Endothelial dysfunction in chronic renal failure: roles of lipoprotein oxidation and pro-inflammatory cytokines.

BACKGROUND: Chronic renal failure (CRF) is associated with an increased risk of ischaemic heart disease (IHD), but the mechanisms responsible are controversial. We investigated the relationship of two sets of candidate mechanisms-indices of LDL oxidation and markers of inflammatory activity-with vascular endothelial dysfunction (VED). METHODS: We carried out cross-sectional analysis of 23 dialysed and 16 non-dialysed CRF patients, 28 healthy controls, and 20 patients with stable angina and normal renal function. The following were determined: (i) LDL oxidation by Cu(2+) and ultraviolet light, serum autoantibodies to oxidized LDL (oxLDL); (ii) forearm flow-mediated vasodilatation, plasma concentrations of adhesion molecules, and von Willebrand factor (vWF); and (iii) circulating levels of TNF-alpha and IL-6, C-reactive protein (CRP), and fibrinogen. RESULTS: Endothelium-dependent vasodilatation (EDV) was lower in angina, pre-dialysis, and dialysis CRF patients than in controls (all P<0.005). Compared with controls, vWf (P<0.005) and adhesion molecules (vCAM-1, P<0.005; iCAM-1, P=0.01; E-selectin, P=0.05) were raised in dialysis, and vCAM-1 (P=0.01) in pre-dialysis CRF patients. Dialysed patients had lower HDL cholesterol (P=0.01) and higher triglyceride (P=0.05) than controls, but LDL-oxidation was similar in all groups. Autoantibodies to oxLDL were raised in angina (P<0.005) and pre-dialysis (P=0.006), but were absent in most dialysed patients. Concentrations of IL-6, TNF-alpha, CRP and fibrinogen were elevated in CRF compared with control and angina patients (P<0.005). In the whole population, IL-6 and TNF-alpha correlated negatively with EDV, HDL cholesterol, and positively with triglyceride, blood pressure, vWf, iCAM-1, vCAM-1 and E-selectin (r=-0.43 to +0.70, all P<0.05). CONCLUSIONS: Endothelial dysfunction is unrelated to LDL oxidation, suggesting that LDL oxidation might not be a major cause of VED in CRF. In contrast VED was more severe in CRF than in angina patients and is associated with increased acute-phase proteins and plasma cytokines, demonstrating a chronic inflammatory state. These observations may explain the VED and increased IHD risk of patients with CRF.

Apolipoproteins A-I, A-II and B, lipoprotein(a) and the risk of ischaemic heart disease: the Caerphilly study.

Apolipoproteins B, A-I and Lp(a) have been proposed as independent predictors of subsequent ischaemic heart disease (IHD) improving on the prediction obtained by routine lipid measurements. In this report we have investigated the relative predictive ability of apolipoproteins and plasma lipids in a prospective study of middle aged men. 2398 men aged 49-65 years from the general population of Caerphilly, South Wales, UK were screened for evidence of IHD. After an overnight fast 2225 men each provided a venous blood sample on which plasma lipids, apolipoproteins B, A-I, A-II, and lipoprotein (a) (Lp(a)) were measured. Over a follow-up period of nearly 9 years, 282 (12%) men developed major IHD. Multiple logistic regression analysis showed that after adjusting for standard cardiovascular risk factors other than lipids there was a strong trend (standardised relative odds (SRO) = 1.20; P = 0.009) for incidence of IHD to increase with apolipoprotein B. However, on further adjusting for total cholesterol this trend largely disappeared (SRO = 1.05; P = 0.57). Similarly, a trend for incidence of IHD to increase with decreasing apolipoprotein A-I (SRO = 1.18; P = 0.02) disappeared when HDL cholesterol was added to the model. Levels of apolipoprotein A-II were not related to risk of subsequent IHD. Incidence of IHD was effectively constant over nearly 90% of the range of Lp(a). Only among the 5% of men with Lp(a) greater than 70 mg dL-1 was the risk of IHD significantly (P = 0.04) greater than among men with Lp(a) less than 10 mg dL-1. Apolipoproteins B and A-I do not improve on the prediction of risk of IHD provided by total and HDL cholesterol, respectively. Apolipoprotein A-II was not related to risk of IHD. Lp(a) may be independently associated with incident IHD among the 5-10% of men with the highest levels.

The influence of lifestyle and diet on the lipoprotein profile of border collies.

Plasma lipoprotein cholesterol and triglycerides were determined in two groups of Border Collies, one actively working and the other pets. Baseline concentrations of total, low density lipoprotein (LDL) and high density lipoprotein (HDL) cholesterol were higher, and HDL triglyceride concentrations lower in the pet dogs. Lifestyle of the dogs was assessed by questionnaire completed by the owners. Measurement of exercise was made by visual observation and using a Caltrac activity monitor. The working dogs were a homogenous group with respect to lifestyle and diet, but the pet dogs showed differences in lipoprotein profile relating to housing, dietary fat and exercise intensity. Two diets with different levels of dietary fat (13 and 20 per cent dry weight) were given for two months each. After two months on either of the diets the cholesterol concentration of the working dogs increased and HDL triglyceride concentration decreased, and there were no significant differences between the groups, but very low density lipoprotein (VLDL) triglyceride increased significantly in the less active pet dogs.

The effect of dietary changes on plasma lipids and lipoproteins of six Labrador retrievers.

