- Email: [email protected]
W09.200 Insulin resistance is associated with increased VLDL triglyceride and VLDL apoC-III production
46
Workshops W9 The metabolic syndrome
Persson
~esults suggested that adipophilin expression might play an important role in atheroma lipid core formation and plaque rupture. Therefore, adipophilin might constitute a new tat'get gene in atherosclerosis treatment.
W9
I w o o q 991 I
•
I
INTERLEUKIN-1I~ AFFECTS MACROPHAGE CHOLESTEROL LEVELS AND EFFLUX
J. Persson, J. Nilsson, M. Wickstr m. Dep. of Medicine, Lund University,
Malmo, Sweden Macrophages pat'take at every stage of atherosclerotic development, as lipid-loaded foam cells and in inflammatory response. In fibroblasts, the pro-inflammatory cytokine interleukin- 1~ (IL- 1~) decrease intracellulat" total cholesterol levels through a complex combination of decreased synthesis, increased esterification and increased effiux of the lipid. The cmxent study assesses the hypothesis that IL-I~ has similar effects on macrophage cholesterol metabolism. If so, this cytokine may exert a beneficial effect, contributing to a decrease in macrophage foam cell formation. Differentiated primary human macrophages o1" THP-1 cells were incubated with IL-I~ (5-5000 ng/ml). In some experiments, the cells were first lipid-loaded by incubation with flee cholesterol o1" lipoproteins. In primat'y cells, incubation with IL-I$ (5 ng/ml) for 24 hours decreased intracellulat" cholesterol levels to 43-4-4% of control (P<0.01, n=5). As macrophage apolipoprotein E (apoE) secretion pat'take in cholesterol effiux, apoE ELISAs were perforrned on conditioned media after IL-I~ treatment. At high concentrations (5000 ng/ml), IL-I~ significantly stimulated apoE secretion fi'om THP-1 cells lipid loaded with cholesterol (356-4-80% of control, P<0.05, n=4) o1"lipoproteins (254-4-40% of control, P<0.05, n=4). There was no significant effect of IL-I~ on cholesterol levels in this cell type, but there was a strong trend towat'ds lower intracellulat" cholesterol levels with increased apoE secretion. It appeat's that IL-I~ does have a dfl'ect effect on macrophage cholesterol levels and that the effect may be mediated by macrophage-specific secretion of apoE, an apolipoprotein capable of facilitating macrophage cholesterol
T H E M E T A B O L I C SYNDROME
SMALL DENSE LDL IS MORE COMMON AMONGST RURAL INDIANS COMPARED TO MIGRANT CONTEMPORARIES: POPULATIONS SUSCEPTIBLE TO INSULIN RESISTANCE AND METABOLIC SYNDROME
J. Patel, M. Caslake, A. Vyas, E. Hughes, D. Prabhakaran, D. Bhatnagar, K. Cruickshank, M. Mackness, P. Durrington. Sandwell and West
Birmingham Hospitals NHS Trust, Birmingham, University of Glasgow, Glasgow, University of Manchester, Manchester, All India Institute of Medical Sciences, United Kingdom Coronat'y heart disease (CHD) is exceptionally prevalent amongst globally dispersed Indian migrant groups, and is linked to insulin resistance (IR). We compared LDL size between age and gender matched Indian Gujaratis living in rural India (294) and migrant contemporat'ies in the UK (242), and tested the association of mean LDL particle diameter (MPD), determined by gradient gel electrophoresis, with components of the metabolic syndrome (MS). These were glucose intolerance and the presence of two other factors of either raised blood pressure, dyslipidaemia or central obesity. All measures were age adjusted. MPD was greater in migrants, although significant only between women (rural, 27.1nm [95% CI: 27-27.2] vs migrant, 27.3nm [27.2-27.5], (p<0.05). Migrants also had a higher proportion of large LDL I 37.3% [35.3-39.2] compared with rural Indians (29.9% [28.8-31]), and less small dense LDLIII (13.3% [12.5-14.2] vs 16.9 [15.7-17.2]). MS was more common amongst migrants (12.6% [8.4-16.7] vs 4.3% [2-6.6%] in rural Indians), in line with greater hyperinsulinaemia, obesity and raised blood pressure (p< 0.001). MS was associated with MPD independently of gender, age and migration status (p
efflux.
20-
~
ANALYSIS OF LIPID EFFLUX IN FIBROBLASTS OF PATIENTS WITH NIEMANN PICK TYPE C DISEASE
i Metabolic syn0r0ma 28.
