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Introduction: Coronary heart disease (CHD) is exceptionally prevalent amongst globally dispersed migrant groups originating from the Indian subcontinent, but the contribution of dyslipidaemia to their increased risk remains poorly defined., Methods: Fasting lipids and lipoproteins, apolipoproteins (Apo), low density lipoprotein (LDL) diameter and oxidised LDL were measured amongst rural Indians in India (n=294) and their migrant contemporaries in the UK (n=242). The performance of qualitative and quantitative measures of lipid metabolism were compared in the discrimination of WHO defined metabolic risk and raised Framingham CHD risk scores (>15%) using Receiver Operating Characteristic (ROC) curves., Results: LDL diameter was correlated with triglycerides (R(2)=0.12, P<0.001) and with high density lipoprotein (HDL) cholesterol levels (R(2)=0.15, P<0.001) in both groups. Migrants had less small dense LDL (95% CI: 12.5-14.2%) vs. rural Indians (15.7-17.2, P<0.05). On ROC analysis, triglycerides were the only consistent discriminators of metabolic and CHD risk scores (all P< or =0.001). Apo B was also a strong indicator of raised CHD risk scores. Irrespective of site, individuals with raised triglycerides also had higher total cholesterol and Apo B, denser LDL, lower HDL and more oxidised LDL (all P< or =0.01)., Discussion: Fasting triglycerides reflect both qualitative and quantitative aspects of lipid metabolism, and are a comprehensive discriminator of CHD risk in this South Asian population., (Crown Copyright 2009. Published by Elsevier Ireland Ltd. All rights reserved.)

Background: Patients with nephrotic range proteinuria have a marked increase in the risk of cardiovascular disease. Qualitative and quantitative changes in lipids and lipoproteins contribute to this increased risk with an abundance of atherogenic triglyceride (TG) rich apolipoprotein B containing lipoproteins. TG rich lipoproteins predominate postprandially and are associated with increased risk of coronary heart disease (CHD). Omega-3 fatty acids derived from fish oils have been shown to have beneficial effects on lipids and lipoproteins in patients without proteinuria., Methods: 17 patients with nephrotic range proteinuria and 17 age and sex matched controls were studied. Postprandial lipaemia was assessed in patients and controls, before and after 8 weeks treatment with 4 g daily of omega-3 fatty acids (Omacor). A standard fat load (90 g) was administered and blood sampling was performed in the fasting state and at 2, 4, 6 and 8h after the fat load. Chylomicrons and VLDL(1) density fraction was isolated from plasma by density ultracentrifugation. Postprandial chylomicron and VLDL(1) triglyceride concentrations were measured and quantified using the incremental area under the curve (AUC) method., Results: Baseline postprandial chylomicron TG AUC was greater in patients compared with controls: median 18.5 mmol/lh (interquartile range 8.9-32.6) vs 9.3 mmol/lh (4.8-14.4) p=0.05. Following treatment patient chylomicron AUC fell [mean reduction 6.8 mmol/lh (95% CI 0.1-13.6) p=0.05]. No significant reduction in chylomicron AUC was observed in the controls [mean reduction 3.9 mmol/lh (95% CI -3.6 to 11.5)]. As a result, following 8 weeks treatment with omega-3 fatty acids, patient and control chylomicron AUC were no longer significantly different [patients 13.5 mmol/lh (7.4-22.9), controls 7.2 mmol/lh (4.6-14.5) both median and IQR, p=nsd]. VLDL(1) TG AUC did not differ at baseline between patients and controls. Furthermore, there was no significant effect on VLDL(1) AUC following treatment in either group., Conclusions: We have shown that there is an excess of postprandial chylomicron density fraction in patients with nephrotic range proteinuria, which is reduced by treatment with omega-3 fatty acids. We suggest that this would be an ideal therapy in combination with statins for this high risk group of patients.

