- Email: [email protected]
Effect of atorvastatin on autoantibodies against oxidized low-density lipoprotein in postmenopausal women with coronary heart disease
Gylling
to 57% at the 40 mg dose, leading to a shift in the peak of the density profile towards larger, buoyant LDL particles. Marked reduction in numbers of apoB100-containing particle acceptors led to a 30% decrease (p<0.02) in CE transfer from HDL. A significant dose-dependent statin-mediated elevation (+15% at 10 mg; p-0.0003 and +35% at 40 mg; p<0.0001 as compared to baseline) in the capacity of plasma from Type IIB subjects to mediate free cholesterol efflux from Fu5AH hepatoma cells was observed. Atorvastatin (40 mg/d) significantly increased plasma ApoAI levels (+24%; p<0.05), suggesting an enhanced production of apoAI and with it formation of HDL cholesterol acceptors. Plasma PLTP activity was not affected by either dose of atorvastatin. We conclude that increasing dose of atorvastatin leads to dose-dependent, preferential and progressive reduction in particle numbers of atherogenic VLDL-2, IDL and dense LDL, and concomitantly, to enhanced cellular cholesterol efflux in Type IIB phenotype, thereby diminishing the atherosclerotic burden in this atherogenic dyslipidemia. ~4--~ ELEVATED CETP ACTIVITY AND ENHANCED CELLULAR CHOLESTEROL EFFLUX ARE KEY FEATURES OF POSTPRANDIAL LIPID METABOLISM IN TYPE IIB HYPERLIPIDEMIA M. Guerin 1, P. Egger 1, C. Soudant 1, W. Le Goff1, A. Van Tol2, R. Dupuis3, M.J. Chapman 1. ]INSERM U551, Paris, France," 2Erasmus University,
Rotterdam, The Netherlands; 3Pfizer, Paris, France Postprandial hyperlipidemia constitutes an independent risk factor for coronary artery disease. We evaluated reverse cholesterol transport (RCT) during the postprandial phase in subjects (n-12) displaying atherogenic Type IIB hyperlipidemia. Following consumption of a mixed meal (1200 kcal; 14% protein, 38% carbohydrate and 48% fat), three key steps of RCT i.e. Cholesteryl ester transfer protein (CETP)-mediated cholesteryl ester (CE) transfer, plasma LCAT-mediated cholesterol esterification and cellular free cholesterol efflux, were determined. Total CETP-mediated CE transfer from HDL to TG-rich lipoproteins (TRL; Chylomicrons (Sf>400) + VLDL (Sf 20400) + IDL (Sf 12 20)) increased progressively from 16.0±1.7 btgCE /h/ml at baseline to 26.8±2.4 btgCE transferred/h/ml (+67%; p-0.0004) at 4 hours postprandially. CE transfer to chylomicrons and VLDL-1 was preferentially stimulated (2.6 fold and 2.3 fold respectively) at 4 hours; such changes occurred concomitantly with elevation in mass and particle number of both chylomicrons (2.3 fold) and VLDL-1 (1.3 fold), and in addition, with a 1.8 fold increase in VLDL-1 particle acceptor capacity for CE. Lecithin:cholesterol acyltransferase (LCAT)-dependent cholesterol esterification was significantly increased by 36% (p<0.005) 2h postprandially and by 25% (p<0.05) 4h postprandially as compared to baseline. The relative capacity of plasma to induce free cholesterol efflux from Fu5AH cells was significantly increased (+23%; p<0.005) 4 hours after meal intake. We conclude that enhanced cellular cholesterol efflux stimulates preferential targeting of CE from HDL to chylomicrons and VLDL-1 via the action of LCAT and CETP during alimentary lipemia, thereby favoring formation and accumulation of CE-rich remnant particles of elevated atherogenicity. ~-~
THE V249I POLYMORPHISM IN THE FRACTALKINE RECEPTOR CX3CR1 IS NOT ASSOCIATED W I T H PERIPHERAL ARTERIAL DISEASE
A. Gugl 1, W. Renner 1, G. Seinost 1, M. Brodmann 1, E. Pabst 1, T.C. Wascher2, B. Paulwebera, B. Iglseder4, E. Pilger 1. 1Division of
Angiology, 2Department of Medicine, Medical University Klinik Graz," 3Department of Medicine, 4Department of Neurology, Landeskliniken Salzburg, Austria Objective: CX3CR1 is a novel chemokine receptor located on monocytes. Recently, a common V249I polymorphism was linked to coronary artery disease (CAD). Carriers of at least one I-allele were found less frequent in patients with CAD compared to controls. The aim of the present study was to investigate the influence of this polymorphism on the develpoment of peripheral arterial disease (PAD). Methods and Results: 522 patients with documented PAD and 522 age and sex matched control subjects were genotyped by polymerase chain reaction followed by restriction digestion. The VV, VI and II-genotypes were found in 53.5%, 39.9% and 6.6% of patients and 53.8%, 41.3% and 4.9% of controls (P-0.51). Adjusted odds ratio (OR) of carriers of the I-allele for PAD was 0.99 (95% confidential interval [CI] from 0.75 to 1.33). The genotype was furthermore not linked to age at onset or severity of the disease. A subgroup of 137 CAD patients, who did not differ in baseline
119
parameters from the remaining PAD patients, showed VV-genotype in 53.4%, VI in 41.3% and II in 5.3% (OR associated with the I-allele for CAD: 0.97; 95% CI: 0.63-1.51; P-0.91). Conclusion: In this study we could not detect a difference in genotype frequencies of the V249I polymorphism in CX3CR1 between PAD patients and controls. CAD concomitant with PAD was also not affected by the I-allele.