I. Zanotti, S. Calandra, P. Tarugi, F. Bernini. Department of
Pharmacological and Biological Sciences and Applied Chemistries, University of Parma, Parma, and Department of Biomedical Sciences, University of Modena and Reggio Emilia, Modena, Italy
~ l u e o ~ in'rol~et.~h o~-
E 27-
m~
Mutations on Niemann Pick Type C (NPC) protein-1 lead to lipid storage disorder. It is conceivable, therefore, that cells fi'om NPC patients might have a defective delivery of cholesterol to the plasma membrane which results in an impairrnent of lipid effiux. We measured cholesterol and phospholipid effiux as well as membrane cholesterol pool in seven genotyped NPC fibroblasts and in four cell lines fi'om normal subjects. Confluent cells were radiolabeled with 3H-cholesterol for cholesterol effiux and oxidase experiment or with 3H-choline for phospholipid effiux; ABCA1 was up-regulated by 22OH-cholesterol and 9-cis retinoic acid. Lipid effiux was promoted to apoA-I o1" HDL; cholesterol membrane pool was measured as cholestenone upon treatment with oxidase. The basal effiux to HDL is lower in NPC cells, suggesting a reduced availability of cholesterol. Up-regulation of ABCA1 showed interesting differences: five NPC fibroblasts showed about 30% reduction of both cholesterol and phospholipid effiux whereas two cell lines had a similar or even higher lipid release than control cells. Similarly, the ABCAl-mediated inclease of cholesterol pool in the membrane was reduced in NPC cells that showed a defective effiux compared to normal cells and to NPC fibroblasts with norrnal efflux. Our results suggest that mutations on NPC-1 may produce an impail-ment of cellulat" lipid metabolism that involve ABCA1 activity. However, the presence of efficient ABCAl-mediated processes in two NPC cell lines indicate that different mutations on NPC may differently influence ABCA1 activity.
~,,,lirs fatter
:~.;.-: koe~ a~4iti,flal --
2~L
[0¢tON
E ._l Rural Indi~r~
~ i ~ r ~ n t Ir,d ~ a ~
Smaller LDL is associated with MS amongst these cohorts of rural and migrant Indians, and may explain theh" particulat" susceptibility to CHD. In addition it appeat's to be more pronounced with the worsening of MS amongst rural Indians compared with migrants, despite a greater prevalence of MS amongst the latter. Greater ch'culating insulin amongst migrants, while underlining IR in this group, may also have an inhibitory effect on hepatic lipase or cholesterol esterase transfer protein activity, which promote small dense LDL.
I W09.200 I INSULIN RESISTANCE IS ASSOCIATED WITH INCREASED VLDL TRIGLYCERIDE AND VLDL APOC-III PRODUCTION J. Cohn, B. Patterson, K. Uffelman, J. Davignon, G. Steiner. Clinical
Research Institute of Montreal, Montreal, Toronto General Hospital, Toronto, Canada; Washington University School of Medicine, St. Louis, USA Patients with the metabolic syndrome at increased risk of coronm'y m'tery disease are often overweight and resistant to insulin. They often have a mild-to-moderate elevation in plasma triglyceride (TG) concentration and have increased levels of plasma and VLDL apoC-III. In order to investigate the relationship between the in vivo production (PR) of VLDL TG and
74th EAS Congress, 17-20 April 2004, Seville, Spain
W9
Workshops The metabolic syndrome
VLDL apoC-III in these individuals, we have studied the plasma kinetics of TG, apoC-III and apoB in VLDL with intravenously injected stable isotopes in 10 male subjects with (n=5, HOMA: 21.9-t-7.5, mean 4- SD) or without (n=5, HOMA:9.74-3.1) insulin-resistance (IR). IR subjects had higher plasma levels of VLDL TG (1.74-1.1 vs 0.74-0.2 mmol/1), VLDL apoC-III (9.94-5.6 vs 4.64-1.6 mg/dl) and VLDL apoB (23.54-12.2 vs 13.04-3.4 mg/dl). They also had increased rates of VLDL TG PR (30.44-11.7 vs 12.8 4- 3.6 ~mol/min, P=0.05), VLDL apoC-III PR (19.14-10.4 vs 8.84-2.9 nmol/min, P=0.07), and VLDL apoB PR (6.54-2.5 vs 2.94-1.3 nmol/min, P=0.02). HOMA was significantly COlrelated with VLDL TG PR (r=0.64, P=0.048), VLDL apoC-III PR (r=0.80, P=0.006), and VLDL apoB PR (1"=0.76, P=0.01). HOMA was not significantly related to VLDL fi'actional catabolic rates (FCR). VLDL apoC-III levels were strongly related to VLDL apoC-III PR and not FCR: r=0.91, P=0.0003 vs r=-0.46, P=0.18). Surprisingly, VLDL apoC-III levels were mole strongly COla'elated with VLDL TG PR than with VLDL TG fractional catabolic rate (FCR) or VLDL apoB FCR (r=0.81, P=0.005 vs r=-0.53, P=0.12 vs r=-0.37, P=0.29). These results suggest that VLDL apoC-III overproduction is characteristic of IR, and is more strongly related to increased VLDL TG production than reduced VLDL TG or VLDL apoB catabolism.