Very low density lipoprotein (VLDL) 1 and 2 were fractionated by heparin affinity chromatography into a bound and an unbound fraction and the different subfractions were quantified in 17 normolipidaemic (NL), 13 hypercholesterolaemic (HC), 10 hypertriglyceridaemic (HTG) and 11 combined hyperlipidaemic subjects (CHL). Unbound VLDL1 and VLDL2 were, respectively, 1.9- and 2.2-fold richer in triglycerides than bound VLDL1 and VLDL2. In HTG and CHL the concentration of all the VLDL subfractions was increased and plasma triglyceride level was correlated to unbound VLDL1 and to bound VLDL1 (respectively, r=0.86 (p<0.001) and r=0.77 (p<0.01) in HTG and r=0.73 (p<0.001) and r=0.62 (p<0.05) in CHL). In HC unbound VLDL2 and bound VLDL2 concentration were increased compared to NL and in CHL, the concentration of bound VLDL2 was particularly increased (3.2-fold compared to NL (p<0.001)). In both HC and CHL bound VLDL2 concentration was correlated to low density lipoprotein cholesterol (LDL-C) concentration (respectively, r=0.67 (p<0.01) and r=0.62 (p<0.05)). In hypertriglyceridaemic states the intravascular accumulation of both unbound and bound VLDL1 appears as the determinant of plasma triglyceride concentration, whereas in moderately hypercholesterolaemic states the concentration of bound VLDL2 is strikingly correlated to LDL-C concentration, suggesting that these two species are linked metabolically, e.g. bound VLDL2 contain the precursor pool of LDL.

Aim: The present clinical study tested the hypothesis that oil-rich fish consumption improves CHD risk factors., Methods: Forty-eight (16 men) non-obese, healthy adults aged 20-55, consumed 125 g/day of salmon for a 4-week period followed by a 4-week period with no-fish (41 completers). Subjects were instructed to maintain dietary and physical activity patterns during the period of study. Blood pressure, anthropometric, body composition and dietary information with fasting blood samples to determine traditional and novel CHD risk markers and plasma fatty acids were obtained before and after each period., Results: Compared to no-fish, eating salmon significantly decreased systolic, diastolic and mean arterial blood pressure by 4%, triglycerides by 15%, and LDL-cholesterol by 7%, and significantly increased HDL-cholesterol by 5% (P<0.05). The changes in blood pressure and lipids alone with salmon intake predict around a 25% reduction in CHD risk based on the PROCAM risk calculator. Plasma adiponectin demonstrated a trend towards improvement (8.39 micromol/L with salmon and 7.52 with no-fish; P=0.086) but no significant changes were found either in plasma leptin, glucose or insulin after salmon consumption., Conclusions: Daily consumption of salmon improves traditional risk predictors of CHD in non-obese subjects. Adiponectin may be involved but the impact on novel risk factors needs study in high-risk subjects.

The aim of our work was to evaluate changes in levels of oxidised low-density lipoprotein (Ox-LDL) during pregnancy and how they correlate with changes in LDL size and serum total antioxidant status (TAS). LDL peak and mean particle diameter (LDL-PPD and LDL-MPD, respectively) and the relative proportion of 3 LDL subfractions were quantified. We evaluated plasma levels of Ox-LDL and serum levels of TAS, total cholesterol (Chol), triglycerides (TG), apolipoprotein A-I (apo A-I), apolipoprotein B (apo B), HDL-cholesterol (HDLc) and LDL-cholesterol (LDLc). A longitudinal study was performed in the three trimesters (T1-T3) of pregnancy in normal pregnant women (n = 23) and a non-pregnant group (n = 18) was used as control. TG levels were significantly elevated whereas LDL-MPD and LDL-PPD were significantly reduced in T1 compared to controls. Ox-LDL, TG, Chol, apo B and LDLc rose markedly throughout pregnancy with significant changes between each trimester; LDL-PPD, LDL-MPD and TAS levels decreased significantly from T1 to T3. Changes in LDL size and in Ox-LDL and TAS levels were more pronounced between T1 and T2 than between T2 and T3. HDLc and apo A-I reached peak concentration in T2 but decreased in T3. TG concentrations correlated inversely with LDL size and positively with Ox-LDL; Ox-LDL was positively and strongly correlated with LDLc. Moreover, relative changes in the levels of Ox-LDL correlated inversely with relative changes in LDL size and TAS between trimesters. In conclusion, during human gestation the change in LDL profile towards smaller species and the decrease in serum TAS are closely associated with increased levels of Ox-LDL. The exact physiological role of the increments in Ox-LDL during pregnancy remains to be clarified.

