of hypertriglyceridemia . . . . . . . . . . . . . . Genetic variants causing postprandial lipemia . . . . . . . . Epidemiological and clinical evidence for high TG levels in CVD 8.1. Evidence for a link between fasting TG and CVD . . . . 8.2. Evidence for a link between non-fasting TG and CVD . . Epidemiological evidence for remnant particles in CVD . . . . Postprandial lipids in populations with CVD: case–control studies Assessment of postprandial TRL metabolism . . . . . . . . . 11.1. Measurement of non-fasting TG levels . . . . . . . . . 11.2. Calculated remnant cholesterol . . . . . . . . . . . . 11.3. Oral fat tolerance test . . . . . . . . . . . . . . . . 11.4. Alternative markers of postprandial lipemia . . . . . . 11.5. Measurement of apoB48 . . . . . . . . . . . . . . . Current and future therapeutic approaches . . . . . . . . . . 12.1. Management of hypertriglyceridemia . . . . . . . . .

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⁎ Corresponding author at: Wallenberg Laboratory, Sahlgrenska University Hospital, 41345 Gothenburg, Sweden. Tel.: +46 313422949. E-mail address: [email protected] (J. Borén). 0009-8981/$ – see front matter © 2014 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.cca.2014.01.015

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12.2. Management of postprandial lipemia 12.3. Potential future therapies . . . . . . 13. Concluding summary . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . .

J. Borén et al. / Clinica Chimica Acta 431 (2014) 131–142

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1. Introduction Despite a dramatic reduction in mortality from cardiovascular disease (CVD) in recent decades, CVD is still the major killer in the western world. In particular, individuals with obesity-associated disturbances in metabolism, such as insulin resistance and type 2 diabetes (T2D), remain at high risk of cardiovascular events [1]. The mechanisms behind this increased risk are not fully understood. Epidemiological studies have identified non-fasting (postprandial) triglyceride (TG) concentrations as a clinically significant risk factor for CVD [2–4]. TGs are carried in chylomicrons (CMs) and very low-density lipoproteins (VLDLs), which are synthesized in the intestine and liver, respectively. Lipolysis of these triglyceride-rich lipoproteins (TRLs) by lipoprotein lipase (LPL) results in the formation of smaller remnant particles that are TG depleted and enriched in cholesteryl esters [5]. For many years, CMs and CM remnants were thought to be the major culprits in postprandial hyperlipidemia [6,7]. However, the major increase in the postprandial lipoproteins after food intake occurs in the liver-derived VLDL remnant particles [8,9].

2. Chylomicrons and VLDL particles TRLs in the plasma consist of CMs carrying TG from the diet, liverderived VLDLs and their respective remnant particles. TRLs consist of a core of neutral lipids (mainly TG but also some cholesteryl esters) surrounded by a monolayer of phospholipids, free cholesterol and proteins. Each TRL particle contains one molecule of apolipoprotein B (apoB), one of the largest proteins in the mammalian cell and the ligand for the low-density lipoprotein (LDL) receptor [10,11]. ApoB exists in two forms, apoB100 and apoB48, which are coded by the same gene. ApoB48 corresponds to the amino-terminal 48% of apoB100 and is formed in the intestine through editing of apoB100 mRNA by an enzyme called apobec-1. Thus, apoB48 is present on CMs and CM remnants, and apoB100 on VLDL, intermediate-density lipoprotein (IDL) and LDL. Although about 80% of the increase in TGs after a fat-load meal comes from apoB48-containing lipoproteins [8], approximately 80% of the increase in particle number is accounted for by VLDL particles [12,13]. ApoB48- and apoB100-containing particles are cleared from the circulation by common pathways and therefore compete for clearance [14]. Increased secretion of VLDL from the liver is therefore an important predictor of postprandial accumulation of CMs and CM remnants [15].

3. Uptake of dietary fat and formation of CMs The human intestine is equipped to efficiently absorb dietary fat predominantly in the form of TGs. After eating a meal, TG is hydrolyzed by lipase to yield fatty acids (FAs) and monoacylglycerol, which are then absorbed into the enterocytes. Within the enterocyte, FAs can be: (1) used for synthesis of cholesteryl esters or phospholipids; (2) oxidized; (3) re-esterified to form TG for incorporation into CMs; or (4) stored as TGs in cytoplasmic lipid droplets. The multistep assembly of CMs within the enterocyte is not as well characterized as the assembly process of VLDL in hepatocytes, but it is presumed that these processes are similar and dependent on the microsomal triglyceride transfer protein (MTTP) for lipidation of apoB [16–21]. Over the past 10 years, two striking characteristics of enterocyte-TG processing have emerged:[19] (1) lipids secreted at the very onset of a meal are those that were consumed in an earlier meal, suggesting the

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presence of an enterocyte storage pool for TG; and (2) a cephalic phase release of CMs is linked to oral stimulation by food intake. The first phenomenon noted is a rise in blood TG concentrations within 10 to 30 min of the consumption of a fat-containing meal [22]. This early rise in TG is termed ‘the early peak’ to delineate it from the primary postprandial peak of blood TG that occurs 3 to 4 h after the start of a meal. The early peak occurs before the meal fat has been absorbed into the enterocytes [23], and is more likely to occur when the previous evening meal was high in fat [23,24]. Parks and coworkers have elegantly shown via utilization of stable isotopes that 10–12% of TGs consumed in the previous evening meal appear in new CMs, first appearing 15 to 20 min after the onset of morning food consumption [19]. This observation indicates that the time between a meal and formation of CMs from TG stored in the intra-enterocyte pool can extend to at least 16 h [24]. The second phenomenon is connected to the overall cephalic phase response [25–28]. The early meal-induced rise in CM-TG concentration can occur when fat is merely tasted and not consumed [29], and also when only glucose is consumed [30]. The existence of an oral taste sensor for lipids is intriguing and has led to the generation of hypotheses on a taste–gut–brain axis, which is currently an active area of investigation [31].

