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Lipoprotein(a) level and phenotypes in primary biliary cirrhosis
Thursday 13 October 1994: Poster Abstracts Lipoprotein(a)
spectively, which supports the involvement of the asialoglycoprotein receptor in the TG (20 A) C-induced liver uptake of lipoproteins. This contrasts with earlier data demonstrating that the cholesterol derivative of a cluster galactoside, with marginal aftinity for the asialoglycoprotein receptor, stimulated hepatic uptake of LDL and Lp(a) via the Kupffer cells. In conclusion, a cholestery! galactoside induced uptake of atherogenic lipoproteins by parenchymal liver cells. The catabolism of atherogenic lipoproteins thus stimulated might prove beneficial for FH/FD patients and patients with high levels of Lp(a), for whom no therapy is currently available. 1 mR,
Influence of human ape(a) gene size polymorphism on the catabolism of lipoprotein(a) Chiesa G, Bilheimer DW, Univ. of Lausanne, Switzer-
land; Southwestern Med. Center, Univ. of Texas, Dallas, TX, USA
Plasma levels of Lp(a) are genetically determined, and in Caucasians about 90% of inter-individual variation is linked to ape(a) gene polymorphism. In our assessment of whether the human ape(a) gene affects the catabolic rate of Lp(a), NZW male rabbits were used as an animal model. Lp(a) was isolated by lysine-Sepharose afftnity chromatography from the plasma of 7 healthy Caucasian subjects with a wide range of plasma Lp(a) levels (17-130mg/dl) and ape(a) gene alleles (2-i12) identified by pulse-field gel electrophoresis. Simultaneous iniection of ‘251- and 13tI-labeled Lda) from two different donors-was performed in a series of 3-6 rabbits under standard diet. Blood samples were collected over 96 h. Kinetic parameters were calculated with the Consam@ (30.1) computer program. The FCR of Lp(a) from a pair of donors with different ape(a) gene alleles (2/4 and 8112) in the same series of rabbits was lower (1.26 f 0.07/2.14 f 0.43 and 2.1 f 0.6/3.28? 1.06 pool/day) for the smaller alleles, while for donors with the same alleles (Y.5) the FCR was similar (2.07 f 0.37/2.06 f 0.5 pool/day). Them was an inverse correlation between plasma Lp(a) levels and ape(a) gene alleles (r = -0.72, P c 0.07) as well between FCR of Lp(a) and Lp(a) plasma levels (r = -0.70, P < 0.08) and a positive correlation between FCR of Lp(a) and ape(a) gene alleles (r = 0.93, P < 0.003). This study suggests that Lp(a) plasma levels am controlled not only by ape(a) synthesis rates. Whether the number of kringles 4 or the structure of ape(a) are a major genetic determinant for the catabolism of Lp(a) remain to be elucidated. Lipoprotein(a) level and phenotypes in primary 1106) biliary cirrhosis &t&&, Nemesansky E, Szalay F, C&z&r A, Ttesch J, Kar&Ii I, 3rd Dept. of Medicine, Semmelweis Univ. of Medicine, Eiitviis tit 12, H-1121 Budapest, Hungary
The liver is recognized as the main organ responsible for plasma Lp(a) production. The object of this study was to determine Lp(a) and other lipoprotein concentrations in patients with primary biliary cirrhosis (PBC). 39 female patients, aged 29-79 years, with PBC were studied. In each case the diagnosis was determined by a combination of clinical, biochemical and histological features. Histopathological staging followed the criteria of Scheuer. 63 healthy female blood donors aged 34-64 years served as controls. Lp(a) concentrations were determined by ELISA, and ape(a) phenotyping was performed by SDS-PAGE of whole plasma samples followed by immunoblotting. Serum Lp(a) levels ranged from 0 to 75.2 mg/dl. The median Lp(a) concentration was not different between PBS patients and controls (10.0 * 19.6 vs 11.5 f 13.4 mg/dl), but the percentage of patients with Lp(a) levels cl mg/dl rose with progressive stage of liver damage: in stage 1, 0%; 2, 13%; 3, 20%; 4, 66%. The apo-
