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Aims Darapladib, a potent inhibitor of lipoprotein-associated phospholipase A2(Lp-PLA2), has not reduced risk of cardiovascular disease outcomes in recent randomized trials. We aimed to test whether Lp-PLA2enzyme activity is causally relevant to coronary heart disease.Methods In 72,657 patients with coronary heart disease and 110,218 controls in 23 epidemiological studies, we genotyped five functional variants: four rare loss-of-function mutations (c.109+2T > C (rs142974898), Arg82His (rs144983904), Val279Phe (rs76863441), Gln287Ter (rs140020965)) and one common modest-impact variant (Val379Ala (rs1051931)) in PLA2G7,the gene encoding Lp-PLA2. We supplemented de-novo genotyping with information on a further 45,823 coronary heart disease patients and 88,680 controls in publicly available databases and other previous studies. We conducted a systematic review of randomized trials to compare effects of darapladib treatment on soluble Lp-PLA2activity, conventional cardiovascular risk factors, and coronary heart disease risk with corresponding effects of Lp-PLA2-lowering alleles.Results Lp-PLA2activity was decreased by 64% (p= 2.4 × 10–25) with carriage of any of the four loss-of-function variants, by 45% (p< 10–300) for every allele inherited at Val279Phe, and by 2.7% (p= 1.9 × 10–12) for every allele inherited at Val379Ala. Darapladib 160 mg once-daily reduced Lp-PLA2activity by 65% (p< 10–300). Causal risk ratios for coronary heart disease per 65% lower Lp-PLA2activity were: 0.95 (0.88–1.03) with Val279Phe; 0.92 (0.74–1.16) with carriage of any loss-of-function variant; 1.01 (0.68–1.51) with Val379Ala; and 0.95 (0.89–1.02) with darapladib treatment.Conclusions In a large-scale human genetic study, none of a series of Lp-PLA2-lowering alleles was related to coronary heart disease risk, suggesting that Lp-PLA2is unlikely to be a causal risk factor.

High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to 192,763 individuals and used ∼155,063 samples for independent replication. We identified 30 new blood pressure– or hypertension-associated genetic regions in the general population, including 3 rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5 mm Hg/allele) than common variants. Multiple rare nonsense and missense variant associations were found in A2ML1, and a low-frequency nonsense variant in ENPEP was identified. Our data extend the spectrum of allelic variation underlying blood pressure traits and hypertension, provide new insights into the pathophysiology of hypertension and indicate new targets for clinical intervention.

Context:Postprandial triglyceride (TG) concentration is independently associated with cardiovascular disease risk. Exercise reduces postprandial TG concentrations, but the mechanisms responsible are unclear.Objective:The objective was to determine the effects of exercise on affinity of chylomicrons, large very low-density lipoproteins (VLDL1), and smaller VLDL (VLDL2) for lipoprotein lipase (LPL)-mediated TG hydrolysis.Design:This was designed as a within-participant crossover study.Setting:The setting was a university metabolic investigation unit.Participants:Participants were 10 overweight/obese men.Interventions:Participants undertook two oral fat tolerance tests, separated by 7–14 days, in which they had blood taken while fasting and for 4 hours after a high-fat mixed meal. On the afternoon before one test, they performed a 90-minute treadmill walk at 50% maximal oxygen uptake (exercise trial [EX]); no exercise was performed before the control trial (CON).Main Outcome Measures:We measured circulating TG-rich lipoprotein concentrations and affinity of chylomicrons, VLDL1, and VLDL2for LPL-mediated TG hydrolysis.Results:Exercise significantly reduced fasting VLDL1-TG concentration (CON, 0.49 [0.33–0.72] mmol.L-1; EX, 0.36 [0.22–0.59] mmol.L-1; geometric means [95% confidence interval]; P= .04). Time-averaged postprandial chylomicron-TG (CON, 0.55 ± 0.10 mmol.L-1; EX, 0.39 ± 0.08 mmol.L-1; mean ± SEM; P= .03) and VLDL1-TG (CON, 0.85 ± 0.13 mmol.L-1; EX, 0.66 ± 0.10 mmol.L-1; P= .01) concentrations were both lower in EX than CON. Affinity of VLDL1for LPL-mediated TG hydrolysis increased by 2.2 (1.3–3.7)-fold [geometric mean (95% confidence interval)] (P= .02) in the fasted state and 2.6 (1.8–2.6)-fold (P= .001) postprandially. Affinity of chylomicrons and VLDL2was not significantly different between trials.Conclusions:Exercise increases affinity of VLDL1for LPL-mediated TG hydrolysis both fasting and postprandially. This mechanism is likely to contribute to the TG-lowering effect of exercise.

