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PO9-253 WALL SHEAR STRESS AND STRETCH DIFFERENTIALLY AFFECT AORTA REMODELING IN RATS
Poster Sessions PO9 Inflammation and atherosclerosis normal subjects during same period as patients with STEMI and were matched with those for age and sex. Venous blood samples were collected and serum levels of sCD40L were measured in the firsts 24 hours of STEMI at 09:00 h (light period) and 02:00 h (dark period). Results: Serum levels of sCD40L are shown in figure (bars represented the mean ± SD). This is the first report that shows diurnal variation of sCD40L serum levels in STEMI patients. Conclusions: These data provide news insights into the extremely complex inflammatory substrate involved in STEMI whereby large numbers of factors are overlapped in both its modulation and enhancement. For all this, the pro-thrombotic processes in the STEMI subjects seem to be, at least in part, carried out by circadian parameters. PO9-251
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Results: AAV-PDGF-A, -C and -D perfusion resulting in increased allograft inflammation, CAV and fibrosis. AAV-PDGF-B perfusion did not induce inflammation or arteriosclerotic changes but was accompanied with enhanced arteriogenesis in the cardiac allografts.
SOLUBLE CD40 LIGAND: INTERLEUKIN-10 RATIO PREDICTS IN-HOSPITAL ADVERSE EVENTS IN PATIENTS WITH MYOCARDIAL INFARCTION
Background: Soluble CD40 ligand (sCD40L) is a marker of inflammatory activity and also promotes thrombosis. Interleukin-10 (IL-10) has antiatherogenic properties in both experimental and clinical studies. We sought to compare the positive predictive values of sCD40L/IL-10 ratio, versus individual sCD40L, and IL-10 measurements regarding in-hospital events in 96 patients with ST-segment elevation myocardial infarction (STEMI). Methods: Serum sCD40L and IL-10 were measured at hospital admission in every patient. The composite of in-hospital death and heart failure represented the study end-point. Heart failure was defined as Killip class >1. Multivariable logistic regression analysis was performed to identify independent variables related to in-hospital events. Results: Thirty two patients (33%) achieved the study end-point and 64 (67%) had no adverse events during hospital admission. IL-10 levels (pg/ml) were lower (28.2 ± 9.8 vs 33.24 ± 11.3, p= 0.03) and sCD40L levels (pg/ml) higher (156.8 ± 54.2 vs 135.4 ± 38.70, p = 0.02) in patients with events compared to those without events. Significantly higher odd ratios were found for sCD40L/IL-10 ratio (OR = 2.10, 95% CI: 1.90 to 2.80, p = 0.01) compared to individual sCD40L (OR = 1.40, 95% CI: 0.90 to 2.20, p = 0.08) and 1/IL-10 (OR = 1.60, 95% CI: 1.10 to 2.73, p = 0.03) measurements. Conclusion: Our study showed that serum ratio of sCD40L/IL-10 is a better independent predictor of in-hospital adverse events than individual sCD40L and IL-10 measurements in patients with STEMI. PO9-252
PERSISTENT PDGF -A, -C, -D TRANSGENE EXPRESSION ACCELERATES DEVELOPMENT OF CARDIAC ALLOGRAFT VASCULOPATHY AND FIBROSIS BUT NOT -B INDUCES MYOCARDIAL ANGIOGENESIS
R. Tuuminen 1 , M.A.I. Keränen 1 , A.I. Nykänen 1 , R. Krebs 1 , K. Alitalo 2 , P.K. Koskinen 1 , K.B. Lemström 1 . 1 Transplantation Laboratory, University of Helsinki, Helsinki, Finland; 2 Biomedicum, University of Helsinki, Helsinki, Finland Background: In chronic rejection, parenchymal fibrosis and cardiac allograft vasculopathy (CAV) are the leading causes of graft loss after heart transplantation. During alloimmune reaction, expression of many growth factors, such as platelet-derived growth factor (PDGF), is induced. The PDGF family (AA, AB, BB, CC, DD) acts mainly on connective tissue cells and is the strongest mitogenic and chemotactic factor for fibroblasts and vascular smooth muscle cells. We characterized the roles of specific PDGF (A-D) isoforms during CAV development. Methods: Heterotopic cardiac transplantations were performed between Dark Agouti to Wistar Furth rats. Allograft coronary arteries were perfused with a recombinant adeno-associated virus (AAV) encoding PDGF (A-D) genes. Allografts were harvested at 100 days for morphometrical analysis of graft arteriosclerosis and fibrosis, immunohistochemical analysis of inflammation and angiogenesis.
