Olle Wiklund

Multivariate analyses of serum apolipoproteins and risk factors in relation to acute myocardial infarction.

In 25 middle-aged infarction survivors and 76 corresponding controls, representative for a well-defined community, multivariate analysis was used to evaluate whether serum apolipoproteins were better discriminators of infarction survivors than serum lipids and other risk factors. Levels of serum cholesterol and triglycerides, alphalipoprotein cholesterol, apolipoproteins A-l, A-ll, B, and D, as well as tobacco smoking and other risk factors, were included. In descending order, serum apo A-ll levels (tb = −3.12, p = 0.002), tobacco consumption (tb = 2.64, p = 0.010), and serum triglycerides (tb = 2.06, p = 0.042) contributed significantly to the multiple regression on myocardial infarction (R = 0.53, p = 0.00001). When entered into a discriminant function, these three variables gave a good separation between survivors and controls. Of the survivors, 50% were above the 90th percentlle in the control group. The relative prevalence of infarction increased continuously with increasing values of the function from zero to more than 6 times the average. Serum apo A-ll levels alone were almost as good in separating cases and controls. From this study, we concluded that, among apolipoproteins, apo A-ll seems to be a more sensitive discriminator of infarction survivors than other risk factors.

A novel cellular marker of insulin resistance and early atherosclerosis in humans is related to impaired fat cell differentiation and low adiponectin

The epidemic increase in type 2 diabetes can be prevented only if markers of risk can be identified and used for early intervention. We examined the clinical phenotype of individuals characterized by normal or low IRS‐1 protein expression in fat cells as well as the potential molecular mechanisms related to the adipose tissue. Twenty‐five non‐obese individuals with low or normal IRS‐1 expression in subcutaneous abdominal fat cells were extensively characterized and the results compared with 71 carefully matched subjects with or without a known genetic predisposition for type 2 diabetes. In contrast to the commonlyused risk marker, knownheredity for diabetes, low cellular IRS‐1 identified individuals who were markedly insulin resistant, had high proinsulin and insulin levels, and exhibited evidence of early atherosclerosis measured as increased intima media thickness in the carotid artery bulb. Circulating levels of adiponectin were also significantly reduced. Gene analyses of fat cells in a parallel study showed attenuated expression of several genes related to fat cell differentiation (adiponectin, aP2, PPARγ, and lipoprotein lipase) in the group of individuals characterized by a low IRS‐1 expression and insulin resistance. A low IRS‐1 expression in fat cells is a marker of insulin resistance and risk for type 2 diabetes and is associated with evidence of early vascular complications. Impaired adipocyte differentiation, including low gene expression and circulating levels of adiponectin, can provide a link between the cellular marker and the in vivo phenotype.—Jansson, P.‐A., Pellmé, F., Hammarstedt, A., Sandqvist, M., Brekke, H., Caidahl, K., Forsberg, M., Volkmann, R., Carvalho, E., Funahashi, T., Matsuzawa, Y., Wiklund, O., Yang, X., Taskinen, M.‐R., Smith, U. A novel cellular marker of insulin resistance and early atherosclerosis in humans is related to impaired fat cell differentiation and low adiponectin. FASEB J. 17, 1434–1440 (2003)

Serum apolipoprotein levels in relation to acute myocardial infarction and its risk factors: Apolipoprotein A-I levels in male survivors of myocardial infarction

The significance of high density lipoproteins in the etiology of clinical complications to atherosclerosis has recently received increased attention. The levels of the major apolipoprotein in high density lipoproteins, apoA-I, have been determined in patients who had had an acute myocardial infarction, and compared with a cholesterol-matched and a randomly selected control group. ApoA-I levels were lower in the patients than in the control groups. ApoA-I levels were also lower in smokers than in non-smokers. The difference between patients and control groups persisted even when the groups were stratified according to smoking habits. This suggests that low levels of apo-A-I as well as alphalipoprotein cholesterol are additional characteristics of the infarction patients, even when the established risk factors, smoking and hyperlipidemia are taken into account.

Binding parameters and concentration modulate formation of complexes between LDL and arterial proteoglycans in serum

The interactions of LDL with extracellular matrix proteoglycans apparently contribute to the accumulation of apo B-lipoproteins in atherogenesis. Serum LDL forms insoluble complexes with human arterial chondroitin sulfate proteoglycans (CSPG). While the amount of insolubilized LDL varies, serum from survivors of myocardial infarcts and ischaemic subjects shows higher values of CSPG-insolubilized LDL than serum from controls. In this study, we explored the relationship between the formation of LDL-CSPG complexes in serum and some LDL properties, using binding isotherms and characterization of isolated LDL from 12 healthy controls and 12 young myocardial infarct survivors. The amount of LDL insolubilized in serum from solutions of CSPG was found to be a function of the product Bt (total binding) x the amount of serum LDL-cholesterol. Furthermore, the Bt values for the isolated LDL from controls and patients could be predicted with more than 70% certainty by using a multiple regression model which included the cholesterol/protein ratio, protein/triglyceride ratio, isoelectric point and the affinity coefficient of the lipoprotein for CSPG. The results indicate that LDL-CSPG measurements in serum are dependent upon both LDL concentration and structural properties which are related to its tendency to form complexes with arterial CSPG.

