- Email: [email protected]
Platelet large cell-ratio and cardiovascular outcomes in acute myocardial infarction – A prospective cohort study
Abstracts / Atherosclerosis 241 (2015) e1ee31
exhibit significant atherosclerosis, effects that are attenuated by AVE0991 (plaque area in untreated vs treated ApoE-/- mice: 6.20±1.05% vs 2.45±0.82%; p<0.05). In perivascular adipose tissue macrophages infiltration was greater in ApoE-/- mice vs controls (265±39cells/mg vs 431±94cells/mg; p<0.05) at 16 weeks and (305±36cells/mg vs 414±44cells/mg; p<0.05) at 24 weeks. This was prevented by AVE0991 (233±44cells/mg; p<0.05 vs ApoE-/-) at 16 weeks and (267±17cells/mg; p¼0.08 vs ApoE-/-) at 24 weeks. To explore the translational aspect of these findings to humans, we studied TNF-a (20ng/ml) estimulated human THP-1 monocytes, pretreated with AVE0991 (10mM). AVE0991 preincubation abolished TNF-a induced increase in mRNA expression of chemokine MCP-1 (114±12.3 vs 73±4.7 fold change to control; p<0.05) and IL-8 (72±4.1 vs 53±8.8 fold change to control; p<0.05) and IL-1b (72±43 vs 16±9.5 fold change to control; p<0.05). CONCLUSION: AVE0991, the Ang1-7 mimetic, inhibited atherosclerotic plaque formation and macrophages infiltration into perivascular tissue. This may occur in part, through reduced monocyte production of IL-1b and MCP-1.
EAS-0907. RGS-1 REGULATES LEUKOCYTE TRAFFICKING IN ATHEROSCLEROSIS AND AORTIC ANEURYSM FORMATION THROUGH ALTERED CHEMOKINE SIGNALLING J. Patel 1, E. McNeill 1, G. Douglas 1, A. Hale 1, J. De Bono 1, R. Lee 1, A. D. Regan-Komito 2, E. Stylianou 3, D. Greaves 2, K. Iqbal 2, Channon 1. 1 Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom; 2 Pathology, University of Oxford, Oxford, United Kingdom; 3 Jenner Institute, University of Oxford, Oxford, United Kingdom The regulation of macrophage recruitment and retention into the artery wall is critical in the progression of atherosclerosis and aortic aneurysms. This can be mediated by chemokine activation of multiple G-protein coupled receptors. The Regulator of G-Protein Signaling-1 (RGS1) acts to deactivate the intracellular response to sustained chemokine stimulation and is up-regulated with atherosclerosis and monocyte activation. Rgs1-/-ApoE-/- macrophages have significantly enhanced migratory responses to atherogenic chemokines and have impaired desensitization to chemokine re-stimulation. In vivo, atherosclerosis is attenuated in early lesions of Rgs1-/-ApoE-/- mice which is accompanied by fewer macrophages. Rgs1-/-ApoE-/- mice are protected from Angiotensin-II induced aneurysm rupture and have significantly fewer macrophages in aortas than ApoE-/- mice after Angiotensin-II infusion. Following bone marrow transplantation, recipient mice receiving ApoE-/bone marrow were more susceptible to aortic aneurysm rupture, indicating bone marrow-derived RGS1 is required for aneurysm rupture. Furthermore, Angiotensin-II treatment increased systolic blood pressure to a greater extent in Rgs1-/-ApoE-/- mice suggesting aneurysm formation is independent of Angiotensin-II induced hypertension.To gain insight into the mechanism by which RGS1 regulates trafficking, we selectively labelled inflammatory monocytes to track their movement into aortas following Angiotensin-II infusion. We found an accumulation of labelled leukocytes in the aortas of ApoE-/- mice from day 3 to day 5 but not in Rgs1-/-ApoE-/- mice indicating RGS1 as a regulator of macrophage accumulation in aortic aneurysms. These findings identify a novel role for RGS1 in leukocyte function and vascular inflammation and identifies RGS1 as a potential target for the treatment of cardiovascular disease.
