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F Kronenberg

Publications and source records attributed to F Kronenberg.

At least 19 recordsLinked to original sources
PubMed1996

Lipoprotein(a) in renal disease.

Lipoprotein(a) [Lp(a)] is a genetically determined risk factor for atherosclerotic vascular disease. Several studies have described a correlation between high Lp(a) plasma levels and coronary heart disease, stroke, and peripheral atherosclerosis. In healthy individuals Lp(a) plasma concentrations are almost exclusively controlled by the apolipoprotein(a) [apo(a)] gene locus on chromosome 6q2.6-q2.7. More than 30 alleles at this highly polymorphic gene locus determine a size polymorphism of apo(a). There exists an inverse correlation between the size (molecular weight) of apo(a) isoforms and Lp(a) plasma concentrations. Average Lp(a) levels are high in individuals with low molecular weight isoforms and low in those with high molecular weight isoforms. Mean Lp(a) plasma levels are elevated over controls in patients with renal disease. Patients with nephrotic syndrome exhibit excessively high Lp(a) plasma concentrations, which can be reduced with antiproteinuric treatment. The mechanism underlying this elevation is unclear, but the general increase in protein synthesis caused by the liver due to high urinary protein loss is a likely explanation. Patients with end-stage renal disease (ESRD) also have elevated Lp(a) levels. These are even higher in patients treated by continuous ambulatory peritoneal dialysis than in those receiving hemodialysis. Lipoprotein(a) concentrations decrease to values observed in controls matched for apo(a) type following renal transplantation. This clearly demonstrates the nongenetic origin of Lp(a) elevation in ESRD. Both the increase in ESRD and the decrease following renal transplantation are apo(a) phenotype dependent. Only patients with high molecular weight phenotypes show the described changes in Lp(a) levels. In patients with low molecular weight types the Lp(a) concentrations remain unchanged during both phases of renal disease. As in the general population, Lp(a) is a risk factor for cardiovascular events in ESRD patients. In this patient group the apo(a) phenotype seems to be equally or better predictive of the degree of atherosclerosis than is Lp(a) concentration. Further prospective studies will be necessary to confirm these observations. Whether Lp(a) also plays a key role in the pathogenesis and progression of renal diseases needs further study. Controversial data on the role of the kidney in Lp(a) metabolism result from insufficient sample sizes of several studies. Due to the broad range and skewed distribution of Lp(a) plasma concentrations, large study groups must be investigated to obtain reliable results.

Arteriosclerosis↗
PubMed1996

Lp(a) levels and atherosclerotic vascular disease in a sample of patients with familial hypercholesterolemia sharing the same gene defect.

There is considerable variation in the severity of cardiovascular disease among patients with familial hypercholesterolemia (FH). Some reports have suggested that plasma lipoprotein(a) [Lp(a)] levels may explain such variation and that FH subjects deficient in LDL receptors, especially those with coronary heart disease, tend to have elevated Lp(a) levels. We have investigated the possible role of the LDL receptor in determining plasma Lp(a) levels in genetically homogeneous FH population and the contribution of Lp(a) to cardiovascular risk. A total of 98 FH subjects and 66 healthy first- and second-degree relatives from 30 families with FH due to the French-Canadian > 10-kilobase deletion of the LDL receptor gene were studied. A reference group of 392 normolipidemic French-Canadian participants in a Heart Health Survey was used for comparison. FH subjects were subdivided into subsets of 63 individuals free from atherosclerotic vascular disease (AVD) and 35 individuals with AVD. A complete cardiovascular evaluation was performed, and plasma lipid, lipoprotein, and Lp(a) levels were measured in all subjects in the absence of medication. Apolipoprotein (a) [apo(a)] phenotype was determined in 112 of FH and non-FH subjects. The log-transformed values for plasma Lp(a) were not significantly different among the three groups: 0.98 +/- 0.54 (mean +/- SD) in FH subjects with AVD, 0.89 +/- 0.51 in FH subjects without AVD, and 0.82 +/- 0.64 in their relatives. The distribution of the apo(a) phenotypes did not differ between the FH and non-FH groups. Comparison of two age- and sex-matched subgroups of FH subjects, with and without AVD, failed to show any differences in Lp(a) level. However, mean Lp(a) log values in the reference group (n = 392) were significantly lower than values obtained for the total FH group (0.79 +/- 0.57 versus 0.92 +/- 0.52, respectively; P < .05) but were not different from those of the unaffected family members. Thus, in our sample, the LDL receptor appears not to influence plasma Lp(a) levels; rather, these levels reflect shared apo(a) genes. The cardiovascular risk in this group of subjects with FH was related to age, male sex, total and LDL cholesterol, and higher apoB but not Lp(a) levels.

