Elevated Levels Of Lp Research Articles

慢性腎不全患者― 特にCAPD患者におけるLp(a)リポ蛋白の検討

Cerebrovascular and cardiovascular diseases are important predictors for survival in patients undergoing continuous ambulatory peritoneal dialysis (CAPD), and account for about half the deaths in these patients. Lipoprotein(a) [Lp(a)] is known to show high values in diabetics with proteinuria, and albuminuric renal disease. The purpose of this study was to determine Lp(a) levels and to investigate the association of Lp(a) and atherosclerotic risk factors in patients treated by CAPD. Lp(a) concentration were measured in 20 CAPD patients in the age range 31 to 83 years. Mean (+/- SD) levels of serum Lp(a) were elevated in the CAPD patients compared to age, sex matched 17 controls (49.5 +/- 27.7 vs. 15.5 +/- 12.4 mg/dl, p < 0.001). The levels of Lp(a) were significantly higher in the diabetic CAPD patients than in non-diabetics. There were significant positive correlations between serum Lp(a) concentrations and fasting blood sugar. However, when the above two groups were matched for age, sex, body mass index and FBS, Lp(a) concentrations were also significantly higher in CAPD patients than those in normal controls. We found no statistically significant correlations of Lp(a) with either age, body mass index, blood pressure, serum lipoprotein, apoprotein, glycated hemoglobin, BUN, creatinine or serum protein levels. There were no correlations between serum Lp(a) levels and albumin and LP(a) concentrations in the dialysate in all CAPD patients. Along with assessment of other known established cardiovascular risk factors such as elevated blood pressure, atherogenic abnormalities of plasma lipids and lipoproteins, and impaired glucose tolerance, we suggest that elevated levels of Lp(a) may lead to the accelerated atherosclerosis in these patients.

Lipoprotein(a) levels, apo(a) isoform size, and coronary heart disease risk in the Framingham Offspring Study

The aim of this study was to assess the independent contributions of plasma levels of lipoprotein(a) (Lp(a)), Lp(a) cholesterol, and of apo(a) isoform size to prospective coronary heart disease (CHD) risk. Plasma Lp(a) and Lp(a) cholesterol levels, and apo(a) isoform size were measured at examination cycle 5 in subjects participating in the Framingham Offspring Study who were free of CHD. After a mean follow-up of 12.3 years, 98 men and 47 women developed new CHD events. In multivariate analysis, the hazard ratio of CHD was approximately two-fold greater in men in the upper tertile of plasma Lp(a) levels, relative to those in the bottom tertile (P < 0.002). The apo(a) isoform size contributed only modestly to the association between Lp(a) and CHD and was not an independent predictor of CHD. In multivariate analysis, Lp(a) cholesterol was not significantly associated with CHD risk in men. In women, no association between Lp(a) and CHD risk was observed. Elevated plasma Lp(a) levels are a significant and independent predictor of CHD risk in men. The assessment of apo(a) isoform size in this cohort does not add significant information about CHD risk. In addition, the cholesterol content in Lp(a) is not a significant predictor of CHD risk.

Livedoid vasculopathy secondary to high levels of lipoprotein(a)

Funding sources: none. Conflicts of interest: none declared. Madam, Livedoid vasculopathy (LV) was first described by Bard and Winkelmann in 1967.1 It is characterized by a long history of recurrent painful ulcerations of the feet and legs2 and scar lesions named atrophie blanche.3 LV is a thrombotic (occlusive) vasculopathy of the small vessels of the lower extremities.3 Histology shows microthromboses and/or segmental hyalinization of the subendothelial intimal layer of blood vessels of the middle and lower dermis.3 Its exact aetiology remains uncertain, but thrombotic and microcirculatory phenomena have been implicated as possible pathogenic factors.3, 4 Several thrombophilic conditions have been reported to be associated with LV (Table 1).2–7 We report two patients with LV secondary to high levels of lipoprotein(a) [Lp(a)]. Patient 1 was a 29‐year‐old white woman, referred to us because of recurrent painful ulcerations in the legs associated with extensive livedo racemosa on her upper and lower limbs. There were several shallow ulcerations in the malleolar regions, necrosis and crusts (Fig. 1). She had previously been treated with oral aspirin and pentoxifylline without response. Skin biopsy confirmed the clinical diagnosis of LV. Results of extensive laboratory testing for the established abnormalities associated with LV were all negative, including thrombophilic states [factor V G1691A gene mutation (Leiden), prothrombin G20210A gene mutation, methylenetetrahydrofolate reductase (MTHFR) mutation and homocysteinaemia, protein C and/or protein S deficiency, antithrombin III deficiency, anticardiolipin antibodies, lupus anticoagulant], hepatitis B and C infection and autoimmune diseases. We introduced oral warfarin and international normalized ratio (INR) was maintained at 3. One week after the treatment onset, the pain ceased. Total healing of the cutaneous ulcerations was obtained after the third month under warfarin therapy. After this, ulcerations relapsed twice, but on both occasions the INR was below the therapeutic level (2–3) and the patient quickly responded after that level was reached. Because of the recent description of an association between LV and elevated levels of Lp(a),6 we reviewed the case and found an increased level of Lp(a) (51 mg dL−1; normal < 30).