287
protein phenotyping data showed a significant (P c 0.01) difference between patients and controls: patients/controls for S4, 0.396/0.230; S3, 0.276/0.3X; S2, 0.030/0.184; Sl, O/0.039; B, 0.0.39; 0,0.307/0.112. Low Lp(a) levels may be one reason why patients with advanced primary biliary cirrhosis with a high serum total cholesterol are not at increased risk for atherosclerosis. 11071
Transfer of Lp(a) and LDL into aortic intbna in normal and cholesterol-fed rabbits Nordestgaard BG, Stender S, Niendorf A, Kjeldsen
m K, Dept. C&t. Biochem, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark
To study the relative atherogenic potential of Lp(a), we compared the aortic permeability to Lp(a) and LDL in normal and cholesterol-fed rabbits. Aortic permeability was calculated by dividing arterial wall radioactivity, 1 or 3 h after intravenous in’ection of a mixed preparation of human 1251-labeled Lp(a) and 1311-labeled LDL, by the average concentration of the appropriate radioactivity in plasma and the duration of the exposure period. The permeability of the aottic arch to Lp(a) and LDL was 84 f 8 and 55 f 6 ni/cm2/h (mean f SEM, n = 19) in the l-h experiments, and 45 f 11 and 68 f 22 nl/cm2/b (n = 6) respectively in the 3-h experiments. Linear regression analysis showed a strong positive association between the aortic permeability to the two lipoproteins in both sets of experiments (P < 0.001). In the same rabbits, immunoreactivity to human apolipoprotein(a) was detected in aortic intima in association with fatty streak lesions, predominantly within the cytoplasm of foam cells. These results suggest that Lp(a) is transferred into the aortic intima by a mechanism similar to LDL, and that Lp(a) can be taken up by foam cells after it has entered the arterial wall. @ w,
Apolipoprotein(a) phenotypes predict ischemic heart disease in a Danish population Klausen IC, Hansen PS, Genies LU, Faergeman 0,
Dept. of Internal Medicine and Cardiol. A, Aarhus Amtssygehus Univ. Hospital, 8000 Aarhus, Denmark
We have compared Lp(a) concentrations and ape(a) phenotypes in 101Danish men (age 35-55, mean 49.8 years) with ischemic heart disease (selected from the Danish participants in the Scandinavian Simvastatin Survival Study) with those in 466 Danish reference men (age 40 years). Lp(a) concentrations wete measured with a two-site immunoradiometric assay, and ape(a) phenotypes were determined by SDS-polyacrylamide gel electrophoresis. The median Lp(a) concentrations were significantly higher in IHD patients (19.0mg/dl; 95% CI 14.4-26.4) than in reference men (6.33 mg/dl; 95% CI 5.5-7.3) by the Mann-Whitney U-test (P<0.00001). The phenotype distribution in II-ID patients and reference men was also significantly different (P = 0.00811): frequencies of the ape(a) low molecular weight isoforms, comprising isoforms F, B, Sl and S2, were higher in BID patients. Median Lp(a) concentrations were significantly higher in BID patients for each of the commonest phenotypes (S2, S3, S4). In conclusion, Lp(a) is a risk factor for IHD in a Danish population. Our findings are consistent with other published studies [1,2]. [I] Saudholzer et al Atheroscler Thromb 1992; 12: 1214-1226. [2] Molgaard et al Atheroscler Thromb 1992; 12: 895-901, Pentanucleotide repeat polymorphism (TTITA)n in the 5’ control region of the ape(a) gene affects Lp(a) plasma concentrations Trommsdorff, Koch1 S, Utermann G, Kraft HG, Inst.for Medi-
pi%J
