Lipoprotein(a) in homozygous familial hypercholesterolemia

Lipoprotein(a) [Lp(a)] is a quantitative genetic trait that in the general population is largely controlled by 1 major locus-the locus for the apolipoprotein(a) [apo(a)] gene. Sibpair studies in families including familial defective apolipoprotein B or familial hypercholesterolemia (FH) heterozygotes have demonstrated that, in addition, mutations in apolipoprotein B and in the LDL receptor (LDL-R) gene may affect Lp(a) plasma concentrations, but this issue is controversial. Here, we have further investigated the influence of mutations in the LDL-R gene on Lp(a) levels by inclusion of FH homozygotes. Sixty-nine members of 22 families with FH were analyzed for mutations in the LDL-R as well as for apo(a) genotypes, apo(a) isoforms, and Lp(a) plasma levels. Twenty-six individuals were found to be homozygous for FH, and 43 were heterozygous for FH. As in our previous analysis, FH heterozygotes had significantly higher Lp(a) than did non-FH individuals from the same population. FH homozygotes with 2 nonfunctional LDL-R alleles had almost 2-fold higher Lp(a) levels than did FH heterozygotes. This increase was not explained by differences in apo(a) allele frequencies. Phenotyping of apo(a) and quantitative analysis of isoforms in family members allowed the assignment of Lp(a) levels to both isoforms in apo(a) heterozygous individuals. Thus, Lp(a) levels associated with apo(a) alleles that were identical by descent could be compared. In the resulting 40 allele pairs, significantly higher Lp(a) levels were detected in association with apo(a) alleles from individuals with 2 defective LDL-R alleles compared with those with only 1 defective allele. This difference of Lp(a) levels between allele pairs was present across the whole size range of apo(a) alleles. Hence, mutations in the LDL-R demonstrate a clear gene-dosage effect on Lp(a) plasma concentrations.     

Catabolism of lipoprotein(a) in familial hypercholesterolaemic subjects.

The in vivo turnover of autologous lipoprotein(a) (Lp(a)) was studied in four heterozygous familial hypercholesterolaemic (FH) subjects and four subjects who were hyperlipidaemic but not FH. Each of the FH subjects exhibited a much lower fractional catabolic rate (FCR) for LDL than each of the non-FH subjects. Lp(a) was purified by sequential density gradient centrifugations and was radio-iodinated. The labelled Lp(a) ran as a single band on electrophoresis in gradient polyacrylamide gels. Less than 5% of the label was in lipid, with about 40% of the remainder on apolipoprotein B (apo B) and 60% on apo(a). Labelled and unlabelled Lp(a) competed equally poorly with LDL for binding to LDL receptors on cultured fibroblasts. The FCR of Lp(a), calculated from the decay of the specific radioactivity of the Lp(a) isolated from the daily blood samples, was the same in FH subjects as in non-FH subjects. There was no consistent relationship between Lp(a) FCR and the plasma Lp(a) concentration or between FCR and the Lp(a) phenotype, at least within this sample of subjects. There was a strong association between Lp(a) concentration and production rate, with values for non-FH and FH subjects falling on the same line. The rate of decline of radioactivity in whole plasma was consistently slower than the fall in specific radioactivity of the isolated Lp(a). This difference was more marked in FH subjects than in non-FH subjects and resulted from the accumulation of radioactivity derived from the injected Lp(a) at a lower density than Lp(a), in the fractions containing LDL. The amount of radioactivity in this fraction increased for the first few days after injection and then fell, the fall being more rapid in non-FH than in FH subjects. These results provide no evidence for the involvement of LDL receptors in the catabolism of Lp(a) itself but suggest that they could be responsible for some of the clearance of the lipid and apo B components after removal of apo(a) in the circulation.     

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.     

Treatment of hypothyroidism reduces low-density lipoproteins but not lipoprotein(a).

Lipoprotein(a) [Lp(a)] is a low-density lipoprotein (LDL) particle in which apolipoprotein B-100 (apo B) is attached to a large plasminogen-like protein called apolipoprotein(a) [apo(a)]. Apo(a) has several genetically determined phenotypes differing in molecular weight, to which Lp(a) concentrations in plasma are inversely correlated. LDL and apo B levels are often elevated in untreated hypothyroidism and lowered by thyroxine (T4) treatment, probably due to an increase in LDL receptors. We measured plasma concentrations of LDL, apo B, and Lp(a) in 13 patients with symptomatic primary hypothyroidism before and during T4 therapy. The mean concentration of LDL decreased significantly (P = .006) from 6.05 mmol/L to 4.07 mmol/L, and the mean concentration of apo B decreased significantly (P = .005) from 1.42 g/L to 1.12 g/L. Median Lp(a) concentrations remained unchanged (P = .77); they were 17.05 mg/dL before and 16.59 mg/dL during T4 treatment. In both the untreated condition and during substitution therapy, Lp(a) levels were higher in patients than in healthy controls, probably due to a relatively high frequency of the small Lp(a) phenotypes in our patients. Since Lp(a) contains apo B, which is a ligand for the LDL receptor, it is surprising that Lp(a) is not reduced along with LDL and apo B. These findings suggest that the catabolism of LDL and Lp(a) differ in some respect, and that thyroid hormones have little, if any, effect on Lp(a).     