Maternal lipids have been studied extensively in pre-eclampsia (PE) and intrauterine growth restriction (IUGR) but little is known about fetal lipids. We hypothesised that the maternal lipid perturbations in PE and IUGR pregnancies would result in similar alterations in the fetal lipid profile. We performed a cross-sectional case control study of maternal and fetal (delivery venous cord blood) lipid and lipoprotein concentrations in third trimester uncomplicated pregnancies (n = 81) and in pregnancies complicated by PE (n = 23) or IUGR (n = 17). In uncomplicated pregnancies, fetal log total cholesterol (TC), log triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C) levels were significantly affected by mode of delivery. Fetal log TC (r = 0.37, P = 0.02), log TG (r = 0.34, P = 0.04) and TC/HDL-C ratio (r = 0.31, P = 0.05) were positively correlated with placental weight. Maternal TC (r = 0.35, P = 0.03) and LDL levels (r = 0.36, P = 0.02) were associated with fetal HDL-C levels. Maternal TC was significantly elevated in PE [mean 6.75 (standard deviation 1.14) mmol/L] compared to BMI-matched controls [5.94 (0.89) mmol/L P = 0.04]. In PE, fetal log TC [mean 0.36 (0.23) versus 0.11 (0.15) log mmol/L, P = 0.03], fetal log TG [-0.21 (0.32) versus -0.49 (0.26) log mmol/L, P = 0.02] and fetal TC/HDL-C ratio [3.64 (1.62) versus 1.80 (0.86), P = 0.001] were higher than in controls, after adjustment for mode of delivery. In IUGR, fetal log TG [-0.17 (0.35) versus -0.57 (0.10) log mmol/L, P = 0.01] was higher than controls, after adjustment for mode of delivery. There were no correlations between maternal and fetal lipid levels, or between fetal birth weight and either maternal or fetal lipids in the PE or IUGR groups. We conclude that although fetal lipids do not show a direct correlation with maternal lipids in PE or IUGR, these complications of pregnancy significantly impact upon fetal lipid levels possibly due to increased fetal stress or compromised placental lipid transport. Our findings are potentially pertinent to understanding the future cardiovascular health of the offspring.

Lipoprotein particles (Lps) in normal human cerebrospinal fluid (CSF) are distinct from those found in plasma and include unique apolipoprotein E (apoE indicates protein; APOE, gene) containing lipoproteins rarely seen in human plasma. Less favourable neurological recovery after subarachnoid hemorrhage (SAH) has been observed in patients who possess the APOE epsilon4 allele raising the possibility that apoE influences neuronal survival after brain injury. We analysed Lps from control and SAH CSF testing the hypotheses that following brain injury CSF Lps undergo remodelling and apoE containing Lps are selectively depleted from brain injury CSF. Lipoproteins were fractionated using CSF from six control pools and six patients with SAH on a sepharose 6HR 10/30 size exclusion column. Fractions were assayed for total cholesterol (TC), free cholesterol (FC), phospholipid, triglyceride (TG), apoE, apolipoprotein B (apoB), and apolipoprotein AI (apoAI). Compared to control CSF there were significant (P<0.05) increases in TC, FC, TG, and apoAI in SAH CSF. Plasma sized apoB-containing lipoproteins and a very small apoAI-containing Lps were identified in the SAH CSF, which were not present in controls. However, despite the release of plasma lipoproteins into the subarachnoid space, there was no significant increase in CSF apoE. These data provide novel indirect evidence suggesting that after SAH CSF Lps undergo remodelling and apoE containing Lps are selectively reduced in brain injury CSF. The remodelling of CSF Lps and selective reduction of apoE containing lipoproteins may reflect an important response of the human brain to injury.

