Higher Apo Research Articles

Is apolipoprotein(a) a susceptibility gene for Type I diabetes mellitus and related to long-term survival?

High lipoprotein(a) [Lp(a)] plasma concentrations are a genetically determined risk factor for atherosclerotic complications. In healthy subjects Lp(a) concentrations are mostly controlled by the apolipoprotein(a) [apo(a)] gene locus which determines a size polymorphism with more than 30 alleles. Subjects with low molecular weight apo(a) phenotypes on average have higher Lp(a) concentrations than those with high molecular weight apo(a) phenotypes. There are many opinions about whether and why Lp(a) is raised in patients with Type I diabetes (insulin-dependent) mellitus. We investigated Lp(a) plasma concentrations and apo(a) phenotypes in 327 patients with Type I diabetes mellitus (disease duration 1-61 years) and in 200 control subjects matched for age and sex. Patients with a disease duration of up to 15 years had significantly higher Lp(a) concentrations (24.3 +/- 34.0 mg/dl vs 16.7 +/- 22.6 mg/dl, p = 0.014) compared with control subjects. This increase can be explained by a considerably higher frequency of low molecular weight apo(a) phenotypes (38.9% vs 23.5%, p < 0.005). The frequency of low molecular weight apo(a) phenotypes decreased continuously with disease duration from 41.7% in those with disease duration of up to 5 years to 18.2% in those with the disease lasting more than 35 years. Our data show that an increase of Lp(a) in Type I diabetic patients can only be observed in groups with short diabetes duration and that this elevation is genetically determined. Therefore, the apo(a) gene, located at 6q26-27, might be a susceptibility gene for Type I diabetes mellitus which is supported by recently published studies reporting evidence for linkage of this region (6q27) with Type I diabetes mellitus. Furthermore, the decreasing frequency of low molecular weight apo(a) phenotypes with disease duration suggests a survivor effect.

Inflammation enhances cardiovascular risk and mortality in hemodialysis patients

Atherosclerosis, a major problem in patients on chronic hemodialysis, has been characterized as an inflammatory disease. C-reactive protein (CRP), the prototypical acute phase protein in humans, is a predictor of cardiovascular mortality in the general population. We hypothesize that several of the classic, as well as nontraditional, cardiovascular risk factors may respond to acute phase reactions. An activated acute phase response may influence or predict cardiovascular risk. In 280 stable hemodialysis patients, serum lipids, apolipoproteins (apo) A-I and B, lipoprotein(a) [Lp(a)], fibrinogen, and serum albumin (Salb) were determined in relation to CRP and serum amyloid A (SAA), two sensitive markers of an acute phase response. Mortality was monitored prospectively over a two year period. Serum CRP and SAA were found to be elevated (more than 8 and more than 10 mg/liter, respectively) in 46% and 47% of the patients in the absence of clinically apparent infection. Patients with elevated CRP or SAA had significantly higher serum levels of Lp(a), higher plasma fibrinogen, and lower serum levels of high-density lipoprotein cholesterol, apo A-I, and Salb than patients with normal CRP or SAA. The rise in Lp(a) concentration was restricted to patients exhibiting high molecular weight apo(a) isoforms. During follow-up, 72 patients (25.7%) had died, mostly due to cardiovascular events (58%). Overall mortality and cardiovascular mortality were significantly higher in patients with elevated CRP (31% vs. 16%, P < 0.0001, and 23% vs. 5%, P < 0.0001, respectively) or SAA (29% vs. 19%, P = 0.004, and 20 vs. 10%, P = 0.008, respectively) and were also higher in patients with Salb of lower than 40 g/liter (44% vs. 14%, P < 0.0001, and 34% vs. 6%, P < 0.0001, respectively). Univariate Cox regression analysis demonstrated that age, diabetes, pre-existing cardiovascular disease, body mass index, CRP, SAA, Salb, fibrinogen, apo A-I, and Lp(a) were significantly associated with the risk of all-cause and cardiovascular mortality. During multivariate regression analysis, SAA, fibrinogen, apo A-I, and Lp(a) lost their predictive values, but age and CRP remained powerful independent predictors of both overall death and cardiovascular death. These results suggest that a considerable number of hemodialysis patients exhibit an activated acute phase response, which is closely related to high levels of atherogenic vascular risk factors and cardiovascular death. The mechanisms of activated acute phase reaction in patients on chronic hemodialysis remain to be identified. A successful treatment of the inflammatory condition may improve long-term survival in these patients.