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.     

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.     

The metabolism of lipoprotein(a) and other apolipoprotein B-containing lipoproteins: a kinetic study in humans

Lipoprotein(a) is a risk factor for cardiovascular disease composed of an apolipoprotein B-containing lipoprotein to which a second protein, apolipoprotein(a), is attached. We investigated in seven subjects with Lp(a) levels of 39--85 mg/dl the metabolism of four apo B-containing lipoproteins (VLDL(1), VLDL(2), IDL and LDL) together with that of apo B and apo(a) isolated from Lp(a). Rates of secretion, catabolism and where appropriate, transfer were determined by intravenous administration of d(3)-leucine, mass spectrometry for measurements of leucine tracer/tracee ratios and kinetic data analysis using multicompartmental metabolic modeling. Apo B in Lp(a) was secreted at a rate of 0.28 (0.17--0.40) mg/kg per day. It was found to originate from two sources -- 53% (43--67) were derived from preformed lipoproteins, i.e. IDL and LDL, the remainder was accounted for by apo B, directly secreted by the liver. The fractional catabolic rates (FCRs) of apo B and of apo(a) prepared from Lp(a) were determined as 0.27 (0.16--0.38) and 0.24 (0.12--0.40) pools per day, respectively, which is less than half of the FCR observed for LDL. Our in vivo data from humans support the view that Lp(a) assembly is an extracellular process and that its two protein components, apo(a) and apo B, are cleared from the circulation at identical rates.     

Lipoprotein(a) as a cardiovascular risk factor

Lipoprotein(a) [Lp(a)] is a class of lipoprotein particles having the lipid composition of plasma low-density lipoprotein (LDL), but with a distinct protein moiety comprised of two proteins linked together by a disulfide bridge. The two proteins are apoB100, the protein moiety of LDL, and apo(a), a heavily glycosylated protein that is specific for Lp(a). Apo(a) has a strong structural similarity to plasminogen and has a wide-size polymorphism that has a genetic origin and is partially responsible for the size and density heterogeneity of Lp(a). High plasma levels of Lp(a) are associated with an increased risk for cardiovascular disease that is related to the atherogenic and thrombogenic potentials of this lipoprotein enhanced by the presence of other risk factors, among which are high plasma levels of LDL or low levels of high-density lipoprotein. The factors determining the plasma levels of Lp(a) have not been clearly identified except for an association with different alleles of the apo(a) gene, which is located in the long arm of chromosome 6. Currently there are no generally accepted ways to normalize the plasma levels of Lp(a) by either dietary and/or pharmacologic means. Until further progress in this area is made, patients with high plasma levels of Lp(a) should be advised to correct modifiable risk factors in order to decrease the cardiovascular pathogenicity of this lipoprotein class.     

Different apoprotein(a) isoform proportions in serum and carotid plaque

INTRODUCTION: Cardio- and/or cerebro-vascular risk are associated with high lipoprotein (a) [Lp(a)] levels and low-molecular-weight (LMW) apo(a) isoforms. Aims of this study were to evaluate the deposition of apo(a) isoforms and apoprotein B (apo B) in atherosclerotic plaque from patients (males and females) who had carotid endarterectomy for severe stenosis, and to identify differences between patients classified by gender and divided according to the stability or instability of their plaques. MATERIALS AND METHODS: We determined lipids, apo B and Lp(a) in serum and plaque extracts from 55 males and 25 females. Apo(a) was phenotyped and isoforms were classified by number of kringle IV (KIV) repeats. RESULTS: Lp(a) levels were higher in female serum and plaque extracts than in male samples, while apo B levels were lower. More Lp(a) than apo B deposition was observed in plaque after normalization for serum levels. Thirty-one different apo(a) isoforms were detected in our patients, with a double band phenotype in 94% of cases. In both sexes, the low/high (L/H) molecular weight apo(a) isoform expression ratio was significantly higher in plaque than in serum. Females with unstable plaques had higher Lp(a) levels in both serum and tissue extracts, and fewer KIV repeats of the principal apo(a) isoform in the serum than the other female group or males. CONCLUSIONS: In both sexes, the same apo(a) isoforms are found in serum and atherosclerotic plaque, but in different proportions: in plaque, LMW apo(a) is almost always more strongly accumulated than HMW apo(a), irrespective of any combination of apo(a) isoforms in double band phenotypes or Lp(a) serum levels. Moreover, serum and tissue Lp(a) levels were higher in females than in males, and particularly in the group with unstable plaques.     