4. Regulation of the secretion of apoB-containing lipoproteins The secretion of TRLs has been extensively studied, but mainly in liver cells. It is today well known that the secretion of VLDL is reduced by insulin, and hepatic insulin resistance is linked to an oversecretion of VLDL [32–38]. Increased liver fat in humans is linked to overproduction of large TG-rich VLDL (VLDL1 particles) [34], which is not surprising given that VLDL formation is dependent on lipid availability. The most common form of liver steatosis is non-alcoholic fatty liver disease [39,40]. This is related to insulin resistance and T2D, and probably explains (at least partly) the dyslipidemia that is observed in subjects with insulin resistance and T2D [41–44]. The results from several groups have clarified at a molecular level that T2D drives VLDL secretion through multiple pathways [38,45]. T2D is characterized by selective insulin resistance: insulin fails to suppress lipolysis in the adipose tissue and FoxO1 in the liver [46], but is still able to activate mammalian target of rapamycin complex 1 (mTORC1) [47,48]. The disinhibition of FoxO1 leads to increased expression of microsomal triglyceride transfer protein (MTTP) and apoCIII, thereby promoting apoB secretion [38,49]. At the same time, the stimulation of mTORC1 in the liver leads to activation of sterol regulatory element binding protein 1c (SREBP-1c) and increased lipogenesis, as well as suppression of sortilin [50]. Because sortilin increases apoB degradation, the suppression of sortilin further promotes apoB secretion [51,52]. Finally, the increase in lipogenesis, coupled with the increased flux of FAs to the liver, expands the cytoplasmic pool of TGs available to lipidate apoB [53], driving the formation of VLDL1 particles. The overall result is increased secretion of apoB in the form of VLDL1 particles in T2D. Thus, the increased level of plasma TGs in T2D is achieved mainly by an increased VLDL1-TG pool that is the effect of an increased number of particles rather than increased particle size [32,36]. The intestinal hormone glucagon-like peptide 1 (GLP-1) is important in the regulation of postprandial glucose levels [20,54–56], and emerging data indicate that GLP-1 also modulates lipid metabolism. GLP-1 has been shown to play an important role in the assembly and secretion of CMs


[57]. Pharmacological augmentation of GLP-1 receptor signaling by GLP-1 agonists or dipeptidyl peptidase 4 (DPP-4) inhibition reduces intestinal lipoprotein secretion in experimental studies [58], suggesting that the GLP-1 receptor is essential for the action of GLP-1 on CM metabolism. Furthermore, a recent study in healthy humans showed that the GLP-1 receptor agonist exenatide can suppress intestinal lipoprotein particle production [59]. GLP-2 is produced by posttranslational proteolytic cleavage of proglucagon from intestinal L-cells [60]. In addition to its intestinotropic effects, GLP-2 has been shown to modulate lipid metabolism. In hamsters, administration of human GLP-2 augmented postprandial lipids by increasing CM secretion in vivo and TRL-apoB48 secretion ex vivo in cultured jejunal fragments [61]. This increased apoB48 secretion was not accompanied by enhanced apoB48 synthesis or increased MTTP mRNA expression. Rather, it was attributed to increased FA uptake by posttranslational modification of the FA transport protein CD36. The direct role of GLP-2 on postprandial lipoprotein metabolism in the intestine and liver, independent of its effects on glucagon and gastric acid secretion, remains to be determined. 5. Metabolism of TRLs in the plasma and hepatic uptake 5.1. Intravascular lipolysis of TRLs After secretion of TRLs from the intestine and liver, TGs are removed from the lipoproteins by LPL allowing the delivery of free FAs to muscle and adipose tissue. As the TGs are removed and density increases [62], CMs become CM remnants, and large TG-rich VLDL1 particles become smaller VLDL2 and subsequently IDL. IDL can be further hydrolyzed by hepatic lipase (HL) to LDL, which is catabolized mainly by hepatic uptake of LDL through LDL receptors [63]. Since the TRLs contain a substantial amount of cholesteryl esters, the smaller remnant particles formed by TG hydrolysis are enriched in cholesteryl esters [5]. 5.2. ApoCIII: a key regulator of TRL metabolism ApoCIII inhibits LPL activity and is therefore closely correlated with increased concentrations of serum and total VLDL-TG [64]. Epidemiological studies have demonstrated that apoCIII and LDL-apoCIII independently predict coronary heart disease (CHD) [65,66], and that lifelong deficiency of apoCIII has a cardioprotective effect [67]. The gene expression of apoCIII is decreased by insulin [68,69], peroxisome proliferator-activated receptor-α (PPARα) [70], and farnesoid X receptor (FXR) [71]. In contrast, Caron et al. recently showed that glucose stimulates expression of apoCIII via hepatic nuclear factor-4 (HNF4) and carbohydrate-responsive element binding protein (ChREBP) [72]. Thus, in states of insulin resistance, the inhibitory role of insulin on apoCIII expression may be lost and higher glucose levels would further stimulate apoCIII expression. Increased plasma free FA delivery to the liver would exacerbate this problem, resulting in defective LPL-mediated lipolysis of TRLs and reduced remnant lipoprotein clearance. Thus, dysregulated apoCIII synthesis and secretion could play a major role in the genesis of the diabetic, insulin-resistant dyslipidemia. In addition, accumulation of apoCIII-enriched apoB-containing lipoproteins might further aggravate the CVD risk [73,74]. Paradoxically, despite an increased plasma concentration of apoCIII in subjects with T2D, the concentration of VLDL-apoCIII does not increase in concert with core lipids [75]. Hiukka et al. described a relative deficiency of apoCIII in all TRL species in subjects with T2D [76]. Thus, T2D does not appear to be associated with high concentrations of apoCIII-containing TRLs, despite increased LDL-apoCIII in T2D subjects [74]. 5.3. Hepatic removal of remnant lipoproteins The plasma level of TG depends not only on the synthesis and lipolysis of the TRLs, but also on the removal of the remnant particles.