Lipoprotein(a) levels and apolipoprotein(a) isoforms related to life style risk factors.

Lipoprotein(a) [Lp(a)] has been considered to be a predictor of premature coronary heart disease and other cardiovascular diseases. Lp(a) levels are largely genetically determined, but the detailed mechanism of Lp(a) elevation is uncertain. We examined the association between Lp(a) levels and apolipoprotein(a) [apo(a)] phenotypes as well as that of Lp(a) level and other various conditions. The subjects were 280 healthy Japanese (102 males and 178 females) aged 39 to 70 years who were living in a rural community in 1992. We obtained apo(a) phenotypes determined by SDS-PAGE as well as Lp(a) levels and other cardiovascular risk factors. We combined apo(a) phenotypes form 4 groups according to molecular weights (from high apo(a) molecular weight to low: I, II, III and IV). Lp(a) levels were associated with apo(a) phenotype-groups, that is, they were inversely associated with apo(a) molecular weight. Small apo(a) phenotypes were less frequent than large ones. The median Lp(a) level was higher in smoking (29.2 mg/dL) than in non-smoking subjects (18.5 mg/dL) in phenotype-group III. Adjusted means of total cholesterol and fibrinogen levels in apo(a) phenotype-group IV were the highest of all phenotype-groups. Age, apo(a) phenotype, smoking status, total cholesterol and fibrinogen were positively correlated with Lp(a) levels by multiple regression analysis. Lp(a) levels were found to be mainly associated with apo(a) phenotype, but varied broadly within the same apo(a) phenotype at various conditions, such as smoking status and high total cholesterol.

Multilocus approach to cardiovascular risk

Until now, our familial studies have showed that shared genetic and environmental factors are involved on lipid parameters variability. More precisely, being working on 119 families we have showed that: a) The apolipo-protein E (apo E) common polymorphism is involved in the total cholesterol, low density lipoprotein cholesterol (LDL-Chol), apo E, apo B levels variability, b) the apolipoprotein A-IV gene had no effect on lipid metabolism parameters variability, apo A-IV levels included, c) the apolipoprotein B gene was associated with total cholesterol, high density lipoprotein cholesterol, LDL-Chol, triglycerides and apo B levels genetic variability, d) the lipoprotein lipase (LPL) gene was responsible for 6.5 % of the triglycerides variability, e) the apo E and LPL 447 polymorphisms influence in conjunction lipid parameters. These preliminary results on effects and combination effects of polymorphic genes show the interest of a multilocus approach.We have used in a subgroup of 416 individuals of a familial cohort (Stanislas Cohort) a prototype assay that genotypes a panel of 35 polymorphic sites on 15 candidate genes of Cardiovascular diseases. Each sample is amplified by two multiplex polymerase chain reactions, then hybridized to an array of immobilized, oligonucleotide probes. The frequencies of the rare alleles were in agreement with those reported by others in caucasian populations. The realisation of this multiplex assay in the 1 006 families of the Stanislas Cohort, which is underway, will allow us a better understanding of the inter-individual variability of lipids and will contribute to the determination of the genetic susceptibility of one's individual to cardiovascular risk.

