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INHALED MILRINONE ADMINISTERED IN PATIENTS UNDERGOING CARDIAC SURGERY
Abstracts
tissue. In vitro, rhPRG4 completely prevented adhesion of cardiac myofibroblasts and attenuated TGF-b1 mediated human cardiac myofibroblast activation.
S227 CONCLUSION:
After inhaled milrinone, mAP/mPAP ratio appears a promising PD marker. Both magnitude of peak response (DRmax-R0) and CPB duration would appear as predictors of DSB.
282 A NOVEL TNF-a INDUCED SECRETOME THERAPY FOR MYOCARDIAL PROTECTION AND REPAIR K Selvasandran, P Jaiswal, R Jurakhan, G Makhoul, L Li, K Ridwan, R Cecere Montréal, Québec BACKGROUND:
281 INHALED MILRINONE ADMINISTERED IN PATIENTS UNDERGOING CARDIAC SURGERY AQ Nguyen, AY Denault, Y Théorêt, F Varin Montréal, Québec BACKGROUND:
Inhaled milrinone before cardiopulmonary bypass (CPB) has been proposed to prevent difficult separation from CPB (DSB) in cardiac patients with pulmonary hypertension. Mean arterial pressure to mean pulmonary arterial pressure ratio (mAP/mPAP) was identified as the best predictor of perioperative complications. We investigated the pharmacokinetic/pharmacodynamic (PK/PD) relationship of inhaled milrinone in these patients using this ratio (R) as a PD marker. METHODS: Before initiation of CPB in 28 consenting patients, milrinone (5 mg) was nebulized and plasma concentrations measured up to 10 hours after inhalation. Baseline (R0), peak (Rmax), and post-CPB (Rpost-CPB) ratios as well as magnitude of peak response (DRmax-R0) were measured. Milrinone concentration-effect relationship was characterized during inhalation by correlating individual area under effect-time (AUEC) and area under plasma concentration-time (AUC) curves. Potential relationships between PD drivers and the clinical endpoint DSB were explored. -1 RESULTS: Milrinone peak concentrations (41-189 ng ml ) and DRmax-R0 (-0.12-1.5; -5-65%) were observed at the end of inhalation (10-30 min). Mean PK estimates agreed with intravenous milrinone published data. Paired comparisons between R0 and Rmax or Rpost-CPB were statistically different (P <0.001) and DRmax-R0 found associated with absence of DSB (P¼0.009). During inhalation, individual AUEC directly correlated with AUC (P¼0.045); significance increased after exclusion of non-responders (P¼0.024). Individual AUEC correlated with DRmax-R0 (P¼0.001). Both DRmax-R0(P¼0.009) and CPB duration (P <0.001) were identified as predictors of DSB.
Bone-marrow mesenchymal stem cells (BMMSC) have been suggested to play a crucial role in promoting the healing process in ischemic hearts post myocardial infarction (MI). However, poor viability and retention of transplanted cells in the harsh microenvironment remains as an obstacle. The paracrine hypothesis suggests that BM-MSCs secrete paracrine factors that work together to manipulate the microenvironment to trigger angiogenesis and anti-apoptotic properties at the infarct site. Tumour necrosis factor-a (TNFa) is a pleiotropic pro-inflammatory cytokine present in ischemic cardiac regions, but the specific roles it plays in cardioprotection remains unknown. The current study aims to understand the regulatory and cardioprotective effects of TNF-a on rat BM-MSCs (rBM-MSC) which may, initiate and sustain the process of cardiac repair post MI. METHODS: Secretome from rBM-MSC cultures treated/untreated with either conditioned rat cardiomyocyte medium (rCM), TNF-a, and/or normoxia/hypoxia in various combinations were collected. Immunocytochemistry, western blot analyses, and trans-well cell migration assays were conducted. In vivo, echocardiography was performed on induced infarcted Lewis rats at 3 weeks following their treatment with a control (rCM, hypoxia, and BM-MSCs) or TNF-a hypoxia-induced secretome. Histological analyses were conducted. ImageJ and Prism were used for statistical analysis. RESULTS: Immunocytochemistry and western blots confirmed the presence of TNF-Receptors 1 and 2 (TNFR1&2) on rBM-MSCs. Western blot analyses on rBM-MSC lysates treated with TNF-a and hypoxia showed an expression of TGF-b, FGF-2 & 7, Ang-1, VEGF-1, and Myogenin. The TNF-a hypoxia-induced secretome exhibited chemotactic properties. In vivo, the TNF-a hypoxia-induced secretome treated rats had a higher left ventricular fractional shortening (LVFS) than the control, while trichrome staining revealed a decrease in the size of infarct. Immunohistochemistry (IHC) revealed increased expression of CD31 and Ki67 near the infarct in TNF-a hypoxia-induced secretome treated rats. CONCLUSION: The presence of TNFR1&2 on rBM-MSCs indicate that TNF-a is able to bind to rBM-MSCs and initiate cell survival pathways. Furthermore, TNF-a in hypoxic conditions express proteins such as TGF-b, FGF-2, FGF-7, Ang1, VEGF-1, and myogenin in rBM-MSCs that either
tissue. In vitro, rhPRG4 completely prevented adhesion of cardiac myofibroblasts and attenuated TGF-b1 mediated human cardiac myofibroblast activation.
