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EXPRESSION OF COLLAGEN BINDING DISCOIDIN DOMAIN RECEPTOR 1 IN HUMAN ATHEROSCLEROSIS AND CARDIAC ALLOGRAFT VASCULOPATHY
S272
(MnTMPyP, PEG-catalase), an inhibitor of either Src kinase (PP2) or PI3-kinase (wortmannin), and intracellular copper chelating agents (neocuproine, tetrathiomolybdate) and were insensitive to cyclooxygenase inhibition (indomethacin), chelating agents for iron (desferroxamine), zinc (histidine), extracellular copper (bathocuproine). EPA:DHA 6:1 induced phosphorylation of Src, Akt and eNOS at Ser 1177; these effects were inhibited by MnTMPyP and PEG-catalase. EPA:DHA 6:1 induced the endothelial formation of ROS in coronary artery sections, this effect was inhibited by MnTMPyP, PEG-catalase, and intracellular copper chelating agents. EPA:DHA 6:1 causes endothelium-dependent NOmediated relaxations in coronary artery rings, and this effect involves an intracellular copper-dependent event triggering the redox-sensitive PI3-kinase/Akt pathway to activate eNOS by phosphorylation at Ser 1177. 421 EXPRESSION OF COLLAGEN BINDING DISCOIDIN DOMAIN RECEPTOR 1 IN HUMAN ATHEROSCLEROSIS AND CARDIAC ALLOGRAFT VASCULOPATHY C Franco, Z Luo, MP Bendeck, B McManus Vancouver, British Columbia BACKGROUND:
The extracellular matrix (ECM) microenvironment of the atherosclerotic plaque is abundant and highly dynamic. Signaling through specific matrix receptors influences the behavior of SMCs and macrophages during plaque development and can have distinct consequences on lesion volume, cellular composition and vulnerability to rupture. The discoidin domain receptors (DDR) are a unique family of cell surface receptor tyrosine kinases that bind to triple helical collagens. Signaling through DDR1 plays a central role during atherogenesis. Atherosclerosis prone mice deficient in DDR1 developed less atherosclerosis, and lesions were smaller, macrophage poor and had robust fibrous caps. However, data on the expression of DDR1 in human atherosclerosis and cardiac allograft vasculopathy (CAV), an accelerated form of atherogenesis occurring in cardiac transplant patients, is lacking. We aimed to identify and characterize the expression of DDR1 in human atherosclerosis and CAV. METHODS: Serial sections from human atherosclerosis and CAV were stained with polyclonal antibodies to the C terminus of DDR1 using avidin-biotin based immunohistochemical techniques. Sections were scored by a blinded observer as to the intensity (0-5) of staining in the media, intima and fibrous cap and lesion characteristics. RESULTS: DDR1 was highly expressed in human atherosclerosis. Staining was localized in SMCs in the media and fibrous cap with occasional staining of plaque macrophages. Abundant staining for DDR1 was also noted in CAV lesions and appeared to be localized in lesion core sites consistent with leukocytes. CONCLUSION: DDR1 is highly expressed in human atherosclerosis and CAV, both novel observations. Given the
Canadian Journal of Cardiology Volume 30 2014
evidence supporting a key functional role for DDR1 in mouse models of atherogenesis further studies aimed at pharmacologic inhibition of DDR1 in atherosclerosis prone or cardiac transplant populations may be warranted.
422 ANALYSIS OF THE BLEEDING AND THROMBOEMBOLIC RISK WITH CONCOMITANT USE OF ANTIPLATELET TREATMENT IN THE AMPLIFY TRIAL A Cohen, G Agnelli, HR Buller, S Chaudhuri, AS Gallus, GE Raskob, P Sanders, J Thompson, JI Weitz Hamilton, Ontario BACKGROUND:
The AMPLIFY trial compared apixaban with conventional anticoagulation consisting of enoxaparin followed by warfarin in patients with acute venous thromboembolism (VTE). In this analysis, we examined the impact of concomitant antiplatelet therapy on the risk of major bleeding, the primary safety endpoint, and recurrent VTE or VTE-related mortality, the primary efficacy endpoint, in patients enrolled in the trial. METHODS: Patients who reported concomitant use of antiplatelet treatment at any time during the clinical trial were identified, and rates for the adjudicated primary safety and efficacy endpoints in these patients were compared with those in patients not taking antiplatelet drugs. RESULTS: Of the 2676 patients treated with apixaban and 2689 treated with conventional therapy, 402 (15%) and 411 (15%), respectively, reported concomitant antiplatelet drug use; primarily with aspirin. In patients taking concomitant antiplatelet therapy, major bleeds occurred in 5 patients in the apixaban group and in 17 patients in the conventional treatment group (relative risk, 0.30; 95% confidence interval, 0.11 to 0.81). In patients randomized to apixaban, the rate of major bleeding in those taking concomitant antiplatelet drugs was 3-fold higher than in those not taking these agents (1.2% and 0.4%, respectively), whereas in those randomized to conventional treatment, the rate of major bleeding in patients taking concomitant antiplatelet drugs was 2.9-fold higher than in those not taking these agents (4.1% and 1.4%, respectively). Rates of VTE or VTE-related death were similar in those taking or not taking concomitant antiplatelet drugs in both the apixaban group (3.6% and 2.0%, respectively) and the warfarin group (3.0% and 2.6%, respectively). CONCLUSION: Although concomitant administration of antiplatelet drugs produced a proportionally similar increase in the risk of major bleeding in patients randomized to apixaban or conventional treatment, there were fewer major bleeds with apixaban. Thus, the overall safety benefit of apixaban over conventional treatment was maintained in patients taking concomitant antiplatelet drugs. Concomitant administration of these drugs did not appear to influence the rates of VTE or VTE-related death. BMS, Pfizer