Lipoprotein(a) Levels and Isoforms and Fibrinolytic Activity in Postmenopause – Influence of Hormone Replacement Therapy

Epidemiological studies suggest that hormone replacement therapy (HRT) decreases the risk of cardiovascular disease in postmenopausal women via several mechanisms, including modifications in the fibrinolytic system and lipoprotein(a) [Lp(a)] levels. The aim of this study was to examine the influence of the levels and isoforms of Lp(a) on fibrinolytic activity in 91 postmenopausal women in comparison with premenopause and analyze the effect of HRT on those parameters. In postmenopause, an increase in plasma Lp(a) and plasminogen activator inhibitor-1 (PAI-1) levels was found. A significant inverse correlation was observed between Lp(a) or PAI-1 levels and plasmin generation. Plasma samples with low molecular weight (MW) apo(a) isoforms showed higher plasmin inhibition than plasmas with high MW apo(a) isoforms and similar levels of total Lp(a) and PAI-1. HRT induced a significant decrease in Lp(a) and PAI-1 levels and an increase in estradiol levels, as well as an increase in fibrinolytic activity. A significant correlation was found between the percentages of variation in Lp(a) levels and in plasmin generation and between the percentages of variation in PAI-1 levels and in the euglobulin lysis time under HRT. In conclusion, the increase in fibrinolytic activity observed in women under HRT could be explained by two independent mechanisms: (a) the decrease in PAI-1 and (b) the decrease in the inhibition of plasmin generation due to the decrease in Lp(a) levels.

Genetic variation in the amino-terminal part of apolipoprotein B: studies in hyperlipidemic patients.

Hypertriglyceridemia is a heterogeneous lipid disorder often running in families. Variation in the apolipoprotein B (apo B) gene has been associated with serum triglyceride levels. Recently, a role of the amino-terminal end of apo B in binding with lipoprotein lipase (LPL) has been suggested. We screened the 5' end of the apo B gene in 76 Finnish severely hypertriglyceridemic (> 6 mmol/l) patients, using a single-strand conformation polymorphism (SSCP) screening method. We detected a previously unreported polymorphic C2316-->A change, causing a Val703-->Ile substitution. The minor 703 Ile allele frequency was 0.04 in hypercholesterolemic and normolipidemic population samples. This allele was associated with lower serum triglyceride levels in a normolipidemic population sample. Analysis of two previously reported polymorphisms also located in the amino-terminal domain of apo B (Thr71-->Ile and Val591-->Ala) revealed elevating effects on serum apo B concentrations in hypertriglyceridemic individuals. The 591 Ala allele was associated with elevated apo B (P=0.011), and individuals with both minor alleles (apo B 591 Ala + and apo B 71 Ile +) had higher apo B levels compared to subjects homozygous for both common alleles (P=0.004). Although no DNA sequence change seemed to be the cause of hypertriglyceridemia in our patients, genetic variation in the 5' end of the apo B gene may contribute to changes in serum apo B levels in hypertriglyceridemic patients.

Mechanized lipoprotein(a) assay as a marker for coronary artery disease illustrates the usefulness of high lipoprotein(a) levels

Only a few simple lipoprotein(a) [Lp(a)] assays are available in kit form for use in clinical laboratories. The present study compares the analytical and clinical performance of a mechanized immunonephelometric method to enzyme-linked immunosorbent assay. Clinical performance was evaluated by measuring lipoprotein markers in 191 patients, with the extent of stenosis defined by angiography. Analytically, both methods showed little or no correlation with cholesterol, high density lipoprotein cholesterol, elevated triglycerides, apo A-I and apo B, while they showed good agreement with one another ( r=0.88). The methods showed comparable well known differences between black and white persons. Logistic regression indicated that Lp(a) was a weak but independent marker for coronary artery disease (CAD). Receiver operator characteristic curve analysis showed an association with CAD only at higher Lp(a) concentrations. We conclude that Lp(a) at higher concentrations may be a contributory marker for CAD and that mechanized nephelometric assays for it can be used in the clinical laboratory.

Lipoprotein(a) levels and apolipoprotein(a) polymorphism in type 1 diabetes mellitus: relationships to microvascular and neurological complications.

