Urinary excretion of apolipoprotein(a) fragments in type 1 diabetes mellitus patients

High levels of plasma lipoprotein(a) [Lp(a)] represent an independent risk factor for cardiovascular morbidity; however, Lp(a) has not yet been identified as a risk factor for type 1 diabetic patients. Results from the limited number of available studies on plasma Lp(a) levels in relation to renal function in type 1 diabetes mellitus are inconclusive. We hypothesized that only type 1 diabetes mellitus patients with impaired renal function show increased plasma Lp(a) levels, due to decreased urinary apolipoprotein(a) [apo(a)] excretion. We therefore measured urinary apo(a) levels in 52 type 1 diabetes mellitus patients and 52 matched controls, and related the urinary apo(a) concentration to the plasma Lp(a) level, kidney function, and metabolic control. Our findings indicate that patients with incipient diabetic nephropathy as evidenced by microalbuminuria (20 to 200 microg/min) exhibit significantly higher plasma Lp(a) levels (median, 15.6 mg/dL) in comparison to normoalbuminuric patients (median, 10.3 mg/dL) and healthy controls (median, 12.0 mg/dL). Urinary apo(a) normalized to creatinine excretion was significantly elevated in both normoalbuminuric (median, 22.3 microg/dL) and microalbuminuric type 1 diabetic patients (median, 29.1 microg/dL) compared with healthy subjects (median, 16.0 microg/dL) and correlated significantly with Lp(a) plasma levels in both patient and control groups (P < .003). No correlation existed between the Lp(a) plasma level or urinary apo(a) concentration and metabolic control in type 1 diabetes mellitus patients. From these studies, we conclude that urinary apo(a) excretion is significantly increased in type 1 diabetic patients and correlates with plasma Lp(a) levels, and only type 1 diabetic patients with microalbuminuria have higher plasma levels of Lp(a) compared with patients with normoalbuminuria and healthy controls.     

Effect of cardiopulmonary bypass and heparin on plasma levels of Lp(a) and Apo(a) fragments

Fragments of apolipoprotein(a) [apo(a)], the distinctive glycoprotein of lipoprotein(a) [Lp(a)], are present in human plasma and urine and have been implicated in the development of atherosclerosis. The mechanism responsible for the generation of apo(a) fragments in vivo is poorly understood. In this study, we examined the plasma levels of Lp(a) and apo(a) fragments [or free apo(a)] and urinary apo(a) in 15 subjects who underwent cardiac surgery necessitating cardiopulmonary bypass. We also measured the plasma concentration and activity of polymorphonuclear elastase, an Lp(a)-cleaving enzyme in vitro, and plasma levels of C-reactive protein. Despite a marked activation of polymorphonuclear cells and a pronounced inflammatory response, as documented by an 8-fold and a 35-fold increase in plasma levels of polymorphonuclear elastase and C-reactive protein, respectively, the proportion of plasma free apo(a) to Lp(a) and urinary excretion of apo(a) remained unchanged over a 7-day period after surgery, and polymorphonuclear elastase activity remained undetectable in plasma. No fragmentation of apo(a) was observed ex vivo in plasma samples collected before and after surgery. These data indicate that in this model, apo(a) is not fragmented in plasma and are consistent with the hypothesis that apo(a) fragments result from a constitutively active tissue mechanism that is not modified by cardiac surgery with cardiopulmonary bypass.     

Major reduction in plasma Lp(a) levels during sepsis and burns

Plasma levels of lipoprotein(a) [Lp(a)], an atherogenic particle, vary widely between individuals and are highly genetically determined. Whether Lp(a) is a positive acute-phase reactant is debated. The present study was designed to evaluate the impact of major inflammatory responses on plasma Lp(a) levels. Plasma levels of C-reactive protein (CRP), low density lipoprotein cholesterol, Lp(a), and apolipoprotein(a) [apo(a)] fragments, as well as urinary apo(a), were measured serially in 9 patients admitted to the intensive care unit for sepsis and 4 patients with extensive burns. Sepsis and burns elicited a major increase in plasma CRP levels. In both conditions, plasma concentrations of Lp(a) declined abruptly and transiently in parallel with plasma low density lipoprotein cholesterol levels and closely mirrored plasma CRP levels. In 5 survivors, the nadir of plasma Lp(a) levels was 5- to 15-fold lower than levels 16 to 18 months after the study period. No change in plasma levels of apo(a) fragments or urinary apo(a) was noticed during the study period. Turnover studies in mice indicated that clearance of Lp(a) was retarded in lipopolysaccharide-treated animals. Taken together, these data demonstrate that Lp(a) behaves as a negative acute-phase reactant during major inflammatory response. Nongenetic factors have a major, acute, and unexpected impact on Lp(a) metabolism in burns and sepsis. Identification of these factors may provide new tools to lower elevated plasma Lp(a) levels.     