•4--•
EFFECT OF ATORVASTATIN ON AUTOANTIBODIES AGAINST OXIDIZED LOW-DENSITY LIPOPROTEIN IN POSTMENOPAUSAL WOMEN W I T H CORONARY HEART DISEASE
V.S. Gurevich 1, S.A. Urazgildeeva 1, L.V. Shatilina 2, M.M. Mnuskina3, L.V. Oganesyana, I.N. Makarova a. IMechnicov" s State Medical Academy,"
2Institute of Cardiology," 3City Central Laboratory Center, St. Petersburg, Russia Background: Autoantibodies against oxidized low density lipoprotein (antioxLDL) have been proposed to be independent predictors of atherosclerotic vascular disease. These antibodies are considered as an indication of oxidative modification of LDL. On the other hand it has been reported that the protection of LDL from oxidation decreases the risk of coronary artery disease in postmenopausal women. Objectives: Since increasing evidence suggests that the anti-inflammatory and immunosuppressive effects of statins play an important role in attenuating atherosclerosis this study was designed to assess the effect of atorvastatin on anti-oxLDL levels in hypercholesterolemic postmenopausal women with coronary heart disease. Methods: Enzyme-linked immunosorbent assay was used to determine anti-oxLDL and anticardiolipin in twenty five hypercholesterolemic postmenopausal women before and after 4 weeks of treatment with 10 mg/d atorvastatin. Reactive oxygen species (ROS) have been detected by chemiluminescent method. Results: LDL cholesterol mean reduction after treatment course with atorvastatin was 32%, (P<0.001). HDL cholesterol increased during the study period by 11%, (p<0,005). Anti-oxLDL titres as well as ROS were significantly lower after atorvastatin treatment as compared to baseline levels. There was no difference in anticardiolipin titres before and after treatment. Conclusion: Our findings indicate that influence of atorvastatin on antioxLDL titres in postmenopausal women is a new evidence for beneficial effect of statins unrelated to lipid lowering in this patient group. ~ - - ~ INHERITANCE OF CHOLESTEROL SYNTHESIS AND ABSORPTION IN FAMILIES W I T H CORONARY HEART DISEASE H. Gylling, T.A. Miettinen. Department of Clinical Nutrition, University of Kuopio and Department of Medicine, University of Helsinki, Finland Coronary patients with high absorption and low synthesis of cholesterol had no reduction of coronary events in 4S, the reduction being significant in those with high synthesis and low absorption. We studied cholesterol synthesis and absorption in relatives (R; includes siblings and children) of coronary patients (probands, P) with low (L) and high (H) absorption. The mean age was 50 years for Rs and 58 for Ps (p<0.01). Total and LDL cholesterol were higher in P than R (p<0.001) but similar within L and H, respectively. In R, the serum ratios to cholesterol ofcholestenol, desmosterol and lathosterol (precursor sterols) were 1.37, 1.18 and 1.30 (p<0.01) and those of cholestanol, campesterol and sitosterol (absorption marker sterols) 0.81, 0.71 and 0.80 (p up to 0.001) times higher in L than H. Cholesterol absorption percentage was also 0.76 times higher in L than H (p<0.001), while fecal elimination of cholesterol as cholesterol was 1.82 (p<0.05) and as bile acids 2.22 times higher in L than H, indicating 2.56 times higher synthesis and 2.13 times higher turnover of cholesterol in L than H. In P, the ratios of the precursor sterols were 2.8, 1.3 and 2.5 (p<0.01) times higher in L than H of the P, and the respective values were 0.58, 0.56 and 0.63 (p<0.01) for the absorption marker sterols. Serum plant sterol ratios of PL were positively related to those in RL. The findings suggest marked genetic regulation of cholesterol metabolism in coronary families, detectable not only by sterol balance techniques, but also by serum noncholesterol sterols. Healthy subjects with high absorption and low synthesis marker sterols in serum may not be predictable to reduce coronary events by cholesterol synthesis inhibitors.