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The CM remnants are normally cleared by the liver through binding to syndecan-1 heparan sulfate proteoglycans (HSPGs) and the LDL receptor [77–82]. The importance of the HSPG pathway has been questioned, but compelling evidence now exists proving that dysfunction of the HSPG syndecan-1 in animal models disrupts defective hepatic remnant clearance [77]. Furthermore, Williams and coworkers have shown that accelerated degradation of HSPG following hepatic induction of a heparan sulfate 6-O-endosulfatase (SULF2) in T2D mice suppresses uptake of remnant lipoproteins [83,84]. The relevance of SULF2 in humans has recently been demonstrated in studies showing that the genetic variation rs2281279 in SULF2 associates with postprandial clearance of TG-rich remnant particles and TG levels in healthy subjects [85,86]. In subjects with T2D, hepatic uptake of VLDL, IDL and LDL is also decreased, resulting in increased plasma residence time of these lipoproteins [87–89]. Thus, individuals with insulin resistance exhibit an impaired lipid tolerance with a severely delayed postprandial lipemia due to suppressed removal of TRL remnants. Although CMs and CM remnants were for many years thought to be the major culprits in postprandial hyperlipidemia [6], the VLDL remnant particles account for the major increase in number of postprandial lipoproteins after food intake [8]. Kinetic studies have demonstrated that CM is the preferred substrate over VLDL1 for LPL-mediated clearance [15]. This finding is in line with earlier studies showing that infusion of CM-like TG emulsions leads to accumulation of apoB100 particles [90]. Furthermore, modest induction of LPL activity induces lipolysis of CM but not of VLDL, whereas more pronounced induction of LPL induces hydrolysis of both CM and VLDL [91]. 6. Definition of hypertriglyceridemia The tradition has been to measure TG after an overnight fast and guidelines have defined a desirable ‘normal’ level of fasting serum TG to be b 1.7 mmol/l (b150 mg/dL) [1,92]. The classification of elevated serum TG is generally based on fasting values, which vary in different guidelines [93]. Fasting TG cut-off values for diagnosis of hypertriglyceridemia have varied from 1.7 to 2.3 mmol/l (from 150 mg/dL to 199 mg/dL). Recently, a re-definition of hypertriglyceridemic states has been proposed to simplify the diagnosis of hypertriglyceridemia (Box 1). 7. Genetic variants causing postprandial lipemia As the metabolic machinery of postprandial TRL species comprises several steps at the intestine level, in the circulation and in the liver the genetic control of these processes has been associated with several variants in multiple genes modifying different steps. The current approach has been to look at identified polymorphisms of specific candidate genes regulating the metabolic steps. The small number of subjects and variability of study designs have further hampered the conclusions reflected in the conflicting results observed between different genetic association studies. The majority of reports have focused on genes regulating lipid absorption, apolipoproteins, and clearance pathways. These genes include NPC1L1, FABP2, FATP, CD36, MTTP, APOAI, APOA4, APOA5, APOE, APO5, APOC1 and APOCIII, CETP, ANGPLT4, PLIN, LPL, HL, GPIHBP1, LDLR, SRB1, ABCA1 and TCF7L2. The Box 1 Definition of hypertriglyceridemia. Adapted from reference [183]. Definition

Value of triglycerides

Normal Mild-to-moderate hypertriglyceridemia Severe hypertriglyceridemia

b1.7 mmol/L (150/dL) 1.7–10.0 mmol/L (150–885 mg/dL) N10.0 mmol/L (885 mg/dL)

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results has been recently reviewed [94–96] highlighting the complex genetic basis of postprandial lipemia. Recently Mendelian randomization approach was used to examine the genetic background of non-fasting remnant cholesterol [97]. Genetic variants modulating non-fasting remnant cholesterol and the risk for ischemic heart disease included TRIB1, GCKR and APOA5. 8. Epidemiological and clinical evidence for high TG levels in CVD The significance of fasting and postprandial TGs in CVD has been debated since Zilversmit's proposal in 1979 that CMs and their remnants are atherogenic [98]. Today it is well accepted that, because of their size, most remnant particles cannot cross the endothelium as efficiently as smaller LDL particles [99]. However, since remnant particles not only contain TGs but also approximately 40 times higher levels of cholesteryl esters per particle compared with LDL [99], elevated levels of remnants may lead to accelerated atherosclerosis and CVD (Fig. 1). In the 1970s, the significance of an elevated TG concentration as a risk marker was largely neglected. The skepticism was based on inconsistent epidemiologic associations between fasting TG levels and CVD and also because subjects with familial chylomicromia (type V hyperlipidemia) and extremely high TG levels (up to 25–300 mmol/L) do not demonstrate enhanced vascular disease [100] (although opposite findings in populations with very high TGs also exist [101,102]). In recent years, the recognition of biological pathways, Mendelian randomization studies and large epidemiologic findings support strong links between remnant cholesterol and atherosclerosis [1](and Box 2). Largely because of technical challenges to accurately measure remnant particle concentrations, the controversy still exists as to whether fasting or postprandial TG measurements reflect the atherogenic potential of diverse TRL metabolic pathways and if measurement of serum TG represents an independent risk factor for CVD. Data accumulated from epidemiological studies to date demonstrate that: (1) TG levels are increased among populations with established CVD or with multiple risk factors predisposing to CVD; and (2) follow-up of subjects in prospective population-based studies link postprandial (and, less robustly, fasting) TG and remnant cholesterol to incidence of CVD events or death [1].

Many patients with CVD remain at high risk of events even when the LDL-cholesterol goal has been achieved with lipid-lowering therapy [1,103]. Studies attempting to explain the residual risk have mostly focused on fasting TG measures. The EUROASPIRE III demonstrated that more than a third of CVD patients have elevated TG levels despite many of them receiving antihyperlipidemic treatment [104]. A study from the Swedish diabetes register reported a similar proportion of hypertriglyceridemic subjects among subjects with T2D [105]. Furthermore, the Prospective Cardiovascular Münster (PROCAM) study found that hypertriglyceridemia is twice as prevalent in myocardial infarction survivors compared with control subjects [106]. Together, these data indicate that high TG levels cluster in populations with established CVD despite lipid-lowering therapy. 8.1. Evidence for a link between fasting TG and CVD Several meta-analyses have evaluated the association between fasting TG and CVD, mostly in western populations. Fasting TG was modestly but independently associated with CVD in a meta-analysis of 17 prospective studies with 2900 CHD endpoints [107]. This study demonstrated that 1 mmol/L increase in fasting TG is associated with a 14% increase in the risk of CVD [107]. Sarwar et al. [108] reported data from two nested case–control comparisons from population-based cohorts [the Reykjavik and the European Prospective Investigation of Cancer (EPIC)-Norfolk studies] and included a total of 3582 incident cases of fatal and non-fatal CHD and 6175 controls. The study gave important insights into the long-term stability of log TG values (within-person correlation coefficients of 0.64 [95% confidence interval (CI), 0.60–0.68] over 4 years and 0.63 [95% CI, 0.57–0.70] over 12 years), with variations that were similar to those reported for blood pressure and total serum cholesterol. After adjustment for baseline values of several established risk factors, the odds ratio (OR) for CHD was 1.76 (95% CI, 1.39–2.21) in the Reykjavik study and 1.57 (95% CI, 1.10–2.24) in the EPIC-Norfolk study between individuals in the top and bottom TG tertiles. These results were in line with those reported in an accompanying meta-analysis involving a total of 10,158 incident CHD cases from 262,525 participants from 29 studies (adjusted OR, 1.72; 95% CI,

