Increased serum lipoprotein(a) concentrations and low molecular weight phenotypes of apolipoprotein(a) are associated with symptomatic peripheral arterial disease

BACKGROUND: Increased concentrations of lipoprotein(a) [Lp(a)] have been considered a genetically determined risk factor for coronary artery and cerebrovascular disease. Only 2 small and conflicting studies have investigated the possibility of an association of peripheral arterial disease (PAD) with high serum Lp(a) concentrations and low molecular weight (LMW) phenotypes of apolipoprotein(a) [apo(a)]. METHODS: We measured serum concentrations of Lp(a) and apo(a) phenotypes in 213 patients with symptomatic PAD and 213 controls matched for sex, age (within 2 years), and presence of diabetes. RESULTS: Patients with PAD showed significantly higher median serum concentrations of Lp(a) (76 vs 47 mg/L; P = 0.003) and a higher frequency of LMW apo(a) phenotypes (41% vs 26%; P = 0.002) than controls. After adjustment for several potential confounders, increased Lp(a) concentrations (>195 mg/L, i.e., 75th percentile of the entire study sample) and LMW apo(a) phenotypes were significant predictors of PAD, with odds ratios of 3.73 (95% CI 2.08-6.67; P <0.001) and 2.21 (95% CI 1.33-3.67; P = 0.002), respectively. CONCLUSIONS: In this study sample, both increased serum concentrations of Lp(a) and the presence of LMW apo(a) phenotypes were associated with the presence of symptomatic PAD independent of traditional and nontraditional cardiovascular risk factors. Because PAD is considered an indicator of systemic atherosclerotic disease, our results suggest a possible role of Lp(a) as a genetically determined marker for systemic atherosclerosis.     

Significance of apolipoprotein(a) phenotypes in acute coronary syndromes: relation with clinical presentation

BACKGROUND: High lipoprotein(a) [Lp(a)] levels and small-sized apolipoprotein(a) [apo(a)] phenotypes have been linked to acute coronary syndromes (ACS). We sought to determine whether Lp(a) concentrations and apo(a) phenotypes may be related to the clinical syndrome of presentation among ACS patients. METHODS: Two hundred ten ACS patients and 105 controls were enrolled. One hundred thirteen patients presented with acute myocardial infarction (AMI) and 97 with unstable angina pectoris (UAP). Lp(a) concentrations were determined by ELISA and apo(a) isoforms were detected with a high-resolution immunoblotting method. RESULTS: Lp(a) levels and the percentage of subjects with at least one small-sized apo(a) isoform were significantly higher both in AMI patients and in UAP subjects as compared with controls. Among ACS patients, the percentage of subjects with at least one small apo(a) phenotype was significantly higher in patients who presented with AMI than in those with UAP (p<0.001). Multivariate logistic regression analysis showed that the presence of at least one small-sized apo(a) isoform was associated with AMI as the patient's clinical syndrome of presentation (OR=2.51, 95% CI: 1.38-4.58, p<0.01). CONCLUSIONS: Among ACS patients, apo(a) isoforms of low molecular weight were associated with AMI onset. High-resolution apo(a) phenotyping might be helpful to identify individuals at high risk for developing AMI.     

Relationship between plasma lipoprotein (a), apolipoprotein (a) phenotypes, and other coronary heart disease risk factors in a Melbourne South Asian population

BACKGROUND: High plasma lipoprotein(a) [Lp(a)] level is a strong and important risk factor for cardiovascular disease (CVD). Small-sized apolipoprotein(a) [apo(a)] isoforms (F, B, S1, and S2) are inversely correlated with the high levels of Lp(a) in plasma and significantly associated with CVD. Although the effects of apo(a) phenotypes and various risk factors on Lp(a) status in South Asian population may have been studied in other countries, there are no reports involving these risk factors in Australia. METHODS AND RESULTS: Factors contributing to variation in Lp(a) were surveyed in 402 (216 males and 186 females) South Asian Melburnians. There was a negative relationship between low alcohol beer per day and Lp(a) in men (P < 0.05). Approximately 21% of the variance of Lp(a) concentration in men and 6% in women were explained by age. Age was positively associated with Lp(a) concentrations in men but negatively in women. The most commonly occurring phenotype was apo(a) S3. In this phenotype, Lp(a) concentrations ranged from non-detectable to 811 mg/l. After adjusting for age, an inverse correlation was observed between Lp(a) concentration and apo(a) phenotypes (P < 0.01). CONCLUSIONS: Although Lp(a) has been reported to be genetically determined, there are clearly other factors contributing to variations in Lp(a) concentrations in a South Asian population.     