Commentary: Lipoprotein(a) and atherosclerosis

Recently, there has been a resurgence of interest in lipoprotein(a) [Lp(a)] as a risk factor for atherosclerotic disease. Lp(a) was first discovered by Kaare Berg in 1962 on the basis of antigenic differences in low-density lipoprotein (LDL) cholesterol detected after injecting rabbits with human LDL particles. The resulting antibodies identified an antigen in some, but not in other individuals. In the early 1970s, Berg reported that Lp(a) was a plasma lipoprotein consisting of an LDL particle linked with an apolipoprotein(a) particle. The size of the LDL particle was fixed, but the apolipoprotein(a) component varied between individuals. The inheritance of Lp(a) was clarified in 1987 by Gerd Utermann, who identified multiple size variants that were strongly associated with plasma levels of Lp(a). But the causal relevance of Lp(a) for coronary disease and for other vascular diseases remained uncertain for almost 50 years after the initial discovery. In 2009, three large studies reported that genetic variants encoding plasma levels of Lp(a) had higher risks of coronary heart disease. These Mendelian randomization studies examined the associations of genetic variants encoding plasma levels of Lp(a), plasma levels of Lp(a) and coronary disease. In the PROCARDIS study, we examined 27 single nucleotide polymorphism (SNPs) at the LPA locus at 6q26-27, and found two SNPs (rs10455872 and rs3798220) that were strongly and independently related to coronary disease. We replicated these associations in a meta-analysis involving a total of 8000 coronary cases. Both LPA SNPs explained about half the genetic variation in plasma levels of Lp(a) and their effect on risk of coronary disease was completely attenuated after adjustment for plasma levels of Lp(a), providing strong support for causality. However, the mechanism by which elevated plasma levels of Lp(a) cause vascular disease remains uncertain. In a Mendelian randomization study reported in this issue, Kivimaki and colleagues examined the associations of LPA variants; and Lp(a) levels with carotid intima–media thickness and brachial artery flow-mediated dilatation. In a population-based study of almost 2000 healthy Finnish individuals, Kivimaki demonstrated no association of a variant at the LPA locus (rs783147), that was strongly associated with Lp(a) levels, with either of these markers of early atherosclerosis. The results of this study require corroboration by larger studies (and meta-analyses of such studies), and with a genotype score involving SNPs associated with greater differences in Lp(a) levels, but the available evidence does not suggest any role for Lp(a) in early atherosclerosis. Whereas the mechanism by which elevated levels of Lp(a) cause coronary disease remains elusive, the Mendelian randomization studies of LPA variants and coronary disease have prompted a paradigm shift in the importance of Lp(a) as a risk factor for coronary disease. Further large-scale studies are required to assess the relevance of LPA variants for stroke and other vascular diseases. The results of ongoing trials of niacin that lower plasma levels of Lp(a) by 30%, and planned trials of cholesterylester transfer protein inhibitors that lower Lp(a) levels by 40%, are required to assess the clinical relevance of lowering plasma levels of Lp(a) for prevention of atherosclerotic vascular diseases.

糖尿病性腎症の病期とLp(a)―特に低蛋白血症の影響について―

Lipoprotein (a) [Lp(a)] has been reported to be an independent risk factor for coronary heart disease. Elevated levels of Lp(a) in diabetic subjects have also been reported, especially in subjects with nephropathy. However, the mechanism and the clinical implication of Lp(a) elevation in diabetics remain obscure. In the present study, to verify the change in Lp(a) concentration with the progression of nephropathy, serum Lp(a) levels were measured in 546 NIDDM patients, 33 hemodialysis NIDDM patients, and 145 non-diabetic controls. 1) The serum Lp(a) levels in diabetics were significantly higher than those in the non-diabetic controls. 2) Serum Lp(a) concentrations in microalbuminuric subjects were significantly higher than those in normoalbuminuric subjects, and were further increased in macroalbuminuric subjects. 3) In macroalbuminuric subjects, serum Lp(a) concentrations were inversely correlated with serum protein concentrations, but not with serum creatinine. 4) Once hemodialysis was started, the decrement of both serum Lp (a) and LDL-C concentrations were associated with the increment of serum protein concentrations. These data indicate that elevation of serum Lp (a) concentration in overt nephropathy could be, at least in part, due to hypoproteinemia.

