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257 ASSOCIATION OF HYPERTENSION WITH SMALL, DENSE LOW-DENSITY-LIPOPROTEIN IN PATIENTS WITHOUT METABOLIC SYNDROME
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Atherosclerosis Supplements 12, no. 1 (2011) 13–184
correlation was observed between Lp(a) levels and PON1 activity (r = −0.76, n = 23, p < 0.001). PON1 exerts a protective effect against lipid peroxidation of lipoproteins and membranes, therefore our results suggest that patients with higher Lp(a) levels are more exposed to oxidative damage. 256 EFFECT OF EZETIMIBE ON MARKERS OF OXIDATIVE STRESS IN PATIENTS WITH HYPERCHOLESTEROLEMIA M.S. Kostapanos1 , A.T. Spyrou1 , C.C. Tellis2 , I.F. Gazi1 , A.D. Tselepis2 , E.N. Liberopoulos1 , M.S. Elisaf1 . 1 Department of Internal Medicine, University of Ioannina School of Medicine, 2 Laboratory of Biochemistry, Department of ´ Chemistry, University of Ioannina, Ioannina, Greece Ezetimibe effectively reduces low-density lipoprotein cholesterol (LDL-C). In this study, we tested the hypothesis that ezetimibe monotherapy may also decrease markers of oxidative stress in subjects with hypercholesterolemia. Methods: Subjects with hypercholesterolemia and no evidence of cardiovascular disease were randomized to open-label ezetimibe monotherapy 10 mg/day (EZT group) or therapeutic lifestyle changes (TLC group). At baseline and 12 weeks post-treatment serum lipoprotein and apolipoprotein levels as well as oxidative stress parameters, including oxidized LDL (ox-LDL), 8-isoprostanes (8-epiPGF2a) and reactive oxygen metabolites (d-ROMs) levels, were blindly determined. Results: A total of 60 patients were included; 30 in each group. Despite a significant decrease in ox-LDL levels (by 20.8%, p < 0.001 vs baseline; p < 0.001 vs TLC group) in the EZT group no change in the ratio ox-LDL to LDL-C was noticed following ezetimibe treatment. A trend towards a decrease in 8-epiPGF2a (by 15.2%, p = 0.09 vs baseline; p = 0.10 vs TLC group) and d-ROMs levels (by 10.0%, p = 0.11 vs baseline; p = 0.09 vs TLC group) in the EZT group was proved unrelated to the degree of LDL-C lowering associated with ezetimibe administration. A significant decrease in 8-epiPGF2a and d-ROMs levels (by 20.4% and 18.2%, respectively, p < 0.01 vs baseline for both), was noted only among patients who exhibited ‘high oxidative stress’ at baseline. No change in any of oxidative stress parameters was noted in the TLC group. Conclusion: Ezetimibe may decrease markers of oxidative stress in hypercholesterolemic subjects. This benefit may be more profound among hyperlipidemic patients who exhibit ‘high oxidative stress’ at baseline. 257 ASSOCIATION OF HYPERTENSION WITH SMALL, DENSE LOW-DENSITY-LIPOPROTEIN IN PATIENTS WITHOUT METABOLIC SYNDROME Y.K. Kim, H.S. Seo, J.O. Na, C.U. Choi, H.E. Lim, E.J. Kim, S.-W. Rha, C.G. Park, D.J. Oh. Korea University Guro-Hospital, Seoul, Republic of Korea A higher proportion of small, dense low-density-lipoprotein (sdLDL) is known to be associated with a high prevalence of cardiovascular disease in association with metabolic syndrome (MS). Hypertension (HTN) is one of the known risk factors for MS. However, whether HTN is associated with sdLDL in patients without MS is not yet clear. Methods: The lipid profiles, including LDL subfractions, of 383 consecutive subjects were evaluated. Seventy-seven of these patients had MS and 306 subjects did not. The patients without MS consisted of 198 hypertensive patients (non-MS/HTN group) and 108 normotensive subjects (non-MS/non-HTN group). Peak and mean particle diameter of LDL were measured by gradient gel electrophoresis; lipid profiles and blood sugar and apolipoprotein levels were also measured. Results: Plasma total cholesterol, LDL-cholesterol, high-density-lipoprotein (HDL)-cholesterol, triglyceride, HDL-C/Apo A1, LDL-C/ApoB, and apolipoprotein (A1, B, CII and E) levels did not differ between the non-MS/non-HTN and non-MS/HTN groups. When analyzing LDL subfraction, the absolute amount of patterns A and B was not different between the non-MS/non-HTN and non-MS/HTN groups. When comparing the non-MS/non-HTN and the nonMS/HTN groups, the proportion of sdLDL was higher in the non-MS/HTN group (37.7% versus 39.9%, P = 0.046). The body mass index, homeostasis model assessment index, and C-reactive protein levels were not different between the non-MS/non-HTN and non-MS/HTN groups. Conclusions: The proportion of sdLDL to total LDL was significantly higher in hypertensive subjects, even those without MS, than in normotensive subjects. This result suggests that HTN can contribute to atherosclerosis and endothelial dysfunction associated with mechanical vascular injury by altering LDL size.