The effect of thyroid hormones on low density lipoprotein receptors in cultured human skin fibroblasts (author's transl)

The catabolic rate of low density lipoprotein (LDL) has been shown to be delayed in hypothyroidism and increased in hyperthyroidism. LDL catabolism is mainly mediated through the LDL receptor pathway in the parenchymal cells. In the present paper the effect of thyroid hormones in LDL receptors was studied in cultured human skin fibroblasts. Human fibroblasts were established from 2 normal subjects, one heterozygous patient and 2 homozygous patients with familial hypercholesterolemia (FH). Human LDL (density 1.020 approximately 1.050 g/ml) from the serum of healthy subjects was prepared by differential ultracentrifugation. 125I-LDL was prepared by the ICl method of MacFarlane. Prior to incubation with 125I-LDL, cells were preincubated in a medium containing 5% lipoprotein-deficient serum obtained from a myxoedematous patient. Uptake and degradation of LDL by normal cells and FH heterozygous cells increased about 20% with 1.0 microgram/ml of L-triiodo-thyronine (T3) or L-thyroxine (T4). In FH homozygous cells, no increase of LDL receptor activity was observed with T3 or T4. These results suggest that thyroid hormones regulate LDL catabolism through the LDL pathway.     

Genetically determined apo B levels and peak LDL density predict angiographic response to intensive lipid-lowering therapy

OBJECTIVE: Lipid-lowering therapy (LL-Rx) reduces coronary artery disease (CAD) but the response varies amongst individuals. We investigated the contribution of three genetic forms of dyslipidaemia characterized by elevated plasma apo B, familial hypercholesterolaemia (FH), familial combined hyperlipidaemia (FCHL), and elevated Lp(a), to the angiographic response with LL-Rx. METHODS AND RESULTS: Fifty-one men, with premature CAD and elevated plasma apo B, were selected in whom a genetic diagnosis was based on lipid phenotypes in relatives. Subjects received conventional (diet +/- colestipol) or intensive LL-Rx (niacin or lovastatin plus colestipol). Clinical parameters and CAD severity were measured before and after 2 years of treatment. Twenty-seven patients had FCHL, 12 FH and 12 elevated Lp(a). Regression of coronary stenosis was dependent on the effect of therapy (P < 0.001), genetic form of dyslipidaemia (P = 0.004) and the interaction between the two variables (P = 0.02). Significant regression of coronary stenosis occurred only in FCHL and Lp(a) (P = 0.03, vs. control groups); CAD progression was only slowed in FH. CONCLUSIONS: Three genetic forms of dyslipidaemia were associated with different angiographic outcomes during intensive LL-Rx. Different forms of dyslipidaemia therefore may require different lipid-lowering strategy. Patients with FH and buoyant LDL require more aggressive reduction of LDL cholesterol whilst those with either FCHL or elevated Lp(a) with dense LDL need LDL cholesterol reduction as well as therapies aimed at reduction of the small, dense LDL particles.     

Lipoprotein(a) in subjects with familial defective apolipoprotein B100.

The plasma lipoprotein(a) (Lp(a)) concentration and apolipoprotein(a) (apo(a)) phenotype were determined in the members of two families affected with familial defective apo B100 (FDB), resulting from the Arg3500----Gln mutation in apo B that disrupts binding to LDL receptors. Eleven different phenotypic species of apo A were identified, five of which were present in both families. Although there was a general increase in Lp(a) concentration as the size of the predominant apo(a) component decreased, there was considerable variability and in three clear instances the concentration of an inherited phenotypic species was atypically low. In five cases where a direct comparison could be made, the plasma Lp(a) concentration was significantly higher in heterozygous FDB subjects than in their non-FDB siblings or close relatives with the same phenotype. However, in vitro competition studies using purified Lp(a) that had been reduced with dithiothreitol to remove the apo(a) component, indicated that the Lp(a) from FDB heterozygotes contained a smaller proportion of defective particles than their LDL. Lp(a) particles containing normal and binding-defective apo B were present at approximately the same concentration, suggesting that the increase in Lp(a) concentration observed in FDB subjects could not be explained by the inability of the particles containing the defective apo B100 to be cleared through LDL-receptor mediated processes.     

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.     