Elevated Lp(a) with a small apo(a) isoform in children: risk factor for the development of premature coronary artery disease

levels of Lp(a) and low-molecular-weight apolipoprotein(a) isoform are strongly associated with the development of early cardiovascular disease. Certain types of apo(a) isoforms in combination with elevated levels of Lp(a) may be important in the determining of premature coronary artery disease. Therefore, we investigated the association of familial history of premature coronary artery disease and apo(a) size and Lp(a) levels in children and adolescents with hypercholesterolemia using a novel method determining apo(a) isoforms. Isoforms were classified in six phenotype patterns: S1-S4, B, F and according to their K-IV repeats. Apo(a) isoforms were divided into two groups: low-molecular- and high-molecular apo(a) isoforms. In subjects with double-banded apo(a) isoforms containing a small- and a large-isoform Lp(a) each contribution was based on the intensity of staining of the two bands. The percentage of patients with elevated levels of Lp(a) and a small apo(a) isoform (i.e. elevated small-isoform Lp(a)) was 46% in the risk group and 20% in the control group, p < 0.05. The percentage number of children and adolescents with elevated Lp(a) levels was higher in the risk group, reaching statistical significance (p < 0.05). Elevated levels of small-isoform Lp(a) might be a strong and independent risk factor for the development of premature coronary artery disease in children and adolescents with hypercholesterolemia.

Abstract 4226: Elevated Levels of Lp(a) Predict Coronary Atherosclerosis as Detected by Coronary Artery Calcium Scanning with Computed Tomography

INTRODUCTION Lipoprotein (a) [Lp(a)] has been established as an independent cardiac risk factor. There is considerable variation among different races and the association between Lp(a) and coronary artery calcium (CAC) is unknown in Asians. METHODS 104 patients (pts) from Jakarta, Indonesia underwent CAC scoring and measurements of various biomarkers including Lp(a) (DAIICHI Pure Chemicals, Japan). Lp(a) &gt;20mg/dl were defined as abnormal; CAC was expressed as Agatston score. Lp(a) values were not normally distributed and Kruskal-Wallis test and median values were used to test Lp(a) levels across CAC ranges (0, 1–100, 101– 400, &gt;400). ROC curve analysis tested the performance of Lp(a) to predict presence of any CAC. RESULTS 53/104 (51%) pts had an abnormal Lp(a) level. Clinical characteristics were similar between the two groups (60% male, 14% DM, 57% HTN, 30% smoker). Pts with abnormal Lp(a) had higher mean total cholesterol (220±48 vs. 199±147, p=0.01), LDL (147±40 vs. 130±38, p =0.02) and Lp(a) level (10.2±5.2 vs. 40.8±5.2, p=0.001) but similar HDL (46±10 vs. 45±9, p=NS) and triglyceride (154±113 vs. 145±95, p=NS) levels. Lp(a) was a good test in predicting presence of CAC as evidenced by an area under the curve (AUC)=0.7 with the optimal cut-point of &gt;17mg/dl (sensitivity 73%, specificity 73%, p&lt;0.001). Kruskal-Wallis analysis showed median Lp(a) levels to be significantly higher across rising CAC ranges: 0=41.5, 1–100=54.9, 101– 400=62.1, &gt;400=64 mg/dl (p=0.026). After adjusting for the above clinical characteristics and biochemical markers in a multivariate logistic regression model Lp(a) levels remained a significant predictor of CAC (p=0.007). CONCLUSION This is the first study to demonstrate a significant relationship between Lp(a) levels and presence of CAC in an Asian population.

Lipoproteína (a) em pacientes portadores de doença arterial obstrutiva periférica e/ou diabetes mellitus tipo 2

INTRODUÇÃO: A doença arterial obstrutiva periférica (DAOP) constitui um excelente marcador para a aterosclerose sistêmica. Entre os fatores de risco para essa doença está o diabetes mellitus tipo 2 (DM2). Acredita-se que a lipoproteína (a) [Lp(a)] esteja ligada a risco aumentado de aterosclerose, embora os mecanismos que levem a esse aumento não sejam completamente conhecidos. Níveis elevados de Lp(a) parecem estar associados a risco aumentado de doença arterial coronariana (DAC), assim como DAOP e doença cerebrovascular. OBJETIVO: Avaliar os níveis plasmáticos de Lp(a) e outras variáveis lipídicas em um grupo de pacientes com DAOP e/ou DM2. MATERIAL E MÉTODOS: Níveis plasmáticos de Lp(a), colesterol total (CT), colesterol da lipoproteína de alta densidade (HDL-c), colesterol da lipoproteína de baixa densidade (LDL-c), triglicérides (TG) e apolipoproteínas A-I e B foram medidos em amostras de sangue de 12 indivíduos comprovadamente não-portadores de DAOP e DM2 (controles), 17 pacientes portadores de DAOP, 18 pacientes com DM2 e 19 pacientes portadores de DAOP e DM2 simultaneamente. Os participantes desse estudo foram selecionados buscando-se homogeneidade e semelhança estatística em relação às variáveis sexo, idade e nível socioeconômico. RESULTADOS: A Lp(a) apresentou tendência a elevação tanto no grupo de pacientes com DAOP quanto naquele com DM2 + DAOP. Foram encontradas diferenças significativas entre os grupos para as dosagens de HDL-c e Apo A-I, inclusive com correlação positiva entre esses parâmetros. A relação CT/HDL-c apresentou diferença estatística significativa entre os grupos. Foram observadas correlações positiva entre Lp(a) e LDL-c, e negativa entre o índice tornozelo-braquial (ITB) e a Lp(a). CONCLUSÃO: Para as variáveis lipídicas estudadas foram observadas diferenças estatísticas significativas apenas entre os níveis plasmáticos de HDL-c e Apo A-I. Para o parâmetro Lp(a) foram observados níveis plasmáticos mais elevados nos grupos DAOP e DM2 + DAOP, os quais também apresentaram uma concomitante e significativa redução de HDL-c.