Conclusions: Persistent PDGF -A, -C, and -D overexpression accelerates the development of CAV whereas PDGF-B may induce physiological arteriogenesis. Specific inhibition of PDGF-A, -C, -D may provide more targeted therapy for preventing and treating CAV and fibrosis after heart transplantation. PO9-253
WALL SHEAR STRESS AND STRETCH DIFFERENTIALLY AFFECT AORTA REMODELING IN RATS
C.M. Prado 1 , S.G. Ramos 1 , J.C. Alves-Filho 2 , J. Elias Jr 3 , F.Q. Cunha 2 , M.A. Rossi 1 . 1 Department of Pathology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil; 2 Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil; 3 Department of Internal Medicine, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil Background: Despite the systemic risk factors, atherosclerosis develops in regions of curvature, bifurcations and branching of vessels, suggesting the crucial localizing role of hemodynamic in plaque formation. The present evaluates the biological events in the proximal and distal areas of the arterial walls of rats in relation to a severe stenosis of the infra-abdominal aorta. Methods: Male Wistar were divided into an operated-stenosed group and a sham-operated group. The infra-diaphragmatic aorta from operated animals was constricted with a ligature of wool thread around a probe 0.94 mm, immediately removed. Results and conclusions: Constricted aortas showed two distinct adaptive remodeling responses. The first is remodeling in the hypertensive prestenotic segment with increased circumferential wall tension associated with normal tensile stress, laminar flow/normal wall shear stress. The remodeling in this segment is characterized by enlarged heterogeneous endothelial cells, elongated in the direction of the blood flow, diffusely distributed neointimal plaques, appearing as discrete bulging toward the vascular lumen, and medial thickening. Our findings suggest that increased circumferential wall tension due to hypertension play a pivotal role in the remodeling of the prestenotic segment through biomechanical effects on oxidative stress and increased TGF-β expression. The second is remodeling in the normotensive poststenotic segment with turbulent flow/low wall shear stress and normal circumferential wall tension and tensile stress. The remodeling in this segment is characterized by groups of endothelial cells with phenotypic alterations and focally distributed neointimal plaques, similar but many of them larger than those found in the prestenotic segments.
76th Congress of the European Atherosclerosis Society, June 10–13, 2007, Helsinki, Finland
POSTER SESSIONS
A. Dominguez-Rodriguez 1 , P. Abreu-Gonzalez 2 , M.J. Garcia-Gonzalez 1 , J.J. Ferrer-Hita 1 , S. Samimi-Fard 1 , J.C. Kaski 3 . 1 Department of Cardiology (Coronary Care Unit), University Hospital of Canarias, Tenerife, Spain; 2 Department of Physiology, University of La Laguna, School of Medicine, Tenerife, Spain; 3 Cardiovascular Biology Research Centre, Division of Cardiac and Vascular Sciences, St. George’s, University of London, London, UK
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Results: AAV-PDGF-A, -C and -D perfusion resulting in increased allograft inflammation, CAV and fibrosis. AAV-PDGF-B perfusion did not induce inflammation or arteriosclerotic changes but was accompanied with enhanced arteriogenesis in the cardiac allografts.
SOLUBLE CD40 LIGAND: INTERLEUKIN-10 RATIO PREDICTS IN-HOSPITAL ADVERSE EVENTS IN PATIENTS WITH MYOCARDIAL INFARCTION
Background: Soluble CD40 ligand (sCD40L) is a marker of inflammatory activity and also promotes thrombosis. Interleukin-10 (IL-10) has antiatherogenic properties in both experimental and clinical studies. We sought to compare the positive predictive values of sCD40L/IL-10 ratio, versus individual sCD40L, and IL-10 measurements regarding in-hospital events in 96 patients with ST-segment elevation myocardial infarction (STEMI). Methods: Serum sCD40L and IL-10 were measured at hospital admission in every patient. The composite of in-hospital death and heart failure represented the study end-point. Heart failure was defined as Killip class >1. Multivariable logistic regression analysis was performed to identify independent variables related to in-hospital events. Results: Thirty two patients (33%) achieved the study end-point and 64 (67%) had no adverse events during hospital admission. IL-10 levels (pg/ml) were lower (28.2 ± 9.8 vs 33.24 ± 11.3, p= 0.03) and sCD40L levels (pg/ml) higher (156.8 ± 54.2 vs 135.4 ± 38.70, p = 0.02) in patients with events compared to those without events. Significantly higher odd ratios were found for sCD40L/IL-10 ratio (OR = 2.10, 95% CI: 1.90 to 2.80, p = 0.01) compared to individual sCD40L (OR = 1.40, 95% CI: 0.90 to 2.20, p = 0.08) and 1/IL-10 (OR = 1.60, 95% CI: 1.10 to 2.73, p = 0.03) measurements. Conclusion: Our study showed that serum ratio of sCD40L/IL-10 is a better independent predictor of in-hospital adverse events than individual sCD40L and IL-10 measurements in patients with STEMI. PO9-252