Fig. 1. Mechanisms for how TRL induce CVD. Atherogenesis is initiated by subendothelial retention of lipoproteins [184,185]. Large VLDL and CM are too large to enter the arterial wall, but smaller remnants and LDL penetrate the arterial intima and bind to artery wall proteoglycans. This explains why patients who are homozygous for rare deleterious mutations in the LPL gene, causing chylomicronemia with extremely high levels of large chylomicrons and VLDLs, have an increased risk of pancreatitis, but not an increased risk of CVD [100]. Remnants may also be involved in the development of CVD by other pathways than by accumulation of cholesterol in the arterial wall. For example, by inducing endothelial dysfunction, such as impaired vasodilation and enhanced inflammatory response (see review [186]). The accumulation of TRLs generates cholesterol-ester enriched small dense HDL and LDL. The HDL is removed from the circulation leading to low HDL cholesterol. The cholesterol-enriched LDL display increased binding affinity to artery wall proteoglycans [187].


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Box 2 Epidemiologic studies reporting non-fasting triglycerides (TG) or remnant lipoproteins and the risk for cardiovascular morbidity and mortality. Study [ref.]

Population

Follow-up

Norwegian counties study [111]

43,641 men and 42, 600 women free of CVD

Prospective, 27 years

Copenhagen Random population sample City Heart of 6391 men and 7581 study women [2,112]

Copenhagen Random population sample City Heart of 6372 men and 7579 study women [113]

The Women's Health study [3]

26,509 initially healthy US women of which 6391 had non-fasting samples

The Framingham study [117] Kugiyama et al. [118]

1567 women offspring of the original Framingham cohort: 83 with and 1484 without CVD 147 consecutive patients with CAD

The Honolulu Heart study [119]

1156 Japanese-American men

Main outcomes

HRs (95%CI) per 1 mmol/L increase in non-fasting TGs for all causes, CVD, IHD, and stroke mortality: Women: 1.16 (1.13–1.20), 1.20 (1.14–1.27), 1.26 (1.19–1.34) and 1.09 (0.96–1.23) Men: 1.03 (1.01–1.04), 1.03 (1.00–1.05), 1.03 (1.00–1.06) and 0.99 (0.92–1.07). Prospective, HRs (95%CI) for total mortality 31 years by non-fasting TGs: (TG b 1 mmol/L: HR 1) TG 1.0–1.99 mmol/L: 1.1 (95%CI: 1.0–1.2) in women and 1.1 (95%CI: 1.1–1.2) in men TG 2.0–2.99 mmol/L: 1.3 (95%CI: 1.2–1.4) in women and 1.2 (95%CI: 1.1–1.4) in men TG 3.0–3.99 mmol/L: 1.4 (95%CI: 1.2–1.7) in women and 1.3 (95%CI: 1.1–1.4) in men TG 4.0–4.99 mmol/L: 1.4 (95%CI: 1.1–1.9) in women and 1.4 (95%CI: 1.2–1.6) in men TG N 5 mmol/L: 2.0 (95%CI: 1.5–2.7) in women and 1.5 (95%CI: 1.2–1.7) in men Prospective, HRs (95%CI) for ischemic stroke 33 years by non-fasting TGs: (TG b 1 mmol/L: HR 1) TG 1.0–1.99 mmol/L: 1.2 (95%CI: 0.9–1.7) in women and 1.2 (95%CI: 0.8–1.7) in men TG N 5 mmol/L: 3.9 (95%CI: 1.3–11.1) in women and 2.3 (95%CI: 1.2–4.3) in men Prospective, HR for CVD event by non-fasting 11 years TG: 2nd tertile: 1.44 (95% CI 0.90–2.29) 3rd tertile: 1.98 (95% CI 1.21–3.25) Cross-sectional RLP-chol + 15.6%; P b 0.0001 and RLP-TG +27.0%; P b 0.0002 in women with prevalent CVD Prospective OR for developing coronary follow-up until event: coronary event or 2nd tertile of remnant levels 2.43 36 months (95%CI: 1.1–5.8) 3rd tertile of remnant levels 6.38 (95%CI:2.3–17.6) Prospective, RLP-chol (P = 0.0022) and RLP17 years TG (P = 0.0045) predicted CHD risk independent of non-lipid risk factors

Remarks Adjustment for major cardiovascular risk factors attenuated the effect

The best predictor for MI in women was non-fasting TG and in men non-fasting cholesterol

The remnant cholesterol increased stepwise as a function of non-fasting TG and cholesterol in cross-sectional analysis of 53,629 subjects (see also Fig. 1.)

TG measured 2 to 4 h postprandially had the strongest association with CVD events (fully adjusted HR [95% CI] for highest vs. lowest tertiles of levels, 4.48 [1.98–10.15] [P b .001 for trend]) Adjusted RLP-chol was significantly associated with prevalent CVD in women in logistic regression analysis Remnant levels were independent predictors of future coronary event in multivariate model

RLP-chol and RLP-TG were only significant lipid predictors of CHD in models with total, HDL and LDL cholesterols as additional covariates

CI, confidence interval; CHD, coronary heart disease; CVD, cardiovascular disease; HR, hazard ratio; MI, myocardial infarction; OR, odds ratio; RLP, remnant-like particles.