Abstract 2755: Insulin Resistance and Coronary Artery Calcification measured by Electron Beam Tomography

Background: Elevation in the ratio of triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) has been suggested as a marker of insulin resistance (IR), conferring an increased risk of atherosclerosis in these patients. The association between TG/HDL-C and coronary artery calcification (CAC) measured by computed tomography has yet to be established. The goal of this study was to examine the relationship between IR, as determined by TG/HDL-C ≥ 3.5, and significant CAC (absolute score ≥ 100). Methods: Fasting lipid levels, homocysteine, C reactive protein and lipoprotein (a) levels of 336 asymptomatic individuals, who also underwent electron beam tomography (EBT), were measured. Results: The mean age of participants was 55 ±10 years. 71.7% were male. 37.4% had hypertension, 52.5% had hypercholesterolemia, 12.4% had diabetes mellitus (DM) and 52.5% had family history of premature CHD. Individuals with IR had higher significant CAC (≥100) than those without IR (70% vs. 27%, P=0.0001). After adjustment for age, gender, hypertension, hypercholesterolemia and DM, multivariate regression analysis demonstrated that individuals with IR had more significant CAC (odds ratio 2.1, 95% CI=1.1–3.9, p=0.01). Further sub-analysis revealed that individuals with IR had significantly higher lipoprotein (a) (Lp(a)) than those without IR (odds ratio 1.31, 95% CI=1.09-.16, p=0.03). No significant differences in C-reactive protein (CRP) and homocysteine were found between the two groups. Conclusion: Insulin resistance, as measured by TG/HDL-C ≥ 3.5, was associated with a significantly higher incidence of accelerated atherosclerosis on EBT (absolute CAC score ≥ 100), independent of age, gender and conventional risk factors. IR was also significantly associated with elevated levels of Lp(a). Further studies regarding the clinical significance of insulin resistance and elevated CAC score, as well as its association with Lp(a), may be warranted.

Lipids and lipoprotein(a) concentrations in Tunisian type 2 diabetic patients: Relationship to glycemic control and coronary heart disease

The aim of this study was to evaluate plasma lipoprotein(a) [Lp(a)] concentrations in Tunisian patients with type 2 diabetes mellitus (DM), to correlate the values with other lipid parameters, and to examine the relationship to glycemic control and coronary heart disease (CHD). Diabetic patients with and without CHD ( n=200) had significantly higher levels of Lp(a) (327.94±239.93 mg/l) and a greater proportion of elevated (>300 mg/l) Lp(a) concentrations (46%) compared with 100 healthy nondiabetic controls (269.83±225.6 mg/l, P<.01, and 26%, P<.01), while there were no statistically significant difference between diabetics without CHD ( n=100) and controls. No significant association of Lp(a) with glycemic control (HbAlc or fasting blood glucose) was noted in diabetic patients. Positive correlations were observed between Lp(a) levels and total cholesterol and LDL-C in all diabetic patients and particularly in diabetic men. Male patients with CHD showed significantly higher plasma Lp(a) levels than those without CHD ( P=.023), and 57.3% of patients with CHD showed increase (>300 mg/l) Lp(a) compared with 33.3% of patients without CHD. Elevated levels of Lp (a) and abnormal lipid profile in diabetic men suggest their involvement in atherogenesis and subsequent development of CHD.

Lp(a) lipoprotein, vascular disease, and mortality in the elderly.