•
SERUM APOB/APOA-I WAS RELATED TO THE METABOLIC SYNDROME AND PREDICTED THE INCREASE IN CAROTID ARTERY IMT IN MIDDLE-AGE MEN
K. Wallenfeldt, J. Hulthe, J. Wikstrand, L. Bokemark, B. Fagerberg.
Wallenberg Laboratory, Sahlgrenska University Hospital, G teborg, Sweden Objective: To examine the relationship between serum apoB/apoA-I and the components of the metabolic syndrome at baseline, and the change in ultrasound-assessed carotid ax'tery intima-media thickness (IMT) in a group of clinically healthy middle-aged men, who were followed during 3 years. Background: Serum apoB/apoA-I has been shown to predict future coronax'y death with higher precision than serum LDL-cholesterol. From a pathophysiological standpoint apoB/apoA-I should be related to the components in the metabolic syndrome. Carotid IMT as assessed by B-mode ultrasound has been found to reliably predict future cax'diovasculax" disease. Methods: High-resolution B-mode ultrasound was used to measure cax'otid IMT bilaterally at baseline and after 3 yeax's in 316 men with varying degrees of obesity and insulin sensitivity All men were clinically healthy and were recruited fi'om the general population. ApoB and apoA-I were measured at baseline with routine methods. Results: ApoB/apoA-I correlated to BMI (r=0.22), waist-hip ratio (r=0.28), HDL-cholesterol (r=-0.60), triglycerides (r=0.57), LDL-pax'ticle size (-0.62), insulin (0.30) (all p<0.001). ApoB/apoA-I was associated with the change in cax'otid IMT during 3 years independent of conventional risk factors in a multiple regression analysis. Conclusion: In this group of 58-yeax" old men apoB/apoA-I was both associated with the metabolic syndrome and the change in cax'otid ax'tery IMT.
MULTIFACTORIAL TREATMENT APPROACH IN PATIENTS WITH CORONARY HEART DISEASE AND THE METABOLIC SYNDROME: A GREACE
SUBSTUDY V. Athyros, D. Mikhailidis, A. Papageorgiou, T. Didangelos, V. Bouloukos, A. Pehlivanidis, A. Symeonidis, M. Elisaf. Aristotelian University, Greek
Society of General Practitioners, Thessaloniki; University of loannina, loannina, Greece; Royal Free University College London, London, United Kingdom Objective: The evaluation of the clinical benefit of statin treatment within a multifactorial treatment approach in patients with coronax'y heax't disease (CHD) and the metabolic syndrome (MetS). Patients and Methods: The NCEP-ATP III criteria were used. From 1,600 CHD patients of the GREek-Atorvastatin-and-CHD-Evaluation (GREACE) Study, 682 had the MetS. Patients were divided into two groups: Group A (n=355) included patients on statins, treatment of arterial hypertension and elevated glucose levels and Group B (n=327) patients were treated with all the above except statins. All patients had lifestyle advice and were followed for a 3-yeax" period. The primary endpoint was "all vasculax" events" comprising all primax'y endpoints of the original study.