Apolipoprotein(a) size polymorphism is associated with coronary heart disease in polygenic hypercholesterolemia

BACKGROUND AND AIM: In addition to high serum cholesterol levels, various cardiovascular risk factors may be involved in the development of coronary heart disease (CHD) in hypercholesterolemic subjects. As the levels of lipoprotein(a) [Lp(a)], an important and independent cardiovascular risk factor, are high in polygenic hypercholesterolemia (PH), we investigated plasma Lp(a) levels and apolipoprotein(a) [apo(a)] phenotypes in relation to occurrence of CHD events in PH patients. METHODS AND RESULTS: Lp(a) levels and apo(a) isoforms were determined in 191 PH patients, 83 normocholesterolemic subjects with CHD, and 94 normocholesterolemic controls without CHD. Lp(a) levels were similar in the hypercholesterolemic subjects with (n=100) or without CHD (n=91): 21.4 (range 6.6-59.23) vs 18.5 (range 5.25-57.25) mg/dL (p=NS). Low molecular weight apo(a) isoforms were more prevalent (55%) in the PH patients with CHD, whereas high molecular weight apo(a) isoforms were more prevalent (62.6%) in those without CHD: this difference was significant (p<0.05). A stepwise multiple-discriminant analysis made in order to determine the independence of common cardiovascular risk factors, Lp(a) levels and low molecular weight apo(a) isoforms in predicting CHD among hypercholesterolemic subjects showed that the presence of a positive family history of CHD, smoking, age, and the presence of at least one apo(a) isoform of low molecular weight were independently associated with CHD. CONCLUSIONS: Despite high Lp(a) levels, our findings do not support the hypothesis that Lp(a) plays an independent role in determining clinical CHD in PH subjects. However, the presence of at least one low molecular weight apo(a) isoform is an independent genetic predictor of CHD in hypercholesterolemic subjects. Together with other cardiovascular risk factors, apo(a) phenotypes should be assessed to evaluate the overall CHD risk status of all subjects with high serum cholesterol levels.     

Urinary excretion of apo(a) fragments in NIDDM patients

Summary Lp(a), one of the most atherogenic lipoproteins, is believed to contribute significantly to vascular diseases in non-insulin-dependent diabetic (NIDDM) patients. Contradictive data have been published on these patients concerning plasma concentrations of Lp(a) and their relation to renal function. Since apo(a) fragments appear in urine, we measured urinary apo(a) in 134 NIDDM patients and 100 matched controls and related urinary apo(a) concentrations to plasma Lp(a) levels and kidney function. Plasma Lp(a) values were found to be significantly higher in NIDDM patients. NIDDM patients also secreted significantly more apo(a) into their urine as compared to control subjects. There was no correlation between creatinine clearance or albumin excretion and urinary apo(a) concentrations. Patients with macroalbuminuria exhibited a twofold higher apparent fractional excretion of apo(a) in comparison to patients with normal renal function. Urinary apo(a) values in both patients and control subjects were highly correlated to plasma Lp(a), yet no correlation was found with HbA_{1 c} or serum lipoproteins. It is concluded that urinary apo(a) excretion is correlated to plasma Lp(a) levels but not to creatinine clearance in patients suffering from NIDDM. [Diabetologia (1997) 40: 1455–1460] Received: 26 May 1997 and in revised form: 21 July 1997     

Atorvastatin lowers lipoprotein(a) but not apolipoprotein(a) fragment levels in hypercholesterolemic subjects at high cardiovascular risk