To investigate plasma concentrations of lipoprotein(a) [Lp(a)] and apolipoprotein(a) [apo(a)] polymorphism in relation to the presence of microvascular and neurological complications in type 1 diabetes mellitus, 118 young diabetic patients and 127 age-matched controls were recruited. Lp(a) levels were higher in patients than in controls, but the apo(a) isoforms distribution did not differ between the two groups [higher prevalence of isoforms of high relative molecular mass (RMM) in both groups]. Microalbuminuric patients had Lp(a) levels significantly greater than normoalbuminuric patients, and normoalbuminuric patients showed higher Lp(a) levels than controls. Patients with retinopathy or neuropathy showed similar Lp(a) levels to those without retinopathy or neuropathy. No differences in apo(a) isoforms frequencies were observed between subgroups with and without complications (higher prevalence of isoforms of high RMM in every subgroup). However, among patients with retinopathy, those with proliferative retinopathy had higher Lp(a) levels and a different apo(a) isoforms distribution (higher prevalence of isoforms of low RMM) than those with non-proliferative and background retinopathy (higher prevalence of isoforms of high RMM). Our data suggest that young type 1 diabetic patients without microalbuminuria have Lp(a) levels higher than healthy subjects of the same age. Lp(a) levels are further increased in microalbuminuric patients. High Lp(a) levels and apo(a) isoforms of low RMM seem to be associated with the presence of proliferative retinopathy, but have no relation to neuropathy.

Phenotype-dependent differences in apolipoprotein E metabolism and in cholesterol homeostasis in human monocyte-derived macrophages.

In this study, we investigated the impact of the common apoE polymorphism on apoE metabolism and cholesterol homeostasis in monocyte-derived macrophages isolated from E2/2, E3/3, and E4/4 subjects. Unloaded cells of all genotypes contained similar amounts of free cholesterol, cholesteryl ester, and apoE mRNA. E3/3 cells secreted 77 and 30% more apoE than E2/2 or E4/4 cells, respectively. Pulse-chase studies confirmed that the apoE secretion rate was greatest in E3/3 and least in E2/2 cells and showed that a portion of apoE2, but not apoE3 or apoE4, was degraded intracellularly. Surface binding of apoE was greatest in E4/4 cells, as revealed by heparinase treatment. On cholesterol loading with acetylated LDL, apoE mRNA levels and protein secretion rose most in E4/4 and least in E2/2 cells. Cholesterol and cholesteryl ester content, however, rose most in E2/2 and least in E3/3 cells. Incubations with 3H-cholesterol-labeled acetylated LDL revealed that E2/2 cells were most efficient at secreting cholesterol. The greatest reuptake of 3H-cholesterol-rich particles was from E4/4 macrophage- conditioned media. Thus, E2/2 macrophages, despite a low apoE secretion rate, are protected from cholesterol storage by apoE-mediated cholesterol efflux. In E3/3 macrophages, cholesterol accumulation is lessened by a high basal apoE secretion rate. E4/4 macrophages secrete the most apoE but lack effective net cholesterol efflux due to enhanced surface binding and reuptake of cholesterol-rich particles.

APOLIPOPROTEIN E PHENOTYPE DOES NOT PREDICT RISK OF RENAL IMPAIRMENT AFTER CABG SURGERY

Introduction. Acute renal failure (ARF) following cardiac surgery is associated with a mortality rate ranging from 24% to 70%. While studies have identified preoperative risk factors for ARF [1], a genetic basis for the development of renal dysfunction after coronary artery bypass (CABG) surgery has not been previously investigated. Certain apolipoprotein E (ApoE) phenotypes have been associated with accelerated atherosclerosis (ApoE4) [2] and end-stage renal disease (ApoE2) [3]. We examined the hypothesis that patients with these high risk ApoE phenotypes are predisposed to renal dysfunction after cardiac surgery. Methods. With IRB approval, perioperative data for 159 elective CABG surgical patients was gathered from the Duke Heart Center and Anesthesia Databases including: age, sex, weight, preoperative ejection fraction, New York Heart Association Functional Class, history of diabetes and hypertension, duration of cardiopulmonary bypass, and number of coronary artery grafts. Postoperative change in creatinine (DCR) was calculated from preoperative and peak postoperative serum creatinine values. Peripheral blood samples were obtained from each patient and stored at 4[degree sign]C before processing. ApoE genotypes were determined using standard methods. ApoE phenotype was designated as E2(E2/2 and 2/3), E3(E3/3), or E4(E4/4, 4/3 and 4/2) before analysis. Associations were assessed by standard t test, and Kruskal-Wallis test (ApoE phenotype vs. DCR), p<0.05 was considered significant. Results. Patient ApoE phenotypes were distributed as follows: ApoE2 - 25 (E2/2 - 4, E2/3 - 21), ApoE3 - 89 and ApoE4 - 45 (E4/4 - 2, E4/3 - 38, E4/2 - 5). No significant differences were noted between ApoE phenotype groups for the recorded variables. The association between ApoE phenotypes and DCR is presented in Table 1.Table 1Discussion. We did not find ApoE phenotypes to be related to renal dysfunction after CABG surgery. ApoE phenotype distribution in this study was similar to that in the general population. We conclude that ApoE risk factors which influence the occurrence of atherosclerosis and renal disease are not important in the development of renal dysfunction following CABG surgery.