The aim of this study was to evaluate changes in lipids, apolipoproteins and lipoproteins in Portuguese pregnant women and their potential involvement in the pathophysiology of preeclampsia. A cross-sectional study was performed by collecting blood samples in the first (n=64), second (n=48) and third (n=67) trimesters and puerperium (n=32) of normal pregnancies. Samples from preeclamptic women were obtained in the third trimester (n=51) and in puerperium (n=26). As normal pregnancy progressed and triglyceride (TG) levels rose there was a decrease in low density lipoprotein (LDL) size, as measured by peak and mean particle diameter (MPD), with an increased proportion of atherogenic small dense LDL. Preeclamptic women exhibited, in the third trimester and puerperium, higher mean serum TG concentration and lower high density lipoprotein (HDL) cholesterol and apolipoprotein A-I (apo A-I) levels compared with healthy pregnant women. In the third trimester, LDL-mean particle diameter (LDL-MPD) and LDL cholesterol-apolipoprotein B (LDLc-apo B) ratio were also significantly reduced in the pathologic group. We conclude that human gestation is associated with an 'atherogenic' lipid profile that is further enhanced in preeclampsia and that this profile may be a potential contributor to endothelial cell dysfunction.

The dyslipidaemia in nephrotic-range proteinuria is believed to contribute to the increased atherogenesis associated with the condition. Excess small dense low density lipoprotein (LDLIII) contributes to this risk. Lipoprotein remnants (RLP) may also be implicated but have not been studied in this population. We measured the plasma concentration of low density lipoprotein (LDL) subfractions (by density gradient ultracentrifugation), RLP (by immunoaffinity gel), very low density lipoprotein (VLDL) subfractions, post heparin lipases and cholesteryl ester transfer protein (CETP) activity in 27 patients with glomerular disease and albuminuria >2.0g. These were compared with 27 age and sex matched controls. Proteinuric patients had increased LDLIII concentration (patients 182 (84:267) vs. controls 31 (27:62); P<0.0001) with reduced lighter LDLI (36 (24:43) vs 69 (46:101); P<0.0005) and LDLII (124 (79:220) vs 178 (129:236); P<0.04, all mg/dl, median+interquartile range). RLP-cholesterol (RLP-C) and triglyceride (RLP-TG) were increased in proteinuric patients (RLP-C 18.9 (11.0:26.9) vs 7.7 (6.0:8.8); P<0.0001, RLP-TG 35.8 (11.8:54.7) vs. 7.2 (4.3:10.0); P<0.0001, all mg/dl). Increased LDLIII and RLP were independent of renal function. VLDL(1) and VLDL(2) concentrations were increased by 258 and 260% (both P<0.0001). CETP activity was increased by 46% (P<0.005). Lipoprotein and hepatic lipase activities did not differ from control values. LDLIII concentration (r(2)=45.7%, P<0.001), RLP-C (r(2)=85.2%, P<0.001) and RLP-TG (r(2)=87.5%, P<0.001) all correlated positively with plasma triglyceride. Moreover, increased LDLIII was associated with both RLP-C (r(2)=31.3%, P<0.002) and RLP-TG (r(2)=33.6%, P<0.002). Excess LDLIII and RLP are present in nephrotic-range proteinuria and add to the spectrum of cardiovascular risk factors present in proteinuric patients. Increases in LDLIII and RLP are closely related to plasma triglyceride. The association between excess RLP and LDLIII suggests that RLP contribute to the increased atherogenicity attributed to the atherogenic lipoprotein phenotype.

The St. Thomas mixed hyperlipidaemic (SMHL) rabbit exhibits an inherited hyperlipidaemia similar to that seen in familial combined hyperlipidaemia (FCHL). In this study, we investigated whether the SMHL rabbit is insulin resistant, a condition often associated with FCHL. Six young and six mature combined hyperlipidaemic SMHL rabbits, age/sex matched New Zealand White (NZW) control rabbits and six young hypercholesterolaemic Watanabe heritable hyperlipidaemic (WHHL) control rabbits were fed a 0.08% (w/w) cholesterol-enriched diet for at least 1 month prior to the start of the experiment. We performed an oral glucose tolerance test after an overnight fast by dosing the rabbits with a solution of 1 g of glucose per kg body weight. Blood was withdrawn just before and 15, 30, 45, 60 and 120 min after administration of the oral glucose dose. Plasma glucose levels were similar in SMHL, WHHL and NZW rabbits throughout the oral glucose tolerance test. Fasting glucose levels were slightly increased in WHHL rabbits but not in young and adult SMHL rabbits as compared to NZW rabbits. The area under the curve (AUC) for the insulin response was significantly increased for both young (P<0.05) and mature (P<0.05) SMHL rabbits, and in WHHL rabbits, compared with NZW rabbits. The AUC for the ratio of glucose:insulin response to the glucose dose was decreased in young and mature SMHL rabbits (P<0.05 and P<0.01, respectively) and in young WHHL rabbits (P<0.05), compared with NZW rabbits. Only WHHL rabbits showed an increased AUC for the non-esterified fatty acid response compared to NZW rabbits. Log-transformed plasma triglycerides values were significantly correlated with the log-transformed AUC for the insulin response in young SMHL rabbits (r=0.81; P<0.05) and with the AUC for the insulin response in mature SMHL rabbits (r=0.84; P<0.05). WHHL rabbits showed no significant correlation. In conclusion, SMHL rabbits are insulin resistant, the severity of which appears to increase with age. Therefore, the SMHL rabbit offers a valuable animal model in which to study the relation between hypertriglyceridaemia and insulin resistance.