73rd EAS Congress
to 57% at the 40 mg dose, leading to a shift in the peak of the density profile towards larger, buoyant LDL particles. Marked reduction in numbers of apoB100-containing particle acceptors led to a 30% decrease (p<0.02) in CE transfer from HDL. A significant dose-dependent statin-mediated elevation (+15% at 10 mg; p-0.0003 and +35% at 40 mg; p<0.0001 as compared to baseline) in the capacity of plasma from Type IIB subjects to mediate free cholesterol efflux from Fu5AH hepatoma cells was observed. Atorvastatin (40 mg/d) significantly increased plasma ApoAI levels (+24%; p<0.05), suggesting an enhanced production of apoAI and with it formation of HDL cholesterol acceptors. Plasma PLTP activity was not affected by either dose of atorvastatin. We conclude that increasing dose of atorvastatin leads to dose-dependent, preferential and progressive reduction in particle numbers of atherogenic VLDL-2, IDL and dense LDL, and concomitantly, to enhanced cellular cholesterol efflux in Type IIB phenotype, thereby diminishing the atherosclerotic burden in this atherogenic dyslipidemia. ~4--~ ELEVATED CETP ACTIVITY AND ENHANCED CELLULAR CHOLESTEROL EFFLUX ARE KEY FEATURES OF POSTPRANDIAL LIPID METABOLISM IN TYPE IIB HYPERLIPIDEMIA M. Guerin 1, P. Egger 1, C. Soudant 1, W. Le Goff1, A. Van Tol2, R. Dupuis3, M.J. Chapman 1. ]INSERM U551, Paris, France," 2Erasmus University,
Rotterdam, The Netherlands; 3Pfizer, Paris, France Postprandial hyperlipidemia constitutes an independent risk factor for coronary artery disease. We evaluated reverse cholesterol transport (RCT) during the postprandial phase in subjects (n-12) displaying atherogenic Type IIB hyperlipidemia. Following consumption of a mixed meal (1200 kcal; 14% protein, 38% carbohydrate and 48% fat), three key steps of RCT i.e. Cholesteryl ester transfer protein (CETP)-mediated cholesteryl ester (CE) transfer, plasma LCAT-mediated cholesterol esterification and cellular free cholesterol efflux, were determined. Total CETP-mediated CE transfer from HDL to TG-rich lipoproteins (TRL; Chylomicrons (Sf>400) + VLDL (Sf 20400) + IDL (Sf 12 20)) increased progressively from 16.0±1.7 btgCE /h/ml at baseline to 26.8±2.4 btgCE transferred/h/ml (+67%; p-0.0004) at 4 hours postprandially. CE transfer to chylomicrons and VLDL-1 was preferentially stimulated (2.6 fold and 2.3 fold respectively) at 4 hours; such changes occurred concomitantly with elevation in mass and particle number of both chylomicrons (2.3 fold) and VLDL-1 (1.3 fold), and in addition, with a 1.8 fold increase in VLDL-1 particle acceptor capacity for CE. Lecithin:cholesterol acyltransferase (LCAT)-dependent cholesterol esterification was significantly increased by 36% (p<0.005) 2h postprandially and by 25% (p<0.05) 4h postprandially as compared to baseline. The relative capacity of plasma to induce free cholesterol efflux from Fu5AH cells was significantly increased (+23%; p<0.005) 4 hours after meal intake. We conclude that enhanced cellular cholesterol efflux stimulates preferential targeting of CE from HDL to chylomicrons and VLDL-1 via the action of LCAT and CETP during alimentary lipemia, thereby favoring formation and accumulation of CE-rich remnant particles of elevated atherogenicity. ~-~
THE V249I POLYMORPHISM IN THE FRACTALKINE RECEPTOR CX3CR1 IS NOT ASSOCIATED W I T H PERIPHERAL ARTERIAL DISEASE
A. Gugl 1, W. Renner 1, G. Seinost 1, M. Brodmann 1, E. Pabst 1, T.C. Wascher2, B. Paulwebera, B. Iglseder4, E. Pilger 1. 1Division of
Angiology, 2Department of Medicine, Medical University Klinik Graz," 3Department of Medicine, 4Department of Neurology, Landeskliniken Salzburg, Austria Objective: CX3CR1 is a novel chemokine receptor located on monocytes. Recently, a common V249I polymorphism was linked to coronary artery disease (CAD). Carriers of at least one I-allele were found less frequent in patients with CAD compared to controls. The aim of the present study was to investigate the influence of this polymorphism on the develpoment of peripheral arterial disease (PAD). Methods and Results: 522 patients with documented PAD and 522 age and sex matched control subjects were genotyped by polymerase chain reaction followed by restriction digestion. The VV, VI and II-genotypes were found in 53.5%, 39.9% and 6.6% of patients and 53.8%, 41.3% and 4.9% of controls (P-0.51). Adjusted odds ratio (OR) of carriers of the I-allele for PAD was 0.99 (95% confidential interval [CI] from 0.75 to 1.33). The genotype was furthermore not linked to age at onset or severity of the disease. A subgroup of 137 CAD patients, who did not differ in baseline
119
parameters from the remaining PAD patients, showed VV-genotype in 53.4%, VI in 41.3% and II in 5.3% (OR associated with the I-allele for CAD: 0.97; 95% CI: 0.63-1.51; P-0.91). Conclusion: In this study we could not detect a difference in genotype frequencies of the V249I polymorphism in CX3CR1 between PAD patients and controls. CAD concomitant with PAD was also not affected by the I-allele.