Factors affecting plasma lipoprotein(a) levels: role of hormones and other nongenetic factors

Lp(a) appears to be one of the most atherogenic lipoproteins. It consists of an low-density lipoprotein core in addition to a covalently bound glycoprotein, apo(a). Apo(a) exists in numerous polymorphic forms. The size of the polymorphism is mediated by the variable number of kringle-4 Type 2 repeats found in apo(a). Plasma Lp(a) levels are determined to more than 90% by genetic factors. Plasma Lp(a) levels in healthy individuals correlate significantly highly with apo(a) biosynthesis, and not with its catabolism. There are several hormones that are known to have a strong effect on Lp(a) metabolism. In certain diseases, such as kidney disease, the Lp(a) catabolism is impaired, leading to elevations that are up to a fivefold increase. Lp(a) levels rise with age but are otherwise only little influenced by diet and lifestyle. There is no safe and efficient way of treating individuals with elevated plasma Lp(a) concentrations. Most of the lipid-lowering drugs have either no significant influence on Lp(a) or exhibit a variable effect in patients with different forms of primary and secondary hyperlipoproteinemia.     

Correlation of apolipoprotein(a) isoproteins with Lp(a) density and distribution in fasting plasma.

Lp(a) is an LDL-like lipoprotein which contains an additional apolipoprotein called apo(a). Apo(a) exhibits a significant size polymorphism and its size is inversely correlated with plasma Lp(a) levels. We investigated the distribution of different apo(a) isoproteins in lipoprotein density fractions. Fasting plasma samples were subjected to non-equilibrium density gradient ultracentrifugation. After SDS-PAGE and anti-apo(a) immunoblotting, apo(a) concentrations in individual density fractions were evaluated by densitometry. In series I, analysis of selected density fractions from 35 coronary heart disease (CHD) patients demonstrated that although most of the apo(a) was present in the Lp(a) density range, apo(a) was consistently found in both the VLDL and IDL fractions as well. In series II, density fractions from 9 normolipidemic subjects with 6 different apo(a) isoproteins were evaluated. A strong association between the size of the apo(a) isoprotein and the density of the associated Lp(a) particle was established (r = 0.976, P less than 0.001). Lp(a) densities ranged from 1.057 g/ml for the B isoprotein to 1.09 g/ml for the S5 isoprotein. Overall, 75% of the total apo(a) was detected in the Lp(a) density range (d = 1.05-1.12 g/ml), with 9% and 10% in the LDL (d = 1.019-1.05 g/ml) and HDL (d = 1.12-1.21 g/ml) fractions, respectively. VLDL contained an average of 4% of the total apo(a) in fasting normolipidemic plasma. Two hypertriglyceridemic subjects had substantially greater amounts of apo(a) in the fasting triglyceride-rich fraction. The results of this study indicate that the size of the apo(a) isoprotein strongly influences the density of its associated Lp(a) particle and that apo(a) is consistently found in the triglyceride-rich lipoproteins of fasting plasma.     

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).     

Low density lipoprotein cholesterol, lipoprotein(a), and apo(a) isoforms in the elderly: relationship to fasting insulin. Associazione Medica Sabin

BACKGROUND AND AIM: Insulin resistance/hyperinsulinemia are often associated with aging and could play an important role in the development of glucose intolerance and dyslipidemia in the elderly. We investigated the relationship between plasma fasting insulin with total cholesterol (TC) and low density lipoprotein LDL cholesterol (LDL-C), triglycerides (TG), lipoprotein(a) [Lp(a)] levels apolipoprotein (a) [apo (a)] isoforms in 100 free-living "healthy" octo-nonagenarians. METHODS AND RESULTS: Fasting insulin was positively correlated with TG, whereas a negative relation was found with TC and LDL-C (r = -0.29 and r = -0.28 respectively; p < 0.01), LDL-C/apo B, HDL-C and apo A-I levels. Fasting insulin was also inversely correlated with Lp(a) levels (r = -0.22; p < 0.03), whereas the latter were significantly related with TC and LDL-C (r = 0.30 and r = 0.31; p < 0.005), TG (r = 0.21; p < 0.05) and apo B (r = 0.26; p < 0.02). There was a negative relation between Lp(a) levels and apo(a) isoforms: the greater the apo(a) molecular weight, the lower the Lp(a) level (p < 0.0001). Fasting insulin increased with apo(a) size, though the difference in insulin levels among apo(a) isoforms was not significant (p = 0.4). Multiple regression analysis showed that fasting insulin was the best predictor of LDL-C (R2 = 0.14; p = 0.002) irrespective of age, gender, BMI, waist circumference and TG, while apo(a) isoform size, BMI and waist circumference were related with Lp(a) irrespective of TC and LDL-C, TG and apo B (R2 = 0.35 to 0.37; p < 0.0001). CONCLUSIONS: These results suggest that fasting insulin levels significantly influence LDL-C metabolism in old age. Lp(a) levels seem to be very strongly related to genetic background, although an indirect relation with insulin through adiposity and/or other associated lipid abnormalities cannot be ruled out.     

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.