Seasonal variations in serum lipid and apolipoprotein levels evaluated by periodic regression analyses

Periodic regression analyses have been employed in a study of the variations in serum lipoprotein variables in 12 men during 12 months. The monthly means in the A-II polypeptide (A-II) and apolipoprotein B (apoB) varied significantly with time according to sine curves. Maxima of +5 and +8% from the annual averages were observed for A-II and apoB, respectively, during the winter months, whereas minima of -5 and -8%, respectively, occurred during summer. There were considerable individual differences in amplitude and phase in serum cholesterol, alpha-lipoprotein cholesterol and apolipoprotein A-I (apoA-I), whereas the variations in monthly means of the whole group were not significant. Storage of sera at -85 degrees C for 1 yr seems not to have influenced the results of determinations of serum cholesterol and triglycerides, apoA-I, and A-II, but may have caused differences observed in apoB between the two months of May 1978 and 1979.

Serum apolipoprotein levels in relation to acute myocardial infarction and its risk factors Determination of apolipoprotein D

Apolipoprotein A-I, A-II and apoD are all primarily found in the density region d > 1.063 g/ml. In the present study the serum apoD level was determined by electroimmunoassay in a random population sample of middle-aged men (n = 76). The mean level was 0.075 g/l with a standard deviation of 0.017. The apoD level was also determined in a group of patients, in the same age range, with sustained acute myocardial infarction (n = 25). The patients were compared with the random population sample and with a control group matched to the patients with regard to age, serum cholesterol level and body weight index. There was no difference in apoD level between patients and either control group. This is in contrast with the earlier reported low apoA-I, A-II as well as alphalipoprotein cholesterol levels in the same patient group.

Lecithin : cholesterol acyl transfer (LACT) and fatty acid composition of lecithin and cholesterol esters in young male myocardial infarction survivors

Lecithin : cholesterol acyl transfer (LCAT) and relative fatty acid composition of serum lecithin and cholesterol esters were studied in 20 young male survivors of myocardial infarction (MI). Comparisons were made with controls matched for serum cholesterol. There was no difference in LCAT rate between MI patients and controls. The relative content of arachidonic acid in cholesterol esters was higher in MI patients. The fatty acid composition of lecithin and cholesterol esters suggests an equal transfer of linoleic and oleic acids from lecithin to cholesterol. Furthermore negative correlations were found between LCAT and linoleic acid content of lecithin (r = --0.43, P less than 0.01) and cholesterol esters (r = --0.45, P less than 0.01). This inverse relationship does not seem to be linked to substrate specificity, but rather to be mediated by influences in common on serum lipid content and turnover.

Arterial cholesterol and DNA contents in relation to serum lipids and apolipoproteins: Studies on cystic artery biopsies

Though various relationships between serum lipoprotein levels and risk for atherosclerotic disease have been shown there are only a few studies on the relationships between serum lipoprotein levels and the lipid contents of the arterial wall. This study presents cholesterol and DNA contents of arterial tissue from biopsies of the cystic artery in 23 patients with uncomplicated cholecystolithiasis. Serum levels of cholesterol, triglycerides, alphalipoprotein cholesterol, apoA-I, A-II and B were determined, and the relationships between artery and serum variables were calculated. There was a positive correlation between serum apoB and the arterial cholesterol, normalized to the DNA contents (r = 0.43, P less than 0.05). There was a tendency towards an inverse correlation between the alpha-lipoprotein cholesterol levels and the arterial cholesterol (r = 0.39, P less than 0.10). There were no significant correlations between serum apoA-I or A-II and the arterial cholesterol contents. These data indicate that deposition of cholesterol in the arterial wall is related to the serum level of apoB, with higher levels of arterial cholesterol at higher serum levels of apoB. Earlier observations of an inverse correlation between alphalipoprotein cholesterol and arterial cholesterol could, however, not be conclusively confirmed.U

The Molecular Basis for Lipoprotein Interaction with Vascular Tissue

Local and focal retention of lipoproteins rather than increased influx appears to be the basis for lipoprotein deposition in arterial tissue during atherogenesis. Binding of low density lipoproteins to arterial chondroitin sulphate rich proteoglycans is mediated by specific hydrophilic peptide sequences in apoB, characterized by a high frequency of basic amino acids. One of these sequences is considered to be involved in the interaction between the lipoproteins and the LDL receptor. Consequently, it might be postulated that the receptor-mediated cellular uptake of LDL could be inhibited in the presence of an excess of arterial proteoglycans. However, LDL which has been precipitated by proteoglycan and subsequently resolubilized is taken up more avidly than native LDL both in macrophages and in smooth muscle cells. This appears to be due to a selection by the proteoglycans of a more reactive fraction of LDL. This fraction has a smaller size and less surface phospholipids. As smaller LDL particles also have a higher transfer rate into the arterial tissue they may be particularly atherogenic. Low density lipoproteins appear to be taken up with higher affinity by arterial macrophages than by smooth muscle cells. The selective transfer of the LDL to macrophages can be inhibited by alpha-tocopherol suggesting that oxidative modification may be involved in this process. In fact, binding of LDL to arterial proteoglycans also appears to increase the susceptibility of the lipoproteins to oxidative modification, as well as the susceptibility to proteolytic degradation. Thus, the interaction of LDL with proteoglycans might be involved in several of the key elements of the atherogenic process.