The effect of statins on Lp(a) levels is controversial; furthermore, the potential action of statins on apo(a) fragmentation is indeterminate. We therefore determined the circulating levels of Lp(a) and of apo(a) fragments in hypercholesterolemic patients before and after treatment (6 weeks) with Atorvastatin 10 mg/day (A10) or Simvastatin 20 mg/day (S20). In a double blind study, hypercholesterolemic patients (n=391) at high cardiovascular risk (LDL-C>=4.13 mmol/l; TG<2.24 mmol/l; 34% with documented CHD; 45% hypertensive; and 29% current smokers) were assigned to treatment with A10 (n=199) or S20 (n=192). Plasma Lp(a) and apo(a) fragment levels (n=206) were measured prior to and after treatment. At baseline, A10 and S20 groups did not differ in plasma levels of lipids, Lp(a) (A10: 0.45+/-0.48 mg/ml, S20: 0.46+/-0.5), and apo(a) fragments (A10: 3.88+/-5.22 microg/ml; S20: 3.25+/-3), and equally in apo(a) isoform size (A10: 26+/-5 kr, S20: 25.5+/-5.3). After treatment, both statins significantly reduced Lp(a) levels (A10: 0.42+/-0.47 mg/ml, 6% variation, P<0.001; S20: 0.45+/-0.53 mg/ml, 0.02% variation, P=0.046). A10 and S20 did not significantly differ in their efficacy to lower Lp(a) levels. In a multivariate logistic regression analysis, the reduction of Lp(a) levels was independently associated with Lp(a) baseline concentration, but not to other variables, including LDL-C reduction. Plasma levels of apo(a) fragments were not modified by either statin. In conclusion, both A10 and S20 significantly lowered Lp(a), although this effect was of greater magnitude in atorvastatin-treated patients.     

Quantification of lipoprotein(a) and apolipoprotein(a) in plasma and lipoprotein fractions in the hypertriglyceridemic state.

Lipoprotein(a) [Lp(a)] is a risk factor for coronary heart disease (CHD) in particular in association with high low density lipoprotein (LDL) cholesterol concentrations. Hypertriglyceridemia on the other hand has been found to be associated with low Lp(a) values. This observation could be confirmed in 851 patients of the outpatient lipid clinic. Lp(a) median levels were 2.7-fold higher in patients with triglycerides below 200 mg/dl as compared with patients expressing triglyceride levels above 200 mg/dl (19 vs 7 mg/dl, P < 0.0001). In contrast to these data apolipoprotein(a) [apo(a)] has been detected in triglyceride-rich lipoproteins (TRL). To find out whether the presence of apo(a) in TRL is determined by the concentration of these particles, apo(a) concentrations were measured in TRL in fasting plasma of ten hypertriglyceridemic patients and ten normal controls with Lp(a) serum levels above 25 mg/dl. The apo(a) concentration in TRL did not show statistically significant differences between controls and patients (2.0+/-0.9 vs 1.8+/-1.6 mg/dl). In the second part of the study apo(a) levels in TRL were measured before and after fat feeding in eight healthy volunteers. Again no significant differences were observed in the apo(a) concentrations of the d < 1.006 a ml fraction before and after fat feeding (1.03+/-1.06 vs 0.81+/-0.63 mg/dl). In summary, this study fails to show an association of apo(a) with TRL for different states of hypertriglyceridemia. This negative finding is shown for constant particle numbers but might not be true if the particle number in TRL increases.     

Lipoprotein Lp(a) in homozygous familial hypercholesterolemia: density profile, particle heterogeneity and apolipoprotein(a) phenotype.