Apolipoprotein(a) isoforms in infarcted men under 60 years old

OBJECTIVE: The aim of this study was to compare the Lp(a) concentration and the frequency distribution of the apo(a) isoforms of a myocardial infarcted male group under 60 years old and a group of healthy subjects (controls). METHODS: A total of 111 infarcted men and 99 men free from disease were enrolled in this study. Lp(a) concentrations were measured by a commercial available rate nephelometry method, and apolipoprotein(a) isoform analysis was performed by sodium dodecyl sulfate (SDS) polyacrilamide gel electrophoresis (PAGE) and immunoblotting. RESULTS: Infarcted patients had higher Lp(a) concentrations (0.33 +/- 0.36 g/l) than noninfarcted subjects did (0.19 +/- 0.22 g/l), and these differences were significant (P = 0.001). Infarcted patients have also shown a greater proportion of elevated (> or = 0.30 g/l) Lp(a) concentrations 37.8% than controls 20.2% (P < 0.01). The distributions of apo(a) phenotypes for patients with myocardial infarction and controls were remarkably different (P < 0.001), and the proportions of smaller isoforms were significantly different by chi-square analysis (P < 0.01). CONCLUSIONS: Infarcted patients under 60 years old display higher Lp(a) concentrations and a significantly higher proportion of low molecular weight apolipoprotein(a) isoforms than controls.     

Apoprotein(a) phenotypes and plasma lipoprotein(a) concentration in patients with diabetes mellitus

OBJECTIVES: To determine whether apo(a) isoforms and plasma Lp(a) concentrations in association with some lipid parameters increase the relative risk for the development of atherosclerosis in patients with diabetes mellitus (IDDM and NIDDM). DESIGN AND METHODS: Apo (a) isoforms, Lp(a) and plasma lipids were determined in 40 IDDM and 65 NIDDM patients and in 182 healthy individuals. Apo(a) isoforms were separated by 3 to 15% gradient SDS-PAGE followed by immunoblotting. RESULTS: Logistical analysis showed that: Lp(a) levels >30 mg/dL (RR = 0.25, p < 0.000001; RR = 0.18, p < 0.00002), HTA (RR = 0.212, p < 0.00001; RR = 0.30, p < 0.00001), LMW-S1 apo(a) isoform (RR = 6.86, p < 0.0131; RR = 7.04, p < 0.0057) play a significant role in aterogenecity in both groups of patients with DM (IDDM and NIDDM). The 6.50-fold increase in risk was found in NIDDM patients with high Lp(a) levels (>30 mg/dL) and plasma total/HDL cholesterol ratio (4.5-5.8). CONCLUSION: Elevated Lp(a) levels, LMW S1 apo(a) isoform, HTA and combination of increased Lp(a) levels and total/HDL cholesterol ratio increase the risk for the development of atherosclerosis in patients with DM (IDDM and NIDDM).     

Relationship between lipoprotein(a) phenotypes and albumin excretion rate in non-insulin-dependent diabetes mellitus: protective effect of ‘null’ phenotype?