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1.56–1.90) [108]. The Emerging Risk Factors Collaboration meta-analysis [109] of 68 prospective long-term studies with more than 302,000 people and 2.79 million years of follow-up demonstrated comparable hazard ratios (HRs) but could not confirm an independent role of TG as a CVD risk factor. This study demonstrated that the HR for CHD with triglyceride was 1.37 (95% CI, 1.31–1.42) after adjustment for non-lipid risk factors, but that it was reduced to 0.99 (95% CI, 0.94–1.05) after further adjustment for high-density lipoprotein (HDL)-cholesterol and nonHDL-cholesterol. Adjusted HRs in subgroups of fasted [1.02 (95% CI 0.95–1.09)] and non-fasted [0.92 (95% CI 0.82–1.03)] subjects did not differ [109]. Observations in Asian Pacific populations are in line with those in western populations [110]. Interestingly, decreased TG values during follow-up were associated with lowered CVD risk in young men. These studies together indicate moderate but highly significant associations between fasting TG values and CHD risk. 8.2. Evidence for a link between non-fasting TG and CVD Prospective epidemiologic studies on non-fasting TG levels in response to normal food intake include three large-scale studies, the Copenhagen City Heart study [2], Women's Health study [3] and the Norwegian counties study [111], all of which found highly significant associations between HRs for cardiovascular events with increases in non-fasting TG. Although the variable timing of lipid sampling and nutrient exposure within and between these studies may attenuate the effect size, these studies were able to provide quantitative information about exposure to postprandial remnant particles and the risk for CVD. The Copenhagen City Heart study [2], a prospective study with 26–31 years' follow-up of 13,000 untreated individuals from the Danish general population, found that non-fasting TG levels above 5 mmol/L (compared with values under 1 mmol/L in age-adjusted analyses) were associated with a 17-fold (women) and five-fold (men) increased risk of myocardial infarction and a four-fold (women) and two-fold (men) increased risk of early death. Furthermore, the findings in the 31 year follow-up of this study were in line with previous data with non-fasting cholesterol and TG being similarly associated with increased risk of myocardial infarction and ischemic heart disease [112], and non-fasting TG also with ischemic stroke [113]. Unexpectedly, elevated non-fasting TG, but not non-fasting cholesterol, was associated with total mortality [112]. In the Women's Health study [3], comprising 26,509 initially healthy US women and 6391 non-fasting samples, the follow-up demonstrated

Lipoprotein cholesterol,mmol/L

7.0

9. Epidemiological evidence for remnant particles in CVD The estimate of circulating atherogenic particles is improved by measuring non-fasting remnant lipoprotein cholesterol in addition to TG. The strongest evidence and validation of non-fasting lipid measurements are from the Copenhagen City Heart study [2,114]. After 31 years of follow-up, non-fasting cholesterol remained the best predictor of myocardial infarction in men [112]. Remnant-like particles (RLP) are isolated from serum samples by the immune adsorption method with the monoclonal antibodies to apoAI and apoB [115], and measurement of fasting RLP-cholesterol may be used as a surrogate to estimate circulating remnant particles [116]. In a subset of 1567 women from the Framingham Heart study, RLPcholesterol was independently associated with prevalent coronary artery disease (CAD) [117]. Furthermore, high levels of RLPcholesterol were predictive for future events independent of other risk factors in a Japanese population with CAD [118]. The Honolulu Heart study [119], with 1156 Japanese-American men and 17 years of follow-up, showed that TG, RLP-TG and RLP-cholesterol predicted CHD independently of other lipid risk factors. In this study, log fasting TG correlated strongly with both RLP-TG and RLPcholesterol (r = 0.93 and r = 0.88, respectively) suggesting that RLP measurements do not add to the prognostic value of fasting TG [119]. An association between remnant particles and ischemic stroke has been analyzed only indirectly in the Copenhagen City Heart study. A stepwise increase in LDL-cholesterol only above levels of 9 mmol/L predicted ischemic stroke in men but not women. Instead, the adjusted non-fasting TG levels correlated with ischemic stroke and remnant cholesterol concentrations, suggesting that TG as a marker for remnant cholesterol should be the treatment target in these patients [113]. 10. Postprandial lipids in populations with CVD: case–control studies

6.0 5.0 4.0 3.0 2.0 1.0 0.0

TG, mmol/L < 1 Number 14906

a strong independent relationship between non-fasting TG levels and cardiovascular events. In fully adjusted models, the HRs for increasing tertiles of non-fasting TG levels were 1.44 (95% CI 0.90–2.29) and 1.98 (95% CI 1.21–3.25). In contrast, fasting TG levels showed little independent relationship. Finally, in the Norwegian counties study [111], an association between non-fasting TG and risk of CVD death was observed in women but not men after controlling for risk factors other than HDL-cholesterol. The Copenhagen City Heart and the Norwegian counties studies both found non-fasting TG to predict future CVD better in women than men, which is in line with the robust data from the Women's Health study. Together, these studies underline the epidemiological link between non-fasting TG and both events and death due to vascular causes.

1–1.99

2–2.99

3–3.99

4–4.99

5–5.99

28,041

10,722

3,826

1,418

982

Fig. 2. Lipoprotein cholesterol as a function of increasing levels of non-fasting triglycerides. Red = remnant cholesterol, blue = LDL-cholesterol and green = HDL-cholesterol. Adapted from reference [97].

Case–control studies comparing the magnitude and time-frame of postprandial lipemia in CHD patients are few and limited in number of subjects. These studies used highly variable fat loads, sampling times and methodology for analysis, and are therefore not directly comparable. Data accumulated from rather small studies on CVD clearly demonstrate abnormal postprandial TG and remnant particle metabolism in both subjects with vascular disease and their relatives (reviewed in [94]). The main findings of these studies are that CAD is associated with delayed TG and retinyl-ester clearance (a sign of impaired CM remnant metabolism) [120]. More specifically, late TG responses 6 and 8 h after a meal are 68% accurate in predicting the presence or absence of CAD by logistic regression [121]. However, in subjects with T2D, the findings are more conflicting (reviewed in [122]). More recently, fasting apoB48 measurements have been reported to correlate with prevalence of CAD [123] and to predict both new-onset and chronic CAD [124].