As compared with what is known about predictors of vascular events in middle-aged persons, less is known about these events in the elderly. Lp(a) lipoprotein, which plays an important part in atherothrombogenesis, has been associated with an increased risk of vascular disease. We investigated this relation among older U.S. adults. In a prospective study of 5888 community-dwelling older adults (65 years of age or older) in the United States, 2375 women and 1597 men who were free of vascular disease provided base-line serum samples for analysis for levels of Lp(a) lipoprotein. These 3972 subjects were followed for a median of 7.4 years to evaluate the development of stroke and to track deaths from vascular causes and all causes. The men and women were divided into quintile groups according to the Lp(a) lipoprotein level at base line. Using Cox proportional-hazards models, we determined the risk associated with each quintile level of Lp(a) lipoprotein, with the lowest quintile serving as the reference group. As compared with those in the lowest quintile, men in the highest quintile had three times the unadjusted risk of stroke (relative risk, 3.00; 95 percent confidence interval, 1.59 to 5.65), almost three times the risk of death associated with vascular events (relative risk, 2.54; 95 percent confidence interval, 1.59 to 4.08), and nearly twice the risk of death from all causes (relative risk, 1.76; 95 percent confidence interval, 1.31 to 2.36). Adjustment for age; sex; the levels of total cholesterol, low-density lipoprotein cholesterol, and triglycerides; carotid-wall thickness; smoking status; the presence or absence of diabetes and systolic and diastolic hypertension; body-mass index; and other traditional risk factors had little effect on the final assessments. Similar analyses for women, which also included adjustment for estrogen use or nonuse, revealed no such relation. Among older adults in the United States, an elevated level of Lp(a) lipoprotein is an independent predictor of stroke, death from vascular disease, and death from any cause in men but not in women. These data support the use of Lp(a) lipoprotein levels in predicting the risk of these events in older men.

Fibrinolytic Parameters and Lipoprotein(a) in Young Women with Myocardial Infarction

Impaired fibrinolysis and elevated lipoprotein(a) (Lp[a]) are possible nonclassic risk factors for myocardial infarction (MI) at young age. The fibrinolytic system in young women with MI has not been evaluated yet and the role of Lp(a) is still controversial. The authors determined fibrinolytic parameters and Lp(a) in premenopausal women (mean age 42+/-3 years, n = 22) 0.5 to 6 (mean 3.5) years after MI, who were all without severe classic risk factors and had an otherwise low risk for MI. Elevated levels of tissue type plasminogen activator (t-PA) (p< 0.05) were measured in comparison to 52 age-matched controls; no difference was found in plasminogen activator inhibitor, plasminogen, fibrinogen, euglobulin clotting time and D-dimers. Significantly more MI patients had Lp(a) levels greater than 300 mg/L compared to controls (36% vs 13.5%, p< 0.05). The combination of elevated Lp(a), mild hyperlipidemia, and nonsevere smoking was found in 62.5% of MI patients who had elevated levels of Lp(a), in 23% of all women with MI, and in none of the controls. Elevated t-PA is probably only a marker of increased risk of MI, whereas elevated Lp(a) probably has a causative role. A combination of elevated Lp(a), hyperlipidemia, and nonsevere smoking seems to be a high-risk profile, relatively common in young women with MI.

High levels of Lp(a) with a small apo(a) isoform are associated with coronary artery disease in African American and white men.

Elevated levels of lipoprotein(a) [Lp(a)] and the presence of small isoforms of apolipoprotein(a) [apo(a)] have been associated with coronary artery disease (CAD) in whites but not in African Americans. Because of marked race/ethnicity differences in the distribution of Lp(a) levels across apo(a) sizes, we tested the hypothesis that apo(a) isoform size determines the association between Lp(a) and CAD. We related Lp(a) levels, apo(a) isoforms, and the levels of Lp(a) associated with different apo(a) isoforms to the presence of CAD (>/=50% stenosis) in 576 white and African American men and women. Only in white men were Lp(a) levels significantly higher among patients with CAD than in those without CAD (28.4 versus 16.5 mg/dL, respectively; P:=0.004), and only in this group was the presence of small apo(a) isoforms (<22 kringle 4 repeats) associated with CAD (P:=0.043). Elevated Lp(a) levels (>/=30 mg/dL) were found in 26% of whites and 68% of African Americans, and of those, 80% of whites but only 26% of African Americans had a small apo(a) isoform. Elevated Lp(a) levels with small apo(a) isoforms were significantly associated with CAD (P:<0.01) in African American and white men but not in women. This association remained significant after adjusting for age, diabetes mellitus, smoking, hypertension, HDL cholesterol, LDL cholesterol, and triglycerides. We conclude that elevated levels of Lp(a) with small apo(a) isoforms independently predict risk for CAD in African American and white men. Our study, by determining the predictive power of Lp(a) levels combined with apo(a) isoform size, provides an explanation for the apparent lack of association of either measure alone with CAD in African Americans. Furthermore, our results suggest that small apo(a) size confers atherogenicity to Lp(a).

