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289 SPONTANEOUS PLAQUE DISRUPTIONS, DISSECTION, EROSION AND INTRAPLAQUE HEMORRHAGE IN MURINE VEIN GRAFTS CAN BE ATTENUATED BY TIMP-1 OVEREXPRESSION
79th EAS Congress
Atherosclerosis Supplements 12, no. 1 (2011) 13–184
ADA 2010 definition (all p < 0.03). All-cause and cardiovascular mortality were not significantly different between subjects with type 2 diabetes according to the ADA 2009 criteria and those with isolated elevation of glycated hemoglobin (p = 0.360 and p = 0.894, respectively). Conclusions: These results support the use of the ADA 2010 criteria for diagnosing diabetes, at least in persons at intermediate to high cardiovascular risk. 289 SPONTANEOUS PLAQUE DISRUPTIONS, DISSECTION, EROSION AND INTRAPLAQUE HEMORRHAGE IN MURINE VEIN GRAFTS CAN BE ATTENUATED BY TIMP-1 OVEREXPRESSION 4 M.R. de Vries1,2 , H.W.M. Niessen3 , C.W. Lowik ¨ , J.W. Jukema2,5 , P.H.A. Quax1,2 . 1 Vascular Surgery, 2 Einthoven Laboratory of Experimental Vascular Medicine, Leiden University Medical Center, Leiden, 3 Pathology and Cardiac Surgery, ICaR-VU, VU University Medical Center, Amsterdam, 4 Endocrinology, 5 Cardiology, Leiden University Medical Center, Leiden, The Netherlands Plaque rupture and erosion are the most common underlying causes of cardiovascular death. Matrixmetalloproteinases (MMP) play a key role in these processes. We hypothesize that overexpression of the endogenous inhibitor of MMPs TIMP-1 results in decreased plaque disruptions in vein grafts in hypercholesterolemic ApoE3Leiden mice. Vein graft lesions in ApoE3Leiden mice consist of foamcells, smooth muscle cells (SMC) and extracellular matrix with necrotic cores, calcifications and inflammatory cells. Lesion neovessels consist of endothelial cells and basement membranes, supporting mural cells were infrequently seen. 79% of 47 vein grafts studied showed spontaneous disruption, 1/3 of these disruptions were dissections, 1/3 were leaky microvessels with extravasated erythrocytes and 1/3 were erosions or intramural thrombosis. Also vein grafts with combined leaky vessels and dissections or erosions were seen. Systemic overexpression of TIMP-1 (and Luciferase as control) was obtained by plasmid electroporation. Near InfraRed Fluorescense imaging was used to detect in vivo (inhibition of) MMP activity and thus TIMP-1 plasmid functionality. TIMP-1 overexpression resulted in a decrease of 73% in MMP activity in the vein graft-region after 28d and a 40% reduction in vein graft thickening after 28d. The lesions showed significant less disruptions (90%) than the control Luciferase group resulting in a more stable phenotype with significant more SMC, collagen and significant less macrophages and fibrinogen. Here we show that murine ApoE3L vein grafts are a relevant model to study plaque stability and subsequent disruptions. Furthermore we demonstrate that MMP inhibition reduced plaque disruptions resulting in a more stable plaque phenotype. 290 ATHEROPROTECTIVE EFFECTS OF ADIPONECTIN OVER-EXPRESSION IN A MODEL OF ANGII-ACCELERATED ATHEROSCLEROSIS C.M.W. van Stijn, J. Kim, D. Becerra, R.K. Tangirala. Medicine/Endocrinology, Diabetes & Hypertension, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA Adiponectin, an adipocytokine derived from adipose tissue, exerts antiinflammatory and anti-atherogenic effects on vascular cells. Low plasma adiponectin levels are associated with the metabolic syndrome, diabetes and cardiovascular disease. It is unknown whether elevation of plasma adiponectin levels provides protection against angiotensin II (AngII)-mediated vascular inflammation and accelerated atherosclerosis. In this study, first, we investigated adiponectin regulation of inflammatory gene expression in human and mouse macrophages. Gene expression analyses of macrophages treated with TNF-a or TNF-a + adiponectin revealed that adiponectin repressed several genes inflammatory/atherogenic genes (ACE, MCP-1, IL-1b, IL-8 and PDGF-b). We determined whether adenoviral adiponectin expression inhibits AngIIaccelerated vascular inflammation and atherosclerosis. Low-density lipoprotein receptor-deficient (LDLR−/− ) mice fed high-fat and infused with Ang-II were injected 5 X 108 particles of adenovirus expressing GFP (Ad-GFP, n = 16) or mouse adiponectin (Ad-APN, n = 16). After eight weeks, plasma adiponectin levels were 12-fold higher in Ad-APN than Ad-GFP (306.4 mg/dL vs 25.3 mg/dL) accompanied by significant elevation of plasma HDL levels in Ad-APN mice (23.6% increase). Quantification of atherosclerosis by en face method, revealed a significant inhibition of atherosclerosis in Ad-APN (45% reduction, p < 0.01 vs. Ad-GFP). Furthermore, adiponectin expression substantially inhibited mRNA levels of inflammatory and atherogenic genes (ICAM-1, osteopontin, MCP-1 and CCR2) in the vessel wall. Interestingly, adiponectin also increased mRNA expression of the reverse cholesterol transport genes, ABCA1 and ABCG1, in the aorta. These data strongly support that concept that increasing plasma adiponectin levels may be an effective therapeutic strategy to inhibit AngIImediated vascular inflammation and acceleration of atherosclerosis.
