Tapio Nikkari

Autoantibodies Against Oxidized Low Density Lipoprotein in Patients With Angiographically Verified Coronary Artery Disease

Oxidation of low density lipoproteins (LDL) obviously plays an important role in the pathogenesis of atherosclerosis. The purpose of the study was to determine whether antibodies against oxidized LDL are associated with coronary artery disease (CAD). We determined the serum levels of antibodies against copper-oxidized LDL by enzyme-linked immunosorbent assay in 58 patients with angiographically verified CAD and 34 controls without CAD. The mean antibody level, expressed in optical density units, was significantly higher in patients than in controls (0.150+/-0.088 versus 0.094+/-0.054, respectively; P=0.00089). In logistic regression analysis, high antibody level against oxidized LDL was associated significantly with CAD (P=0.0114), independent of age (P=0.00137), gender (P=0.0021), body mass index (P=0.5947), triglyceride concentration (P=0.9813), and total cholesterol-high density lipoprotein (HDL) cholesterol (P=0.0080) group. Similar analysis in nondiabetic subjects (n=79) and in men only (n=75) showed analogous results, with only minor changes in P values. The antibody level against oxidized LDL differed significantly between nonsmokers and smokers in CAD patients (P<0.00197) but not in controls (P=NS). In addition, the antibody level against oxidized LDL differed significantly between nonsmokers and smokers in subjects with low HDL cholesterol (</=0.9 mmol/L) but not in subjects with high HDL cholesterol (>0.9 mmol/L). In conclusion, elevated levels of antibodies against oxidized LDL were associated with CAD. The data suggest that oxidized LDL plays a role in the pathogenesis of atherosclerosis and suggest a protective function for HDL against LDL oxidation.

Expression of LDL Receptor, VLDL Receptor, LDL Receptor–Related Protein, and Scavenger Receptor in Rabbit Atherosclerotic Lesions Marked Induction of Scavenger Receptor and VLDL Receptor Expression During Lesion Development

BACKGROUND Atherosclerotic lesions contain foam cells that arise from monocyte-macrophages and smooth muscle cells (SMCs) by excessive uptake of lipoproteins. There are many candidate receptors for the lipid accumulation, such as LDL receptor (LDLR), VLDL receptor (VLDLR), LDL receptor-related protein (LRP), and scavenger receptors (SRs). However, little quantitative information exists on the expression of these receptors in normal and atherosclerotic arteries. METHODS AND RESULTS Competitive reverse transcription-polymerase chain reaction and in situ hybridization were used for the studies in New Zealand White (NZW) and Watanabe heritable hyperlipidemic (WHHL) rabbit aortic intima-medias. NZW rabbits were fed a 1% cholesterol diet for 0 (control group), 3, 6, or 14 weeks. LDLR mRNA expression was low in aortic intima-medias of all groups. Of the analyzed receptors, LRP had the highest expression in the control group, and its mRNA was induced threefold in the 14-week group, the aortas of which had extensive lesions. SR expression was low and VLDLR expression moderate in the control group. Both receptors were highly induced during cholesterol feeding (SRs, 3-fold and 270-fold induction; VLDLR, 15-fold and 100-fold induction in the 3-week and 14-week groups, respectively). Comparable results were obtained from WHHL rabbits: high basal LRP mRNA in normal intima-medias; moderate induction of LRP and marked induction of SRs and VLDLR in fatty streaks and fatty plaques. In situ hybridization indicated that LRP and VLDLR were expressed in SMCs and macrophages. VLDLR expression was also observed in endothelial cells. SR expression was detected only in macrophages. CONCLUSIONS SR and VLDLR mRNAs were highly induced in atherosclerotic lesions. VLDLR and LRP may be involved in the formation of both SMC-and macrophage-derived foam cells, whereas SRs play an important role in lipid uptake in macrophages.

Fatty Acid Composition of Serum Lipid Fractions in Relation to Gender and Quality of Dietary Fat

UNLABELLED The fatty acid compositions of serum lipid fractions are believed to reflect the quality of dietary fat, but only a few cross-sectional studies have examined these relationships in a representative free-living population. We related the composition of dietary fat obtained by 7-day food records from 84 free-living middle-aged married couples, on their habitual diets, to gas chromatographic analyses of the percentage compositions of fatty acids in three lipid fractions of fasting sera. Dietary polyunsaturated fat had Pearsons correlation coefficients of 0.63, 0.73 and 0.44 with n-6 polyunsaturated fatty acids in serum cholesteryl esters, triglycerides and phospholipids, respectively. Intake of fish showed correlations of 0.60, 0.36 and 0.52 with the percentage of eicosapentaenoate in the respective fractions. Dietary saturated fat had correlations of 0.57 and 0.54 with saturated fatty acids in serum cholesteryl esters and triglycerides, respectively. Dietary monounsaturated fat did not correlate positively with monounsaturated fatty acids in any serum lipid fraction. There were some small but significant gender differences in the serum fatty acid compositions. CONCLUSIONS of the three serum lipid fractions, triglycerides appear to be the best reflectors of dietary polyunsaturated and saturated fat, but the intake of monounsaturated fat is poorly reflected in all serum lipid fractions. Intake of fish is mirrored in all serum lipid fractions, best in cholesteryl esters and phospholipids.