B 15

10

5

0 0

5

10

15

Plasma ApoB48 (Elisa) (mg/dl)

Total lipoprotein ApoB48 (SDS PAGE) (mg/dl*h)

Total lipoprotein ApoB48 (SDS PAGE) (mg/dl)

A

137

150

100

50

0 0

50

100

150

Plasma ApoB48 (Elisa) (mg/dl*h)

Fig. 3. Comparison of total apoB48 in plasma measured by ELISA, and quantification of apoB48 in the TRL fractions measured by SDS-PAGE (sum of IDL, VLDL2, VLDL1 and chylomicron fractions). 10 subjects were studied at 6 time points (0, 2, 3, 4, 6 and 8 h) after a standardized mixed meal. Panel A shows the correlation between the data point at 4 h for each individual (r = 0.59, P b 0.01). Panel B shows the correlation between the calculated area under the curve (AUC) (r = 0.88, P b 0.001) (unpublished data).

11. Assessment of postprandial TRL metabolism Emerging evidence in support of the power of non-fasting TG levels to predict CVD risk and postprandial dysmetabolism identifies an urgent need to define accurate and standardized methodology to assess different components of TRLs in the postprandial state. The heterogeneity of TRLs with respect to size and apolipoprotein composition represents a challenge. In addition, there is a need to set clinical reference standards for each component, and the methodology to measure these markers should be applicable to large-scale clinical intervention trials. 11.1. Measurement of non-fasting TG levels Recent indications suggest that non-fasting TG concentration is a potentially good surrogate marker that reflects the burden of postprandial dysmetabolism [114,125]. However, the use of non-fasting TG values in clinical practice has been hampered by a lack of standardization of non-fasting TG measures (with respect to the time since last meal) and population-based reference values. It should be recognized that intra-individual variation of plasma TG values is between 15 and 30% [126] and seems to increase during the day [127]. Recent data have demonstrated that changes of non-fasting TG values taken at random time-points after normal food intake seem to be modest with a mean maximum increase of 0.3 mmol/L [125]. This contrasts with the observed increase of 1–2 mmol/L after a fat tolerance test [128,129]. An expert panel statement has proposed that a non-fasting TG concentration of b2.0 mmol/(180 mg/dL) is considered to be desirable [129]. If non-fasting TG levels exceed 2.2 mmol/L (200 mg/dL), further testing by repeat measurements of fasting TG or a fat tolerance test is recommended [92,129]. 11.2. Calculated remnant cholesterol Recently, the calculated remnant cholesterol values in non-fasting state have been introduced as a surrogate market of postprandial TRL load. This parameter comprises all TRL particles, including not only VLDL and CMs but also their remnants [130]. The equation for the calculation is: remnant cholesterol = total cholesterol − [LDL-cholesterol and HDL-cholesterol]. LDL-cholesterol is recommended to be measured using a direct assay but can also be estimated using the Friedewald equation. In a study of 73,513 subjects from Copenhagen, remnant cholesterol values correlated strongly with plasma TG (Fig. 2). Remnant cholesterol values associated negatively with nonfasting HDL-cholesterol but the strength of the correlation with LDLcholesterol was less robust as remnant cholesterol showed more variability than respective LDL-cholesterol values [97]. A 1 mmol/l (39 mg/dL) increase in non-fasting remnant cholesterol is associated with a 2.8-fold increased risk of ischemic heart disease [97]. Thus,

calculated remnant cholesterol emerges as a useful parameter for CVD risk prediction as its assessment is easy in clinical practice and allows analyses of many samples in large clinical trials. 11.3. Oral fat tolerance test The oral fat tolerance test (OFTT) has been used to follow the dynamics of postprandial lipoprotein metabolism in parallel with the use of the oral glucose tolerance (OGTT) test to evaluate glucose tolerance. The major determinants of the postprandial TG response to a test meal are the ambient fasting concentration of serum TG and the fat content and quality of the meal. However, the composition of the fat-rich test meal has been highly variable, from a mixed meal mimicking a rich breakfast to liquid cream shakes, making it difficult to compare the different studies. Based on a systematic meta-analysis of 119 studies [131], an OFTT meal consisting of 75 g fat is recommended to be served after an 8 hour fast. In normal subjects, postprandial TG values increase for up to 3 or 4 h after a meal and remain elevated for up to 6 or 8 h. The response is exaggerated and delayed in subjects with various metabolic disorders or genetic variants causing hypertriglyceridemia. The TG response to an OFTT is commonly analyzed from sequential blood samples (taken every 1 or 2 h for up to 6 or 8 h) as the area under the curve (AUC) or incremental AUC (iAUC) (i.e. ignoring the area beneath the fasting concentration). The fasting TG measurement is represented by the lowest TG value in a setting of regular daily meals and snacks. In a normal population, a strong correlation exists between the fasting and postprandial serum TG response. The lack of a standardized meal and sampling times has hampered the assessment of the postprandial TG response and no standard reference ranges exist for either TG-AUC or TG-iAUC values. Thus, no consensus exists on the definition and assessment of postprandial lipemia in contrast to the widely used OGTT to diagnose glucose tolerance. However, data from the meta-analysis indicates that a single TG measurement 4 h after an OFTT can be used for assessment of postprandial lipemia, and that a TG concentration b2.5 mmol/L (220 mg/dL) can be considered a desirable postprandial TG value [129]. 11.4. Alternative markers of postprandial lipemia Two methods to quantitate RLP-cholesterol and RLP-TG are available [132]. The first assay is based on immune-specific separation of particles containing apoB100 and apoA-I using antibodies coupled to Sepharose4B [115,133]. All apoB48-containing particles and partly lipolyzed apoB100-containing VLDL remnants are recovered in the RLP fraction, and both cholesterol and TG content are measured [134]. Both RLPcholesterol and RLP-TG have been shown to increase after an OFFT. Interestingly, VLDL remnants rather than CM remnants are the major