IL-1β AND TNF-α SUPPRESS APOLIPOPROTEIN (APO) E SECRETION AND APO A-I EXPRESSION IN HepG2 CELLS

The effect of cytokines on apolipoprotein E (apo E) production and secretion was investigated in a human hepatoma cell line HepG2. Incubation of HepG2 cells with interleukin 1β (IL-1β) or tumour necrosis factor α (TNF-α) for 48 h resulted in a significant dose-related decrease of apo E concentration in the culture medium, while intracellular apo E content increased without change in mRNA level. In contrast, IL-1β and TNF-α decreased both intracellular and medium apo A-I. Elution profiles of cholesterol and apolipoproteins revealed that apo E was present in apo E-rich high density lipoprotein (HDL) fraction and apo A-I was in apo E-rich HDL and small HDL fractions. IL-1β and TNF-α decreased both apo E and apo A-I in these fractions. The present results suggest that IL-1β and TNF-α suppress hepatic apo A-I expression and secretion but not expression of apo E, which could contribute to the abnormal lipid metabolism in certain cytokine-mediated inflammatory diseases.

Increased VLDL in nephrotic patients results from a decreased catabolism while increased LDL results from increased synthesis

Increased VLDL in nephrotic patients results from a decreased catabolism while increased LDL results from increased synthesis

Apolipoprotein screening in Australian children: feasibility and the effect of age, sex, and ethnicity.

(i) To evaluate the feasibility of detecting adverse lipid profiles in schoolchildren by measuring capillary dried blood spot apolipoprotein levels, and (ii) to assess the effect of age, sex and ethnicity on apolipoprotein levels. We measured capillary dried blood spot apolipoproteins B and A-I (apo B and apo A-I); assessed levels in relation to age, sex and ethnicity; and recalled children with elevated levels for a full lipid profile measurement. 6992 children (3501 boys and 3491 girls), aged 5-13 years, from schools in eastern Sydney, 1991-1995. Capillary blood levels of apolipoproteins B and A-I, and serum total cholesterol level. Of the 6951 children who provided an adequate fingerprick blood sample, we recalled 1465 children (21.1%) (640 boys [43.7%] and 825 girls [56.3%]) with elevated apo B levels and/or apo B:apo A-I ratios for further testing, either by us or by their family doctor (overall estimated compliance rate up to 70%). Among the 458 children who returned to us, there was a 90% positive predictive value for a total cholesterol level of over 4.5 mmol/L in those with both elevated apo B levels and high apo B:apo A-I ratios. Girls had higher apo B levels and apo B:apo A-I ratios than boys (P < 0.00001 for both), and in both sexes there was a trend downwards for apo B and upwards for apo B:apo A-I ratio over the age range tested, but levels were relatively stable between the ages of 6 and 10 years. Indian children (1.5% of the screened population) had the highest apo B levels, followed by white children (71.1%); Asian children (9.2%) had the lowest (P < 0.00001 compared with Indian and white children). The high positive predictive value of capillary blood apolipoprotein levels for an adverse lipid profile in children suggests that measuring apolipoprotein levels by this method is a useful initial approach to cardiovascular risk assessment.