Isotopic tracer methods of determining triglyceride-rich lipoprotein (TRL) kinetics are costly, time-consuming, and labor-intensive. This study aimed to develop a simpler and cost-effective method of obtaining TRL kinetic data, based on the fact that chylomicrons compete with large VLDL (VLDL1; Sf= 60–400) for the same catalytic pathway. Ten healthy subjects [seven men; fasting triglyceride (TG), 44.3–407.6 mg/dl; body mass index, 21–35 kg/m2] were given an intravenous infusion of a chylomicron-like TG emulsion (Intralipid; 0.1 g/kg bolus followed by 0.1 g/kg/h infusion) for 75–120 min to prevent the clearance of VLDL1by lipoprotein lipase. Multiple blood samples were taken during and after infusion for separation of Intralipid, VLDL1, and VLDL2by ultracentrifugation. VLDL1-apolipoprotein B (apoB) and TG production rates were calculated from their linear increases in the VLDL1fraction during the infusion. Intralipid-TG clearance rate was determined from its exponential decay after infusion. The production rates of VLDL1-apoB and VLDL1-TG were (mean ± SEM) 25.4 ± 3.9 and 1,076.7 ± 224.7 mg/h, respectively, and the Intralipid-TG clearance rate was 66.9 ± 11.7 pools/day. Kinetic data obtained from this method agree with values obtained from stable isotope methods and show the expected relationships with indices of body fatness and insulin resistance (all P < 0.05). The protocol is relatively quick, inexpensive, and transferable to nonspecialist laboratories.

Isotopic tracer methods of determining triglyceride-rich lipoprotein (TRL) kinetics are costly, time-consuming, and labor-intensive. This study aimed to develop a simpler and cost-effective method of obtaining TRL kinetic data, based on the fact that chylomicrons compete with large VLDL (VLDL1; Sf= 60–400) for the same catalytic pathway. Ten healthy subjects [seven men; fasting triglyceride (TG), 44.3–407.6 mg/dl; body mass index, 21–35 kg/m2] were given an intravenous infusion of a chylomicron-like TG emulsion (Intralipid; 0.1 g/kg bolus followed by 0.1 g/kg/h infusion) for 75–120 min to prevent the clearance of VLDL1by lipoprotein lipase. Multiple blood samples were taken during and after infusion for separation of Intralipid, VLDL1, and VLDL2by ultracentrifugation. VLDL1-apolipoprotein B (apoB) and TG production rates were calculated from their linear increases in the VLDL1fraction during the infusion. Intralipid-TG clearance rate was determined from its exponential decay after infusion. The production rates of VLDL1-apoB and VLDL1-TG were (mean ± SEM) 25.4 ± 3.9 and 1,076.7 ± 224.7 mg/h, respectively, and the Intralipid-TG clearance rate was 66.9 ± 11.7 pools/day. Kinetic data obtained from this method agree with values obtained from stable isotope methods and show the expected relationships with indices of body fatness and insulin resistance (all P< 0.05). The protocol is relatively quick, inexpensive, and transferable to nonspecialist laboratories.