(MnTMPyP, PEG-catalase), an inhibitor of either Src kinase (PP2) or PI3-kinase (wortmannin), and intracellular copper chelating agents (neocuproine, tetrathiomolybdate) and were insensitive to cyclooxygenase inhibition (indomethacin), chelating agents for iron (desferroxamine), zinc (histidine), extracellular copper (bathocuproine). EPA:DHA 6:1 induced phosphorylation of Src, Akt and eNOS at Ser 1177; these effects were inhibited by MnTMPyP and PEG-catalase. EPA:DHA 6:1 induced the endothelial formation of ROS in coronary artery sections, this effect was inhibited by MnTMPyP, PEG-catalase, and intracellular copper chelating agents. EPA:DHA 6:1 causes endothelium-dependent NOmediated relaxations in coronary artery rings, and this effect involves an intracellular copper-dependent event triggering the redox-sensitive PI3-kinase/Akt pathway to activate eNOS by phosphorylation at Ser 1177. 421 EXPRESSION OF COLLAGEN BINDING DISCOIDIN DOMAIN RECEPTOR 1 IN HUMAN ATHEROSCLEROSIS AND CARDIAC ALLOGRAFT VASCULOPATHY C Franco, Z Luo, MP Bendeck, B McManus Vancouver, British Columbia BACKGROUND:
The extracellular matrix (ECM) microenvironment of the atherosclerotic plaque is abundant and highly dynamic. Signaling through specific matrix receptors influences the behavior of SMCs and macrophages during plaque development and can have distinct consequences on lesion volume, cellular composition and vulnerability to rupture. The discoidin domain receptors (DDR) are a unique family of cell surface receptor tyrosine kinases that bind to triple helical collagens. Signaling through DDR1 plays a central role during atherogenesis. Atherosclerosis prone mice deficient in DDR1 developed less atherosclerosis, and lesions were smaller, macrophage poor and had robust fibrous caps. However, data on the expression of DDR1 in human atherosclerosis and cardiac allograft vasculopathy (CAV), an accelerated form of atherogenesis occurring in cardiac transplant patients, is lacking. We aimed to identify and characterize the expression of DDR1 in human atherosclerosis and CAV. METHODS: Serial sections from human atherosclerosis and CAV were stained with polyclonal antibodies to the C terminus of DDR1 using avidin-biotin based immunohistochemical techniques. Sections were scored by a blinded observer as to the intensity (0-5) of staining in the media, intima and fibrous cap and lesion characteristics. RESULTS: DDR1 was highly expressed in human atherosclerosis. Staining was localized in SMCs in the media and fibrous cap with occasional staining of plaque macrophages. Abundant staining for DDR1 was also noted in CAV lesions and appeared to be localized in lesion core sites consistent with leukocytes. CONCLUSION: DDR1 is highly expressed in human atherosclerosis and CAV, both novel observations. Given the
Canadian Journal of Cardiology Volume 30 2014
evidence supporting a key functional role for DDR1 in mouse models of atherogenesis further studies aimed at pharmacologic inhibition of DDR1 in atherosclerosis prone or cardiac transplant populations may be warranted.
422 ANALYSIS OF THE BLEEDING AND THROMBOEMBOLIC RISK WITH CONCOMITANT USE OF ANTIPLATELET TREATMENT IN THE AMPLIFY TRIAL A Cohen, G Agnelli, HR Buller, S Chaudhuri, AS Gallus, GE Raskob, P Sanders, J Thompson, JI Weitz Hamilton, Ontario BACKGROUND:
The AMPLIFY trial compared apixaban with conventional anticoagulation consisting of enoxaparin followed by warfarin in patients with acute venous thromboembolism (VTE). In this analysis, we examined the impact of concomitant antiplatelet therapy on the risk of major bleeding, the primary safety endpoint, and recurrent VTE or VTE-related mortality, the primary efficacy endpoint, in patients enrolled in the trial. METHODS: Patients who reported concomitant use of antiplatelet treatment at any time during the clinical trial were identified, and rates for the adjudicated primary safety and efficacy endpoints in these patients were compared with those in patients not taking antiplatelet drugs. RESULTS: Of the 2676 patients treated with apixaban and 2689 treated with conventional therapy, 402 (15%) and 411 (15%), respectively, reported concomitant antiplatelet drug use; primarily with aspirin. In patients taking concomitant antiplatelet therapy, major bleeds occurred in 5 patients in the apixaban group and in 17 patients in the conventional treatment group (relative risk, 0.30; 95% confidence interval, 0.11 to 0.81). In patients randomized to apixaban, the rate of major bleeding in those taking concomitant antiplatelet drugs was 3-fold higher than in those not taking these agents (1.2% and 0.4%, respectively), whereas in those randomized to conventional treatment, the rate of major bleeding in patients taking concomitant antiplatelet drugs was 2.9-fold higher than in those not taking these agents (4.1% and 1.4%, respectively). Rates of VTE or VTE-related death were similar in those taking or not taking concomitant antiplatelet drugs in both the apixaban group (3.6% and 2.0%, respectively) and the warfarin group (3.0% and 2.6%, respectively). CONCLUSION: Although concomitant administration of antiplatelet drugs produced a proportionally similar increase in the risk of major bleeding in patients randomized to apixaban or conventional treatment, there were fewer major bleeds with apixaban. Thus, the overall safety benefit of apixaban over conventional treatment was maintained in patients taking concomitant antiplatelet drugs. Concomitant administration of these drugs did not appear to influence the rates of VTE or VTE-related death. BMS, Pfizer