Ionizing radiation and genetic risks

This paper provides a broad overview of the epidemiological and genetical aspects of common multifactorial diseases in man with focus on three well-studied ones, namely, coronary heart disease (CHD), essential hypertension (EHYT) and diabetes mellitus (DM). In contrast to mendelian diseases, for which a mutant gene either in the heterozygous or homozygous condition is generally sufficient to cause disease, for most multifactorial diseases, the concepts of genetic susceptibility' and risk factors' are more appropriate. For these diseases, genetic susceptibility is heterogeneous. The well-studied diseases such as CHD permit one to conceptualize the complex relationships between genotype and phenotype for chronic multifactorial diseases in general, namely that allelic variations in genes, through their products interacting with environmental factors, contribute to the quantitative variability of biological risk factor traits and thus ultimately to disease outcome. Two types of such allelic variations can be distinguished, namely those in genes whose mutant alleles have (i) small to moderate effects on the risk factor trait, are common in the population (polymorphic alleles) and therefore contribute substantially to the variability of biological risk factor traits and (ii) profound effects, are rare in the population and therefore contribute far less to the variability of biological risk factor traits. For all the three diseases considered in this review, a positive family history is a strong risk factor. CHD is one of the major contributors to mortality in most industrialized countries. Evidence from epidemiological studies, clinical correlations, genetic hyperlipidaemias etc., indicate that lipids play a key role in the pathogenesis of CHD. The known lipid-related risk factors include: high levels of low density lipoprotein cholesterol, low levels of high density lipoprotein cholesterol, high apoB levels (the major protein fraction of the low density lipoprotein particles) and elevated levels of Lp(a) lipoprotein. Among the risk factors which are not related to lipids are: high levels of homocysteine, low activity of paraoxonase and possibly also elevated plasma fibrinogen levels. In addition to the above, hypertension, diabetes and obesity (which themselves have genetic determinants) are important risk factors for CHD. Among the environmental risk factors are: high dietary fat intake, smoking, stress, lack of exercise etc. About 60% of the variability of the plasma cholesterol is genetic in origin. While a few genes have been identified whose mutant alleles have large effects on this trait (e.g., LDLR, familial defective apoB-100), variability in cholesterol levels among individuals in most families is influenced by allelic variation in many genes (polymorphisms) as well as environmental exposures. A proportion of this variation can be accounted for by two alleles of the apoE locus that increase (&epsi;4) and decrease (&epsi;2) cholesterol levels, respectively. A polymorphism at the apoB gene (XbaI) also has similar effects, but is probably not mediated through lipids. High density lipoprotein cholesterol levels are genetically influenced and are related to apoA1 and hepatic lipase (LIPC) gene functions. Mutations in the apoA1 gene are rare and there are data which suggest a role of allelic variation at or linked LIPC gene in high density lipoprotein cholesterol levels. Polymorphism at the apoA1--C3 loci is often associated with hypertriglyceridemia. The apo(a) gene which codes for Lp(a) is highly polymorphic, each allele determining a specific number of multiple tandem repeats of a unique coding sequence known as Kringle 4. The size of the gene correlates with the size of the Lp(a) protein. The smaller the size of the Lp(a) protein, the higher are the Lp(a) levels. (ABSTRACT TRUNCATED)

Lipoprotein(a) Is a Potent Chemoattractant for Human Peripheral Monocytes

AbstractWe have previously reported that the serine protease plasmin triggers chemotaxis in human peripheral monocytes, but not in polymorphonuclear leukocyte. We now show that the structurally related lipoprotein(a) (Lp[a]) as well as recombinant apolipoprotein(a) (apo[a]) trigger chemotactic responses in human monocytes equipotent to that observed with the standard chemoattractant FMLP. The chemotactic effects of Lp(a) and FMLP were additive. Low density lipoprotein (LDL) did not elicit any significant chemotactic response nor did it interfere with that triggered by Lp(a). As assessed by checkerboard analysis, Lp(a)-mediated monocyte locomotion was a true chemotaxis. Both plasminogen as well as catalytically inactivated plasmin inhibited monocyte migration elicited by Lp(a), suggesting binding of Lp(a) to plasminogen binding sites. Lp(a)-mediated signaling proceeds through a pertussis toxin-sensitive guanosine triphosphate (GTP)-binding protein and activation of protein kinase C as implicated by the effects of 1-O-hexadecyl-2-O-methyl-rac-glycerol and chelerythrine. Lp(a) induced generation of guanosine 3′,5′-cyclic monophosphate (cGMP), apparently crucial for the Lp(a)-mediated chemotaxis, because an inhibitor of soluble guanylyl cyclase, LY83583, reduced both the Lp(a)-induced cGMP formation as well as the monocyte migration. The latter effect of LY83583 was antagonized by the stable cGMP analog 8-pCPT-cGMP. The data indicate that Lp(a) triggers chemotaxis in human monocytes by way of a cGMP-dependent mechanism. Our findings may have important implications for the atherogenesis associated with elevated levels of Lp(a).