The possible association between lipoprotein(a) [Lp(a)] and albumin excretion rate (AER) is a topic that generates conflicting views. In addition, Lp(a) phenotypes have not previously been considered as factors influencing AER. In order to clarify this issue, we studied 70 non-insulin-dependent diabetes mellitus (NIDDM) patients without clinically detectable macroangiopathy, 27 with microalbuminuria and 43 without it. Both groups were matched for the known variables that could influence AER and serum Lp(a) levels. Lp(a) was determined by enzyme-linked immunosorbent assay (ELISA), and Lp(a) phenotypes were assessed by electrophoresis followed by immunoblotting. Lp(a) phenotypes were grouped as follows: 'small' (F, S1 and S2), 'big' (S3 and S4) and 'null'. The NIDDM patients with microalbuminuria presented higher serum Lp(a) concentrations than the patients without it [15.7 mg dL⁻¹ (95% CI 0.5–36.5) vs. 4.5 mg dL⁻¹ (95% CI 0.1–18.5); P  < 0.001] and a direct correlation between Lp(a) and AER was observed ( r  = 0.34; P  < 0.01). AER was significantly different when Lp(a) phenotypes were considered ['small': median 19 μg min⁻¹ (range 1–195); 'big': median 9.5 μg min⁻¹ (range 1–186); 'null': 4 μg min⁻¹ (range 1–9); P  = 0.04]. None of the NIDDM patients with a 'null' phenotype showed an AER of > 10 μg min⁻¹. In conclusion, this case–control study provides evidence that microalbuminuria is associated with high serum Lp(a) in NIDDM without clinically detectable macroangiopathy. Furthermore, NIDDM patients with a 'null' phenotype could be considered at low risk for the development of microalbuminuria.     

Apolipoprotein(a) size and lipoprotein(a) concentration and future risk of angina pectoris with evidence of severe coronary atherosclerosis in men: The Physicians' Health Study

BACKGROUND: The relationship of lipoprotein (a) [Lp(a)] concentrations with risk of coronary heart disease needs clarification, especially for threshold values for increased risk and for possible interactions with LDL-cholesterol concentrations and apolipoprotein (a) [apo(a)] size polymorphism. This study was designed to examine the ability of baseline Lp(a) concentration and apo(a) size to predict future severe angina pectoris in apparently healthy men. METHODS: Baseline Lp(a) concentration and apo(a) size were determined in 195 men who subsequently developed angina and in 195 men who remained free of cardiovascular disease for 5 years. RESULTS: Cases had higher median Lp(a) concentrations than did controls (30.6 vs 22.5 nmol/L; P = 0.02). Lp(a) concentration was predictive of angina [relative risk (RR) from lowest to highest quintiles: 1.0, 1.5, 1.0, 1.8, and 2.6; P for trend = 0.015]. The increased risk was approximately 4-fold (95% confidence interval, 1.4- to 11-fold) among men who had Lp(a) above the 95th percentile (>158 nmol/L). Men with Lp(a) concentrations in the highest quintile and LDL-cholesterol concentrations >1600 mg/L had a 12-fold increased risk (95% confidence interval, 1.5- to 43-fold). Small apo(a) size isoforms also significantly predicted risk of angina (RR for lowest quintile = 4.1; P for trend = 0.004). When the independent effect of Lp(a) concentration and apo(a) size was assessed by including them in the same multivariate model, only the association between apo(a) size and risk remained significant. CONCLUSIONS: High Lp(a) predicts risk of angina, and the risk is substantially increased with high concomitant LDL-cholesterol. Small apo(a) size predicts angina with greater strength and independence than Lp(a) concentration.     

High lipoprotein(a) levels with predominance of high molecular weight apo(a) isoforms in patients with pulmonary embolism

Abstract. Lipoprotein(a) (Lp(a)) may interact with the cellular components and protein co-factors of fibrino-lysis. To evaluate the effect of Lp(a) in thromboem-bolic diseases of the venous system, we measured serum levels and the isoform distribution of apo(a) in 25 patients with pulmonary embolism (18 men, 7 women, aged 21—77 years). The control group was adjusted for sex and age ( P = 0.189). Serum Lp(a) concentration was significantly higher in the study group (median: 9.3 vs. 4.3 mg dL^-1). As the distribution of high and low molecular weight subtypes of apo(a) did not show any differences ( P = 0.127) between the two groups, the elevated Lp(a) levels in patients with pulmonary embolism could not be attributed to the investigated kringle-4 polymorphism of the apo(a) gene and therefore other genetic or non-genetic implications are indicated.     