Six healthy, spayed female Labrador Retrievers (aged 5.5 to 11 years), kept under controlled conditions of exercise and housing, were fed a diet of 15 per cent fat, 24 per cent carbohydrate and 33 per cent protein for two weeks before and between each of three test diets, of differing fat to carbohydrate ratios (A 13:44, B 20:33, C 25:26 fat:carbohydrate gm per cent dry weight) given in a predetermined order for four weeks each. Fasting plasma lipoproteins and total fatty acids were measured weekly. In the fourth week of each test period post-prandial plasma lipoproteins were measured. Diets B and C increased total (P < 0.001) and LDL cholesterol (P < 0.05) whilst diet A increased HDL triglyceride (P < 0.05). Eicosapentaenoic acid (C20:5) increased on diets B and C, and oleic acid (C18:1) on diet A. Post-prandial hypertriglyceridaemia occurred on all diets. Chylomicron clearance was slower on higher fat diets. Relatively small dietary changes produced significant alterations of plasma lipids, lipoproteins and chylomicron clearance.

Changes in plasma lipoprotein during the oestrous cycle of the bitch.

Five bitches were kept under controlled conditions of diet and exercise for up to four months. They were monitored at regular time intervals for fasting plasma concentrations of cholesterol, triacylglycerols and apolipoproteins AI and B. Lipoprotein cholesterol and triacylglycerol concentrations were also determined in the fasting plasma. Vaginal cytology and plasma progesterone were monitored at weekly intervals to determine the oestrous state of the bitches. Lipoprotein and apolipoprotein concentrations remained steady during anoestrus but large increases and wide fluctuations were shown in the concentrations of both cholesterol and triacylglycerols during metoestrus. Metabolic studies involving the measurement of lipids in canine blood must take into account the stage of oestrus of any bitches involved.

Lipoprotein levels following treatment with cyproterone acetate or LHRH analogues.

Fasting serum lipoproteins were measured in patients with carcinoma of the prostate. Twelve patients were on no hormonal treatment (Group 1). Fifteen were on cyproterone acetate (Group 3), 17 were on the long-acting LHRH analogue Zoladex (Group 4) and 11 on a combination of cyproterone acetate and Zoladex (group 5). In addition, 27 patients with benign urological disease were taken as controls (Group 2). In both groups in which cyproterone acetate was part of the treatment the total high density lipoprotein cholesterol levels were significantly lower than in the other groups. Patients on cyproterone acetate alone had significantly higher levels of very low density lipoprotein (VLDL) triglyceride levels than those not on cyproterone acetate. These results confirm changes in serum lipoprotein levels in patients taking cyproterone acetate and these changes may have potential adverse effects if the treatment is prolonged.

Plasma lipoprotein lipids in five different breeds of dogs.

Plasma and lipoprotein cholesterol and triglycerides, and apolipoproteins AI and B, were determined in five common breeds of pet dogs, labrador, beagle, West Highland terrier, cairn terrier and dachshund, kept under carefully controlled conditions approximating as closely as possible to normal domestic living. Although the total levels of both cholesterol and triglycerides in plasma did not vary significantly between the breeds, there were significant interbreed differences in the lipoprotein fractions. Thus high density lipoproteins (HDL) which are the major carriers of cholesterol in all dogs, was higher in the smallest breed, the cairn, than in the largest, the labrador. In contrast, the low density lipoprotein (LDL) was lowest in the cairn and highest in the labrador. Variation in HDL cholesterol levels arose from both subfractions, HDL2 and HDL3. Thus metabolic studies involving canine lipids should include measurement of lipoprotein lipids and take account of interbreed variation.

Coffee, blood pressure and plasma lipids: a randomized controlled trial.

A randomized controlled trial was conducted to examine the effects of coffee (as commonly drunk in Britain) on blood pressure and plasma lipids in healthy subjects. Fifty-four subjects followed three regimens successively, the order being randomized according to a Latin square design: five or more cups of coffee daily for 4 weeks; five or more cups of decaffeinated coffee daily for 4 weeks but no ordinary coffee; no coffee for 4 weeks. Coffee appeared to cause a small rise (of 3 mm Hg) in recumbent systolic blood pressure; this effect was less than, and obscured by, changes induced by posture and mild stress. No consistent changes attributable to coffee were found in diastolic blood pressure or pulse rate. Small changes in the expected directions occurred in plasma high density lipoprotein (HDL) cholesterol and apolipoprotein AI (decrease), and in total cholesterol, non-HDL cholesterol and apolipoprotein B (increase), but none of these were statistically significant. The effect of coffee on risk of heart disease in Britain is probably small.

Plasma and lipoprotein lipids and apolipoproteins AI, AII and B in patients with chronic airflow limitation.

Plasma and lipoprotein cholesterol and triglycerides, and plasma apolipoproteins AI, AII and B were compared in patients with chronic airflow limitation, and normal controls matched for body mass index. The controls were non-smokers, and free from respiratory disease. High-density lipoprotein (HDL) cholesterol concentration was significantly elevated in the patients, due mainly to a raised HDL2 cholesterol level. HDL triglyceride was significantly lower in the patients. All other lipids were not different from normal. Apolipoprotein AI levels were significantly raised in the patients but other apolipoproteins were unchanged. The changes found may account in part for the fact that patients with chronic airflow limitation have a lower incidence of atherosclerotic heart disease.