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291 CORONARY ARTERY CALCIFICATION AND DIABETES MELLITUS: SEX-SPECIFIC IMPACT ON INCIDENCE OF CARDIOVASCULAR DISEASE − RESULTS OF THE HEINZ NIXDORF RECALL-STUDY 2 S. Moebus1 , S. Mohlenkamp ¨ , N. Dragano1 , U. Slomiany1 , S. Pechlivanis1 , 1 R. Erbel2 , K. Mann3 , K.-H. Jockel ¨ , Heinz Nixdorf Recall Study Group. 1 University Hospital, University of Duisburg-Essen, Institute for Medical Informatics, Biometry and Epidemiology, 2 University Hospital, University of Duisburg-Essen, West German Heart Center Essen, 3 University Hospital, University Duisburg-Essen, Department of Endocrinology and Division of Laboratory Research, Essen, Germany Aims: To examine the impact of coronary artery calcification (CAC), a specific marker of subclinical atherosclerosis, on cardiovascular disease (CVD) with regard to diabetes status (DM). Methods: We included 4,265 participants (aged 45−75 years) without overt CVD at baseline of the population-based Heinz Nixdorf Recall Study. Baseline examination included blood analyses and electron-beam tomography. DM is based on self-report and/or intake of diabetes medication. We calculated hazard ratios (HR) and 95%-confidence intervals (95%-CI) for events (myocardial infarction/stroke) with cox proportional hazards models adjusting for age, CAC (dichotomized by 75th age- and sex-specific percentile), waist circumference, smoking, lipid-lowering medication and blood pressure. Results: The mean follow-up time was 7.2 (±1.44) years, with 194 (128 men) events, of these 31 (18 men) with DM. Overall diabetic subjects had a 2.5fold higher risk for CVD. However, in women with a CAC above the 75th age- and sex-specific percentile we observed a 3-fold increased risk for CVD (ageadjusted HR 3.02; 95% CI: 1.36–6.70, full model: 3.61;1.59–8.21) for diabetic women compared to women without diabetes, whereas the HR attenuates to 1.99 (0.73–5.41, full model: 2.34;0.89–6.13) in diabetic women with less CAC. These high risks and differences are not observed in diabetic men with high CAC or with CAC to a lesser extent (full model: HR 1.28;0.64–2.54, respective 1.59;0.75–3.36). Conclusions: Our study confirms the high risk for CVD in subjects with Diabetes mellitus. Moreover, we found that diabetic women exposed to a high CAC are especially susceptible for CVD. 292 A POSSIBLE LINK BETWEEN ATHEROSCLEROTIC PLAQUE INFLAMMATION AND VISCERAL FAT INFLAMMATION S.E. Kim1 , E.J. Kim2 , J.S. Yeo3 , H.S. Seog2 . 1 Nuclear Medicine, 2 Cardiovascular Center, Korea University Guro Hospital, Seoul, 3 Nuclear Medicine, Dongkuk University Ilsan Hospital, Goyang-si, Republic of Korea Background: We hypothesized that active atherosclerotic change in the major arteries would accompany increased inflammation within visceral fat and it could be detected in humans using F-18 FDG PET/CT. Methods: We observed 44 consecutive subjects with cardiovascular disease. For all of them, an one-hour PET/CT was performed after injection of FDG (370–555 MBq). FDG uptake in the aorta or its major branches was evaluated visually and semiquantitatively. Maximal standard uptake values (SUV) of the highest regions of interest were calculated in the subcutaneous fat and visceral fat area, separately. Results: Significant FDG uptake in the arterial wall was noted in 21 patients (plaque positive; PP group), all of whom have