Association of lipoprotein(a) concentration and apo(a) isoform size with restenosis after percutaneous transluminal coronary angioplasty

Lp(a) is a unique class of lipoprotein particles that exhibits a considerable size heterogeneity resulting from the size polymorphism of apo(a), its unique protein component. An elevated level of Lp(a) in plasma has been proposed to be a risk factor for premature development of coronary artery disease. To evaluate the relationship between Lp(a) concentration and apo(a) isoform size with restenosis after percutaneous transluminal coronary angioplasty, Lp(a) levels and apo(a) phenotypes were determined in 204 patients who underwent a successful coronary angioplasty procedure and stent implantation. The patients were followed with clinical examinations and exercise tests at 1, 3, and 6 months, and a control coronary angiography was performed after 6 months to evaluate restenosis. Lp(a) levels were determined with an ELISA that is insensitive to the size heterogeneity of Lp(a), and the apo(a) isoforms were determined by a high-resolution agarose gel electrophoresis method followed by immunoblotting with a specific monoclonal antibody. Of the 146 patients who underwent angiographic evaluation, 57 (39%) had restenosis, whereas 89 (61%) did not. Lp(a) levels and the distribution of the expressed apo(a) phenotypes were compared in these two groups of patients. Although the mean and median Lp(a) levels were higher in the restenosed group, the difference was not statistically significant. However, a significant difference in Lp(a) values was found in women (P=0.043), even though, because of the small number of women in the study (n=35), no sound conclusions can be reached on the predictive role of Lp(a) in restenosis. There also was no difference in the distribution of apo(a) phenotypes between the two groups. Because of their wide distribution, Lp(a) values and apo(a) isoforms do not seem to be a useful indicator of risk of restenosis after percutaneous transluminal coronary angioplasty in our study cohort.     

Decrease in lipoprotein(a) after renal transplantation is related to the glucocorticoid dose

Abstract. Serum lipoprotein(a) [Lp(a)] concentrations and apolipoprotein(a) phenotypes were determined in 46 patients with end-stage renal disease both before as well as 1 week and 1, 3 and 6 months after renal transplantation. Immunosuppressive therapy consisted of cyclosporin A, prednisone and azathioprine. Before transplantation median Lp(a) levels did not differ between the patients and a healthy control group. A highly significant decrease ( P <0.001) in Lp(a) levels was observed in both male and female patients 1 week after transplantation. This marked reduction in Lp(a) occurred at a time when patients were receiving the highest doses of corticosteroids. As steroid doses were gradually tapered. Lp(a) concentrations subsequently increased, although at 6 months levels were still significantly reduced ( P <0.01) in women. No significant correlation was observed between Lp(a) and whole-blood cyclosporin levels, nor was there any correlation with the azathioprine dose. The reduction in Lp(a) concentrations was seen for all apo(a) phenotypes observed in the study.     

Further characterization of the plasma lipoprotein(a) distribution

The plasma lipoprotein(a) [Lp(a)] distribution in caucasians is heavily skewed to the right, with evidence of bimodality. As there is a well-described inverse relationship between apolipoprotein(a) [apo(a)] size and Lp(a) concentration, it is likely that the presence of multiple apo(a) isoforms of differing frequency has a significant impact on the final distribution of Lp(a) concentrations. We have previously described an immunoblot method for examining the relationship between apolipoprotein(a) [apo(a)] size and lipoprotein(a) [Lp(a)] mass among samples heterozygous for apo(a) size, thus eliminating confounding by null or undetected apo(a) isoforms. In the present study, this method has been applied to examine the plasma Lp(a) distribution, independent of the effects of apo(a) isoform size and frequency. Seventy subjects heterozygous for apo(a) size were studied. To take into account the inverse relationship (P <0.001) between apo(a) isoform size and Lp(a) concentration, Lp(a) data associated with each apo(a) isoform were normalized as multiples of the median Lp(a) concentration for that isoform. These apo(a) isoform-independent Lp(a) data demonstrated a strikingly multimodal distribution, with five major peaks. The relative frequencies of Lp(a) peaks 1–5 were 17.1%, 15.0%, 35.7%, 23.6%, and 8.6%, and associated median Lp(a) concentrations were 1.0, 6.2,15.0, 21.8, and 39.6 mg/dL, respectively. Multivariate analysis demonstrated that apo(a) isoform size accounted for 23% and isoform-independent Lp(a) peaks for 59.5% of the variation in Lp(a) concentration. Further investigation of the characteristics of the apo(a) isoform-independent Lp(a) distribution is warranted.     