Risk factors identified by the Framingham Heart Study are useful for assessing a person's risk of cardiovascular disease; however, additional risk factors are needed. In this review, the potential role of lipoprotein-associated phospholipase A2as a novel inflammatory marker for cardiovascular risk assessment is discussed.

The use of stable isotopes in conjunction with compartmental modeling analysis has greatly facilitated studies of the metabolism of the apolipoprotein B (apoB)-containing lipoproteins in humans. The aim of this study was to develop a multicompartment model that allows us to simultaneously determine the kinetics of apoB and triglyceride (TG) in VLDL1and VLDL2after a bolus injection of [2H3]leucine and [2H5]glycerol and to follow the catabolism and transfer of the lipoprotein particles. Here, we describe the model and present the results of its application in a fasting steady-state situation in 17 subjects with lipid values representative of a Western population. Analysis of the correlations showed that plasma TG was determined by the VLDL1and VLDL2apoB and TG fractional catabolic rate. Furthermore, the model showed a linear correlation between VLDL1TG and apoB production. A novel observation was that VLDL TG entered the circulation within 21 min after its synthesis, whereas VLDL apoB entered the circulation after 33 min.

Response to statin treatment can vary widely from person to person as a result of inherited traits (genotype) and acquired characteristics such as obesity (phenotype). The aim of this review is to describe what is known about factors that determine a patient's response, and to offer a mechanism to explain how plasma triglyceride influences the nature and magnitude of lipid lowering on statin therapy.

Plasma lipoproteins carry a number of highly active enzymes in the circulation. One of these is lipoprotein-associated phospholipase A2(Lp-PLA2), also known as platelet-activating factor acetylhydrolase. This review addresses the molecular properties of Lp-PLA2, the controversy surrounding its role in atherosclerosis and the regulation of its plasma levels in humans.

The association between possession of the APOE ε4 allele and unfavourable outcome after traumatic brain injury (TBI) suggests that the apolipoprotein E protein (apoE) plays a key role in the response of the human brain to injury. ApoE is known to regulate cholesterol metabolism in the periphery through its action as a ligand for receptor mediated uptake of lipoprotein particles (Lps). Greater understanding of cholesterol metabolism in the human central nervous system may identify novel treatment strategies applicable to acute brain injury. We report findings from the analysis of lipoproteins in the cerebrospinal fluid (CSF) of patients with TBI and non-injured controls, testing the hypothesis that remodeling of CSF lipoproteins reflects the response of the brain to TBI. CSF Lps were isolated from the CSF of controls and patients with severe TBI by size exclusion chromatography, and the lipoprotein fractions analysed for cholesterol, phospholipid, apoAI, and apoE. There was a marked decrease in apoE containing Lps in the TBI CSF compared to controls (p = 0.002). After TBI there was no significant decrease in apoAI containing CSF Lps (CSF LpAI), but the apoAI resided on smaller sized particles than in control CSF. There was a population of very small sized Lps in TBI CSF, which were associated with the increased cholesterol (p = 0.0001) and phospholipid (p = 0.040) seen after TBI. The dramatic loss of apoE containing Lps from the CSF, and the substantial increase in CSF cholesterol, support the concept that apoE and cholesterol metabolism are intimately linked in the context of acute brain injury. Treatment strategies targeting CNS lipid transport, required for neuronal sprouting and synaptogenesis, may be applicable to traumatic brain injury.