Poster presentations
258 LIPID PROFILE IN PATIENTS WITH INFLAMMATORY POLYARTHRITIS PRIOR TO THERAPY A.Z. Alhusain1 , S.M. Verstappen1 , H. Mirjafari1 , D. Symmons1 , V. CharltonMenys2 , P. Durrington2 , D. Bunn3 , I.N. Bruce1 . 1 Arthritis Research UK Epidemiology Unit, 2 Cardiovascular Research Group, University of Manchester, Manchester, 3 Norfalk Arthritis Research Group, University of East Anglia, Norwich, UK Rheumatoid arthritis (RA) is a chronic inflammatory condition with established disease-associated dislipidaemia. Previous studies noted that lipid profiles of patients with active RA are mainly characterised by reduced serum levels of high density lipoprotein (HDL-C) while contrasting results of serum total cholesterol TC and low density lipoprotein (LDL-C) were found. The objectives of this study were i) to determine lipid profiles in a group of patients with early inflammatory polyarthritis (IP) not exposed to treatment and ii) to examine the association between inflammation and clinical markers of disease activity with serum lipid profiles. Patients with early IP (2 swollen joints for 4 weeks) from The Norfolk Arthritis Register (NOAR), were included in this study. 339 (37%) of them were not on any treatment at time of recruitment. Baseline clinical assessments and examinations were conducted and blood samples were collected to measure autoimmune and lipid profile. Baseline results are; age = 50(19.7), TC 4.79 [3.85, 5.58] mmol/l, HDL 0.98 [0.75, 1.3] mmol/l, LDL 2.96 [2.14, 3.75] mmol/l, TG 1.56 [1.15, 2.05] mmol/l, apoA-1 1.82 [1.47, 2.18] U/l, and apoB 0.83 [0.62, 1.04] U/l. Regression analysis revealed a negative association between CRP and TG (b coefficient [95% CI]) = (−0.07 [−0.01, −0.003]) which remained significant even after adjustment for age and gender (−0.09 [−0.02, −0.002]). A similar association with DAS28 score was observed (−0.1[−0.17, −0.03]) after adjustment (−0.1 [−0.2, −0.01]). In patients with early arthritis, inflammation mainly affects TG; alterations in TG may contribute to atherogenesis in the active phase of RA. Table 1 Variable
Mean (SD)/Median (IQR)
Age TC TG HDL LDL CRP DAS-28
50.7 (19.7) 4.79 (3.85, 5.58) 1.56 (1.15, 2.05) 0.98 (0.75, 1.3) 2.9 (2.1, 3.7) 14.6 (20) 3.5 (1.2)
259 PROTEIN DISULFIDE ISOMERASE INHIBITION BY 4-HYDROXYNONENAL-ADDUCTS CONTRIBUTES TO OXIDIZED LOW DENSITY LIPOPROTEIN-INDUCED APOPTOSIS C. Muller, J. Bandemer, C. Vindis, R. Salvayre, A. Negre-Salvayre. INSERM U1048, University of Toulouse III, Toulouse, France The proteine disulfide isomerase (PDI), is an endoplasmic reticulum (ER)associated chaperon protein, that plays a role in neosynthesized protein maturation, and protects against apoptosis induced by various stress-inducing agents. Its role in atherosclerosis is not known so far. We aimed to investigate the role of PDI in apoptosis elicited by oxidized LDLs (oxLDLs) in human vascular cells (HMEC-1) and in macrophagic U937 cells. Toxic pro-apoptotic oxLDL concentrations inhibit PDI activity, together with an increased expression of proapoptotic ER stress markers (CHOP and spliced XBP1mRNAs). PDI inhibition by bacitracine or by transfection of a vector coding for a mutant enzymatically inactive form, increased the expression of CHOP and promoted apoptosis at non-toxic oxLDL concentrations, in both HMEC-1 and U937, suggesting a protective function for this chaperon against oxLDL-induced cell death. The inhibitory effect on PDI oxLDLs may result from an accumulation of 4-hydroxynonenal (4-HNE)-adducts, which alter its enzyme activity. The antioxidant N-acetyl cysteine (NAC) neutralized 4-HNE adduct formation and restored the enzyme activity of PDI. 4-HNE-modified PDI was detected in macrophages in human endarterectomy lesions, suggesting a possible loss of function for this chaperon, in instable atherosclerotic plaques.