Homozygous familial hypercholesterolemia (FH) is a genetic disorder featuring a functional defect in cellular LDL receptors, marked elevation in circulating LDL concentrations, and premature atherosclerosis. The potential atherogenic role of apo B-containing lipoproteins other than LDL in this disease is indeterminate. We describe the quantitative and qualitative characteristics of Lp(a) as a function of apo(a) phenotype in a group of eight, unrelated homozygous FH patients. Plasma Lp(a) levels were significantly elevated (2.5-fold; mean 50 +/- 32 mg/dl) as compared to those in healthy subjects. The S2 isoform of apo(a) occurred most frequently (6 of eight patients); the rare B isoform presented in three patients. Plasma Lp(a) levels in homozygous FH did not correspond to those predicted by apo(a) phenotype. Analyses of the density distribution of Lp(a) and of Lp(a) particle size and heterogeneity as a function of density did not reveal any anomalies characteristic of homozygous FH. However, comparison of the hydrated density of Lp(a) particles as a function of apo(a) isoform content revealed a clear influence of isoform on this parameter; thus, in a B/S2 heterozygous patient, the density distribution of Lp(a) fractions containing isoform B alone, B and S2, and S2 alone, demonstrated that the apparent molecular weight of apo(a) plays a determining role in controlling the hydrated density and size of the resulting Lp(a) particle. Indeed, patients expressing the high molecular weight, S2 isoform uniformly displayed a dense form of Lp(a) (hydrated density approximately 1.055 g/ml). In subjects presenting two apo(a) isoforms, each isoform resided on distinct lipoprotein particles; in such cases, the plasma levels of the denser isoform predominated, suggesting differences in rates of formation, or rates of tissular catabolism, or in the plasma stability of the particles, or a combination of these mechanisms. Considered together, our data may be interpreted to suggest that the elevated circulating levels of Lp(a) in homozygous FH patients may reflect either an increased biosynthesis, or diminished catabolism via the cellular LDL receptor pathway, or a combination of both.     

Defects in the low density lipoprotein receptor gene affect lipoprotein (a) levels: multiplicative interaction of two gene loci associated with premature atherosclerosis.

The lipoprotein (a) [Lp(a)] contains two nonidentical protein species, apolipoprotein (apo) B-100 and a specific high molecular weight glycoprotein, apo(a). Lp(a) represents a continuous quantitative genetic trait, the genetics of which are only poorly understood. Genetic variation at the apo(a) locus affects plasma Lp(a) levels and explains at least 40% of the variability of this trait. Lp(a) levels were found to be elevated 3-fold in the plasma from patients with the heterozygous form of familial hypercholesterolemia who have one mutant low density lipoprotein receptor gene. This elevation was not due to a higher frequency of those apo(a) types that are associated with high Lp(a) levels in familial hypercholesterolemia patients. Rather Lp(a) levels were elevated for each of the apo(a) phenotypes examined. The effects of the apo(a) and low density lipoprotein receptor genes on Lp(a) levels are not additive but multiplicative. This is a situation not commonly considered in quantitative human genetics. We conclude that Lp(a) levels in plasma may be determined by variation at more than one gene locus.     

Association of lipoprotein(a) levels and apolipoprotein(a) phenotypes with coronary artery disease in Type 2 diabetic patients and in non-diabetic subjects.

AIMS: We investigated whether in Type 2 diabetic patients lipoprotein(a) (Lp(a)) levels and apolipoprotein(a) (apo(a)) polymorphism are associated with angiographically documented coronary artery disease (CAD). We also examined whether there are differences in the distributions of Lp(a) levels and apo(a) phenotypes between CAD patients with and without diabetes. METHODS: A hundred and seven diabetic patients with CAD, 274 diabetic patients without CAD, 201 non-diabetic patients with CAD, and 358 controls were enrolled. RESULTS: Diabetic patients with CAD showed Lp(a) levels (21.2 +/- 17.7 vs. 15.1 +/- 17.8 mg/dl; P = 0.0018) and a percentage of subjects with at least one apo(a) isoform of low molecular weight (MW) (67.2% vs. 27.7%; P = 0.0000) significantly greater than diabetic patients without CAD. Multivariate analysis showed that in diabetic patients Lp(a) levels and apo(a) phenotypes were significantly associated with CAD; odds ratios (ORs) of high Lp(a) levels for CAD were 2.17 (1.28-3.66), while ORs of the presence of at least one apo(a) isoform of low MW were 5.35 (3.30-8.60). Lp(a) levels (30.2 +/- 23.7 vs. 21.2 +/- 17.7 mg/dl; P = 0.0005) and the percentage of subjects with at least one apo(a) isoform of low MW (87.0% vs. 67.2%; P = 0.0001) were significantly higher in CAD patients without than in those with diabetes. CONCLUSIONS: Our data suggest that Lp(a) levels and apo(a) phenotypes are independently associated with CAD in Type 2 diabetic patients; thus both these parameters may be helpful in selecting diabetic subjects at high genetic cardiovascular risk. However, Lp(a) levels and apo(a) polymorphism seem to be cardiovascular risk factors less important in diabetic than in non-diabetic subjects. Diabet. Med. 18, 589-594 (2001)     

Plasma lipoprotein (a) concentrations in hypothyroid, euthyroid and hyperthyroid subjects.