138


contributors to RLP-TG [135]. Although RLP-cholesterol has been reported to predict cardiovascular events in patients with CAD, this assay has not been used to any great extent in clinical practice [136]. The second assay system uses a specific detergent to modify CM and VLDL remnants to allow direct measurements of cholesterol content in these particles [137,138]. However, the available data based on this specific assay are currently limited [139]. 11.5. Measurement of apoB48 The measurement of apoB48 reflects the number of CM particles as each CM carries a single molecule of apoB48 [140]. Thus, apoB48 is an exclusive marker to reflect the dynamics of CMs and their remnants. The major problem in the quantification of apoB48 is that its concentration in fasting plasma is very low compared with apoB100. As expected, plasma apoB48 concentrations increase in parallel with those of plasma TG following an OFTT [141]. The most common method to quantitate apoB involves sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) combined with Coomassie Brilliant Blue to stain the apoB48 and apoB100 bands [142]. This method enables measurement of apoB48 in different TRL fractions [Svedberg flotation rate (Sf) N400, Sf 60–400 and Sf 20–60] [143]. The sensitivity can be improved by immunoblotting with monoclonal and polyclonal antibodies to apoB48 [144]. However, the method is impractical to measure apoB48 in large population samples because of the time-consuming procedure of gel casting combined with different techniques for gel scanning that result in major variability between laboratories. Several enzyme-linked immunosorbent assays (ELISAs) have been introduced that allow the measurement of apoB48 in both fasting and postprandial samples [145,146]. However, the low concentration of apoB48 (about 20% of the total apoB100) hampers the measurements of apoB48 in different TRL subspecies [147]. The lack of internationally recognized standardized assays and population-based reference ranges has so far prevented the utilization of apoB48 measurements in clinical practice and randomized trials. However, the development of ELISAs with increased sensitivity and accuracy indicates their potential for use in large clinical cohorts. We recently used an ELISA to measure plasma total apoB48 in response to a standardized mixed meal and showed that the plasma values correlated well with apoB48 in the TRL fractions measured by SDS-PAGE (Fig. 3) (Matikainen et al. Unpublished results). 12. Current and future therapeutic approaches 12.1. Management of hypertriglyceridemia Current guidelines acknowledge elevated fasting and postprandial TG levels as important risk factors for CVD [1,148]. It is also well established that the risk of pancreatitis is clinically significant if plasma TG values exceed 10 mmol/L, and that subjects with such high TG levels need immediate pharmacotherapy in addition to intense dietary changes and restriction of calories and fat content in the diet. Data from randomized clinical trials on the clinical benefits of lowering TG are much less robust than for the benefits of lowering LDL-cholesterol with statins [148]. Importantly, the lack of high-grade evidence for benefits of TG-lowering drugs is reflected in the lack of specific target goals for both fasting and postprandial lipid values. Consequently, the control of secondary factors and lifestyle modification are considered to be the first-line approach of the clinical management of both fasting hypertriglyceridemia and postprandial lipemia. Appropriate dietary changes limiting fat content, caloric restriction resulting in weight loss, restriction of alcohol intake and increased exercise are fundamental for management of hypertriglyceridemia [1,148–151]. There are multiple examples of beneficial effects of lifestyle modifications on postprandial dysmetabolism, but the data are based on relatively small case–control studies [149–151]. As statin

treatment is the well-established therapy to reduce CVD risk and outcomes, elevated LDL-cholesterol is also the primary target for lipidlowering therapy in subjects with hypertriglyceridemia. Consequently, intensification of statin therapy is recommended as the first pharmacological step to reduce elevated TG levels in individuals with high or very high CVD risk based on global risk assessment, particularly in subjects with the metabolic syndrome and diabetes [148,152]. Overall, statin therapy decreases TG levels modestly but reductions of up to 30% may be seen depending on baseline TG level and the dose of statin [153]. Fibrates, niacin and 3-omega fatty acids have been commonly used to reduce plasma TG, particularly in subjects with high residual risk on statin therapy [1,149,150]. The clinical utility of niacin has been questioned following results from both the AIM-HIGH [154] and the HPS2-THRIVE [155] studies, and the European Medicines Agency (EMA) recently suspended niacin/laropiprant products in Europe [152,156]. Likewise, data from randomized clinical trials of 3-omega fatty acids have not confirmed clinical benefits on CVD outcomes [157,158]. Thus, fibrates remain the only available option as add-on therapy to statins to reduce the residual risk, and evidence in support of these drugs is from subgroup analyses of the ACCORD [159] and FIELD [160] trials as well as meta-analyses [161]. 12.2. Management of postprandial lipemia Current guidelines do not stipulate the atherogenic lipid profile in the postprandial state as a target for therapy nor do they give any target values for the parameters of postprandial lipemia. This is because randomized clinical trials of lipid-lowering therapy have not specified any of the biomarkers for postprandial lipemia as an endpoint. The available data from lipid-lowering studies are from small and shortterm case–control studies and do not provide high-grade evidence suitable for guidelines, although the results may be useful for treating individual patients. Fibrate studies have given consistent results reporting significant lowering of postprandial TG levels in response to a standardized fat challenge [129,151]. Furthermore, fenofibrate also reduces apoB48 and biomarkers for remnants [162]. Recently, the lipid response was assessed in a pre-specified subgroup (n = 139) of the ACCORD study [163]. The repeat measurement of biomarkers was performed after at least four months on fenofibrate or placebo added to the statin therapy. Fenofibrate therapy significantly reduced both the responses of plasma TG and apoB48 measured as the iAUC. Available data indicate that statins also reduce postprandial TG values [129], but the effect seems to be variable depending on the dose and the efficacy of the statin. Recent data suggest that ezetimibe, which exerts its effect on cholesterol lowering by inhibition of cholesterol absorption, also reduces postprandial lipemia [164–166]. Interestingly, ezetimibe has been reported to reduce apoB48 secretion in humans, suggesting a direct effect on TRL metabolism in enterocytes [167]. Although fenofibrate seems to be the best option to add on to statin therapy for reduction of postprandial lipemia, there is an urgent need for large-scale intervention studies specifying biomarkers of postprandial lipemia as a therapeutic target and assessing the benefits on cardiovascular endpoints. 12.3. Potential future therapies Emerging evidence suggests that incretin-based therapies may not only improve glucose metabolism but may also influence postprandial lipid metabolism. GLP-1 and -2, which are secreted after meals and modulate insulin secretion [168,169], have both been reported to participate in the regulation of intestinal CM secretion [170]. Pharmacological augmentation of GLP-1 receptor signaling by GLP-1 agonists or DPP-4 inhibition reduces intestinal lipoprotein secretion in experimental studies, suggesting that incretin-based therapies may ameliorate