Atherosclerosis Supplements 12, no. 1 (2011) 13–184
correlation was observed between Lp(a) levels and PON1 activity (r = −0.76, n = 23, p < 0.001). PON1 exerts a protective effect against lipid peroxidation of lipoproteins and membranes, therefore our results suggest that patients with higher Lp(a) levels are more exposed to oxidative damage. 256 EFFECT OF EZETIMIBE ON MARKERS OF OXIDATIVE STRESS IN PATIENTS WITH HYPERCHOLESTEROLEMIA M.S. Kostapanos1 , A.T. Spyrou1 , C.C. Tellis2 , I.F. Gazi1 , A.D. Tselepis2 , E.N. Liberopoulos1 , M.S. Elisaf1 . 1 Department of Internal Medicine, University of Ioannina School of Medicine, 2 Laboratory of Biochemistry, Department of ´ Chemistry, University of Ioannina, Ioannina, Greece Ezetimibe effectively reduces low-density lipoprotein cholesterol (LDL-C). In this study, we tested the hypothesis that ezetimibe monotherapy may also decrease markers of oxidative stress in subjects with hypercholesterolemia. Methods: Subjects with hypercholesterolemia and no evidence of cardiovascular disease were randomized to open-label ezetimibe monotherapy 10 mg/day (EZT group) or therapeutic lifestyle changes (TLC group). At baseline and 12 weeks post-treatment serum lipoprotein and apolipoprotein levels as well as oxidative stress parameters, including oxidized LDL (ox-LDL), 8-isoprostanes (8-epiPGF2a) and reactive oxygen metabolites (d-ROMs) levels, were blindly determined. Results: A total of 60 patients were included; 30 in each group. Despite a significant decrease in ox-LDL levels (by 20.8%, p < 0.001 vs baseline; p < 0.001 vs TLC group) in the EZT group no change in the ratio ox-LDL to LDL-C was noticed following ezetimibe treatment. A trend towards a decrease in 8-epiPGF2a (by 15.2%, p = 0.09 vs baseline; p = 0.10 vs TLC group) and d-ROMs levels (by 10.0%, p = 0.11 vs baseline; p = 0.09 vs TLC group) in the EZT group was proved unrelated to the degree of LDL-C lowering associated with ezetimibe administration. A significant decrease in 8-epiPGF2a and d-ROMs levels (by 20.4% and 18.2%, respectively, p < 0.01 vs baseline for both), was noted only among patients who exhibited ‘high oxidative stress’ at baseline. No change in any of oxidative stress parameters was noted in the TLC group. Conclusion: Ezetimibe may decrease markers of oxidative stress in hypercholesterolemic subjects. This benefit may be more profound among hyperlipidemic patients who exhibit ‘high oxidative stress’ at baseline. 257 ASSOCIATION OF HYPERTENSION WITH SMALL, DENSE LOW-DENSITY-LIPOPROTEIN IN PATIENTS WITHOUT METABOLIC SYNDROME Y.K. Kim, H.S. Seo, J.O. Na, C.U. Choi, H.E. Lim, E.J. Kim, S.-W. Rha, C.G. Park, D.J. Oh. Korea University Guro-Hospital, Seoul, Republic of Korea A higher proportion of small, dense low-density-lipoprotein (sdLDL) is known to be associated with a high prevalence of cardiovascular disease in association with metabolic syndrome (MS). Hypertension (HTN) is one of the known risk factors for MS. However, whether HTN is associated with sdLDL in patients without MS is not yet clear. Methods: The lipid profiles, including LDL subfractions, of 383 consecutive subjects were evaluated. Seventy-seven of these patients had MS and 306 subjects did not. The patients without MS consisted of 198 hypertensive patients (non-MS/HTN group) and 108 normotensive subjects (non-MS/non-HTN group). Peak and mean particle diameter of LDL were measured by gradient gel electrophoresis; lipid profiles and blood sugar and apolipoprotein levels were also measured. Results: Plasma total cholesterol, LDL-cholesterol, high-density-lipoprotein (HDL)-cholesterol, triglyceride, HDL-C/Apo A1, LDL-C/ApoB, and apolipoprotein (A1, B, CII and E) levels did not differ between the non-MS/non-HTN and non-MS/HTN groups. When analyzing LDL subfraction, the absolute amount of patterns A and B was not different between the non-MS/non-HTN and non-MS/HTN groups. When comparing the non-MS/non-HTN and the nonMS/HTN groups, the proportion of sdLDL was higher in the non-MS/HTN group (37.7% versus 39.9%, P = 0.046). The body mass index, homeostasis model assessment index, and C-reactive protein levels were not different between the non-MS/non-HTN and non-MS/HTN groups. Conclusions: The proportion of sdLDL to total LDL was significantly higher in hypertensive subjects, even those without MS, than in normotensive subjects. This result suggests that HTN can contribute to atherosclerosis and endothelial dysfunction associated with mechanical vascular injury by altering LDL size.