Regional serum cholesterol differences in Belgium: do genetically determined cardiovascular risk factors contribute?

Differences in serum lipid distribution and mortality from ischaemic heart disease have repeatedly been reported between Belgian northerners and southerners. We investigated whether serum lipoprotein(a) (Lp(a)) and apolipoprotein (apo) E polymorphism were involved. Fasting serum lipids, apo A-I and B, and Lp(a) levels were examined in randomly selected, 20-39 year old Belgian males and females from the north (Flanders) and the south (Wallonia) of Belgium (N = 900). Apo E phenotype distribution was investigated in random subsamples from either region (N = 249). Mean serum cholesterol, low density lipoprotein cholesterol (LDL-c), apo B and triglyceride levels were higher in Walloons compared to Flemings within each gender, the difference being significant in 30-39 year old males. Average high density lipoprotein cholesterol and apo A-I levels were significantly lower in 30-39 year old male southerners, compared to their northern counterparts. Median Lp(a) was 67 mg/l in northerners and 75 mg/l in southerners (NS). The apo E phenotype distribution was similar in both regions (chi2 = 7.213; d.f. = 5; P = 0.2053), whereas the average effects of the apo E alleles differed between the regions. In southerners the epsilon4 effect upon adjusted apo B and LDL-c levels was approximately+12% and the epsilon2 effect was approximately-15%; in northerners the epsilon4 and epsilon2 effects were approximately+5% and approximately-25%, respectively. The apo E polymorphism did not affect serum Lp(a) levels. Regional cholesterol differences between Flemings and Walloons cannot be explained by differences in serum Lp(a) or apo E phenotype distribution. The less favourable epsilon2 and epsilon4 effects in southerners compared to northerners reflect modulation of the apo E gene by particular environments.

Heparan Sulfate Proteoglycans Participate in Hepatic Lipaseand Apolipoprotein E-mediated Binding and Uptake of Plasma Lipoproteins, Including High Density Lipoproteins

High density lipoprotein (HDL) particles and HDL cholesteryl esters are taken up by both receptor-mediated and non-receptor-mediated pathways. Here we show that cell surface heparan sulfate proteoglycans (HSPG) participate in hepatic lipase (HL)- and apolipoprotein (apo) E-mediated binding and uptake of mouse and human HDL by cultured hepatocytes. The HL secreted by HL-transfected McA-RH7777 cells enhanced both HDL binding at 4 degrees C (approximately 2-4-fold) and HDL uptake at 37 degrees C (approximately 2-5-fold). The enhanced binding and uptake of HDL were partially inhibited by the 39-kDa protein, an inhibitor of low density lipoprotein receptor-related protein (LRP), but were almost totally blocked by heparinase, which removes the sulfated glycosaminoglycan chains from HSPG. Therefore, HL may mediate the uptake of HDL by two pathways: an HSPG-dependent LRP pathway and an HSPG-dependent but LRP-independent pathway. The HL-mediated binding and uptake of HDL were only minimally reduced when catalytically inactive HL or LRP binding-defective HL was substituted for wild-type HL, indicating that much of the HDL uptake required neither HL binding to the LRP nor lipolytic processing. To study the role of HL in facilitating the selective uptake of cholesteryl esters, we used HDL into which radiolabeled cholesteryl ether had been incorporated. HL increased the selective uptake of HDL cholesteryl ether; this enhanced uptake was reduced by more than 80% by heparinase but was unaffected by the 39-kDa protein. Like HL, apoE enhanced the binding and uptake of HDL (approximately 2-fold) but had little effect on the selective uptake of HDL cholesteryl ether. In the presence of HL, apoE did not further increase the uptake of HDL, and at a high concentration apoE impaired or decreased the HL-mediated uptake of HDL. Therefore, HL and apoE may utilize similar (but not identical) binding sites to mediate HDL uptake. Although the relative importance of cell surface HSPG in the overall metabolism of HDL in vivo remains to be determined, cultured hepatocytes clearly displayed an HSPG-dependent pathway that mediates the binding and uptake of HDL. This study also demonstrates the importance of HL in enhancing the binding and uptake of remnant and low density lipoproteins via an HSPG-dependent pathway.