experienced acute cardiovascular events (acute coronary syndrome or ischemic stroke) within a week. The other 23 patients (plaque negative; PN group) had chronic stable angina or asymptomatic carotid stenosis. Visceral fat SUV was significantly higher as compared to subcutaneous fat SUV (0.49±0.15 vs. 0.15±0.05, p < 0.001) in PP group, whereas there was no significant difference in PN group (0.18±.07 vs. 0.16±.03, p = 0.622). When we compared two groups, PP group showed higher visceral fat SUV than PN group (p < 0.001). In terms of subcutaneous fat SUV, the results were similar in two groups (p = 0.773). Conclusions: We demonstrated that atherosclerotic plaque inflammation was associated with increased inflammation within visceral fat. Further evaluation to determine whether metabolic activity of visceral adipose tissue is a marker or mediator of vascular inflammation is also needed. 293 UROKINASE PLASMINOGEN ACTIVATOR (UPA) AND ATHEROSCLEROSIS B. Fuhrman, J. Khateeb, Y. Lati, M. Aviram. Lipid Research Laboratory, Technion Faculty of Medicine/Rambam Medical Center, Haifa, Israel Background: The urokinase plasminogen activator (uPA) and its receptor uPAR, play a role in the pathogenesis of atherosclerosis. Increased plasma levels of uPA were shown to be associated with plaque rupture. The atherosclerotic plaque is characterized by cholesterol-loaded macrophage-foam cells and oxidized lipids. The goal of our project is to study in detail the functions of the uPA/uPAR system in atherosclerosis, in relation to macrophage-foam cell formation. Results: Our key findings show that uPA increases macrophage atherogenicity. We have shown that uPA increased cellular cholesterol accumulation, resulting from an increase in cellular cholesterol biosynthesis. This effect required the
Atherosclerosis Supplements 12, no. 1 (2011) 13–184
ADA 2010 definition (all p < 0.03). All-cause and cardiovascular mortality were not significantly different between subjects with type 2 diabetes according to the ADA 2009 criteria and those with isolated elevation of glycated hemoglobin (p = 0.360 and p = 0.894, respectively). Conclusions: These results support the use of the ADA 2010 criteria for diagnosing diabetes, at least in persons at intermediate to high cardiovascular risk. 289 SPONTANEOUS PLAQUE DISRUPTIONS, DISSECTION, EROSION AND INTRAPLAQUE HEMORRHAGE IN MURINE VEIN GRAFTS CAN BE ATTENUATED BY TIMP-1 OVEREXPRESSION 4 M.R. de Vries1,2 , H.W.M. Niessen3 , C.W. Lowik ¨ , J.W. Jukema2,5 , P.H.A. Quax1,2 . 1 Vascular Surgery, 2 Einthoven Laboratory of Experimental Vascular Medicine, Leiden University Medical Center, Leiden, 3 Pathology and Cardiac Surgery, ICaR-VU, VU University Medical Center, Amsterdam, 4 Endocrinology, 5 Cardiology, Leiden University Medical Center, Leiden, The Netherlands Plaque rupture and erosion are the most common underlying causes of cardiovascular death. Matrixmetalloproteinases (MMP) play a key role in these processes. We hypothesize that overexpression of the endogenous inhibitor of MMPs TIMP-1 results in decreased plaque disruptions in vein grafts in hypercholesterolemic ApoE3Leiden mice. Vein graft lesions in ApoE3Leiden mice consist of foamcells, smooth muscle cells (SMC) and extracellular matrix with necrotic cores, calcifications and inflammatory cells. Lesion neovessels consist of endothelial cells and basement membranes, supporting