OBJECTIVE: Alterations of the lipid profile are a well known phenomenon in thyroid dysfunction. Thyroid hormones regulate lipid metabolism through various mechanisms, but a key role is played by the LDL receptor pathway. Thyroid hormone influence on lipoprotein (a) [Lp(a)] metabolism is known. METHODS AND RESULTS: Therefore we studied Lp(a) concentrations in a group of 16 hypothyroid patients and in a group of 22 hyperthyroid patients. Twenty-six euthyroid subjects were used as a control group. Plasma Lp(a) concentrations in hyperthyroid patients (23.2 +/- 28.1 mg/dl) were significantly lower than those of the hypothyroid patients (27.1 +/- 19.2, p < 0.05). There were negative correlations between plasma Lp(a) concentrations and total T4 levels in patients with hyperthyroidism and hypothyroidism (r: -0.49, p < 0.05; r: -0.40, p < 0.05, respectively). Also, decreased HDL-C levels, increased LDL-C, total cholesterol and apo B levels in the hypothyroid patients according to euthyroid subjects were observed (p < 0.05). Decreased LDL-C levels, increased HDL-C and apo Al levels in the hyperthyroid patients according to euthyroid subjects were determined (p < 0.05). CONCLUSIONS: It was concluded that plasma Lp(a) concentrations increase in hypothyroid patients and the observed relationships between thyroid status and Lp(a) levels can be explained by impaired catabolism of apo B and Lp(a) in hypothyroidism.     

High lipoprotein(a) levels and small apolipoprotein(a) sizes are associated with endothelial dysfunction in a multiethnic cohort

OBJECTIVES: This study sought to determine the effect of lipoprotein(a), or Lp(a), levels and apolipoprotein(a), or apo(a), sizes on endothelial function and to explore ethnic differences in their effects. BACKGROUND: Although high levels of Lp(a) have been shown to confer increased cardiovascular risk in Caucasians, its significance in non-Caucasian populations is uncertain. The pathogenic role of the apo(a) component of Lp(a) is also unclear. METHODS: The relationship of Lp(a) levels and apo(a) sizes to endothelial function was examined in a multiethnic cohort of 89 healthy subjects (age 42 +/- 9 years; 50 men, 39 women) free of other cardiac risk factors. Endothelium-dependent, flow-mediated dilation (FMD) and endothelium-independent, nitrate-induced dilation (NTG) were assessed by ultrasound imaging of the brachial artery. RESULTS: Plasma Lp(a) levels were lowest in Caucasians (18.3 +/- 21.1 mg/dl, n = 40); intermediate in Hispanics (30.2 +/- 30.5 mg/dl, n = 21); and highest in African Americans (68.8 +/- 46.0 mg/dl, n = 28). Lipoprotein(a) levels were found to correlate inversely to FMD (r = -0.33, p < 0.005) but not to NTG (r = 0.06, p = 0.60). This association remained significant after adjusting for gender (p = 0.002). In addition, subjects with small apo(a) size of 相似文献   

Fish intake, independent of apo(a) size, accounts for lower plasma lipoprotein(a) levels in Bantu fishermen of Tanzania: The Lugalawa Study.

Plasma lipoprotein(a) [Lp(a)] levels are largely genetically determined by sequences linked to the gene encoding apolipoprotein(a) [apo(a)], the distinct protein component of Lp(a). Apo(a) is highly polymorphic in length due to variation in the numbers of a sequence encoding the apo(a) kringle 4 domain, and plasma levels of Lp(a) are inversely correlated with apo(a) size. In 2 racially homogeneous Bantu populations from Tanzania differing in their dietary habits, we found that median plasma levels of Lp(a) were 48% lower in those living on a fish diet than in those living on a vegetarian diet. Considering the relationship between apo(a) size and Lp(a) plasma concentration, we have extensively evaluated apo(a) isoform distribution in the 2 populations to determine the impact of apo(a) size in the determination of Lp(a) values. The majority of individuals (82% of the fishermen and 80% of the vegetarians) had 2 expressed apo(a) alleles. Additionally, the fishermen had a high frequency of large apo(a) isoforms, whereas a higher frequency of small isoforms was found in the vegetarians. When subjects from the 2 groups were matched for apo(a) phenotype, the median Lp(a) value was 40% lower in Bantus on the fish diet than in those on the vegetarian diet. A significant inverse relationship was also found between plasma n-3 polyunsaturated fatty acids and Lp(a) levels (r=-0.24, P=0.01). The results of this study are consistent with the concept that a diet rich in n-3 polyunsaturated fatty acids, and not genetic differences, is responsible for the lower plasma levels of Lp(a) in the fish-eating Bantus and strongly suggest that a sustained fish-based diet is able to lower plasma levels of Lp(a).     

