4943Remnant cholesterol increases the risk for recurrent vascular events independent of LDL-cholesterol in patients with clinical manifest vascular disease

Background For many years, low density lipoprotein cholesterol (LDL-C) is recognized as an important risk factor for the development of atherosclerosis and cardiovascular disease. However, even with normal LDL-C levels there is a residual risk for cardiovascular disease and mortality. Previous research in patients with ischemic heart disease, diabetes mellitus type 2 (T2DM) and in the general population has shown that this residual risk could be explained by elevated plasma levels of very low density lipoprotein- (VLDL) and chylomicron-remnant cholesterol. Purpose We evaluated the relation between plasma levels of VLDL- and chylomicron-remnant cholesterol and recurrent vascular disease and all-cause mortality in a cohort of patients with clinical manifest arterial disease. Methods Prospective cohort study in 8057 patients with manifest arterial disease from the UCC-SMART study. Patients with triglyceride levels >9 mmol/L or known homozygote Apo E2 genotype were excluded. Cox proportional hazard models were used to evaluate the effect of fasting VLDL- and chylomicron-remnant cholesterol (calculated by total cholesterol - high density lipoprotein cholesterol (HDL-C) - LDL-C) on occurence of myocardial infarction (MI), stroke, vascular death, a composite endpoint (i.e. MI, stroke, vascular death) and all-cause mortality. Models were adjusted for LDL-C, current smoking, waist circumference, creatinine and systolic blood pressure. Effect modification of HDL-C and T2DM on the relation between remnant cholesterol and vascular endpoints was evaluated. Results Patients mean age was 60.0±10.3 years, 74% were male, 4894 (61%) had a prior history of coronary artery disease (CAD), 2445 (30%) of stroke and 1990 (25%) patients had peripheral arterial disease (PAD) or aneurysm abdominal aorta (AAA). There were 1544 vascular events and 1792 deaths during a median follow up of 8.2 (interquartile range (IQR) 4.5–12.2) years and a total follow up of 68699 person-years. For every 1 mmol/L increase in remnant cholesterol, risk for recurrent vascular events was increased in patients with manifest vascular disease (HR 1.17; 95% CI 1.05–1.31 for the composite endpoint (figure 1)). There was no effect for all-cause mortality in this population. Furthermore, there was no significant effect modification of HDL-C and the presence of T2DM on the relation between remnant cholesterol and vascular endpoints. Figure 1 Conclusion In patients with clinically manifest arterial disease plasma remnant cholesterol confers an increased risk for recurrent vascular events, independent of traditional risk factors such as LDL-C levels.

Dietary fat and physiological determinants of plasma chylomicron remnant homoeostasis in normolipidaemic subjects: insight into atherogenic risk

TAG depleted remnants of postprandial chylomicrons are a risk factor for atherosclerosis. Recent studies have demonstrated that in the fasted state, the majority of chylomicrons are small enough for transcytosis to arterial subendothelial space and accelerate atherogenesis. However, the size distribution of chylomicrons in the absorptive state is unclear. This study explored in normolipidaemic subjects the postprandial distribution of the chylomicron marker, apoB-48, in a TAG-rich lipoprotein plasma fraction (Svedberg flotation rate (Sf>400), in partially hydrolysed remnants (Sf 20–400) and in a TAG-deplete fraction (Sf<20), following ingestion of isoenergetic meals with either palm oil (PO), rice bran or coconut oil. Results from this study show that the majority of fasting chylomicrons are within the potentially pro-atherogenic Sf<20 fraction (70–75 %). Following the ingestion of test meals, chylomicronaemia was also principally distributed within the Sf<20 fraction. However, approximately 40 % of subjects demonstrated exaggerated postprandial lipaemia specifically in response to the SFA-rich PO meal, with a transient shift to more buoyant chylomicron fractions. The latter demonstrates that heterogeneity in the magnitude and duration of hyper-remnantaemia is dependent on both the nature of the meal fatty acids ingested and possible metabolic determinants that influence chylomicron metabolism. The study findings reiterate that fasting plasma TAG is a poor indicator of atherogenic chylomicron remnant homoeostasis and emphasises the merits of considering specifically, chylomicron remnant abundance and kinetics in the context of atherogenic risk. Few studies address the latter, despite the majority of life being spent in the postprandial and absorptive state.

Phospholipase A2 Mediates Apolipoprotein-Independent Uptake of Chylomicron Remnant-Like Particles by Human Macrophages

Apolipoprotein E-receptor-mediated pathways are the main routes by which macrophages take up chylomicron remnants, but uptake may also be mediated by receptor-independent routes. To investigate these mechanisms, triacylglycerol (TG) accumulation induced by apolipoprotein-free chylomicron remnant-like particles (CRLPw/o) in human monocyte-derived macrophages was evaluated. Macrophage TG content increased about 5-fold after incubation with CRLPw/o, and this effect was not reduced by the inhibition of phagocytosis, macropinocytosis, apolipoprotein E function, or proteoglycan bridging. The role of lipases, including lipoprotein lipase, cholesteryl ester hydrolase, and secretory (sPLA2) and cytosolic phospholipase A2, was studied using [3H]TG-labelled CRLPw/o. Total cell radioactivity after incubation with [3H]TG CRLPw/o was reduced by 15–30% by inhibitors of lipoprotein lipase and cholesteryl ester hydrolase and by about 45% by inhibitors of sPLA2 and cytosolic PLA2. These results suggest that macrophage lipolytic enzymes mediate the internalization of postprandial TG-rich lipoproteins and that sPLA2and cytosolic PLA2, play a more important role than extracellular lipoprotein lipase-mediated TG hydrolysis.

Dietary fat impacts fetal growth and metabolism: uptake of chylomicron remnant core lipids by the placenta

The fetus requires significant energy for growth and development. Although glucose is a major source of energy for the fetus, other maternal nutrients also appear to promote growth. Thus, the goal of these studies was to determine whether triglyceride-rich remnants are taken up by the placenta and whether maternal dietary lipids, independently of adiposity, can impact fetal growth. To accomplish our first goal, chylomicron particles were duallly labeled with cholesteryl ester and triglycerides. The placenta took up remnant particles/core lipids at rates greater than adipose tissue and skeletal muscle but less than the liver. Although the placenta expresses apoE receptors, uptake of chylomicron remnants and/or core lipids can occur independently of apoE. To determine the impact of dietary lipid on fetal growth, independent of maternal adiposity, females were fed high-fat diets (HFD) for 1 mo; there was no change in adiposity or leptin levels prior to or during pregnancy of dams fed HFD. Fetal masses were greater in dams fed HFD, and mRNA levels of proteins involved in fatty acid oxidation (CPT I, PPARα), but not glucose oxidation (pyruvate kinase) or other regulatory processes (HNF-4α, LXR), were increased with maternal dietary fat. There was also no change in mRNA levels of proteins involved in placental glucose and fatty acid transport, and GLUT1 protein levels in microvillous membranes were similar in placentas of dams fed either diet. Thus, the ability of the placenta to take up chylomicron remnant core lipids likely contributes to accelerated fetal growth in females fed high fat diets.