EAS-0920. MICRORNA BIOGENESIS IN MACROPHAGES MITOCHONDRIAL ENERGY METABOLISM AND ATHEROSCLEROSIS e PRESENTATION CANCELLED
REGULATES PREVENTS
n-Campos 1, F. Erhard 2, K. Heyll 1, R. Zimmer 2, A. Y. Wei 1, J. Corbala €t (LMU) München, Institut für Schober 1. 1 Ludwig-Maximilians-Universita Prophylaxe und Epidemiologie der Kreislaufkrankheiten, München,
e11
€t (LMU) München, Institut für Germany; 2 Ludwig-Maximilians-Universita Informatik, München, Germany Aim: Macrophages are the main cell type in atherosclerotic lesions and can polarize into different functional phenotypes with pro- and anti-inflammatory roles. In contrast to inflammatory macrophages, the anti-inflammatory phenotype is mediated by increased mitochondrial respiration. We aim to determine the role of microRNA biogenesis in the metabolic reprogramming during macrophage polarization and the effect on atherosclerosis. Methods and results: Dicer deletion resulted in down-regulation of 137 miRNAs in bone marrow-derived macrophages (BMDMs) from myeloid cell-specific Dicer knockout mice (LysMCre-Dicer/) determined by microRNA qPCR array. The pro-inflammatory genes Il1b and Nos2 were increased, whereas the anti-inflammatory markers Mrc1 and Fizz1 were down-regulated in LysMCre-Dicer/ BMDMs. Accordingly, the mitochondrial oxygen-consumption rate (OCR) determined by extracellular flux analysis and the expression of genes involved in mitochondrial respiration and fatty acid oxidation were reduced in LysMCre-Dicer/ BMDMs. Argonaute2 (Ago2)-RIP-Chip analysis revealed that Dicer deletion resulted in reduced enrichment of 97 up-regulated genes in LysMCreDicer/ BMDMs with Ago2 protein that is required for RNA-induced silencing complexes. Among these genes, the highest number of predicted highly conserved binding sites of the down-regulated miRNAs was found in the 3’UTR of ligand-dependent co-repressor (Lcor). Silencing Lcor in macrophages up-regulated genes involved in mitochondrial respiration. In vivo, atherosclerosis was enhanced in LysMCre-Dicer/Apoe/ mice compared to the control LysMCre-Dicer+/+Apoe/ mice fed a high cholesterol diet for 12 weeks (n ¼ 13-14, P < 0.05). Conclusion: These data indicate that microRNA biogenesis promotes mitochondrial respiration and inhibits pro-inflammatory activation in macrophages, and may thus limit the development of atherosclerosis. Risk factors & biomarkers young investigator communication 5 EAS-0195. PLATELET LARGE CELL-RATIO AND CARDIOVASCULAR OUTCOMES IN ACUTE MYOCARDIAL INFARCTION e A PROSPECTIVE COHORT STUDY M.P. Ranjith, M.N. krishnan. Cardiology, Government Medical College Kozhikode, Kozhikode, India Background: Larger platelets have been associated with enhanced reactivity, increased cardiovascular risk, and higher rates of complications. The plateletelarger cell ratio (P-LCR) identifies the largest-sized fraction of platelets, the proportion potentially more closely related to thrombotic events. However, studies looking into the utility of P-LCR for prognostication of patients after myocardial infarction (MI) are few. The aim of this study was to explore the correlation of P-LCR at the time of presentation of MI with major adverse cardiac events at one year follow up. Methods: Study included consecutive patients with MI admitted to a tertiary care hospital during a period of 1year. P-LCR was done at admission. Patients were followed-up for a period of 1year primary composite outcome of death; stroke and nonfatal MI. Patients were classified according to baseline P-LCR level. Value more than median (19.5fl) was defined as high P-LCR. Results: A total of 1206 MI patients, including 934 males (77.4%) and 272 females (22.6%) were studied. The mean age of the study population was 55.93±11.07 years. At 1year follow up 30.2% in high P-LCR group and 13.5% in low P-LCR group had a composite of adverse cardiac events (RR¼2.76, 95% CI: 2.01-3.79; p<0.001). Mortality alone was also more in high P-LCR group (RR¼3.25, 95%CI: 1.91-5.54; p<0.001). Logistic regression analysis also showed significant association of primary outcome with high P-LCR (OR¼2.01, 95%CI: 1.43-2.81;p<0.001). Conclusion: Elevated P-LCR is associated with a worse outcome in patients with acute MI.