•4--•
EFFECT OF ATORVASTATIN ON AUTOANTIBODIES AGAINST OXIDIZED LOW-DENSITY LIPOPROTEIN IN POSTMENOPAUSAL WOMEN W I T H CORONARY HEART DISEASE
V.S. Gurevich 1, S.A. Urazgildeeva 1, L.V. Shatilina 2, M.M. Mnuskina3, L.V. Oganesyana, I.N. Makarova a. IMechnicov" s State Medical Academy,"
2Institute of Cardiology," 3City Central Laboratory Center, St. Petersburg, Russia Background: Autoantibodies against oxidized low density lipoprotein (antioxLDL) have been proposed to be independent predictors of atherosclerotic vascular disease. These antibodies are considered as an indication of oxidative modification of LDL. On the other hand it has been reported that the protection of LDL from oxidation decreases the risk of coronary artery disease in postmenopausal women. Objectives: Since increasing evidence suggests that the anti-inflammatory and immunosuppressive effects of statins play an important role in attenuating atherosclerosis this study was designed to assess the effect of atorvastatin on anti-oxLDL levels in hypercholesterolemic postmenopausal women with coronary heart disease. Methods: Enzyme-linked immunosorbent assay was used to determine anti-oxLDL and anticardiolipin in twenty five hypercholesterolemic postmenopausal women before and after 4 weeks of treatment with 10 mg/d atorvastatin. Reactive oxygen species (ROS) have been detected by chemiluminescent method. Results: LDL cholesterol mean reduction after treatment course with atorvastatin was 32%, (P<0.001). HDL cholesterol increased during the study period by 11%, (p<0,005). Anti-oxLDL titres as well as ROS were significantly lower after atorvastatin treatment as compared to baseline levels. There was no difference in anticardiolipin titres before and after treatment. Conclusion: Our findings indicate that influence of atorvastatin on antioxLDL titres in postmenopausal women is a new evidence for beneficial effect of statins unrelated to lipid lowering in this patient group. ~ - - ~ INHERITANCE OF CHOLESTEROL SYNTHESIS AND ABSORPTION IN FAMILIES W I T H CORONARY HEART DISEASE H. Gylling, T.A. Miettinen. Department of Clinical Nutrition, University of Kuopio and Department of Medicine, University of Helsinki, Finland Coronary patients with high absorption and low synthesis of cholesterol had no reduction of coronary events in 4S, the reduction being significant in those with high synthesis and low absorption. We studied cholesterol synthesis and absorption in relatives (R; includes siblings and children) of coronary patients (probands, P) with low (L) and high (H) absorption. The mean age was 50 years for Rs and 58 for Ps (p<0.01). Total and LDL cholesterol were higher in P than R (p<0.001) but similar within L and H, respectively. In R, the serum ratios to cholesterol ofcholestenol, desmosterol and lathosterol (precursor sterols) were 1.37, 1.18 and 1.30 (p<0.01) and those of cholestanol, campesterol and sitosterol (absorption marker sterols) 0.81, 0.71 and 0.80 (p up to 0.001) times higher in L than H. Cholesterol absorption percentage was also 0.76 times higher in L than H (p<0.001), while fecal elimination of cholesterol as cholesterol was 1.82 (p<0.05) and as bile acids 2.22 times higher in L than H, indicating 2.56 times higher synthesis and 2.13 times higher turnover of cholesterol in L than H. In P, the ratios of the precursor sterols were 2.8, 1.3 and 2.5 (p<0.01) times higher in L than H of the P, and the respective values were 0.58, 0.56 and 0.63 (p<0.01) for the absorption marker sterols. Serum plant sterol ratios of PL were positively related to those in RL. The findings suggest marked genetic regulation of cholesterol metabolism in coronary families, detectable not only by sterol balance techniques, but also by serum noncholesterol sterols. Healthy subjects with high absorption and low synthesis marker sterols in serum may not be predictable to reduce coronary events by cholesterol synthesis inhibitors.
73rd EAS Congress