cine Biology and Human Genetics, Schiipfstr. 41, 6020 Innsbruck, Austria
Atherosclerosis X, Montreal, October 1994
spectively, which supports the involvement of the asialoglycoprotein receptor in the TG (20 A) C-induced liver uptake of lipoproteins. This contrasts with earlier data demonstrating that the cholesterol derivative of a cluster galactoside, with marginal aftinity for the asialoglycoprotein receptor, stimulated hepatic uptake of LDL and Lp(a) via the Kupffer cells. In conclusion, a cholestery! galactoside induced uptake of atherogenic lipoproteins by parenchymal liver cells. The catabolism of atherogenic lipoproteins thus stimulated might prove beneficial for FH/FD patients and patients with high levels of Lp(a), for whom no therapy is currently available. 1 mR,
Influence of human ape(a) gene size polymorphism on the catabolism of lipoprotein(a) Chiesa G, Bilheimer DW, Univ. of Lausanne, Switzer-
land; Southwestern Med. Center, Univ. of Texas, Dallas, TX, USA
Plasma levels of Lp(a) are genetically determined, and in Caucasians about 90% of inter-individual variation is linked to ape(a) gene polymorphism. In our assessment of whether the human ape(a) gene affects the catabolic rate of Lp(a), NZW male rabbits were used as an animal model. Lp(a) was isolated by lysine-Sepharose afftnity chromatography from the plasma of 7 healthy Caucasian subjects with a wide range of plasma Lp(a) levels (17-130mg/dl) and ape(a) gene alleles (2-i12) identified by pulse-field gel electrophoresis. Simultaneous iniection of ‘251- and 13tI-labeled Lda) from two different donors-was performed in a series of 3-6 rabbits under standard diet. Blood samples were collected over 96 h. Kinetic parameters were calculated with the Consam@ (30.1) computer program. The FCR of Lp(a) from a pair of donors with different ape(a) gene alleles (2/4 and 8112) in the same series of rabbits was lower (1.26 f 0.07/2.14 f 0.43 and 2.1 f 0.6/3.28? 1.06 pool/day) for the smaller alleles, while for donors with the same alleles (Y.5) the FCR was similar (2.07 f 0.37/2.06 f 0.5 pool/day). Them was an inverse correlation between plasma Lp(a) levels and ape(a) gene alleles (r = -0.72, P c 0.07) as well between FCR of Lp(a) and Lp(a) plasma levels (r = -0.70, P < 0.08) and a positive correlation between FCR of Lp(a) and ape(a) gene alleles (r = 0.93, P < 0.003). This study suggests that Lp(a) plasma levels am controlled not only by ape(a) synthesis rates. Whether the number of kringles 4 or the structure of ape(a) are a major genetic determinant for the catabolism of Lp(a) remain to be elucidated. Lipoprotein(a) level and phenotypes in primary 1106) biliary cirrhosis &t&&, Nemesansky E, Szalay F, C&z&r A, Ttesch J, Kar&Ii I, 3rd Dept. of Medicine, Semmelweis Univ. of Medicine, Eiitviis tit 12, H-1121 Budapest, Hungary
The liver is recognized as the main organ responsible for plasma Lp(a) production. The object of this study was to determine Lp(a) and other lipoprotein concentrations in patients with primary biliary cirrhosis (PBC). 39 female patients, aged 29-79 years, with PBC were studied. In each case the diagnosis was determined by a combination of clinical, biochemical and histological features. Histopathological staging followed the criteria of Scheuer. 63 healthy female blood donors aged 34-64 years served as controls. Lp(a) concentrations were determined by ELISA, and ape(a) phenotyping was performed by SDS-PAGE of whole plasma samples followed by immunoblotting. Serum Lp(a) levels ranged from 0 to 75.2 mg/dl. The median Lp(a) concentration was not different between PBS patients and controls (10.0 * 19.6 vs 11.5 f 13.4 mg/dl), but the percentage of patients with Lp(a) levels cl mg/dl rose with progressive stage of liver damage: in stage 1, 0%; 2, 13%; 3, 20%; 4, 66%. The apo-