47
Results: In Group A all patients were on statins and 91% of them (n=324) were at the NCEP LDL-C goal (< 100 mg/dL;2.6mmol/L). In group B 6 (2%) patients reached the LDL-C goal with lifestyle changes. During the study 90 patients (27.5%) of Group B had a primax'y endpoint vs 43 (12%) of patients in Group A; relative risk leduction=56%,p<0.0001. Event rate curves stax'ted deviating from the ffh Ueatment month, but differences became statistically significant at thh'd u'eatment yeax: A statin should be added to other ueatments in 6.5 patients for a 3-yeax" period to avoid one cardiovasculax" event. Conclusions: Lifestyle changes and other U'eatments axe not effective enough in the absence of statin use, at least in CHD patients with the MetS. Aggressive statin treatment reduces cax'diovasculax" events by more than one-half within a 3-yeax"period, in comparison to unU'eated patients.
~
THE PREVALENCE OF THE METABOLIC SYNDROME IN GREECE: THE MetS-GREECE STUDY
V. Athyros, V. Bouloukos, A. Pehlivanidis, A. Papageorgiou, Dionysopoulou, A. Symeonidis, D. Petridis, M. Kapousouzi, E. Satsoglou, D. Mikhailidis. Aristotelian University and Greek Society of General
Practitioners, Thessaloniki; Kilkis Hospital, Kilkis; Hospital of Goumenissa, Goumenissa, Greece; Royal Free University London, London, United Kingdom Background: Limited information is available about the plevalence of the metabolic syndrome (MetS), according to the NCEP-ATPIII criteria, in Europe. Objective: To estimate the prevalence of the MetS in Greece. Design and Participants: A cross sectional analysis of a representative sample of Greek adults (3,456 participants older than 18 years). One group of militax'y personnel (n=300) and another one fi'om a Greek Muslim Community (n=300) were used for compax'ison. In all, 4,056 subjects wele studied. Results: All subjects were Caucasian men (48%) and women (52%), living in urban (55%), semi-urban (25%), and rural (20%) areas. The agestandax'dized prevalence of the MetS was 22.8% (CI 95%:21.5-24.6). This was similar in men (23.7%) and women (21.9%, p=NS). The prevalence increased with age in both sexes; 4.7% among participants aged 18-29 years and 44.2% for participants over 60 yeax's old. Most of those with MetS had 3 components of the syndrome (62%); 28% had 4, and 10% had all 5 components. Abdominal obesity and arterial hypertension were the most common abnormalities in both sexes. The Greek Muslim Community, on a high saturated fat diet had the highest prevalence of the MetS (34.6%), and the militax'y group, with a high physical activity level and a Mediterranean diet, had the lowest (9.1%). We estimate that about 2.4 million Greeks may have the MetS. Conclusions: MetS is highly prevalent in the Greek adult population. This may have major implications on the incidence of CVD. Promoting healthy diets, low caloric intake, and physical activity must be urgently undertaken.
~
~
BatTeR
FENOFIBRATE INCREASES HDL LPAI:AH PRODUCTION IN MEN WITH THE METABOLIC SYNDROME
H. Bax'rett, J. Ji, A. Johnson, A. Serone, F. Loehrer, G. Watts. University of
Western Australia, Perth, GlaxoSmithKline, Sydney, Australia The metabolic syndrome (MS) is associated with increased risk for cardiovasculax" disease (CVD). This may in pax't be related to low plasma levels of HDL. ApoAI (AI) and apoAII (AII) play important roles in regulating HDL metabolism, and LpAI:AII particles may be particulax'ly anti-atherogenic in MS subjects. Fibrates have been shown to reduce CVD although theft" precise mechanisms of action on HDL metabolism have not yet been established. The aim of this study was to examine the effect of fenofibrate (FF) on HDL AI and AII kinetics. We studied 11 MS men (BMI>27 kg/m 2, HOMA 5.1-4-2.1, plasma cholesterol (C) 5.9-4-0.5 retool/L, HDL C 0.9-4-0.1 retool/L, TG 2.4-4-1.0 retool/L, apoB 1.1-4-0.1 g/L, apoAI 1.1-4-0.2 g/L, apoAII 0.3-4-0.01 g/L, LpAI 0.25-4-0.12 g/L, LpAI:AII 0.87-4-0.2 g/L) in a double-blind, randomized, cross-over tlial. Subjects were treated once daily with micronised FF (200rag) or placebo (P) for 6-week periods with 2-week washouts. HDL AI and AII turnover was measured following iv administration of d3-1eucine. AI and AII metabolic pax'ameters were estimated by compartment model. Compax'ed with P, FF treatment reduced plasma TG 24% (p=0.003), apoB 12% (p=0.023) and increased HDL C 9% (p=0.010).