Lipoprotein (a) in the regulation of fibrinolysis.

Elevated plasma levels of lipoprotein(a) [LP(a)] are associated with increased an risk of developing atherosclerosis. This increased risk may be due to an Lp(a)-mediated depression of fibrinolytic activity. Lp(a) regulates fibrinolysis by controlling the activity of plasminogen activators. Lp(a) is a low density lipoprotein with an apoprotein(a) subunit which has a high degree of homology with the fibrinolytic zymogen plasminogen. The apoprotein(a) subunit contains up to thirty seven copies of a domain homologous to the plasminogen kringle 4 domain, which enables Lp(a) to bind to fibrin. The subunit also has a zymogen domain, but it is not activated by plasminogen activators. Lp(a) inhibits plasminogen activation by competing with plasminogen for access to plasminogen activators bound to vascular surfaces. Lp(a) also competes with the irreversible inhibitor of plasminogen activators, plasminogen activator inhibitor-1. Therefore increases in Lp(a) concentration may decrease fibrinolytic activity by preventing activation of plasminogen, but Lp(a) may also prolong plasminogen activation by preventing the irreversible inhibition of the activators. At elevated levels of Lp(a) the decreased rate of plasmin generation may not be offset by the prolongation in plasminogen activation, and fibrinolysis will be inhibited.

Hyperlipidemia and hemostatic system.

The plasma levels of blood coagulation and fibrinolytic factors and the serum levels of lipids were measured in 62 subjects (22 normolipidemia and 40 hyperlipidemia) to investigate whether hyperlipidemia may affect the hemostatic system. Prothrombin, factors VII, IX and X were elevated in hyperlipidemic patients. The positive correlations were found between factors VII, IX and X, and triglyceride. The significant correlations were also found between VII and IX, and total cholesterol. Plasma levels of thrombin-antithrombin III complex (TAT), which reflects activation of coagulation system, were slightly but significantly higher in type IIb hyperlipidemia, although they were within normal range. Plasma levels of active plasminogen activator inhibitor (PAI) in type IIb and IV were significantly higher than in normals. A significant correlation was found between active PAI and triglyceride (r = 0.76, p < 0.0001). After the administration of fat emulsion to 18 patients with various diseases, which induced artificial hypertriglyceridemia, PAI levels as well as triglyceride levels significantly increased. These results suggest that hypertriglyceridemia may increase the synthesis and/or release of PAI, inducing a hypofibrinolytic condition, which could lead to thrombosis. It has been established that lipoprotein (a) [Lp(a)], which has a molecular structure homology to plasminogen, impairs fibrinolysis by its competitive inhibition of adsorption of plasminogen to vascular endothelial surface and/or fibrin. We assayed plasma levels of Lp(a) and parameters of blood coagulation and fibrinolysis in 168 patients with type II diabetes mellitus and 48 normal controls. In the diabetics, the levels of Lp(a) as well as levels of tissue-type plasminogen activator (t-PA) antigen and PAI activity were significantly higher than normal controls. Furthermore, it was shown that Lp(a) had a weakly negative correlation with t-PA antigen in the diabetics. These results suggest that an elevated level of Lp(a) may decrease release of t-PA, although the underlying mechanism remains unsolved.

The effect of reduction of lipoprotein (a) on cellular cholesterol synthesis in non-diabetic and Type 2 diabetic subjects

This study investigates the effect of Lipoprotein (a) (Lp(a)) on cellular cholesterol synthesis in non-diabetic ( n = 7) and Type 2 (non-insulin-dependent) diabetic subjects ( n = 7) with elevated levels of Lp(a) (> 20 mg/dl). N-Acetylcysteine was used to lower Lp(a) in the control subjects and their lipoproteins were re-examined after 7 days of treatment. Low-density lipoprotein (LDL) was isolated and separated from Lp(a) by sequential ultracentrifugation. Regulation of cellular cholesterol synthesis was assessed by measuring incorporation of [ 14C]acetate into mononuclear leucocytes in the presence of LDL and Lp(a). Cellular cholesterol content was determined by a fluorometric assay. Delivery of cholesterol to the cell was examined using [ 3H]cholesteryl oleate-labelled LDL or Lp(a). LDL (5 μg/ml) from non-diabetic subjects suppressed cellular cholesterol synthesis by 66.2%, while Lp(a) at a similar concentration only suppressed cholesterol synthesis by 5.8% ( P < 0.001). At a concentration of 20 μg/ml, Lp(a) suppressed cholesterol synthesis by 31.7%. The situation was similar in the diabetic subjects. Serum LDL cholesterol in non-diabetic subjects was 4.2 ± 0.5 mmol/1 and the LDL esterified/free cholesterol ratio was 2.6 ± 0.2. Following treatment with N-acetylcysteine, LDL cholesterol did not change, while Lp(a) decreased significantly by 24% ( P < 0.05). The LDL esterified/free cholesterol ratio decreased to 2.2 ± 0.2 ( P < 0.05) and there was a significant increase in the ability of the subjects LDL to inhibit cellular cholesterol synthesis ( P < 0.05). There was a significant negative correlation between plasma Lp(a) and the ability of the patients' LDL to inhibit cellular cholesterol synthesis ( r = − 0.68, P < 0.01). [ 3H]Cholesteryl-oleate-LDL (5 μg/ml) delivered 266 ± 13 ng cholesteryl oleate/mg cell protein, while it took 20 μg of [ 3H]cholesteryl oleate-labelled-Lp(a) to deliver a similar concentration (315 ± 21 ng cholesteryl oleate/mg cell protein). In conclusion it appears possible that the atherogenicity of Lp(a) may be associated with its effect on the LDL receptor which alters LDL receptor uptake, LDL composition and cellular cholesterol synthesis.