287
protein phenotyping data showed a significant (P c 0.01) difference between patients and controls: patients/controls for S4, 0.396/0.230; S3, 0.276/0.3X; S2, 0.030/0.184; Sl, O/0.039; B, 0.0.39; 0,0.307/0.112. Low Lp(a) levels may be one reason why patients with advanced primary biliary cirrhosis with a high serum total cholesterol are not at increased risk for atherosclerosis. 11071
Transfer of Lp(a) and LDL into aortic intbna in normal and cholesterol-fed rabbits Nordestgaard BG, Stender S, Niendorf A, Kjeldsen
m K, Dept. C&t. Biochem, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark
To study the relative atherogenic potential of Lp(a), we compared the aortic permeability to Lp(a) and LDL in normal and cholesterol-fed rabbits. Aortic permeability was calculated by dividing arterial wall radioactivity, 1 or 3 h after intravenous in’ection of a mixed preparation of human 1251-labeled Lp(a) and 1311-labeled LDL, by the average concentration of the appropriate radioactivity in plasma and the duration of the exposure period. The permeability of the aottic arch to Lp(a) and LDL was 84 f 8 and 55 f 6 ni/cm2/h (mean f SEM, n = 19) in the l-h experiments, and 45 f 11 and 68 f 22 nl/cm2/b (n = 6) respectively in the 3-h experiments. Linear regression analysis showed a strong positive association between the aortic permeability to the two lipoproteins in both sets of experiments (P < 0.001). In the same rabbits, immunoreactivity to human apolipoprotein(a) was detected in aortic intima in association with fatty streak lesions, predominantly within the cytoplasm of foam cells. These results suggest that Lp(a) is transferred into the aortic intima by a mechanism similar to LDL, and that Lp(a) can be taken up by foam cells after it has entered the arterial wall. @ w,
Apolipoprotein(a) phenotypes predict ischemic heart disease in a Danish population Klausen IC, Hansen PS, Genies LU, Faergeman 0,
Dept. of Internal Medicine and Cardiol. A, Aarhus Amtssygehus Univ. Hospital, 8000 Aarhus, Denmark
We have compared Lp(a) concentrations and ape(a) phenotypes in 101Danish men (age 35-55, mean 49.8 years) with ischemic heart disease (selected from the Danish participants in the Scandinavian Simvastatin Survival Study) with those in 466 Danish reference men (age 40 years). Lp(a) concentrations wete measured with a two-site immunoradiometric assay, and ape(a) phenotypes were determined by SDS-polyacrylamide gel electrophoresis. The median Lp(a) concentrations were significantly higher in IHD patients (19.0mg/dl; 95% CI 14.4-26.4) than in reference men (6.33 mg/dl; 95% CI 5.5-7.3) by the Mann-Whitney U-test (P<0.00001). The phenotype distribution in II-ID patients and reference men was also significantly different (P = 0.00811): frequencies of the ape(a) low molecular weight isoforms, comprising isoforms F, B, Sl and S2, were higher in BID patients. Median Lp(a) concentrations were significantly higher in BID patients for each of the commonest phenotypes (S2, S3, S4). In conclusion, Lp(a) is a risk factor for IHD in a Danish population. Our findings are consistent with other published studies [1,2]. [I] Saudholzer et al Atheroscler Thromb 1992; 12: 1214-1226. [2] Molgaard et al Atheroscler Thromb 1992; 12: 895-901, Pentanucleotide repeat polymorphism (TTITA)n in the 5’ control region of the ape(a) gene affects Lp(a) plasma concentrations Trommsdorff, Koch1 S, Utermann G, Kraft HG, Inst.for Medi-
pi%J
cine Biology and Human Genetics, Schiipfstr. 41, 6020 Innsbruck, Austria
Atherosclerosis X, Montreal, October 1994