74th EAS Congress, 17-20 April 2004, Seville, Spain
iiiiiiiiiiiiiiii iiii
iiiiiiiiiiiiiii iiiii iiiiii.-~.'iiiiiiiiiiiiiiii
Workshops W9 The metabolic syndrome
Persson
~esults suggested that adipophilin expression might play an important role in atheroma lipid core formation and plaque rupture. Therefore, adipophilin might constitute a new tat'get gene in atherosclerosis treatment.
W9
I w o o q 991 I
•
I
INTERLEUKIN-1I~ AFFECTS MACROPHAGE CHOLESTEROL LEVELS AND EFFLUX
J. Persson, J. Nilsson, M. Wickstr m. Dep. of Medicine, Lund University,
Malmo, Sweden Macrophages pat'take at every stage of atherosclerotic development, as lipid-loaded foam cells and in inflammatory response. In fibroblasts, the pro-inflammatory cytokine interleukin- 1~ (IL- 1~) decrease intracellulat" total cholesterol levels through a complex combination of decreased synthesis, increased esterification and increased effiux of the lipid. The cmxent study assesses the hypothesis that IL-I~ has similar effects on macrophage cholesterol metabolism. If so, this cytokine may exert a beneficial effect, contributing to a decrease in macrophage foam cell formation. Differentiated primary human macrophages o1" THP-1 cells were incubated with IL-I~ (5-5000 ng/ml). In some experiments, the cells were first lipid-loaded by incubation with flee cholesterol o1" lipoproteins. In primat'y cells, incubation with IL-I$ (5 ng/ml) for 24 hours decreased intracellulat" cholesterol levels to 43-4-4% of control (P<0.01, n=5). As macrophage apolipoprotein E (apoE) secretion pat'take in cholesterol effiux, apoE ELISAs were perforrned on conditioned media after IL-I~ treatment. At high concentrations (5000 ng/ml), IL-I~ significantly stimulated apoE secretion fi'om THP-1 cells lipid loaded with cholesterol (356-4-80% of control, P<0.05, n=4) o1"lipoproteins (254-4-40% of control, P<0.05, n=4). There was no significant effect of IL-I~ on cholesterol levels in this cell type, but there was a strong trend towat'ds lower intracellulat" cholesterol levels with increased apoE secretion. It appeat's that IL-I~ does have a dfl'ect effect on macrophage cholesterol levels and that the effect may be mediated by macrophage-specific secretion of apoE, an apolipoprotein capable of facilitating macrophage cholesterol
T H E M E T A B O L I C SYNDROME
SMALL DENSE LDL IS MORE COMMON AMONGST RURAL INDIANS COMPARED TO MIGRANT CONTEMPORARIES: POPULATIONS SUSCEPTIBLE TO INSULIN RESISTANCE AND METABOLIC SYNDROME
J. Patel, M. Caslake, A. Vyas, E. Hughes, D. Prabhakaran, D. Bhatnagar, K. Cruickshank, M. Mackness, P. Durrington. Sandwell and West
Birmingham Hospitals NHS Trust, Birmingham, University of Glasgow, Glasgow, University of Manchester, Manchester, All India Institute of Medical Sciences, United Kingdom Coronat'y heart disease (CHD) is exceptionally prevalent amongst globally dispersed Indian migrant groups, and is linked to insulin resistance (IR). We compared LDL size between age and gender matched Indian Gujaratis living in rural India (294) and migrant contemporat'ies in the UK (242), and tested the association of mean LDL particle diameter (MPD), determined by gradient gel electrophoresis, with components of the metabolic syndrome (MS). These were glucose intolerance and the presence of two other factors of either raised blood pressure, dyslipidaemia or central obesity. All measures were age adjusted. MPD was greater in migrants, although significant only between women (rural, 27.1nm [95% CI: 27-27.2] vs migrant, 27.3nm [27.2-27.5], (p<0.05). Migrants also had a higher proportion of large LDL I 37.3% [35.3-39.2] compared with rural Indians (29.9% [28.8-31]), and less small dense LDLIII (13.3% [12.5-14.2] vs 16.9 [15.7-17.2]). MS was more common amongst migrants (12.6% [8.4-16.7] vs 4.3% [2-6.6%] in rural Indians), in line with greater hyperinsulinaemia, obesity and raised blood pressure (p< 0.001). MS was associated with MPD independently of gender, age and migration status (p
efflux.