Relationship between apolipoprotein E and the amyloid deposits and dystrophic neurites of Alzheimer's disease.

Although the inheritance of certain apolipoprotein E (ApoE) alleles has been recognized as a genetic risk factor for Alzheimer's disease, the role of ApoE in the pathology underlying this disease is unclear. Several reports have emphasized the association of ApoE with either beta-amyloid plaque formation or the development of neurofibrillary pathology. Utilization of multiple label immunohistochemical methods enabled us to examine directly the localization of ApoE immunoreactivity relative to beta-amyloid plaques, dystrophic neurites and neurofibrillary tangles. In Alzheimer's disease cases, beta-amyloid plaques showing high ApoE immunoreactivity were localized to layers II, III and V of the neocortex. In layer I, beta-amyloid plaques were unlabelled for ApoE relative to beta-amyloid. Dense core plaques labelled for beta-amyloid often had only the central portions labelled for ApoE. Conversely, ApoE labelled spherical structures within some plaques were not immunoreactive for beta-amyloid or dystrophic neurite markers. Unlike beta-amyloid labelled plaques, all ApoE immunoreactive plaques were associated with dystrophic neurites. In preclinical Alzheimer's disease cases, most plaques were double labelled for beta-amyloid and ApoE. ApoE did not label dystrophic neurites or the early stages of neurofibrillary tangle formation, indicating that ApoE may not be directly involved in neurofibrillary pathology. The specific presence of ApoE in plaques associated with dystrophic neurites in demented patients suggests that ApoE may contribute toward a higher degree of beta-amyloid fibrillogenesis, enhancing the ability of certain plaques to cause damage to surrounding axons.

Lp(a) lipoprotein is a major risk factor for cardiovascular disease: pathogenic mechanisms and clinical significance.

The results of two previous and two recent studies of middle-aged males and females are presented to exemplify the clinical importance of lipoprotein(a) (Lp(a)) as a risk factor for atherosclerosis and coronary heart disease. In these studies various conventional and recently suggested risk factors were included and different methods for Lp(a) quantification were used. Lp(a) was a significant risk factor in all four studies. In the recent prospective case-control study, Lp(a) and cholesterol were found to act synergistically and predict primary acute myocardial infarction in Swedish males. A cholesterol level above 6.5 mmol/l increased the risk of acute myocardial infarction if the Lp(a) level was above 200 mg/l. The plasma apo A-I level was a protective factor. In the other recent case-control study, an Lp(a) level above 500 mg/l was a highly significant risk factor in Black and White US women with myocardial infarction or advanced coronary artery disease in addition to low density lipoprotein cholesterol levels above 130 mg/dl. A high apo A-I level was a protective factor. In these studies no other factors tested reached significance in multivariate logistic regression analysis. A hypothetical association between high Lp(a) levels and intracellular infection with Chlamydia pneumoniae is discussed. The results suggest that the Lp(a) level is useful in identifying high-risk individuals. Lowering low density lipoprotein cholesterol below 100 mg/dl (<2.6 mmol/l) seems to be most important in both males and females with high-risk Lp(a) levels.

High frequency of apolipoprotein E epsilon 2 allele in hemorrhage due to cerebral amyloid angiopathy.

From the somewhat conflicting published data on apolipoprotein E (apoE) genotype in hemorrhage due to cerebral amyloid angiopathy (CAA), it is unclear whether apoE genotype influences the risk of CAA-related hemorrhage independently of its association with concomitant Alzheimer's disease (AD). We determined the apoE genotypes of 36 patients presenting with cerebral hemorrhage associated with histologically confirmed CAA. The frequency of apoE epsilon 2 was 0.25 and the frequency of apoE epsilon 4 was 0.18. Patients with CAA-related hemorrhage and concomitant AD pathology (CERAD criteria, n = 17) had a high apoE epsilon 4 frequency, close to that in AD cases without hemorrhage. Patients in whom CAA-related hemorrhage occurred in the absence of significant AD pathology (n = 13) had an apoE epsilon 4 frequency somewhat lower than non-AD controls without hemorrhage. However, in CAA-related hemorrhage, the apoE epsilon 2 frequency was high regardless of whether significant AD pathology was present. We conclude that whereas possession of apoE epsilon 2 may be a risk factor for cerebral hemorrhage due to CAA, apoE epsilon 4 is a risk factor for concomitant AD but not an independent risk factor for CAA-related hemorrhage.