Apolipoprotein(a) polymorphism predicts the increase of Lp(a) by pravastatin in patients with familial hypercholesterolaemia treated with bile acid sequestration

Abstract. HMG-CoA reductase inhibitors effectively reduce the concentration of low density lipoproteins (LDL) in plasma. Lipoprotein(a) [Lp(a)] may be as atherogenic as LDL. A few studies, only one of which was placebo controlled, suggest that the HMG CoA reductase inhibitors either do not affect Lp(a) or they increase Lp(a). The response of Lp(a) to HMG-CoA reductase inhibition has not been related to apolipo-protein(a) phenotypes in previous studies. We conducted a double-blind, placebo controlled study of pravastatin in 51 patients with familial hypercholester-olemia (FH) ( n = 43) or probable FH ( n = 8). All patients had LDL-cholesterol concentrations above 4.1 mmol 1^-1 despite treatment with diet and bile acid sequestration. In patients assigned to pravastatin ( n = 34), the mean concentrations of total cholesterol and LDL cholesterol fell significantly ( P< 0.01) when compared to placebo. Lp(a) increased ( P< 0.01) from a mean (±SD) of 33.6 ± 40.8 mgdl^-1 to 411 ± 46.1 mg dl^-1 on pravastatin but was unchanged during placebo treatment. The percentage increase in Lp(a) was the same in patients with different apo(a) phenotypes, and hence the absolute increase in Lp(a) was greatest in patients with the low molecular weight apo(a) phenotypes.     

Association of lipoprotein(a) and apolipoprotein(a) phenotypes with coronary and carotid atherosclerosis in CHD men

AIM: To evaluate in a case-control cross-sectional study whether lipoprotein(a) concentration and apo(a) phenotypes are associated with the presence and severity of coronary and carotid atherosclerosis. MATERIALS AND METHODS: We have examined 198 male CHD patients (mean age 53 +/- 8) years) with stenosis more than 50% at least in one main coronary artery or its major branches. Duplex scanning was performed in 168 patients to assess the degree of carotid atherosclerosis. Seventy six apparently healthy men (mean age 39 +/- 9 years) formed the control group. Lp(a) concentration was measured by ELISA, apo(a) phenotyping was performed by immunoblotting. RESULTS: Lp(a) level was significantly higher in cases compared to controls: 37 +/- 31 mg/dl vs. 18 +/- 27 mg/dl, p < 0.05. Patients had low-molecular weight apo(a) phenotypes more frequently than controls: 46% vs. 29%, p = 0.01. Patients aged 45 years and younger had low-molecular weight apo(a) phenotypes more frequently than older ones (65% vs. 42%, p < 0.05) and controls (65% vs. 29%, respectively, p = 0.001). High Lp(a) level and low-molecular weight apo(a) phenotypes correlated with presence and number of coronary occlusions. CONCLUSION: There was association between Lp(a) level, low-molecular weight apo(a) phenotypes and presence, severity, extension of carotid atherosclerosis. No differences in distribution of other CHD risk factors among all subgroups of patients were found.     

The antifibrinolytic effect of lipoprotein(a) in heterozygous subjects is modulated by the relative concentration of each of the apolipoprotein(a) isoforms and their affinity for fibrin

Individuals heterozygous for the apolipoprotein(a) [apo(a)] trait have phenotypes combining two different lipoprotein(a) [Lp(a)] particle suspecies that are present in plasma at a different concentration. Evaluation of the ability of each of these isoforms to bind to fibrin and affect plasminogen binding is essential to assess the pathogenic role of Lp(a) in these subjects; therefore, fractions containing different ratios of Lp(a) with distinct apo(a) isoforms (e.g. B/S3, S1/S4) were prepared by density gradient ultracentrifugation of plasma, and tested. Lp(a) fractions containing mainly small apo(a) isoforms (either B or S1) showed the highest affinity for fibrin ( K _d ∼ 150 nmol L⁻¹) and the best competitor activity for plasminogen, whereas fractions containing mainly the high molecular mass isoforms (either S3 or S4) showed the lowest affinities ( K _d ≥ 500 nmol L⁻¹). An increase in K _d was observed as a function of the relative content in isoforms of high molecular mass in these fractions. This inverse relationship between affinity for fibrin and apo(a) size indicates that Lp(a) subspecies in heterozygotes may have different pathogenic potential. Thus, the antifibrinolytic effect of Lp(a) in heterozygous subjects would depend on the relative concentration of the isoform with the highest affinity for fibrin.     