20-
~
ANALYSIS OF LIPID EFFLUX IN FIBROBLASTS OF PATIENTS WITH NIEMANN PICK TYPE C DISEASE
i Metabolic syn0r0ma 28.
I. Zanotti, S. Calandra, P. Tarugi, F. Bernini. Department of
Pharmacological and Biological Sciences and Applied Chemistries, University of Parma, Parma, and Department of Biomedical Sciences, University of Modena and Reggio Emilia, Modena, Italy
~ l u e o ~ in'rol~et.~h o~-
E 27-
m~
Mutations on Niemann Pick Type C (NPC) protein-1 lead to lipid storage disorder. It is conceivable, therefore, that cells fi'om NPC patients might have a defective delivery of cholesterol to the plasma membrane which results in an impairrnent of lipid effiux. We measured cholesterol and phospholipid effiux as well as membrane cholesterol pool in seven genotyped NPC fibroblasts and in four cell lines fi'om normal subjects. Confluent cells were radiolabeled with 3H-cholesterol for cholesterol effiux and oxidase experiment or with 3H-choline for phospholipid effiux; ABCA1 was up-regulated by 22OH-cholesterol and 9-cis retinoic acid. Lipid effiux was promoted to apoA-I o1" HDL; cholesterol membrane pool was measured as cholestenone upon treatment with oxidase. The basal effiux to HDL is lower in NPC cells, suggesting a reduced availability of cholesterol. Up-regulation of ABCA1 showed interesting differences: five NPC fibroblasts showed about 30% reduction of both cholesterol and phospholipid effiux whereas two cell lines had a similar or even higher lipid release than control cells. Similarly, the ABCAl-mediated inclease of cholesterol pool in the membrane was reduced in NPC cells that showed a defective effiux compared to normal cells and to NPC fibroblasts with norrnal efflux. Our results suggest that mutations on NPC-1 may produce an impail-ment of cellulat" lipid metabolism that involve ABCA1 activity. However, the presence of efficient ABCAl-mediated processes in two NPC cell lines indicate that different mutations on NPC may differently influence ABCA1 activity.
~,,,lirs fatter
:~.;.-: koe~ a~4iti,flal --
2~L
[0¢tON
E ._l Rural Indi~r~
~ i ~ r ~ n t Ir,d ~ a ~
Smaller LDL is associated with MS amongst these cohorts of rural and migrant Indians, and may explain theh" particulat" susceptibility to CHD. In addition it appeat's to be more pronounced with the worsening of MS amongst rural Indians compared with migrants, despite a greater prevalence of MS amongst the latter. Greater ch'culating insulin amongst migrants, while underlining IR in this group, may also have an inhibitory effect on hepatic lipase or cholesterol esterase transfer protein activity, which promote small dense LDL.
I W09.200 I INSULIN RESISTANCE IS ASSOCIATED WITH INCREASED VLDL TRIGLYCERIDE AND VLDL APOC-III PRODUCTION J. Cohn, B. Patterson, K. Uffelman, J. Davignon, G. Steiner. Clinical
Research Institute of Montreal, Montreal, Toronto General Hospital, Toronto, Canada; Washington University School of Medicine, St. Louis, USA Patients with the metabolic syndrome at increased risk of coronm'y m'tery disease are often overweight and resistant to insulin. They often have a mild-to-moderate elevation in plasma triglyceride (TG) concentration and have increased levels of plasma and VLDL apoC-III. In order to investigate the relationship between the in vivo production (PR) of VLDL TG and
74th EAS Congress, 17-20 April 2004, Seville, Spain
W9
Workshops The metabolic syndrome
VLDL apoC-III in these individuals, we have studied the plasma kinetics of TG, apoC-III and apoB in VLDL with intravenously injected stable isotopes in 10 male subjects with (n=5, HOMA: 21.9-t-7.5, mean 4- SD) or without (n=5, HOMA:9.74-3.1) insulin-resistance (IR). IR subjects had higher plasma levels of VLDL TG (1.74-1.1 vs 0.74-0.2 mmol/1), VLDL apoC-III (9.94-5.6 vs 4.64-1.6 mg/dl) and VLDL apoB (23.54-12.2 vs 13.04-3.4 mg/dl). They also had increased rates of VLDL TG PR (30.44-11.7 vs 12.8 4- 3.6 ~mol/min, P=0.05), VLDL apoC-III PR (19.14-10.4 vs 8.84-2.9 nmol/min, P=0.07), and VLDL apoB PR (6.54-2.5 vs 2.94-1.3 nmol/min, P=0.02). HOMA was significantly COlrelated with VLDL TG PR (r=0.64, P=0.048), VLDL apoC-III PR (r=0.80, P=0.006), and VLDL apoB PR (1"=0.76, P=0.01). HOMA was not significantly related to VLDL fi'actional catabolic rates (FCR). VLDL apoC-III levels were strongly related to VLDL apoC-III PR and not FCR: r=0.91, P=0.0003 vs r=-0.46, P=0.18). Surprisingly, VLDL apoC-III levels were mole strongly COla'elated with VLDL TG PR than with VLDL TG fractional catabolic rate (FCR) or VLDL apoB FCR (r=0.81, P=0.005 vs r=-0.53, P=0.12 vs r=-0.37, P=0.29). These results suggest that VLDL apoC-III overproduction is characteristic of IR, and is more strongly related to increased VLDL TG production than reduced VLDL TG or VLDL apoB catabolism.