Associations between diet and the hyperapobetalipoproteinemia phenotype expression in children and young adults: the Cardiovascular Risk in Young Finns Study.

The effect of diet on blood lipids has been under intensive study during recent decades. However, diet in the context of the hyperapobetalipoproteinemia (hyperapoB) phenotype has received less attention. The hyperapoB phenotype is commonly encountered in patients with premature coronary heart disease. It is defined as a combination of an increased concentration of apolipoprotein B (apo B), a normal concentration of LDL cholesterol (LDL-C), and as a result, a low LDL-C/apo B ratio. We studied the associations between diet and blood lipids in a cohort of 534 children and young adults 9 to 24 years old. The ratio of polyunsaturated to saturated fats (P/S ratio) correlated (r=-0.19, P<.001) with the LDL-C/apo B ratio. This association was also found when the model was adjusted with triglycerides (r=-0.24, P<.001). A change in the P/S ratio from 0.10 to 0.60 corresponded to a decrease of 0.12 in the LDL-C/apo B ratio, and in the highest apo B decile, the P/S value was higher in hyperapoB individuals (0.33) than in others (0.28, P=.019). Our results imply that the fatty acid composition of the diet may be one of the environmental factors that influence the hyperapoB phenotype expression.

Reviews and Original Articles Lipoprotein(A) and Apolipoprotein(A) Phenotypes in Patients with End-Stage Renal Disease

To evaluate the distribution pattern of apolipoprotein(a) [Apo(a)] phenotypes in Koreans and the effect of dialysis modality on serum lipoprotein(a) [Lp(a)] concentration according to apo(a) phenotype in patients with end-stage renal disease (ESRD). Cross-sectional study. A university hospital. 153 normal controls, 99 hemodialysis (HD) patients and 82 continuous ambulatory peritoneal dialysis (CAPD) patients. Fasting serum Lp(a), lipids, and apo(a) phenotypes were measured. The frequencies of the subjects with apo(a) phenotypes of high-molecular weight only, including S3, S4, or S5 or null type were 95.4% of control, 100% of HD patients, and 95.1% of CAPD patients. The frequent apo(a) phenotypes in Koreans consisted of S4, S4S5, S5, and S5S5 isoforms. Significant difference was found in serum Lp(a) concentration among controls and HD and CAPD patients [median (Interquartile range): 0.05 g/L, (0.01-0.19); 0.19 g/L, (0.10-0.35); 0.63 g/L, (0.28-0.90), p < 0.001]. Lp(a) levels in CAPD patients were significantly higher than in HD patients for all four common apo(a) isoforms found in Korean subjects. CAPD patients had higher total and LDL cholesterol levels, and higher ApoB levels than HD patients. Significant differences were found in serum albumin levels between controls and HD and CAPD patients (44 +/- 3 g/L, 40 +/- 4 g/L, 32 +/- 7 g/L, respectively, p < 0.05). There were significant inverse correlations between serum albumin and Lp(a) (r = -0.33, p < 0.01), total cholesterol (r = -0.31, p < 0.01), LDL (r = -0.39, p < 0.01) or ApoB (r = -0.35, p < 0.01) in ESRD patients. A significant positive correlation was found between serum albumin and ApoA1 (r = 0.24, p < 0.01). These findings indicate that Koreans have mainly high molecular weight apo(a) phenotypes and serum Lp(a) is elevated in CAPD patients compared to HD patients for common apo(a) phenotypes, which may contribute to the frequent cardiovascular mortality in CAPD patients.