Heparin, when administered to patients undergoing operations using cardiopulmonary bypass, induces plasma changes that gradually impair platelet macroaggregation, but heparinization of whole blood in vitro does not have this effect. The plasma changes induced by heparin in vivo continue to progress in whole blood ex vivo. Heparin releases several endothelial proteins, including lipoprotein lipase, hepatic lipase, platelet factor-4 and superoxide dismutase. These enzymes, which remain active in plasma ex vivo, may impair platelet macroaggregation after in vivo heparinization and during cardiopulmonary bypass. In the present study, proteins were added in vitro to hirudin (200units·ml-1)-anticoagulated blood from healthy volunteers, and the platelet macroaggregatory responses to ex vivo stimulation with collagen (0.6μg·ml-1) were assessed by whole-blood impedance aggregometry. Over a 4h period, human lipoprotein lipase and human hepatic lipase reduced the platelet macroaggregatory response from 17.0±2.3 to 1.5±1.3 and 1.2±0.6Ω respectively (means±S.D.) (both P<0.01; n = 6). Other lipoprotein lipases also impaired platelet macroaggregation, but platelet factor-4 and superoxide dismutase did not. Platelet macroaggregation showed an inverse linear correlation with plasma concentrations of non-esterified fatty acids (r2 = 0.69; two-sided P<0.0001; n = 8), suggesting that heparin-induced lipolysis inhibits platelet macroaggregation. Lipoprotein degradation products may cause this inhibition by interfering with eicosanoids and other lipid mediators of metabolism.

End-stage renal failure (ESRF) is associated with dyslipidemia and accelerated atherosclerosis. Triglyceride-rich lipoproteins accumulate and qualitative changes take place in low-density lipoprotein (LDL), with a predominance of the small dense LDL phenotype. Increased small dense LDL (LDLIII) is a known risk factor for cardiovascular disease. To assess the extent of LDLIII formation in ESRF and identify factors contributing to LDLIII production, we analyzed LDL subfractions by density-gradient ultracentrifugation, very low-density lipoprotein subfractions, and lipase activity in 75 patients with ESRF (25 hemodialysis [HD], 25 peritoneal dialysis [PD], and 25 predialysis patients) and 40 age- and sex-matched controls. The percentage of LDLIII was increased in all three patient groups compared with controls (PD, 33% ± 29% [mean ± SD]; P< 0.005; HD, 30% ± 22%; P< 0.01; predialysis, 26% ± 26%; P< 0.01; all versus controls, 14% ± 10%). Plasma LDLIII concentration was increased only in PD patients (median, 84 mg/dL; interquartile range [IQR], 29 to 160 mg/dL versus controls; median, 31 mg/dL; IQR, 26 to 54 mg/dL). In other patient groups, total LDL level was less, with heterogeneity in LDLIII concentrations. Forty percent of PD patients and 28% of HD and predialysis patients had LDLIII concentrations greater than 100 mg/dL compared with 2.5% of controls (P= 0.002). Plasma triglyceride levels (r2= 38.4%; P< 0.001) and hepatic lipase activity (r2= 6.7%; P< 0.03) were independent predictors of LDLIII concentration. The strong association between LDLIII concentration and triglyceride level was present in all three patient groups (HD, r2= 47.9%; PD, r2= 45.2%; predialysis, r2= 25.8%); plasma triglyceride levels greater than 177 mg/dL (2.0 mmol/L) had an 86% specificity and 79% sensitivity for predicting an LDLIII concentration greater than 100 mg/dL. We conclude that the atherogenic lipoprotein phenotype predominates in ESRF, with excess LDLIII particularly prominent in PD patients. Atherogenic levels of LDLIII are found in patients with triglyceride levels greater than 177 mg/dL. This is likely to represent a further cardiovascular risk factor in this population.

