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Macrophage Migration Inhibitory Factor (MIF) Regulates Inflammatory Mediators and MMP-9 Levels in Ischemic Hearts and Peripheral Blood Mononuclear Cells
S30
Heart, Lung and Circulation 2010;19S:S1–S268
Abstracts
ABSTRACTS
Results: CS-pre and CS-post were identical excluding activation due to sampling. Mean coronary artery % diameter stenosis was 53.1 ± 9.1% and mean shear stress was 87.8 ± 128.8 Pa. Lesions >50% diameter stenosis had increased trans-lesion (DA > PA) upregulation of platelet CD62P, PM-Agg and monocyte CD11b (all p < 0.05), but not PAC-1 or sCD62P. Peak shear stress correlated with trans-lesion upregulation of platelet CD62P (r = 0.55, p = 0.02), PM-Agg (r = 0.62, p < 0.01), and monocyte CD11b (r = 0.76, p = 0.01) but not PAC-1 or sCD62P. Conclusions: These data provide the first direct evidence of intracoronary shear-related platelet activation in stable coronary disease despite aspirin and clopidogrel, and specifically implicate platelet P-selectin in this process. doi:10.1016/j.hlc.2010.06.733 67 Long-Term Outcomes on Medically Managed Patients having Favourable Coronary Fractional Flow Reserve A. Puri ∗ , M. Liang, S. Perera, M. Menon, G. Devlin Department of Cardiology, Waikato Hospital, Hamilton, New Zealand Background: Fractional flow reserve (FFR) is an invasive physiological index of the functional severity of coronary artery stenosis. The FAME study demonstrated FFR ≥ 0.80 as being associated with a good clinical outcome at 12 months in patients managed conservatively. We aim to assess longer-term outcomes of patients with angiographic coronary artery disease (CAD) in whom FFR was ≥0.80; did not undergo percutaneous coronary intervention (PCI) and continued with medical management. Method: Patients with symptomatic CAD who underwent coronary angiography between January 2006 and December 2008, and having an FFR ≥ 0.80 in target vessels which were not intervened with PCI were identified. Clinical outcomes of death, angina, target vessel revascularization were assessed. Results: 177 patients underwent FFR for intermediate lesions. 113 (64%) patients, 133 lesions, having FFR ≥ 0.80 and not intervened were included in this study. The mean age was 64.5 ± 9.1 years (58% males). Lesions assessed were in the Left Main 8%, LAD 55%, Circumflex 20% and RCA 17%. Under conditions of maximal hyperaemia the mean FFR for the cohort was 0.87(range 0.80–0.98). Symptoms were minimal during a mean follow-up of 25 ± 10 months. 25% patients reporting recurrent chest pain; 17% had angina, 8% had atypical chest pain and only 8% required revascularization. 4 (4%) non-cardiac death were reported. Conclusion: An FFR ≥ 0.80 in patients presenting with symptomatic CAD predicts an excellent longer term mortality outcome at 3 years with conservative management. Recurrent chest discomfort is noted in one in four patients with revascularisation however undertaken infrequently.