exhibit significant atherosclerosis, effects that are attenuated by AVE0991 (plaque area in untreated vs treated ApoE-/- mice: 6.20±1.05% vs 2.45±0.82%; p<0.05). In perivascular adipose tissue macrophages infiltration was greater in ApoE-/- mice vs controls (265±39cells/mg vs 431±94cells/mg; p<0.05) at 16 weeks and (305±36cells/mg vs 414±44cells/mg; p<0.05) at 24 weeks. This was prevented by AVE0991 (233±44cells/mg; p<0.05 vs ApoE-/-) at 16 weeks and (267±17cells/mg; p¼0.08 vs ApoE-/-) at 24 weeks. To explore the translational aspect of these findings to humans, we studied TNF-a (20ng/ml) estimulated human THP-1 monocytes, pretreated with AVE0991 (10mM). AVE0991 preincubation abolished TNF-a induced increase in mRNA expression of chemokine MCP-1 (114±12.3 vs 73±4.7 fold change to control; p<0.05) and IL-8 (72±4.1 vs 53±8.8 fold change to control; p<0.05) and IL-1b (72±43 vs 16±9.5 fold change to control; p<0.05). CONCLUSION: AVE0991, the Ang1-7 mimetic, inhibited atherosclerotic plaque formation and macrophages infiltration into perivascular tissue. This may occur in part, through reduced monocyte production of IL-1b and MCP-1.
EAS-0907. RGS-1 REGULATES LEUKOCYTE TRAFFICKING IN ATHEROSCLEROSIS AND AORTIC ANEURYSM FORMATION THROUGH ALTERED CHEMOKINE SIGNALLING J. Patel 1, E. McNeill 1, G. Douglas 1, A. Hale 1, J. De Bono 1, R. Lee 1, A. D. Regan-Komito 2, E. Stylianou 3, D. Greaves 2, K. Iqbal 2, Channon 1. 1 Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom; 2 Pathology, University of Oxford, Oxford, United Kingdom; 3 Jenner Institute, University of Oxford, Oxford, United Kingdom The regulation of macrophage recruitment and retention into the artery wall is critical in the progression of atherosclerosis and aortic aneurysms. This can be mediated by chemokine activation of multiple G-protein coupled receptors. The Regulator of G-Protein Signaling-1 (RGS1) acts to deactivate the intracellular response to sustained chemokine stimulation and is up-regulated with atherosclerosis and monocyte activation. Rgs1-/-ApoE-/- macrophages have significantly enhanced migratory responses to atherogenic chemokines and have impaired desensitization to chemokine re-stimulation. In vivo, atherosclerosis is attenuated in early lesions of Rgs1-/-ApoE-/- mice which is accompanied by fewer macrophages. Rgs1-/-ApoE-/- mice are protected from Angiotensin-II induced aneurysm rupture and have significantly fewer macrophages in aortas than ApoE-/- mice after Angiotensin-II infusion. Following bone marrow transplantation, recipient mice receiving ApoE-/bone marrow were more susceptible to aortic aneurysm rupture, indicating bone marrow-derived RGS1 is required for aneurysm rupture. Furthermore, Angiotensin-II treatment increased systolic blood pressure to a greater extent in Rgs1-/-ApoE-/- mice suggesting aneurysm formation is independent of Angiotensin-II induced hypertension.To gain insight into the mechanism by which RGS1 regulates trafficking, we selectively labelled inflammatory monocytes to track their movement into aortas following Angiotensin-II infusion. We found an accumulation of labelled leukocytes in the aortas of ApoE-/- mice from day 3 to day 5 but not in Rgs1-/-ApoE-/- mice indicating RGS1 as a regulator of macrophage accumulation in aortic aneurysms. These findings identify a novel role for RGS1 in leukocyte function and vascular inflammation and identifies RGS1 as a potential target for the treatment of cardiovascular disease.