S227 CONCLUSION:
After inhaled milrinone, mAP/mPAP ratio appears a promising PD marker. Both magnitude of peak response (DRmax-R0) and CPB duration would appear as predictors of DSB.
282 A NOVEL TNF-a INDUCED SECRETOME THERAPY FOR MYOCARDIAL PROTECTION AND REPAIR K Selvasandran, P Jaiswal, R Jurakhan, G Makhoul, L Li, K Ridwan, R Cecere Montréal, Québec BACKGROUND:
281 INHALED MILRINONE ADMINISTERED IN PATIENTS UNDERGOING CARDIAC SURGERY AQ Nguyen, AY Denault, Y Théorêt, F Varin Montréal, Québec BACKGROUND:
Inhaled milrinone before cardiopulmonary bypass (CPB) has been proposed to prevent difficult separation from CPB (DSB) in cardiac patients with pulmonary hypertension. Mean arterial pressure to mean pulmonary arterial pressure ratio (mAP/mPAP) was identified as the best predictor of perioperative complications. We investigated the pharmacokinetic/pharmacodynamic (PK/PD) relationship of inhaled milrinone in these patients using this ratio (R) as a PD marker. METHODS: Before initiation of CPB in 28 consenting patients, milrinone (5 mg) was nebulized and plasma concentrations measured up to 10 hours after inhalation. Baseline (R0), peak (Rmax), and post-CPB (Rpost-CPB) ratios as well as magnitude of peak response (DRmax-R0) were measured. Milrinone concentration-effect relationship was characterized during inhalation by correlating individual area under effect-time (AUEC) and area under plasma concentration-time (AUC) curves. Potential relationships between PD drivers and the clinical endpoint DSB were explored. -1 RESULTS: Milrinone peak concentrations (41-189 ng ml ) and DRmax-R0 (-0.12-1.5; -5-65%) were observed at the end of inhalation (10-30 min). Mean PK estimates agreed with intravenous milrinone published data. Paired comparisons between R0 and Rmax or Rpost-CPB were statistically different (P <0.001) and DRmax-R0 found associated with absence of DSB (P¼0.009). During inhalation, individual AUEC directly correlated with AUC (P¼0.045); significance increased after exclusion of non-responders (P¼0.024). Individual AUEC correlated with DRmax-R0 (P¼0.001). Both DRmax-R0(P¼0.009) and CPB duration (P <0.001) were identified as predictors of DSB.
Bone-marrow mesenchymal stem cells (BMMSC) have been suggested to play a crucial role in promoting the healing process in ischemic hearts post myocardial infarction (MI). However, poor viability and retention of transplanted cells in the harsh microenvironment remains as an obstacle. The paracrine hypothesis suggests that BM-MSCs secrete paracrine factors that work together to manipulate the microenvironment to trigger angiogenesis and anti-apoptotic properties at the infarct site. Tumour necrosis factor-a (TNFa) is a pleiotropic pro-inflammatory cytokine present in ischemic cardiac regions, but the specific roles it plays in cardioprotection remains unknown. The current study aims to understand the regulatory and cardioprotective effects of TNF-a on rat BM-MSCs (rBM-MSC) which may, initiate and sustain the process of cardiac repair post MI. METHODS: Secretome from rBM-MSC cultures treated/untreated with either conditioned rat cardiomyocyte medium (rCM), TNF-a, and/or normoxia/hypoxia in various combinations were collected. Immunocytochemistry, western blot analyses, and trans-well cell migration assays were conducted. In vivo, echocardiography was performed on induced infarcted Lewis rats at 3 weeks following their treatment with a control (rCM, hypoxia, and BM-MSCs) or TNF-a hypoxia-induced secretome. Histological analyses were conducted. ImageJ and Prism were used for statistical analysis. RESULTS: Immunocytochemistry and western blots confirmed the presence of TNF-Receptors 1 and 2 (TNFR1&2) on rBM-MSCs. Western blot analyses on rBM-MSC lysates treated with TNF-a and hypoxia showed an expression of TGF-b, FGF-2 & 7, Ang-1, VEGF-1, and Myogenin. The TNF-a hypoxia-induced secretome exhibited chemotactic properties. In vivo, the TNF-a hypoxia-induced secretome treated rats had a higher left ventricular fractional shortening (LVFS) than the control, while trichrome staining revealed a decrease in the size of infarct. Immunohistochemistry (IHC) revealed increased expression of CD31 and Ki67 near the infarct in TNF-a hypoxia-induced secretome treated rats. CONCLUSION: The presence of TNFR1&2 on rBM-MSCs indicate that TNF-a is able to bind to rBM-MSCs and initiate cell survival pathways. Furthermore, TNF-a in hypoxic conditions express proteins such as TGF-b, FGF-2, FGF-7, Ang1, VEGF-1, and myogenin in rBM-MSCs that either