Childhood Levels of Serum Apolipoproteins B and A-I Predict Carotid Intima-Media Thickness and Brachial Endothelial Function in Adulthood : The Cardiovascular Risk in Young Finns Study

OBJECTIVES The aim of this study was to determine whether apolipoproteins (apo) B and A-I measured in childhood and adolescence predict atherosclerosis in adulthood. BACKGROUND Exposure to dyslipidemia in childhood predicts the development of atherosclerosis. Apolipoproteins B and A-I might be good markers of atherogenic dyslipidemia, but there is a paucity of information concerning their importance in childhood. METHODS Apolipoproteins B and A-I, low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)-cholesterol, triglycerides, blood pressure, obesity, insulin, C-reactive protein, and smoking were assessed in 1980 and 2001 among 879 subjects in the Cardiovascular Risk in Young Finns Study (ages 3 to 18 years at baseline). Carotid artery intima-media thickness (IMT) and brachial artery flow-mediated dilation (FMD) were measured in 2001 at the age of 24 to 39 years. RESULTS In subjects ages 12 to 18 years at baseline, apoB and apoB/apoA-I ratio were directly (p < 0.001) related and apoA-I was inversely (p = 0.01) related with adulthood IMT. In subjects ages 3 to 18 years at baseline, apoB (p = 0.02) and the apoB/apoA-I ratio (p < 0.001) were inversely related and apoA-I (p = 0.003) was directly related to adulthood FMD. These relations were not altered when the effects of nonlipid risk factors and adulthood apolipoproteins were taken into account. The apoB/apoA-I ratio measured in adolescence was superior to LDL/HDL ratio (c-values, 0.623 vs. 0.569, p = 0.03) in predicting increased IMT in adulthood (IMT >or=90th percentile and/or carotid plaque). CONCLUSIONS Apolipoproteins B and A-I measured in children and adolescents reflect a lipoprotein profile predisposing to the development of subclinical atherosclerosis in adulthood. These markers might have value in pediatric lipid risk assessment.

Apolipoprotein E (apoE) polymorphism and its influence on ApoE concentrations in the cerebrospinal fluid in Finnish patients with Alzheimer's disease

The apoE phenotype of 83 patients with probable Alzheimers disease (AD) and of 164 non-demented controls was determined by isoelectric focusing and Western blotting. The proportion of the e4 allele was 0.548 in AD and 0.202 in controls (P<0.0001). The effect was seen in both early-onset and late-onset AD patients. The risk of AD in ɛ4 homozygotes was 18-fold greater than in individuals without the ɛ4 allele. ApoE concentrations were measured in serum and cerebrospinal fluid (CSF) from a subgroup of patients with AD (n=72) and controls (n=84) by a sandwich enzyme-linked immunosorbent assay. Although serum apoE concentrations were lower in individuals with the ɛ4 allele than in those without the e4 allele, CSF apoE concentrations did not vary in different phenotype groups. However, CSF apoE levels were lower in AD patients than in controls. We conclude that the inheritance of the ɛ4 allele of apoE is a risk factor for AD in the Finnish population.

The effect of storage on the fatty acid composition of human serum

The composition of fatty acids in blood plasma gives a rough estimate of the quality of dietary fat. In epidemiological studies serum is often used instead of plasma and the samples are stored at various temperatures for different time periods before analysis. Since blood contains enzymes capable of esterifying and hydrolysing lipids, it is possible that fatty acids are transferred from one lipid fraction to another and thus the fatty acid composition of a given lipid fraction may change, e.g. when blood is allowed to clot at room temperature. During prolonged storage the polyunsaturated fatty acids may autooxidise. Because of insufficient information about the subject in the literature, the present study aimed at quantifying changes in serum fatty acid composition possibly taking place during clotting or storage. Fatty acids of cholesteryl esters (CE), triacylglycerols (TG), free fatty acids (FFA) and phospholipids (PL), were analysed by gas chromatography. Plasma samples served as controls: they were immediately cooled and analysed within an hour.