Adolescent↗
PubMed1996

Apolipoprotein(a) kringle IV repeat number predicts risk for coronary heart disease.

A high plasma concentration of lipoprotein(a) [Lp(a)] has been suggested as a risk factor for coronary heart disease (CHD), but some recent prospective studies have questioned the significance of Lp(a). Lp(a) concentrations are determined to a large extent by the hypervariable apo(a) gene locus on chromosome 6q2.7, which contains a variable number of identical tandemly arranged transcribed kringle IV type 2 repeats. The number of these repeats correlates inversely with plasma Lp(a) concentration. We analyzed whether apo(a) gene variation (kringle IV repeat number) is associated with CHD. Apo(a) genotypes were determined by pulsed-field gel electrophoresis/genomic blotting in CHD patients who had undergone angiography (n = 69) and control subjects matched for age, sex, and ethnicity (n = 69) and were related to Lp(a) concentration, apo(a) isoform in plasma, and disease status. Apo(a) alleles with a low kringle IV copy number ( < 22) and high Lp(a) concentration were significantly more frequent in the CHD group (P < .001), whereas large nonexpressed alleles were more frequent in control subjects. The odds ratio for CHD increased continuously with a decreasing number of kringle IV repeats and ranged from 0.3 in individuals with > 25 kringle IV repeats on both alleles to 4.6 in those with < 20 repeats on at least one allele. This provides direct genetic evidence that variation at the apo(a) gene locus, which determines Lp(a) levels, is also a determinant of CHD risk.

Alleles↗
PubMed1995

Sequence polymorphism in kringle IV 37 in linkage disequilibrium with the apolipoprotein (a) size polymorphism.

Apolipoprotein(a) [apo(a)] contains a variable number of identical (K-IV A/B) or nearly identical (K-IV 1, K-IV 30-37) kringle repeats that are homologous to K-IV from plasminogen. The sizes of 414 apo(a) alleles were determined by pulsed-field gel electrophoresis (PFGE) of KpnI-digested DNA. Furthermore, sequence variation in the apo(a) K-IV 30-37 domain was analysed. Reverse transcription/polymerase chain reaction (RT-PCR) cloning of human liver poly A+ RNA followed by sequencing revealed a single nucleotide exchange in the ultimate K-IV (K-IV 37) of apo(a) (codon 4168); this results in an ATG (Met) to ACG (Thr) substitution. A PCR-based restriction assay of genomic DNA demonstrated that this substitution represents a common polymorphism. In 231 unrelated Tyroleans, the frequencies for the K-IV 37 Thr and K-IV 37 Met alleles were 0.66 and 0.34, respectively. The phase between the K-IV 37 Met/Thr and the KpnI size polymorphism was determined for 224 alleles. A significant linkage disequilibrium was detected between the sequence and size polymorphisms of apo(a). K-IV 37 Met was significantly associated with KpnI allele no. 18 (DAB = 0.0267 +/- 0.0101; chi 2 = 10.09, df = 1). The Met/Thr polymorphism was further used to test whether deletions or duplications of K-IV 37 occur frequently in the apo(a) gene. Some 40 apo(a) alleles, 22 of which were from subjects that appeared to be double heterozygotes for K-IV repeat number and the Met/Thr variation were separated by PFGE and analysed for the 4168 Met/Thr polymorphism. The Met and Thr sequences were always present on different size alleles and no evidence for a duplication or deletion of K-IV 37 was obtained. This suggests that the copy number of K-IV 37 is invariable, in contrast to the highly variable K-IV A/B domain of the gene. The 4168 Met/Thr polymorphism had no effect on Lp(a) concentration, neither did it influence the lysine-binding property of the Lp(a) particle.

Adult↗
PubMed1995

A pentanucleotide repeat polymorphism in the 5' control region of the apolipoprotein(a) gene is associated with lipoprotein(a) plasma concentrations in Caucasians.