dyslipidemia and thus improve cardiovascular risk profile in patients with T2D. Recently, both GLP-1 agonists and DPP-4 inhibitors have been reported to suppress the TG and apoB48 responses to a standardized fat-rich meal in patients with T2D [56,59,171–174]. Thus, the available data suggest that the incretin-based therapies have a class effect on intestinal lipid metabolism and offer a potential strategy to reduce postprandial lipemia [175]. Improved understanding of the physiology and genetic regulation of postprandial lipid metabolism may identify new targets for therapy [97,176]. This prospect is highlighted by the genetic approaches to target LPL expression as well as apoCIII, apoB and proprotein convertase subtilisin/kexin type 9 (PCSK9) [150]. Recently, intramuscular injection of the human LPL S447X has been approved by the EMA [177]. Furthermore, administration of the alipogene tiparvovec reduced markedly postprandial lipemia in patients with LPL deficiency [178–181]. Antisense oligonucleotide inhibition of apoCIII has also been reported to reduce plasma TG in rodents and primates (both non-human and human) [182]. 13. Concluding summary In the postprandial state, TRLs comprise CMs synthesized in the intestine, VLDL particles produced in the liver and their cholesterol-rich remnants. Postprandial hypertriglyceridemia can be initiated by both overproduction and/or defective catabolism of TRLs and is caused by both genetic variations and non-genetic factors such as obesity or T2D. Remnants can accumulate in the arterial wall and will deliver more cholesterol than LDL particles. Recent data strongly indicate that both non-fasting triglycerides and remnant cholesterol are not only CHD risk factors but are causally linked to atherogenesis. To date, no randomized clinical trials have addressed the effects of TRL-lowering measures on CVD outcomes, thus hampering recommendations for management. This is partly due to the lack of consensus on clinical measures of biomarkers to screen and assess the postprandial burden of TRLs. Likewise, the failure of clinical intervention trials that aimed to reduce CVD endpoints by lowering plasma TG has raised the urgent need for more extensive clinical endpoint data specifically testing the benefits of lowering postprandial hypertriglyceridemia and remnant cholesterol. However, novel therapy concepts utilizing anti-sense oligonucleotides or siRNA to target regulatory genes of postprandial lipid metabolism provide hope for future management. References [1] Chapman MJ, Ginsberg HN, Amarenco P, et al. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur Heart J 2011;32:1345–61. [2] Nordestgaard BG, Benn M, Schnohr P, Tybjaerg-Hansen A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA 2007;298:299–308. [3] Bansal S, Buring JE, Rifai N, Mora S, Sacks FM, Ridker PM. Fasting compared with nonfasting triglycerides and risk of cardiovascular events in women. JAMA 2007;298:309–16. [4] Freiberg JJ, Tybjaerg-Hansen A, Jensen JS, Nordestgaard BG. Nonfasting triglycerides and risk of ischemic stroke in the general population. JAMA 2008;300:2142–52. [5] Dallinga-Thie GM, Franssen R, Mooij HL, et al. The metabolism of triglyceride-rich lipoproteins revisited: new players, new insight. Atherosclerosis 2010;211:1–8. [6] Zilversmit DB. A proposal linking atherogenesis to the interaction of endothelial lipoprotein lipase with triglyceride-rich lipoproteins. Circ Res 1973;33:633–8. [7] Moreton JR. Atherosclerosis and alimentary hyperlipidemia. Science 1947;106:190–1. [8] Cohn JS, Johnson EJ, Millar JS, et al. Contribution of apoB-48 and apoB-100 triglyceride-rich lipoproteins (TRL) to postprandial increases in the plasma concentration of TRL triglycerides and retinyl esters. J Lipid Res 1993;34:2033–40. [9] Nakajima K, Nakano T, Tokita Y, et al. Postprandial lipoprotein metabolism: VLDL vs chylomicrons. Clin Chim Acta Int J Clin Chem 2011;412:1306–18. [10] Olofsson SO, Wiklund O, Boren J. Apolipoproteins A-I and B: biosynthesis, role in the development of atherosclerosis and targets for intervention against cardiovascular disease. Vasc Health Risk Manag 2007;3:491–502. [11] Olofsson SO, Boren J. Apolipoprotein B: a clinically important apolipoprotein which assembles atherogenic lipoproteins and promotes the development of atherosclerosis. J Intern Med 2005;258:395–410.

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Postprandial lipemia as a cardiometabolic risk factor.

Hypertriglyceridemia: a too long unfairly neglected major cardiovascular risk factor.

Cholesterol as a risk factor for coronary heart disease.

Hyperuricemia as a risk factor in coronary heart disease.

Hypertriglyceridemia in an outpatient department--Significance as an atherosclerotic risk factor.

Postprandial hypotension as a risk marker for asymptomatic lacunar infarction.

Is hypertriglyceridemia a prognostic factor in sepsis?

Childhood Obesity Is a High-risk Factor for Hypertriglyceridemia: A Case-control Study in Vietnam.

Hypertriglyceridemia is a risk factor for acute kidney injury in the early phase of acute pancreatitis.

Depression as a risk factor for acute coronary syndrome: a review.

Age as a Risk factor for Atrial Fibrillation and Flutter after Coronary Artery Bypass Grafting.

C-peptide as a risk factor of coronary artery disease in the general population.

Postprandial lipemia, fenofibrate and coronary artery disease.

Short left coronary artery trunk as a risk factor in the development of coronary atherosclerosis. Pathological study.

Risk factor variability and coronary heart disease.

Acute Effect of Metformin on Postprandial Hypertriglyceridemia through Delayed Gastric Emptying.

Premature hair graying: a probable coronary risk factor.

Hyperhomocysteinemia as a risk factor for stroke.

Ethyl alcohol as a cardiac risk factor.

Plasma viscosity as a cardiovascular risk factor.

The coronary risk factor problem: a behavioral perspective.

Periodontitis as a risk factor of atherosclerosis.

[Anemia as a surgical risk factor].

Delirium as a Risk Factor for POCD.