Electrophoretic measurement of lipoprotein(a) cholesterol in plasma with and without ultracentrifugation: comparison with an immunoturbidimetric lipoprotein(a) method

OBJECTIVES: Elevated plasma lipoprotein(a) [Lp(a)] is a significant risk factor for vascular disease. Standardization of Lp(a) mass measurement is complicated by the heterogeneity of apolipoprotein(a) [apo(a)]. We investigated whether Lp(a) cholesterol measurement, which is not influenced by apo(a) size, is a viable alternative to measuring Lp(a) mass. DESIGN AND METHODS: Plasma Lp(a) cholesterol was measured electrophoretically, with and without ultracentrifugation, and results were compared to each other and to immunoturbidimetrically measured Lp(a) mass in 470 subjects. RESULTS: Ultracentrifuged and whole plasma Lp(a) cholesterol levels demonstrated high correlation (R = 0.964). All samples with detectable (>/=2.0 mg/dl) Lp(a) cholesterol had Lp(a) mass >30 mg/dl (the clinically relevant cutpoint), while 59 samples with Lp(a) mass >30 mg/dl did not have detectable Lp(a) cholesterol. CONCLUSIONS: Lp(a) cholesterol can be measured in whole plasma without interference from VLDL lipoproteins. The relative clinical merits of measuring Lp(a) cholesterol vs. Lp(a) mass or both in combination deserves investigation.     

apo(a)表型与维持性透析患者高Lp(a)水平关系研究

目的 研究载脂蛋白（a）[apo（a）]表型与维持性透析患者高脂蛋白（a）[Lp（a）]水平关系,探索血液透析患者Lp（a）代谢紊乱机制。方法 维持性透析患者66例,持续性透析治疗两年以上。终末期肾病患者51例,未经过血液透析、腹膜透析及肾移植治疗。随机选择62例体检健康者作为对照组。应用SDS-琼脂糖电泳连接蛋白免疫印迹方法检测各组患者apo（a）表型,免疫透射比浊法检测Lp（a）。结果 HMW apo（a）表型所占比例在MHD组、ESRD组与对照组三组中无显著性差异（P〉0.05）。在HMW apo（a）表型中,Lp（a）中位数浓度在MHD组、ESRD组与对照组分别为100.9mg/L8、3.5 mg/L5、6.5 mg/L,MHD组与ESRD组及对照组之间都存在显著性差异（P〈0.05）。对于LMW apo（a）表型,MHD组和ESRD组Lp（a）中位数浓度分别为220.5 mg/L2、15.8 mg/L,无显著性差异（P〉0.05）,但两组分别与对照组（163.0mg/L）相比,则均有显著性差异（P〈0.05）。结论 MHD治疗可促使Lp（a）浓度增加,并且以HMW apo（a）表型的Lp（a）浓度增高更为显著。     

Relationship between apo(a) length polymorphism and lipoprotein(a) concentration in healthy Ivorian subjects with single or double apo(a) isoforms

Objectives

To determine the relationship between apo(a) size and Lp(a) concentration in healthy Ivorian subjects.

Methods

Serum Lp(a) was measured by immunonephelometry and electroimmunodiffusion, and apo(a) size determined by immunoblotting.

Results

Both assay methods provided comparable information. Lp(a) concentrations showed a non-Gaussian distribution and skewed towards higher values. Apo(a) isoform size distribution exhibited three frequency peaks at 18, 22 and 25 kringles. Single and double apo(a) isoforms were detected in 36% and 64% of subjects, respectively. Lp(a) values were higher in subjects with double isoforms, the major isoform being of lower size. An inverse correlation between apo(a) size and Lp(a) concentration was found, apo(a) size accounting for more than 30% of Lp(a) concentration in “single-band” group, whereas being weaker in “double-band” group. Low size isoforms were associated with higher Lp(a) concentrations, high size isoforms with higher variability.

Conclusions

Lp(a) concentrations were inversely correlated to apo(a) size. This study has shown the relationship between apo(a) size and Lp(a), the influence of apo(a) size varying according to the phenotype. Apo(a) “double isoform” phenotype confers elevated levels to Lp(a) in healthy Ivorian subject.     