mural cells were infrequently seen. 79% of 47 vein grafts studied showed spontaneous disruption, 1/3 of these disruptions were dissections, 1/3 were leaky microvessels with extravasated erythrocytes and 1/3 were erosions or intramural thrombosis. Also vein grafts with combined leaky vessels and dissections or erosions were seen. Systemic overexpression of TIMP-1 (and Luciferase as control) was obtained by plasmid electroporation. Near InfraRed Fluorescense imaging was used to detect in vivo (inhibition of) MMP activity and thus TIMP-1 plasmid functionality. TIMP-1 overexpression resulted in a decrease of 73% in MMP activity in the vein graft-region after 28d and a 40% reduction in vein graft thickening after 28d. The lesions showed significant less disruptions (90%) than the control Luciferase group resulting in a more stable phenotype with significant more SMC, collagen and significant less macrophages and fibrinogen. Here we show that murine ApoE3L vein grafts are a relevant model to study plaque stability and subsequent disruptions. Furthermore we demonstrate that MMP inhibition reduced plaque disruptions resulting in a more stable plaque phenotype. 290 ATHEROPROTECTIVE EFFECTS OF ADIPONECTIN OVER-EXPRESSION IN A MODEL OF ANGII-ACCELERATED ATHEROSCLEROSIS C.M.W. van Stijn, J. Kim, D. Becerra, R.K. Tangirala. Medicine/Endocrinology, Diabetes & Hypertension, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA Adiponectin, an adipocytokine derived from adipose tissue, exerts antiinflammatory and anti-atherogenic effects on vascular cells. Low plasma adiponectin levels are associated with the metabolic syndrome, diabetes and cardiovascular disease. It is unknown whether elevation of plasma adiponectin levels provides protection against angiotensin II (AngII)-mediated vascular inflammation and accelerated atherosclerosis. In this study, first, we investigated adiponectin regulation of inflammatory gene expression in human and mouse macrophages. Gene expression analyses of macrophages treated with TNF-a or TNF-a + adiponectin revealed that adiponectin repressed several genes inflammatory/atherogenic genes (ACE, MCP-1, IL-1b, IL-8 and PDGF-b). We determined whether adenoviral adiponectin expression inhibits AngIIaccelerated vascular inflammation and atherosclerosis. Low-density lipoprotein receptor-deficient (LDLR−/− ) mice fed high-fat and infused with Ang-II were injected 5 X 108 particles of adenovirus expressing GFP (Ad-GFP, n = 16) or mouse adiponectin (Ad-APN, n = 16). After eight weeks, plasma adiponectin levels were 12-fold higher in Ad-APN than Ad-GFP (306.4 mg/dL vs 25.3 mg/dL) accompanied by significant elevation of plasma HDL levels in Ad-APN mice (23.6% increase). Quantification of atherosclerosis by en face method, revealed a significant inhibition of atherosclerosis in Ad-APN (45% reduction, p < 0.01 vs. Ad-GFP). Furthermore, adiponectin expression substantially inhibited mRNA levels of inflammatory and atherogenic genes (ICAM-1, osteopontin, MCP-1 and CCR2) in the vessel wall. Interestingly, adiponectin also increased mRNA expression of the reverse cholesterol transport genes, ABCA1 and ABCG1, in the aorta. These data strongly support that concept that increasing plasma adiponectin levels may be an effective therapeutic strategy to inhibit AngIImediated vascular inflammation and acceleration of atherosclerosis.