The enormous interindividual variation in the plasma concentrations of the atherogenic lipoprotein(a) [Lp(a)] is almost entirely controlled by the apo(a) locus on chromosome 6q26-q27. A variable number of transcribed kringle4 repeats (K4-VNTR) in the gene explains a large fraction of this variation, whereas the rest is presently unexplained. We here have analyzed the effect of the K4-VNTR and of a pentanucleotide repeat polymorphism (TTTTA)n (n = 6-11) in the 5' control region of the apo(a) gene on plasma Lp(a) levels in unrelated healthy Tyroleans (n = 130), Danes (n = 154), and Black South Africans (n = 112). The K4-VNTR had a significant effect on plasma Lp(a) levels in Caucasians and explained 41 and 45% of the variation in Lp(a) plasma concentration in Tyroleans and Danes, respectively. Both, the pentanucleotide repeat (PNR) allele frequencies and their effects on Lp(a) concentrations were heterogeneous among populations. A significant negative correlation between the number of pentanucleotide repeats and the plasma Lp(a) concentration was observed in Tyroleans and Danes. The effect of the 5' PNRP on plasma Lp(a) concentrations was independent from the K4-VNTR and explained from 10 to 14% of the variation in Lp(a) concentrations in Caucasians. No significant effect of the PNRP was present in Black Africans. This suggests allelic association between PNR alleles and sequences affecting Lp(a) levels in Caucasians. Thus, in Caucasians but not in Blacks, concentrations of the atherogenic Lp(a) particle are strongly associated with two repeat polymorphisms in the apo(a) gene.

Adult↗
PubMed1995

Multicenter study of lipoprotein(a) and apolipoprotein(a) phenotypes in patients with end-stage renal disease treated by hemodialysis or continuous ambulatory peritoneal dialysis.

Numerous studies have investigated lipoprotein(a) (Lp(a)) plasma concentrations in patients with ESRD, a patient group with an enormous risk for atherosclerosis. The reported differences in Lp(a) between controls and patients vary from a decrease of 49% to an increase of more than 1,000%. However, data are not consistent, mostly because of problems with statistical analysis, and only limited data are available for patients treated by continuous ambulatory peritoneal dialysis (CAPD). To estimate the significance of Lp(a) in ESRD and to demonstrate the statistical pitfalls concerning Lp(a) in case-control studies, a large multicenter study including 702 patients treated by either hemodialysis (HD) (N = 534) or CAPD (N = 168) was conducted, and results were compared with results from 256 healthy controls. Both patient groups showed significantly elevated Lp(a) levels in comparison with controls: 23.4 +/- 25.0 mg/dL (P < 0.005; HD) and 34.6 +/- 38.4 mg/dL (P < 0.0001; CAPD) versus 18.4 +/- 22.8 mg/dL (controls). CAPD patients showed significantly higher Lp(a) values than did patients treated by HD (P < 0.001). The difference between the two treatment groups possibly reflects an overproduction of Lp(a) to compensate for protein losses in CAPD patients. Both treatment groups included significantly more patients with Lp(a) values greater than the 75th percentile (25.6 mg/dL) of the control group (33.9 and 41.7% for HD and CAPD, respectively; P < 0.005). The higher Lp(a) values in patients were not explained by differences in isoform frequencies and the increase in Lp(a) was apolipoprotein(a) type specific: only patients with high-molecular-weight apolipoprotein(a) isoforms showed a significant elevation in Lp(a) levels. The increased plasma concentrations of Lp(a) may contribute to the high risk for atherosclerosis in ESRD, especially in patients treated by CAPD. Finally, it is believed that small sample sizes are responsible for the diverging results in Lp(a) literature.

Adult↗
PubMed1995

Low molecular weight heparin does not necessarily reduce lipids and lipoproteins in hemodialysis patients.

Recent studies have indicated a beneficial effect of one particular low molecular weight heparin preparation (Fragmin) on lipid metabolism in patients on chronic hemodialysis as compared to unfractionated heparin. We conducted a prospective crossover study with paired comparison of two different anticoagulant agents to examine the effects of a recently released new low molecular weight heparin (Sandoparin) on lipid and lipoprotein parameters in 24 patients starting hemodialysis. During the first six months of observation patients received Sandoparin. Then patients were switched to unfractionated heparin and observed for further six months. After switching from Sandoparin to unfractionated heparin we observed significant decreases in total cholesterol (from 168.6 +/- 42.2 to 154.4 +/- 41.9 mg/dl, p < 0.02), LDL cholesterol (from 106.4 +/- 35.2 to 89.9 +/- 32.3 mg/dl, p < 0.005), triglycerides (from 148.7 +/- 85.0 to 121.4 +/- 88.8 mg/dl, p < 0.05) and apolipoprotein B (from 100.0 +/- 35.3 to 89.9 +/- 30.4 mg/dl, p < 0.05) and a significant increase in HDL cholesterol (from 32.8 +/- 12.5 to 37.7 +/- 17.5 mg/dl, p < 0.02). This is in contrast to earlier results and can possibly be explained by a higher percentage of fractions with high M(r) in the investigated Sandoparin, which results in a more pronounced depletion of lipoprotein lipase. Together with the enhanced hepatic clearance of lipoprotein lipase induced by low molecular weight heparins, this may decrease lipoprotein lipase activity with a subsequent increase in plasma triglycerides, total and LDL cholesterol. We conclude from our data that a general recommendation for clinical use of low molecular weight heparin in hemodialysis patients cannot be given.