•
SERUM APOB/APOA-I WAS RELATED TO THE METABOLIC SYNDROME AND PREDICTED THE INCREASE IN CAROTID ARTERY IMT IN MIDDLE-AGE MEN
K. Wallenfeldt, J. Hulthe, J. Wikstrand, L. Bokemark, B. Fagerberg.
Wallenberg Laboratory, Sahlgrenska University Hospital, G teborg, Sweden Objective: To examine the relationship between serum apoB/apoA-I and the components of the metabolic syndrome at baseline, and the change in ultrasound-assessed carotid ax'tery intima-media thickness (IMT) in a group of clinically healthy middle-aged men, who were followed during 3 years. Background: Serum apoB/apoA-I has been shown to predict future coronax'y death with higher precision than serum LDL-cholesterol. From a pathophysiological standpoint apoB/apoA-I should be related to the components in the metabolic syndrome. Carotid IMT as assessed by B-mode ultrasound has been found to reliably predict future cax'diovasculax" disease. Methods: High-resolution B-mode ultrasound was used to measure cax'otid IMT bilaterally at baseline and after 3 yeax's in 316 men with varying degrees of obesity and insulin sensitivity All men were clinically healthy and were recruited fi'om the general population. ApoB and apoA-I were measured at baseline with routine methods. Results: ApoB/apoA-I correlated to BMI (r=0.22), waist-hip ratio (r=0.28), HDL-cholesterol (r=-0.60), triglycerides (r=0.57), LDL-pax'ticle size (-0.62), insulin (0.30) (all p<0.001). ApoB/apoA-I was associated with the change in cax'otid IMT during 3 years independent of conventional risk factors in a multiple regression analysis. Conclusion: In this group of 58-yeax" old men apoB/apoA-I was both associated with the metabolic syndrome and the change in cax'otid ax'tery IMT.
MULTIFACTORIAL TREATMENT APPROACH IN PATIENTS WITH CORONARY HEART DISEASE AND THE METABOLIC SYNDROME: A GREACE
SUBSTUDY V. Athyros, D. Mikhailidis, A. Papageorgiou, T. Didangelos, V. Bouloukos, A. Pehlivanidis, A. Symeonidis, M. Elisaf. Aristotelian University, Greek
Society of General Practitioners, Thessaloniki; University of loannina, loannina, Greece; Royal Free University College London, London, United Kingdom Objective: The evaluation of the clinical benefit of statin treatment within a multifactorial treatment approach in patients with coronax'y heax't disease (CHD) and the metabolic syndrome (MetS). Patients and Methods: The NCEP-ATP III criteria were used. From 1,600 CHD patients of the GREek-Atorvastatin-and-CHD-Evaluation (GREACE) Study, 682 had the MetS. Patients were divided into two groups: Group A (n=355) included patients on statins, treatment of arterial hypertension and elevated glucose levels and Group B (n=327) patients were treated with all the above except statins. All patients had lifestyle advice and were followed for a 3-yeax" period. The primary endpoint was "all vasculax" events" comprising all primax'y endpoints of the original study.