To assess the short-term effects of a micronised formulation of fenofibrate on lipids, lipoproteins and their composition, reflecting an atherogenic lipoprotein phenotype (ALP), in patients with stable Type 2 diabetes. Thirty-two (18 male, 14 female) patients with Type 2 diabetes were randomised to a double-blind, placebo-controlled parallel group study after a 4-week diet run-in phase to a 12-week treatment period with either daily micronised fenofibrate 200 mg (Lipantil Micro^®) or placebo. Baseline mean lipid and lipoproteins were similar in both groups: total cholesterol (TC) 7.5 mmol/l, serum triglyceride (TG) 3.1 mmol/l, HDL-cholesterol (HDL-c) 1.2 mmol/l, LDL-cholesterol (LDL-c) 4.7 mmol/l, and a predominance (52%) of small dense LDL-III at concentration of 192 mg lipoprotein/100 ml, reflecting an ALP. Treatment with micronised fenofibrate resulted in significant changes in TC (−17%, p&lt;0.001), serum TG (−44%, p&lt;0.05), HDL-c (+20%, p&lt;0.01), LDL-c (−22%, p&lt;0.001), apo-B (−18%, p&lt;0.05) and alterations in LDL subfraction masses (LDL-I +64%, p&lt;0.05; LDL-II +53%, p&lt;0.05; LDL-III −51%, p&lt;0.001) resulting in LDL-III comprising 28% of total LDL (p&lt;0.001). In the placebo group the only significant changes were in TG (+21%, p&lt;0.05) and apo-B (+9%, p&lt;0.05). Micronised fenofibrate therapy in patients with Type 2 diabetes improved an establisheded ALP resulting in a more favourable lipid and LDL subfraction profile. The long-term clinical implications of these changes await the results of the major intervention trials of lipid modification in Type 2 diabetes. Copyright © 1999 John Wiley & Sons, Ltd.

1. The lipid and protein composition of subfractions of plasma low-density lipoprotein (LDL) has been determined in nine patients with primary hypothyroidism before and after 3 months of thyroxine therapy. Analyses were also made of subfractions of very-low-density lipoprotein (VLDL) in four of the patients. 2. Before therapy seven of the patients had elevated LDL-cholesterol and two had increased VLDL-cholesterol concentrations. On thyroxine replacement the mean LDL-cholesterol fell to normal. No significant change occurred in the concentration of cholesterol in VLDL or in high-density lipoprotein (HDL). 3. The concentrations of cholesterol, triglyceride and apolipoprotein B (apoB) were increased in the LDL subfraction of Sf 10·4–20, which corresponds mainly to intermediate-density lipoprotein. This subfraction showed a marked fall on therapy. The cholesterol and apoB concentrations in the major LDL fraction of Sf 5·7–12 also decreased on therapy, but the fall in the subfraction of Sf 3·5–6·5 did not reach statistical significance. 4. Only the VLDL subfraction of smallest size (Sf 20–60) had any abnormality before therapy, with an increased concentration of cholesterol. On thyroxine the concentration of triglyceride rose in the VLDL subfractions. 5. These data suggest that thyroxine exerts its major effect on lipoprotein metabolism by promoting the conversion into LDL of intermediate-density lipoprotein, formed by catabolism of VLDL.

High resolution density gradient ultracentrifugation (DGUC) and non-denaturing gradient gel electrophoresis (GGE) indicate that low density lipoprotein (LDL) in both normal and hyperlipidaemic subjects is composed of overlapping particle populations. A new centrifugation procedure has been developed which permits the separation of LDL subspecies directly from plasma within 24 h. The profiles obtained were analogous to those seen on gradient gel electrophoresis. LDL was divided into 3 fractions. The plasma concentration of LDL-I seen in young females was twice that in men (85.6 ± 28.8 vs. 42.3 ± 25.7 mg/dl, P< 0.005). LDL-II was not significantly different in any group while LDL-III was specifically elevated in coronary artery disease (CAD) patients (207.1 ± 92.6 mg/dl inCAD vs. 87.4 ± 79.6 mg/dl in normal men, P< 0.05). The presence of small, dense LDL detected either by density gradient centrifugation or gel electrophoresis was associated with raised triglyceride (TG) and low high density lipoprotein (HDL) cholesterol and may be a risk marker for coronary artery disease.

A missense variant in GLP1R associated with lower fasting glucose levels and protective against T2D is associated with lower risk of coronary heart disease, suggesting that GLP1R agonists are not associated with an unacceptable increase in cardiovascular risk.