Adult↗
PubMed1995

Influence of various heparin preparations on lipoproteins in hemodialysis patients: a multicentre study.

Recent studies have indicated controversial effects of low molecular weight heparin (LMWH) on lipid metabolism in patients on chronic hemodialysis as compared to unfractionated heparin (UFH). We therefore conducted a cross-sectional multicentre study comparing 153 patients treated with LMWH and 153 patients with UFH, matched for sex, age and diabetes mellitus. Both groups have been treated with LMWH or UFH for six months or longer (14.9 vs. 23.4 months). We observed no differences between the UFH and LMWH treatment groups for total cholesterol, LDL cholesterol, triglycerides, apoB, apoA-IV or Lp(a). The only significant differences were seen for HDL cholesterol and the corresponding apolipoprotein apoA-I, which were significantly higher in the UFH group (HDL cholesterol: 0.97 +/- 0.35 mM/l vs. 0.87 +/- 0.37 mM/l, p < 0.05; apoA-I 1.23 +/- 0.27 g/l vs. 1.15 +/- 0.27 g/l, p < 0.05). We conclude that the results of studies investigating the influence of LMWH on lipid metabolism are as heterogeneous as the substances themselves. This challenges the beneficial influence supposedly had by LMWH preparations on lipid metabolism.

Adult↗
PubMed1994

Rehabilitation medicine and alternative therapies: new words, old practices.

"Alternative" medicine is receiving increased interest from the public, the media, government, and academic medical centers. Although currently being defined as encompassing practices outside of the medical mainstream, what are now being called "alternative" therapies have long been used by practitioners of physical medicine and rehabilitation. Recently identified by the National Institutes of Health as a legitimate area for research, alternative medicine is now receiving new sources of funding. Physical medicine and rehabilitation (PM&R) expertise encompasses many of the therapies and health care issues that are being categorized as alternative. Practitioners and researchers in PM&R should seize the opportunity to provide leadership in this emerging area in American medicine.

Complementary Therapies↗
PubMed1994

Apolipoprotein(a) phenotype-associated decrease in lipoprotein(a) plasma concentrations after renal transplantation.

High lipoprotein(a) [Lp(a)] plasma concentrations are an independent risk factor for atherosclerosis. In the general population, Lp(a) levels are primarily determined by allelic variation at the apolipoprotein(a) [apo(a)] gene locus. Apo(a) isoforms of various sizes are associated with different Lp(a) concentrations. Patients with end-stage renal disease (ESRD) have elevated plasma concentrations of Lp(a), which are not explained by the size variation at the apo(a) gene locus. To further investigate the origin of the elevated Lp(a) plasma concentrations, we examined Lp(a) concentrations and apo(a) phenotypes in 154 ESRD patients undergoing renal transplantation. In a prospective longitudinal study we observed a rapid normalization of Lp(a) levels from an average concentration of 25.9 +/- 28.7 mg/dL before to 17.9 +/- 25.5 mg/dL 3 weeks after renal transplantation (P < .0001). Only patients with high-molecular-weight phenotypes had a significant decrease in Lp(a) plasma concentrations. This study demonstrates the nongenetic origin of elevated Lp(a) concentrations in ESRD patients, which is obviously caused by the disease. It further confirms a phenotype-associated elevation of Lp(a) concentrations in ESRD.

Adolescent↗
PubMed1994

Apolipoprotein(a) phenotypes predict the risk for carotid atherosclerosis in patients with end-stage renal disease.