47
Results: In Group A all patients were on statins and 91% of them (n=324) were at the NCEP LDL-C goal (< 100 mg/dL;2.6mmol/L). In group B 6 (2%) patients reached the LDL-C goal with lifestyle changes. During the study 90 patients (27.5%) of Group B had a primax'y endpoint vs 43 (12%) of patients in Group A; relative risk leduction=56%,p<0.0001. Event rate curves stax'ted deviating from the ffh Ueatment month, but differences became statistically significant at thh'd u'eatment yeax: A statin should be added to other ueatments in 6.5 patients for a 3-yeax" period to avoid one cardiovasculax" event. Conclusions: Lifestyle changes and other U'eatments axe not effective enough in the absence of statin use, at least in CHD patients with the MetS. Aggressive statin treatment reduces cax'diovasculax" events by more than one-half within a 3-yeax"period, in comparison to unU'eated patients.
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THE PREVALENCE OF THE METABOLIC SYNDROME IN GREECE: THE MetS-GREECE STUDY
V. Athyros, V. Bouloukos, A. Pehlivanidis, A. Papageorgiou, Dionysopoulou, A. Symeonidis, D. Petridis, M. Kapousouzi, E. Satsoglou, D. Mikhailidis. Aristotelian University and Greek Society of General
Practitioners, Thessaloniki; Kilkis Hospital, Kilkis; Hospital of Goumenissa, Goumenissa, Greece; Royal Free University London, London, United Kingdom Background: Limited information is available about the plevalence of the metabolic syndrome (MetS), according to the NCEP-ATPIII criteria, in Europe. Objective: To estimate the prevalence of the MetS in Greece. Design and Participants: A cross sectional analysis of a representative sample of Greek adults (3,456 participants older than 18 years). One group of militax'y personnel (n=300) and another one fi'om a Greek Muslim Community (n=300) were used for compax'ison. In all, 4,056 subjects wele studied. Results: All subjects were Caucasian men (48%) and women (52%), living in urban (55%), semi-urban (25%), and rural (20%) areas. The agestandax'dized prevalence of the MetS was 22.8% (CI 95%:21.5-24.6). This was similar in men (23.7%) and women (21.9%, p=NS). The prevalence increased with age in both sexes; 4.7% among participants aged 18-29 years and 44.2% for participants over 60 yeax's old. Most of those with MetS had 3 components of the syndrome (62%); 28% had 4, and 10% had all 5 components. Abdominal obesity and arterial hypertension were the most common abnormalities in both sexes. The Greek Muslim Community, on a high saturated fat diet had the highest prevalence of the MetS (34.6%), and the militax'y group, with a high physical activity level and a Mediterranean diet, had the lowest (9.1%). We estimate that about 2.4 million Greeks may have the MetS. Conclusions: MetS is highly prevalent in the Greek adult population. This may have major implications on the incidence of CVD. Promoting healthy diets, low caloric intake, and physical activity must be urgently undertaken.
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FENOFIBRATE INCREASES HDL LPAI:AH PRODUCTION IN MEN WITH THE METABOLIC SYNDROME
H. Bax'rett, J. Ji, A. Johnson, A. Serone, F. Loehrer, G. Watts. University of
Western Australia, Perth, GlaxoSmithKline, Sydney, Australia The metabolic syndrome (MS) is associated with increased risk for cardiovasculax" disease (CVD). This may in pax't be related to low plasma levels of HDL. ApoAI (AI) and apoAII (AII) play important roles in regulating HDL metabolism, and LpAI:AII particles may be particulax'ly anti-atherogenic in MS subjects. Fibrates have been shown to reduce CVD although theft" precise mechanisms of action on HDL metabolism have not yet been established. The aim of this study was to examine the effect of fenofibrate (FF) on HDL AI and AII kinetics. We studied 11 MS men (BMI>27 kg/m 2, HOMA 5.1-4-2.1, plasma cholesterol (C) 5.9-4-0.5 retool/L, HDL C 0.9-4-0.1 retool/L, TG 2.4-4-1.0 retool/L, apoB 1.1-4-0.1 g/L, apoAI 1.1-4-0.2 g/L, apoAII 0.3-4-0.01 g/L, LpAI 0.25-4-0.12 g/L, LpAI:AII 0.87-4-0.2 g/L) in a double-blind, randomized, cross-over tlial. Subjects were treated once daily with micronised FF (200rag) or placebo (P) for 6-week periods with 2-week washouts. HDL AI and AII turnover was measured following iv administration of d3-1eucine. AI and AII metabolic pax'ameters were estimated by compartment model. Compax'ed with P, FF treatment reduced plasma TG 24% (p=0.003), apoB 12% (p=0.023) and increased HDL C 9% (p=0.010).
74th EAS Congress, 17-20 April 2004, Seville, Spain
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