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291 CORONARY ARTERY CALCIFICATION AND DIABETES MELLITUS: SEX-SPECIFIC IMPACT ON INCIDENCE OF CARDIOVASCULAR DISEASE − RESULTS OF THE HEINZ NIXDORF RECALL-STUDY 2 S. Moebus1 , S. Mohlenkamp ¨ , N. Dragano1 , U. Slomiany1 , S. Pechlivanis1 , 1 R. Erbel2 , K. Mann3 , K.-H. Jockel ¨ , Heinz Nixdorf Recall Study Group. 1 University Hospital, University of Duisburg-Essen, Institute for Medical Informatics, Biometry and Epidemiology, 2 University Hospital, University of Duisburg-Essen, West German Heart Center Essen, 3 University Hospital, University Duisburg-Essen, Department of Endocrinology and Division of Laboratory Research, Essen, Germany Aims: To examine the impact of coronary artery calcification (CAC), a specific marker of subclinical atherosclerosis, on cardiovascular disease (CVD) with regard to diabetes status (DM). Methods: We included 4,265 participants (aged 45−75 years) without overt CVD at baseline of the population-based Heinz Nixdorf Recall Study. Baseline examination included blood analyses and electron-beam tomography. DM is based on self-report and/or intake of diabetes medication. We calculated hazard ratios (HR) and 95%-confidence intervals (95%-CI) for events (myocardial infarction/stroke) with cox proportional hazards models adjusting for age, CAC (dichotomized by 75th age- and sex-specific percentile), waist circumference, smoking, lipid-lowering medication and blood pressure. Results: The mean follow-up time was 7.2 (±1.44) years, with 194 (128 men) events, of these 31 (18 men) with DM. Overall diabetic subjects had a 2.5fold higher risk for CVD. However, in women with a CAC above the 75th age- and sex-specific percentile we observed a 3-fold increased risk for CVD (ageadjusted HR 3.02; 95% CI: 1.36–6.70, full model: 3.61;1.59–8.21) for diabetic women compared to women without diabetes, whereas the HR attenuates to 1.99 (0.73–5.41, full model: 2.34;0.89–6.13) in diabetic women with less CAC. These high risks and differences are not observed in diabetic men with high CAC or with CAC to a lesser extent (full model: HR 1.28;0.64–2.54, respective 1.59;0.75–3.36). Conclusions: Our study confirms the high risk for CVD in subjects with Diabetes mellitus. Moreover, we found that diabetic women exposed to a high CAC are especially susceptible for CVD. 292 A POSSIBLE LINK BETWEEN ATHEROSCLEROTIC PLAQUE INFLAMMATION AND VISCERAL FAT INFLAMMATION S.E. Kim1 , E.J. Kim2 , J.S. Yeo3 , H.S. Seog2 . 1 Nuclear Medicine, 2 Cardiovascular Center, Korea University Guro Hospital, Seoul, 3 Nuclear Medicine, Dongkuk University Ilsan Hospital, Goyang-si, Republic of Korea Background: We hypothesized that active atherosclerotic change in the major arteries would accompany increased inflammation within visceral fat and it could be detected in humans using F-18 FDG PET/CT. Methods: We observed 44 consecutive subjects with cardiovascular disease. For all of them, an one-hour PET/CT was performed after injection of FDG (370–555 MBq). FDG uptake in the aorta or its major branches was evaluated visually and semiquantitatively. Maximal standard uptake values (SUV) of the highest regions of interest were calculated in the subcutaneous fat and visceral fat area, separately. Results: Significant FDG uptake in the arterial wall was noted in 21 patients (plaque positive; PP group), all of whom have experienced acute cardiovascular events (acute coronary syndrome or ischemic stroke) within a week. The other 23 patients (plaque negative; PN group) had chronic stable angina or asymptomatic carotid stenosis. Visceral fat SUV was significantly higher as compared to subcutaneous fat SUV (0.49±0.15 vs. 0.15±0.05, p < 0.001) in PP group, whereas there was no significant difference in PN group (0.18±.07 vs. 0.16±.03, p = 0.622). When we compared two groups, PP group showed higher visceral fat SUV than PN group (p < 0.001). In terms of subcutaneous fat SUV, the results were similar in two groups (p = 0.773). Conclusions: We demonstrated that atherosclerotic plaque inflammation was associated with increased inflammation within visceral fat. Further evaluation to determine whether metabolic activity of visceral adipose tissue is a marker or mediator of vascular inflammation is also needed. 293 UROKINASE PLASMINOGEN ACTIVATOR (UPA) AND ATHEROSCLEROSIS B. Fuhrman, J. Khateeb, Y. Lati, M. Aviram. Lipid Research Laboratory, Technion Faculty of Medicine/Rambam Medical Center, Haifa, Israel Background: The urokinase plasminogen activator (uPA) and its receptor uPAR, play a role in the pathogenesis of atherosclerosis. Increased plasma levels of uPA were shown to be associated with plaque rupture. The atherosclerotic plaque is characterized by cholesterol-loaded macrophage-foam cells and oxidized lipids. The goal of our project is to study in detail the functions of the uPA/uPAR system in atherosclerosis, in relation to macrophage-foam cell formation. Results: Our key findings show that uPA increases macrophage atherogenicity. We have shown that uPA increased cellular cholesterol accumulation, resulting from an increase in cellular cholesterol biosynthesis. This effect required the