The concentration of plasma LDL subfractions is described in four groups of normocholesterolaemic (total plasma cholesterol < 6.5 mmol/l) male subjects consisting of men with and without coronary artery disease (CAD+/-), as determined by angiography, post-myocardial infarct survivors (PMI) and normal, healthy controls. The CAD(+) and PMI groups were distinguished from the CAD(-) and controls by raised concentrations of plasma triglyceride, very low density lipoprotein (VLDL) cholesterol, small, dense LDL (LDL-III density (d) 1.044-1.060 g/ml) and lower concentrations of high density lipoprotein (HDL) cholesterol and large, buoyant LDL (LDL-I d 1.025-1.034 g/ml). In all groups, a subfraction of intermediate density, LDL-II (d 1.034-1.044 g/ml), was the predominant LDL species but was not related to coronary heart disease risk. Plasma triglyceride showed a positive association with LDL-II (r = 0.51, P < 0.001) below a triglyceride level of 1.5 mmol/l. Above this threshold of 1.5 mmol/l, LDL-II and LDL-I showed significant negative associations with triglyceride (LDL-II r = -0.5, P < 0.001; LDL-I r = -0.45, P < 0.001). Small, dense LDL-III showed a weak positive association with triglyceride that became highly significant above the 1.5 mmol/l threshold (r = 0.54, P < 0.001). While age was positively related to LDL-II within the control subjects (r = 0.3, P < 0.05), there was no difference in the percentage abundance or concentration of LDL-III within control and CAD(-) subjects above and below the age of 40 years. Smoking was associated with a relative deficiency of the LDL-I subfraction (LDL-I to LDL-III ratio in smokers = 0.77, in ex-smokers = 0.95, in non-smokers = 1.89; P < 0.01), as was beta-blocker medication (% LDL-I, users vs. non-users, P < 0.05). Both of these effects could be explained by their primary influence on plasma triglyceride. Analysis of the frequency distributions for the three LDL subfractions revealed the concentration of small, dense LDL-III to be bimodal around a concentration of 100 mg (lipoprotein mass)/100 ml plasma. The calculation of odds ratios based on this figure indicated relative risk estimates of 4.5 (chi 2: P < 0.01) for the presence of coronary artery disease and 6.9 (chi 2: P < 0.001) for myocardial infarction.(ABSTRACT TRUNCATED AT 400 WORDS)

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 less than 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 in CAD vs. 87.4 +/- 79.6 mg/dl in normal men, P less than 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.

This study examined the effect of single dose etofibrate (1.0 g/day) on plasma lipids and lipoproteins in a group of eleven hypercholesterolemic individuals. The drug lowered plasma triglyceride and cholesterol by 32% and 14%, respectively (P less than 0.005). The cholesterol reduction came from a decrement in both VLDL and LDL. The cholesterol content of HDL did not change although its mass as determined by analytical ultracentrifugation rose by 29%. LDL metabolism was followed before and during drug therapy. Treatment increased catabolism of this lipoprotein by 14%, without affecting synthesis. The increased clearance resulted from activation (64%) of the LDL receptor pathway. There was a reciprocal decrease in the amount of lipoprotein channelled into the receptor-independent route.