Poster presentations
258 LIPID PROFILE IN PATIENTS WITH INFLAMMATORY POLYARTHRITIS PRIOR TO THERAPY A.Z. Alhusain1 , S.M. Verstappen1 , H. Mirjafari1 , D. Symmons1 , V. CharltonMenys2 , P. Durrington2 , D. Bunn3 , I.N. Bruce1 . 1 Arthritis Research UK Epidemiology Unit, 2 Cardiovascular Research Group, University of Manchester, Manchester, 3 Norfalk Arthritis Research Group, University of East Anglia, Norwich, UK Rheumatoid arthritis (RA) is a chronic inflammatory condition with established disease-associated dislipidaemia. Previous studies noted that lipid profiles of patients with active RA are mainly characterised by reduced serum levels of high density lipoprotein (HDL-C) while contrasting results of serum total cholesterol TC and low density lipoprotein (LDL-C) were found. The objectives of this study were i) to determine lipid profiles in a group of patients with early inflammatory polyarthritis (IP) not exposed to treatment and ii) to examine the association between inflammation and clinical markers of disease activity with serum lipid profiles. Patients with early IP (2 swollen joints for 4 weeks) from The Norfolk Arthritis Register (NOAR), were included in this study. 339 (37%) of them were not on any treatment at time of recruitment. Baseline clinical assessments and examinations were conducted and blood samples were collected to measure autoimmune and lipid profile. Baseline results are; age = 50(19.7), TC 4.79 [3.85, 5.58] mmol/l, HDL 0.98 [0.75, 1.3] mmol/l, LDL 2.96 [2.14, 3.75] mmol/l, TG 1.56 [1.15, 2.05] mmol/l, apoA-1 1.82 [1.47, 2.18] U/l, and apoB 0.83 [0.62, 1.04] U/l. Regression analysis revealed a negative association between CRP and TG (b coefficient [95% CI]) = (−0.07 [−0.01, −0.003]) which remained significant even after adjustment for age and gender (−0.09 [−0.02, −0.002]). A similar association with DAS28 score was observed (−0.1[−0.17, −0.03]) after adjustment (−0.1 [−0.2, −0.01]). In patients with early arthritis, inflammation mainly affects TG; alterations in TG may contribute to atherogenesis in the active phase of RA. Table 1 Variable
Mean (SD)/Median (IQR)
Age TC TG HDL LDL CRP DAS-28
50.7 (19.7) 4.79 (3.85, 5.58) 1.56 (1.15, 2.05) 0.98 (0.75, 1.3) 2.9 (2.1, 3.7) 14.6 (20) 3.5 (1.2)
259 PROTEIN DISULFIDE ISOMERASE INHIBITION BY 4-HYDROXYNONENAL-ADDUCTS CONTRIBUTES TO OXIDIZED LOW DENSITY LIPOPROTEIN-INDUCED APOPTOSIS C. Muller, J. Bandemer, C. Vindis, R. Salvayre, A. Negre-Salvayre. INSERM U1048, University of Toulouse III, Toulouse, France The proteine disulfide isomerase (PDI), is an endoplasmic reticulum (ER)associated chaperon protein, that plays a role in neosynthesized protein maturation, and protects against apoptosis induced by various stress-inducing agents. Its role in atherosclerosis is not known so far. We aimed to investigate the role of PDI in apoptosis elicited by oxidized LDLs (oxLDLs) in human vascular cells (HMEC-1) and in macrophagic U937 cells. Toxic pro-apoptotic oxLDL concentrations inhibit PDI activity, together with an increased expression of proapoptotic ER stress markers (CHOP and spliced XBP1mRNAs). PDI inhibition by bacitracine or by transfection of a vector coding for a mutant enzymatically inactive form, increased the expression of CHOP and promoted apoptosis at non-toxic oxLDL concentrations, in both HMEC-1 and U937, suggesting a protective function for this chaperon against oxLDL-induced cell death. The inhibitory effect on PDI oxLDLs may result from an accumulation of 4-hydroxynonenal (4-HNE)-adducts, which alter its enzyme activity. The antioxidant N-acetyl cysteine (NAC) neutralized 4-HNE adduct formation and restored the enzyme activity of PDI. 4-HNE-modified PDI was detected in macrophages in human endarterectomy lesions, suggesting a possible loss of function for this chaperon, in instable atherosclerotic plaques.