Several studies have demonstrated that atherosclerotic complications are the major cause of morbidity and mortality in hemodialysis patients. High lipoprotein(a) [Lp(a)] plasma concentrations are an independent risk factor for atherosclerosis. Patients with end-stage renal disease (ESRD) have elevated plasma concentrations of Lp(a), which are not explained by size variation at the apolipoprotein(a) [apo(a)] gene locus. The aim of our study was to investigate whether Lp(a) concentrations and/or apo(a) phenotypes are predictive of the degree of atherosclerosis in the extracranial carotid arteries in ESRD patients. Of 167 patients, 108 showed atherosclerotic plaques (65%). Univariate analysis showed that the plaque-affected group was significantly older and had a higher frequency of angina pectoris, previous myocardial infarction, or cerebrovascular accident. Furthermore, this group included significantly more patients with low-molecular-weight apo(a) isoforms (26.9% versus 8.5%, P < .005) and had significantly higher mean Lp(a) plasma concentrations (29.3 +/- 31.0 versus 19.7 +/- 25.7 mg/dL, P < .05). Lp(a) plasma concentration increased significantly with the number of affected arterial sites, from 19.7 mg/dL in patients without plaques to 40.1 mg/dL in patients with seven or eight affected sites. In patients with low-molecular-weight phenotypes, significantly more arterial sites were affected (3.62 versus 2.08, P < .001). Multivariate regression analysis showed that age, angina pectoris, and the apo(a) phenotype were the only significant predictors of the degree of atherosclerosis. We conclude that, besides age, the apo(a) phenotype is the best predictor of carotid atherosclerosis in ESRD patients and may be used for assessment of general atherosclerosis risk in this patient group.

Adult↗
PubMed1994

Effect of sample storage on the measurement of lipoprotein[a], apolipoproteins B and A-IV, total and high density lipoprotein cholesterol and triglycerides.

This study investigated the influence of long-term storage, for periods up to 24 months, and multiple freezing and thawing on the measured values of lipoprotein[a] (Lp[a]), apolipoproteins B and A-IV, total and high density lipoprotein (HDL) cholesterol and triglycerides using plasma samples stored at -80 degrees C, -20 degrees C, and 4 degrees C. Samples stored at -80 degrees C or -20 degrees C showed significant changes in Lp[a] after 24 months, with a mean decrease of 7% and 13%, respectively (P < 0.01). The major part of the decrease occurred during the first freezing and thawing. In contrast, apolipoproteins B and A-IV decreased continuously over time (P < 0.05). The increase in plasma concentrations of total and HDL cholesterol and triglycerides was small but significant because of its uniformity. Multiple freezing and thawing influenced only the measured values of Lp[a] and apolipoprotein B. Comparison of samples stored at -80 degrees C and -20 degrees C showed no difference in any of the parameters at any time with the exception of Lp[a] after 18 and 24 months (P < 0.05). After a storage period of 24 months, immunoblotting with detection of apo[a] was possible from samples under each storage condition. ApoB and apoA-IV were detectable only in samples stored at -20 degrees C or -80 degrees C. These data, when compared to recent studies, suggest a critical role of the assay methodology in the reproducibility of measured Lp[a] and apolipoprotein plasma concentrations. We therefore recommend the examination of each system for measurement of long-term stored plasma samples.

Apolipoproteins A↗
PubMed1993

Elevated plasma concentrations of lipoprotein(a) in patients with end-stage renal disease are not related to the size polymorphism of apolipoprotein(a).

Patients with terminal renal insufficiency suffer from an increased incidence of atherosclerotic diseases. Elevated plasma concentrations of lipoprotein(a) [Lp(a)] have been established as a genetically controlled risk factor for these diseases. Variable alleles at the apo(a) gene locus determine to a large extent the Lp(a) concentration in the general population. In addition, other genetic and nongenetic factors also contribute to the plasma concentrations of Lp(a). We therefore investigated Apo(a) phenotypes and Lp(a) plasma concentrations in a large group of patients with end-stage renal disease (ESRD) and in a control group. Lp(a) concentrations were significantly elevated in ESRD patients (20.1 +/- 20.3 mg/dl) as compared with the controls (12.1 +/- 15.5 mg/dl, P < 0.001). However, no difference was found in apo(a) isoform frequency between the ESRD group and the controls. Interestingly, only patients with large size apo(a) isoforms exhibited two- to fourfold elevated levels of Lp(a), whereas the small-size isoforms had similar concentrations in ESRD patients and controls. Beside elevated Lp(a) concentrations, ESRD patients had lower levels of plasma cholesterol and apolipoprotein B. These results show that elevated Lp(a) plasma levels might significantly contribute to the risk for atherosclerotic diseases in ESRD. They further indicate that nongenetic factors related to renal insufficiency or other genes beside the apo(a) structural gene locus must be responsible for the high Lp(a) levels.

Adult↗