The metabolism of apolipoproteins (a) and B-100 within plasma lipoprotein (a) in human beings

The metabolism of apolipoproteins (apo) (a) and B-100 within plasma lipoprotein (a) [Lp(a)] was examined in the fed state in 23 subjects aged 41 to 79 years who received a primed-constant infusion of [5,5,5-2H3] leucine over 15 hours. Lipoprotein (a) was isolated from the whole plasma using a lectin affinity-based method. Apolipoprotein (a) and apoB-100 were separated by gel electrophoresis, and tracer enrichment of each apolipoprotein was measured using gas chromatography/mass spectrometry. Data were fit to a multicompartmental model to determine fractional catabolic rates (FCRs) and secretion rates (SRs). The FCRs of apo(a) and apoB-100 (mean +/- SEM) within plasma Lp(a) were significantly different (0.220 +/- 0.030 pool/d and 0.416 +/- 0.040 pool/d, respectively; P < .001). Apolipoprotein (a) SR (0.50 +/- 0.08 mg/[kg per d]) was significantly lower than that of apoB-100 SR (1.53 +/- 0.22 mg/[kg per d]; P < .001) of Lp(a). Plasma concentrations of Lp(a) were correlated significantly with both apo(a) SR and apoB-100 SR (r = 0.837 and r = 0.789, respectively; P < .001) and negatively with apo(a) FCR and Lp(a) apoB-100 FCR (r = -0.547 and r = -0.717, respectively; P < .01). These data implicate different metabolic fates for apo(a) and apoB-100 within Lp(a) in the fed state. We therefore hypothesize that apo(a) does not remain covalently linked to a single apoB-100 lipoprotein but that it rather reassociates at least once with another apoB-100 particle, probably newly synthesized, during its plasma metabolism.     

Plasma lipoprotein(a) concentration in familial hypercholesterolemic patients without coronary artery disease.

Familial Hypercholesterolemia (FH) is a condition characterized by markedly elevated blood cholesterol, low-density lipoproteins (LDL), and apolipoprotein B-100 (apo B). The molecular basis of this monogenic disease is the defective functioning of the cellular receptor for LDL that recognizes apo B. Lipoprotein(a) [Lp(a)] is a circulating lipoprotein that is structurally related to LDL, as it also contains apo B. To assess the impact of the LDL receptor deficiency on the plasma Lp(a) concentration, we measured Lp(a) in 28 FH patients and in 31 unaffected relatives. Because elevation of Lp(a) concentration in plasma of patients with coronary artery disease (CAD) appears to occur independently from plasma cholesterol levels, to avoid potentially confounding problems, members of the families chosen had no history for the disease. Whereas apo B clearly showed a bimodality of distribution by being significantly higher in the FH patients (166 +/- 38 mg/dL) than in the unaffected relatives (92 +/- 18 mg/dL), Lp(a) concentration did not differ in the two groups of patients (30 +/- 24 mg/dL in the FH patients v 31 +/- 23 in the normolipidemic relatives). Similar results were obtained when only siblings were further considered. We conclude that although Lp(a) is closely related to LDL structurally, its level in plasma is not significantly affected by the LDL receptor activity.     