Cyclosporin A has divergent effects on plasma LDL cholesterol (LDL-C) and lipoprotein(a) [Lp(a)] levels in renal transplant recipients. Evidence for renal involvement in the maintenance of LDL-C and the elevation of Lp(a) concentrations in hemodialysis patients.

Cardiovascular disease is the major cause of mortality in renal transplant recipients. Plasma levels of low-density lipoprotein cholesterol (LDL-C) are often elevated following renal transplantation, and the immunosuppressant cyclosporin A has been implicated as a predisposing factor for posttransplantation hyperlipidemia. Lipoprotein(a) [Lp(a)] is an LDL-like lipoprotein particle; elevated levels of Lp(a) provide an independent and significant risk factor for cardiovascular disease. Plasma concentrations of Lp(a) vary greatly among individuals, and the mechanisms that govern changes in their levels in transplant patients are unknown. The effect(s) of cyclosporin A on Lp(a) was studied in two groups of renal transplantation patients. In group I plasma lipoproteins including Lp(a) were measured before and after successful renal transplantation; this group received both prednisone and cyclosporin A for immunosuppression. Group II patients were studied after renal transplantation and received prednisone alone for immunosuppression. Following surgery, group I patients demonstrated increased plasma concentrations of LDL-C (mean +/- SEM range, 111 +/- 6 to 142 +/- 17 mg/dL; P < .005). In contrast, plasma Lp(a) levels for this group were markedly decreased after renal transplantation (median, 34.3 to 19.7 mg/dL). Patients not treated with cyclosporin A (group II) exhibited mean LDL-C and median Lp(a) levels (118 +/- 42 and 33.1 mg/dL, respectively) that were remarkably similar to those observed before renal transplantation (group I). These data confirm that hyperlipidemia following renal transplantation is associated with cyclosporin A therapy and show that this drug has opposing effects on plasma Lp(a) and LDL-C accumulations.(ABSTRACT TRUNCATED AT 250 WORDS)

Association of elevated lipoprotein(a) levels and coronary heart disease in NIDDM patients. Relationship with apolipoprotein(a) phenotypes

Non-insulin-dependent diabetes mellitus (NIDDM) is a strong and independent risk factor for coronary heart disease. We assessed the potential relationship between plasma Lp(a) levels, apo(a) phenotypes and coronary heart disease in a population of NIDDM patients. Seventy-one patients with coronary heart disease, who previously have had transmural myocardial infarction, or significant stenosis on coronary angiography, or positive myocardial thallium scintigraphy, or in combination, were compared with 67 patients without coronary heart disease, who tested negatively upon either coronary angiography, myocardial thallium scintigraphy or a maximal exercise test. The prevalence of plasma Lp(a) levels elevated above the threshold for increased cardiovascular risk (> 0.30 g/l) was significantly higher (p = 0.005) in patients with coronary heart disease (33.8%) compared to the control group (13.4%). The relative risk (odds ratio) of coronary heart disease among patients with high Lp(a) concentrations was 3.1 (95% confidence interval, 1.31-7.34; p = 0.01). The overall frequency distribution of apo(a) phenotypes differed significantly between the two groups (p = 0.043). However, the frequency of apo(a) isoforms of low apparent molecular mass (< or = 700 kDa) was of borderline significance (p = 0.067) between patients with or without coronary heart disease (29.6% and 16.4%, respectively). In this Caucasian population of NIDDM patients, elevated Lp(a) levels were associated with coronary heart disease, an association which was partially accounted for by the higher frequency of apo(a) isoforms of small size. In multivariate analyses, elevated levels of Lp(a) were independently associated with coronary heart disease (odds ratio 3.48, p = 0.0233).