EAS-0920. MICRORNA BIOGENESIS IN MACROPHAGES MITOCHONDRIAL ENERGY METABOLISM AND ATHEROSCLEROSIS e PRESENTATION CANCELLED
REGULATES PREVENTS
n-Campos 1, F. Erhard 2, K. Heyll 1, R. Zimmer 2, A. Y. Wei 1, J. Corbala €t (LMU) München, Institut für Schober 1. 1 Ludwig-Maximilians-Universita Prophylaxe und Epidemiologie der Kreislaufkrankheiten, München,
e11
€t (LMU) München, Institut für Germany; 2 Ludwig-Maximilians-Universita Informatik, München, Germany Aim: Macrophages are the main cell type in atherosclerotic lesions and can polarize into different functional phenotypes with pro- and anti-inflammatory roles. In contrast to inflammatory macrophages, the anti-inflammatory phenotype is mediated by increased mitochondrial respiration. We aim to determine the role of microRNA biogenesis in the metabolic reprogramming during macrophage polarization and the effect on atherosclerosis. Methods and results: Dicer deletion resulted in down-regulation of 137 miRNAs in bone marrow-derived macrophages (BMDMs) from myeloid cell-specific Dicer knockout mice (LysMCre-Dicer/) determined by microRNA qPCR array. The pro-inflammatory genes Il1b and Nos2 were increased, whereas the anti-inflammatory markers Mrc1 and Fizz1 were down-regulated in LysMCre-Dicer/ BMDMs. Accordingly, the mitochondrial oxygen-consumption rate (OCR) determined by extracellular flux analysis and the expression of genes involved in mitochondrial respiration and fatty acid oxidation were reduced in LysMCre-Dicer/ BMDMs. Argonaute2 (Ago2)-RIP-Chip analysis revealed that Dicer deletion resulted in reduced enrichment of 97 up-regulated genes in LysMCreDicer/ BMDMs with Ago2 protein that is required for RNA-induced silencing complexes. Among these genes, the highest number of predicted highly conserved binding sites of the down-regulated miRNAs was found in the 3’UTR of ligand-dependent co-repressor (Lcor). Silencing Lcor in macrophages up-regulated genes involved in mitochondrial respiration. In vivo, atherosclerosis was enhanced in LysMCre-Dicer/Apoe/ mice compared to the control LysMCre-Dicer+/+Apoe/ mice fed a high cholesterol diet for 12 weeks (n ¼ 13-14, P < 0.05). Conclusion: These data indicate that microRNA biogenesis promotes mitochondrial respiration and inhibits pro-inflammatory activation in macrophages, and may thus limit the development of atherosclerosis. Risk factors & biomarkers young investigator communication 5 EAS-0195. PLATELET LARGE CELL-RATIO AND CARDIOVASCULAR OUTCOMES IN ACUTE MYOCARDIAL INFARCTION e A PROSPECTIVE COHORT STUDY M.P. Ranjith, M.N. krishnan. Cardiology, Government Medical College Kozhikode, Kozhikode, India Background: Larger platelets have been associated with enhanced reactivity, increased cardiovascular risk, and higher rates of complications. The plateletelarger cell ratio (P-LCR) identifies the largest-sized fraction of platelets, the proportion potentially more closely related to thrombotic events. However, studies looking into the utility of P-LCR for prognostication of patients after myocardial infarction (MI) are few. The aim of this study was to explore the correlation of P-LCR at the time of presentation of MI with major adverse cardiac events at one year follow up. Methods: Study included consecutive patients with MI admitted to a tertiary care hospital during a period of 1year. P-LCR was done at admission. Patients were followed-up for a period of 1year primary composite outcome of death; stroke and nonfatal MI. Patients were classified according to baseline P-LCR level. Value more than median (19.5fl) was defined as high P-LCR. Results: A total of 1206 MI patients, including 934 males (77.4%) and 272 females (22.6%) were studied. The mean age of the study population was 55.93±11.07 years. At 1year follow up 30.2% in high P-LCR group and 13.5% in low P-LCR group had a composite of adverse cardiac events (RR¼2.76, 95% CI: 2.01-3.79; p<0.001). Mortality alone was also more in high P-LCR group (RR¼3.25, 95%CI: 1.91-5.54; p<0.001). Logistic regression analysis also showed significant association of primary outcome with high P-LCR (OR¼2.01, 95%CI: 1.43-2.81;p<0.001). Conclusion: Elevated P-LCR is associated with a worse outcome in patients with acute MI.