HMG CoA reductase inhibitors lower LDL cholesterol without reducing Lp(a) levels

Lp(a) is a plasma lipoprotein particle consisting of a plasminogenlike protein [apo(a)] disulfide bonded to the apo B moiety of low-density lipoprotein (LDL). Increased plasma levels of Lp(a), either independently or interactively with LDL levels, have been shown to be a risk factor for atherosclerosis. Recently, a new class of lipid-lowering drugs, HMG CoA reductase inhibitors, have been introduced. These drugs act by decreasing liver cholesterol synthesis resulting in up-regulation of LDL receptors, increased clearance of LDL from plasma, and diminution of plasma LDL levels. In this study, we examined the effect of HMG CoA reductase inhibitors on Lp(a) levels in three groups of subjects, five volunteers and two groups of five and 14 patients. In all 24 subjects, mean decreases were observed in total cholesterol (43 +/- 5%), total triglyceride (35 +/- 8%), very low-density lipoprotein (45 +/- 9%), and LDL cholesterol (43 +/- 5%). The mean change in high-density lipoprotein cholesterol was an increase of 7 +/- 8%. Despite the very significant decrease in LDL cholesterol levels (p less than 0.001), Lp(a) levels increased by 33 +/- 12% (p less than 0.005). This was not associated with a measurable change in the chemical composition or size of the Lp(a) particle. This emphatically suggests that Lp(a) particles, despite consisting principally of LDL, are cleared from plasma differently than LDL. The surprising finding of an increase in Lp(a) levels suggests this class of drugs may have a direct effect on Lp(a) synthesis or clearance independent of its effect on LDL receptors.     

Plasma lipoprotein (a) levels in Turkish NIDDM patients with and without vascular diabetic complications.

OBJECTIVE: Plasma concentrations of lipoprotein (a) [Lp(a)], an independent risk factor for atherosclerosis, were measured in 59 non-insulin-dependent diabetes mellitus (NIDDM) patients with and without vascular complications, and 21 non-diabetic healthy subjects. RESULTS: The plasma log Lp(a) levels were found to be significantly increased in the NIDDM patients (1.40 +/- 0.36) compared with the healthy subjects (1.02 +/- 0.53; p < 0.05). Plasma Lp(a) levels in NIDDM patients with diabetic vascular complications (1.51 +/- 0.27) were significantly higher than those of the NIDDM patients without diabetic vascular complications (1.23 +/- 0.43) and healthy subjects (p < 0.05). There were significant correlations between plasma log Lp(a) levels and apolipoprotein B (apo B) in all NIDDM patients (r: 0.68, p < 0.05). No correlation was observed between Lp(a) levels and age, sex, duration of diabetes, fasting blood glucose, haemoglobin Alc, the mode of treatment, triglycerides, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and apolipoprotein Al levels in all patients. CONCLUSIONS: It was concluded that Lp(a) was a risk factor for angiopathy in NIDDM patients and the patients who have a high plasma Lp(a) concentration should be kept under strict glycaemic control.     

Postprandial lipoprotein(a) response to a single meal containing either saturated or omega-3 polyunsaturated fatty acids in subjects with hypoalphalipoproteinemia.

We have recently reported that the apolipoprotein (apo) B-100-apo(a) complex, the protein moiety of lipoprotein(a) [Lp(a)], has a high affinity for triglyceride(TG)-rich particles (TRP) and that this complex can affiliate with endogenous TG-rich lipoproteins. To shed more light on the apo B-100-apo(a) complex associated with plasma TRP during postprandial lipidemia, we fed five male subjects presenting with primary hypoalphalipoproteinemia (HP) and four male controls a single fat meal (60 g/m2) containing saturated fatty acids (SFA) and, 6 weeks later, an isocaloric meal containing omega-3 polyunsaturated fatty acids. The subjects were phenotyped for plasma Lp(a) and apo C-III levels, apo(a) and apo E isoforms, and lipoprotein lipase and hepatic lipase activities. Vitamin A was included in the meal as a marker of intestinally derived TRP. Following the SFA meal, three of the HP subjects showed a decrease in plasma levels of Lp(a) that lasted 10 to 12 hours in the presence of an increased hypertriglyceridemic response. Two HP subjects who had low preprandial lipoprotein lipase activity and elevated plasma apo C-III levels showed an increase in plasma Lp(a) levels along with the hypertriglyceridemic excursion. However, in all cases, inclusive of the controls, there was an elevation in plasma levels of TRP of Sf greater than 1,000 that contained apo B-100-apo(a) 6 to 8 hours after the meal. This TRP excursion appeared not to be related to the basal levels of plasma Lp(a), high-density lipoprotein (HDL) cholesterol, TGs, or apo(a) and apo E isoforms, and it did not coincide with the retinyl ester peak.(ABSTRACT TRUNCATED AT 250 WORDS)     

Associations among serum lipoprotein(a) levels, apolipoprotein(a) phenotypes, and myocardial infarction in patients with extremely low and high levels of serum lipoprotein(a).