In Vivo Low Density Lipoprotein Oxidation Relates to Coronary Reactivity in Young Men

OBJECTIVES This study was undertaken to examine the relation of in vivo low density lipoprotein (LDL) oxidation and other lipid risk factors to coronary reactivity in normal subjects. BACKGROUND Experimental studies have shown that oxidized LDL (ox-LDL) particles are injurious to the vascular wall by impairing its normal vasodilator function. METHODS We used noninvasive positron emission tomographic (PET) imaging with intravenous dipyridamole to measure coronary flow reserve, a marker of coronary endothelial and smooth muscle function, in 30 healthy men (mean [+/-SD] age 34.4 +/- 3.2 years). As a marker of in vivo LDL oxidation, the autoantibody titer against ox-LDL was measured by the enzyme-linked immunosorbent assay method. RESULTS Plasma levels of autoantibody titer against ox-LDL were inversely associated with coronary flow reserve (r = -0.42, p = 0.023). High LDL cholesterol levels (above median > 3.0 mmol/liter) were associated with a low coronary flow reserve only in subjects expressing simultaneously high levels of ox-LDL titer (above median). Subjects with simultaneously high levels of LDL cholesterol and ox-LDL titer had lower coronary flow reserve values than subjects in other groups (3.89 vs. > 5.0 in other groups, p = 0.066). CONCLUSIONS These data provide evidence for the role of ox-LDL in affecting the coronary reactivity in vivo and support the concept that oxidative modification of LDL particles provides a mechanism by which high LDL concentrations exhibit injurious effects on the coronary vascular bed.

Changes in the Fatty Acid Composition of Preterm and Term Human Milk from 1 Week to 6 Months of Lactation

Using capillary gas chromatography, we analyzed the fatty acid composition of human milk from 23 women who had delivered prematurely and 16 women who had delivered at term. Milk samples were obtained at 1, 2, 4, 12, and 26 weeks after delivery. The relative amounts of saturated and monounsaturated fatty acids in preterm and term milk remained stable throughout the 6 months of lactation. The proportions of linoleate (18:2n-6) and α-linolenate (18:3n-3) were similar in preterm and term milk and showed an increasing trend from transitional (8.7–9.9% and 0.9–1.1% of total fatty acids, respectively) to mature milk (9.9–11.8% and 1.2–1.5%, respectively). The proportions of the major long-chain polyun-saturated fatty acids (LCP), 20:3n-6, 20:4n-6, 22:5n-3 and 22:6n-3, were highest at 1 week and decreased thereafter in both types of milk. In term milk, the proportion of LCP continued to decrease from 1 month to 6 months, whereas in preterm milk it was fairly constant. Consequently, at 6 months of lactation, the relative content of arachidonate (20:4n-6) was 1.5 times (p < 0.05) and that of docosa-hexaenoate (22:6n-3) was two times higher (p < 0.01) in preterm than in term milk. We conclude that in long-term lactation, preterm human milk provides a significantly higher relative supply of LCP than term human milk. This higher LCP content may be of special benefit to the development of a preterm infant.

Atherosclerosis precursors in Finnish children and adolescents. IV. Serum lipids in newborns, children and adolescents

ABSTRACT. A multicentre study on atherosclerosis precursors in Finnish children and adolescents was carried out in five urban and 12 rural areas in the autumn of 1980 and spring of 1981. Serum lipids, i.e. cholesterol (TC), HDL‐cholesterol (HDL‐C) and triglyceride (TG) concentrations were determined and LDL‐cholesterol (LDL‐C) was calculated in 630 newborns and 3,596 children aged 3, 6, 9, 12, 15 and 18 years. In the newborns the mean serum TC concentration was 1.50 mmol/l, and the ratio of HDL‐C to TC was 0.44. Newborn boys had lower mean TC, HDL‐C and LDL‐C values than the girls. In 3 to 18‐year‐old children the mean TC, LDL‐C and HDL‐C concentrations were 4.83 mmol/l, 3.09 mmol/l and 1.38 mmol/l, respectively. During puberty, TC mean values decreased, more so in boys. The serum levels of HDL‐C also decreased, especially in boys, and after passing puberty boys had lower mean HDL‐C levels than girls (1.26 vs. 1.39 mmol/l, p

Down's syndrome and atherosclerosis

Necropsy findings in patients with Downs syndrome have suggested an absence of atherosclerosis throughout the cardiovascular system, but there are also contradictory results. We compared the left coronary arteries of 15 institutionalised Downs syndrome patients (5 males, 10 females, mean age 51 years) with those of 6 other institutionalised mentally retarded patients (4 males, 2 females, mean age 49) and 20 normal, free-living subjects (10 males, 10 females, mean age 48) by macroscopic inspection of the opened coronary arteries and by biochemical analysis of their intima-media. The arteries of Down patients contained a lower percentage of raised lesions and less calcium than the arteries of the control groups. Thus, even though the coronary arteries of mongoloids were not completely free of atherosclerosis, it was milder than in other mental patients and free-living subjects of the same age.