PERSISTENT PDGF -A, -C, -D TRANSGENE EXPRESSION ACCELERATES DEVELOPMENT OF CARDIAC ALLOGRAFT VASCULOPATHY AND FIBROSIS BUT NOT -B INDUCES MYOCARDIAL ANGIOGENESIS
R. Tuuminen 1 , M.A.I. Keränen 1 , A.I. Nykänen 1 , R. Krebs 1 , K. Alitalo 2 , P.K. Koskinen 1 , K.B. Lemström 1 . 1 Transplantation Laboratory, University of Helsinki, Helsinki, Finland; 2 Biomedicum, University of Helsinki, Helsinki, Finland Background: In chronic rejection, parenchymal fibrosis and cardiac allograft vasculopathy (CAV) are the leading causes of graft loss after heart transplantation. During alloimmune reaction, expression of many growth factors, such as platelet-derived growth factor (PDGF), is induced. The PDGF family (AA, AB, BB, CC, DD) acts mainly on connective tissue cells and is the strongest mitogenic and chemotactic factor for fibroblasts and vascular smooth muscle cells. We characterized the roles of specific PDGF (A-D) isoforms during CAV development. Methods: Heterotopic cardiac transplantations were performed between Dark Agouti to Wistar Furth rats. Allograft coronary arteries were perfused with a recombinant adeno-associated virus (AAV) encoding PDGF (A-D) genes. Allografts were harvested at 100 days for morphometrical analysis of graft arteriosclerosis and fibrosis, immunohistochemical analysis of inflammation and angiogenesis.
Conclusions: Persistent PDGF -A, -C, and -D overexpression accelerates the development of CAV whereas PDGF-B may induce physiological arteriogenesis. Specific inhibition of PDGF-A, -C, -D may provide more targeted therapy for preventing and treating CAV and fibrosis after heart transplantation. PO9-253
WALL SHEAR STRESS AND STRETCH DIFFERENTIALLY AFFECT AORTA REMODELING IN RATS
C.M. Prado 1 , S.G. Ramos 1 , J.C. Alves-Filho 2 , J. Elias Jr 3 , F.Q. Cunha 2 , M.A. Rossi 1 . 1 Department of Pathology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil; 2 Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil; 3 Department of Internal Medicine, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil Background: Despite the systemic risk factors, atherosclerosis develops in regions of curvature, bifurcations and branching of vessels, suggesting the crucial localizing role of hemodynamic in plaque formation. The present evaluates the biological events in the proximal and distal areas of the arterial walls of rats in relation to a severe stenosis of the infra-abdominal aorta. Methods: Male Wistar were divided into an operated-stenosed group and a sham-operated group. The infra-diaphragmatic aorta from operated animals was constricted with a ligature of wool thread around a probe 0.94 mm, immediately removed. Results and conclusions: Constricted aortas showed two distinct adaptive remodeling responses. The first is remodeling in the hypertensive prestenotic segment with increased circumferential wall tension associated with normal tensile stress, laminar flow/normal wall shear stress. The remodeling in this segment is characterized by enlarged heterogeneous endothelial cells, elongated in the direction of the blood flow, diffusely distributed neointimal plaques, appearing as discrete bulging toward the vascular lumen, and medial thickening. Our findings suggest that increased circumferential wall tension due to hypertension play a pivotal role in the remodeling of the prestenotic segment through biomechanical effects on oxidative stress and increased TGF-β expression. The second is remodeling in the normotensive poststenotic segment with turbulent flow/low wall shear stress and normal circumferential wall tension and tensile stress. The remodeling in this segment is characterized by groups of endothelial cells with phenotypic alterations and focally distributed neointimal plaques, similar but many of them larger than those found in the prestenotic segments.
76th Congress of the European Atherosclerosis Society, June 10–13, 2007, Helsinki, Finland
POSTER SESSIONS
A. Dominguez-Rodriguez 1 , P. Abreu-Gonzalez 2 , M.J. Garcia-Gonzalez 1 , J.J. Ferrer-Hita 1 , S. Samimi-Fard 1 , J.C. Kaski 3 . 1 Department of Cardiology (Coronary Care Unit), University Hospital of Canarias, Tenerife, Spain; 2 Department of Physiology, University of La Laguna, School of Medicine, Tenerife, Spain; 3 Cardiovascular Biology Research Centre, Division of Cardiac and Vascular Sciences, St. George’s, University of London, London, UK