A high serum lipoprotein(a) [Lp(a)] level, which is genetically determined by apolipoprotein(a) [apo(a)] size polymorphism, is an independent risk factor for coronary atherosclerosis. However, the associations among Lp(a) levels, apo(a) phenotypes, and myocardial infarction (MI) have not been studied. Patients with MI (cases, n = 101, M/F: 86/15, age: 62+/-10y) and control subjects (n = 92, M/F: 53/39, age: 58+/-14y) were classified into quintile groups (Groups I to V) according to Lp(a) levels. Apo(a) isoform phenotyping was performed by a sensitive, high-resolution technique using sodium dodecyl sulfate-agarose/gradient polyacrylamide gel electrophoresis (3-6%), which identified 26 different apo(a) phenotypes, including a null type. Groups with higher Lp(a) levels (Groups II, III, and V) had higher percentages of MI patients than that with the lowest Lp(a) levels (Group I) (54%, 56%, or 75% vs. 32%, p<0.05). Groups with different Lp(a) levels had different frequency distributions of apo(a) isoprotein phenotypes: Groups II, III, IV, and V, which had increasing Lp(a) levels, had increasingly higher percentages of smaller isoforms (A1-A4, A5-A9) and decreasingly lower percentages of large isoforms (A10-A20, A21-A25) compared to Group I. An apparent inverse relationship existed between Lp(a) and the apo(a) phenotype. Subjects with the highest Lp(a) levels (Group V) had significantly (p<0.05) higher serum levels of total cholesterol, apo B, and Lp(a). Patients with MI and the controls had different distributions of apo(a) phenotypes: i.e., more small isoforms and more large size isoforms, respectively (A1-A4/A5-A9/A10-A20/A21-A25: 35.7%/27.7%/20.8%/15.8% and 22.8%/23.9%/29.4%/23.9%, respectively). Lp(a) (parameter estimate +/- standard error: 0.70+/-0.20, Wald chi2 = 12.4, p = 0.0004), apo(a) phenotype (-0.43+/-0.15, Wald chi2 = 8.17, p = 0.004), High-density lipoprotein-cholesterol, apo A-I, and apo B were significantly associated with MI after adjusting for age, gender, and conventional risk factors, as assessed by a univariate logistic regression analysis. The association between Lp(a) and MI was independent of the apo(a) phenotype, but the association between the apo(a) phenotype and MI was not independent of Lp(a), as assessed by a multivariate logistic regression analysis. This association was not influenced by other MI- or Lp(a)-related lipid variables. These results suggest that apo(a) phenotype contributes to, but does not completely explain, the increased Lp(a) levels in MI. A stepwise logistic regression analysis with and without Lp(a) in the model identified Lp(a) and the apo(a) phenotype as significant predictors for MI, respectively.     

Plasma Lp(a) values in familial hypercholesterolemia and its relation to coronary heart disease

BACKGROUND AND AIM: To analyze plasma Lp(a) levels and examine different risk factors and coronary heart disease (CHD) in a sample of genetically diagnosed familial hypercholesterolemia (FH) patients. METHODS AND RESULTS: Ninety heterozygous FH patients and 41 non-FH relatives were enrolled in a study to evaluate their plasma and lipoprotein cholesterol, as well as their triglyceride and Lp(a) levels. We found no differences in plasma Lp(a) levels and log transformed values between 90 FH subjects and their 41 unaffected relatives (22.3 mg/dl +/- 19.4 vs 17.7 mg/dl +/- 21.3 and 1.12 +/- 0.5 vs 0.96 +/- 0.54) nor between null allele and defective allele FH subjects (log Lp (a) levels 2.013 +/- 0.282 vs 1.959 +/- 0.151). FH CHD+ were significantly older, and had higher mean systolic and diastolic blood pressure and higher mean plasma triglyceride levels than FH CHD-. No differences in mean and log transformed Lp(a) plasma concentrations were found. CONCLUSIONS: Plasma Lp(a) levels are not related to LDL receptor status and class mutations, nor to the presence of CHD in FH patients.