Influence of apolipoprotein(a) phenotype on lipoprotein(a) quantification: Evaluation of three methods

Three commercially available assays (an enzyme-linked immunosorbent assay ELISA, an immunoradiometric assay, IRMA, and a nephelometric assay) for the determination of lipoprotein(a) [Lp(a)] were compared with respect to the dependency of these assays on the various apolipoprotein(a) [apo(a)] isoforms. Although there was a strong correlation between the three methods, a significant difference between the absolute values (mg/L) was observed (p < 0.001). Using purified Lp(a) preparations, we showed that the ELISA assay quantifies the Lp(a) concentration on a molar basis, independently of the apo(a) isoform size. The IRMA and the nephelometric assay however are apo(a) isoform size dependent and overestimate the Lp(a) concentration of large apo(a) isoforms whereas the amount of small apo(a) isoforms is underestimated. In general, the isoform dependency of the Lp(a) quantification is of limited clinical relevance. In this study, inconsistent risk assignments are made in approximately 3% of the cases, when the Lp(a) concentrations obtained with the apo(a) isoform dependent assays are compared with the isoform independent ELISA.     

Apolipoprotein(a) phenotypes, Lp(a) concentration and plasma lipid levels in relation to coronary heart disease in a Chinese population: evidence for the role of the apo(a) gene in coronary heart disease.

Elevated lipoprotein(a) (Lp[a]) concentrations are associated with premature coronary heart disease (CHD). In the general population, Lp(a) levels are largely determined by alleles at the hypervariable apolipoprotein(a) (apo[a]) gene locus, but other genetic and environmental factors also affect plasma Lp(a) levels. In addition, Lp(a) has been hypothesized to be an acute phase protein. It is therefore unclear whether the association of Lp(a) concentrations with CHD is primary in nature. We have analyzed apo(a) phenotypes, Lp(a) levels, total cholesterol, and HDL-cholesterol in patients with CHD, and in controls from the general population. Both samples were Chinese individuals residing in Singapore. Lp(a) concentrations were significantly higher in the patients than in the population (mean 20.7 +/- 23.9 mg/dl vs 8.9 +/- 12.9 mg/dl). Apo(a) isoforms associated with high Lp(a) levels (B, S1, S2) were significantly more frequent in the CHD patients than in the population sample (15.9% vs 8.5%, P less than 0.01). Higher Lp(a) concentrations in the patients were in part explained by this difference in apo(a) allele frequencies. Results from stepwise logistic regression analysis indicate that apo(a) type was a significant predictor of CHD, independent of total cholesterol and HDL cholesterol, but not independent of Lp(a) levels. The data demonstrate that alleles at the apo(a) locus determine the risk for CHD through their effects on Lp(a) levels, and firmly establish the role of Lp(a) as a primary genetic risk factor for CHD.     

Effect of insulin treatment on serum lipoprotein(a) in non-insulin-dependent diabetes

Abstract. In order to evaluate whether Lp(a), a lipoprotein that is potentially thrombogenic and atherogenic, is a potential risk factor for CAD in non-insulin-dependent diabetes (NIDDM), we compared the Lp(a) and its distribution in 145 NIDDM patients with that in 94 healthy control subjects. Furthermore, we studied the effect of insulin treatment on serum Lp(a) in 108 patients with NIDDM. Male and female NIDDM patients had similar Lp(a) concentrations to healthy controls (median value 167 mg L^-1, range 15–1550 mg L^-1 vs. 157 mg L^-1, range 15–919 mg L^-1, NS and 92, range 15–1190 mg L^-1 vs. 103 mg L^-1, range 15–842 mg L^-1, NS). Also, the cumulative distribution of Lp(a) did not differ between the NIDDM patients and healthy subjects. Insulin treatment increased Lp(a) in diabetics with a Lp(a) concentration of less than 300 mg ^-1L, but this effect was not related to the concomitant improvement in metabolic control (mean change (±SEM) of HbA_1c from 9.80±0.15 to 8.00±0.12; P < 0.001). In subjects with elevated Lp(a) concentrations (>300 mg L^-1) the Lp(a) concentration was unaffected by insulin, despite a similar improvement in glycaemic control. These results suggest that insulin may modulate the concentration of Lp(a).