Assessment of FFR may prevent unnecessary interventions in equivocal lesions. doi:10.1016/j.hlc.2010.06.734 68 Macrophage Migration Inhibitory Factor (MIF) Regulates Inflammatory Mediators and MMP-9 Levels in Ischemic Hearts and Peripheral Blood Mononuclear Cells D. White 1,∗ , K. Lu Fang 2 , Y. Liu 1 , Y. Su 1 , X. Du 1 , A. Dart 2 , X. Gao 1 1 Baker 2 Alfred
IDI Heart and Diabetes Institute, Australia Hospital Heart Centre, Australia
Inflammatory responses following ischemic injury result in the activation of matrix metalloproteinase9 (MMP-9), which is crucial for cardiac remodelling. Demonstration of set-point mediators that influence inflammatory response is vital for better therapies. Methods: First, we studied the role of MIF in regulating levels of MMP-9 and inflammatory mediators in mouse hearts following ischemia/reperfusion (I/R). Wild-type (WT) and MIF knockout (MIFKO) mice were subjected to I/R (1 h/24 h) or sham operation. Gene expression of MMP9, and other inflammatory cytokines and mediators were examined by qRT-PCR. MMP9 levels were tested by gelatin zymography. Second, the influence of MIF in MMP9 production/activation from human peripheral blood mononuclear cells (PBMCs) was examined. PBMCs from healthy human were prepared and cultured for 24 h, and then stimulated with interleukin-1 (IL-1, 10n g/mL) with or without the MIF antagonist COR100140 (at 10, 25, 50 and 100 M). MMP9 levels were determined by zymography. Results: Compared with the baseline level, I/R in WT mice resulted in an increase in gene expression of MMP-9 (76-folds), TNF␣ (2.6-folds), IL-1 56-folds), IL-6 (129-folds), MCP-1 (104-folds), ICAM-1 (3-folds), VCAM1 (2.3-folds) and MIF (1.3-folds). All these changes were significantly suppressed in MIFKO mice (all p < 0.05–0.01). IL-1 stimulation to human PBMCs elevated MMP-9 release while MIF-inhibitor COR100140 at 50 and 100 M significantly reduced MMP-9 activity and gene expression of TNF␣ (both p < 0.05). Conclusion: Disruption of MIF gene halted the expression of MMP-9 and pro-inflammatory cytokines in the heart following IR injury. Pharmacological inhibition of MIF in human PBMCs similarly suppressed IL-1 stimulated MMP-9 synthesis. Thus, MIF likely functions as a master cytokine in promoting inflammatory responses. doi:10.1016/j.hlc.2010.06.735
Heart, Lung and Circulation 2010;19S:S1–S268
Abstracts
ABSTRACTS
Results: CS-pre and CS-post were identical excluding activation due to sampling. Mean coronary artery % diameter stenosis was 53.1 ± 9.1% and mean shear stress was 87.8 ± 128.8 Pa. Lesions >50% diameter stenosis had increased trans-lesion (DA > PA) upregulation of platelet CD62P, PM-Agg and monocyte CD11b (all p < 0.05), but not PAC-1 or sCD62P. Peak shear stress correlated with trans-lesion upregulation of platelet CD62P (r = 0.55, p = 0.02), PM-Agg (r = 0.62, p < 0.01), and monocyte CD11b (r = 0.76, p = 0.01) but not PAC-1 or sCD62P. Conclusions: These data provide the first direct evidence of intracoronary shear-related platelet activation in stable coronary disease despite aspirin and clopidogrel, and specifically implicate platelet P-selectin in this process. doi:10.1016/j.hlc.2010.06.733 67 Long-Term Outcomes on Medically Managed Patients having Favourable Coronary Fractional Flow Reserve A. Puri ∗ , M. Liang, S. Perera, M. Menon, G. Devlin Department of Cardiology, Waikato Hospital, Hamilton, New Zealand Background: Fractional flow reserve (FFR) is an invasive physiological index of the functional severity of coronary artery stenosis. The FAME study demonstrated FFR ≥ 0.80 as being associated with a good clinical outcome at 12 months in patients managed conservatively. We aim to assess longer-term outcomes of patients with angiographic coronary artery disease (CAD) in whom FFR was ≥0.80; did not undergo percutaneous coronary intervention (PCI) and continued with medical management. Method: Patients with symptomatic CAD who underwent coronary angiography between January 2006 and December 2008, and having an FFR ≥ 0.80 in target vessels which were not intervened with PCI were identified. Clinical outcomes of death, angina, target vessel revascularization were assessed. Results: 177 patients underwent FFR for intermediate lesions. 113 (64%) patients, 133 lesions, having FFR ≥ 0.80 and not intervened were included in this study. The mean age was 64.5 ± 9.1 years (58% males). Lesions assessed were in the Left Main 8%, LAD 55%, Circumflex 20% and RCA 17%. Under conditions of maximal hyperaemia the mean FFR for the cohort was 0.87(range 0.80–0.98). Symptoms were minimal during a mean follow-up of 25 ± 10 months. 25% patients reporting recurrent chest pain; 17% had angina, 8% had atypical chest pain and only 8% required revascularization. 4 (4%) non-cardiac death were reported. Conclusion: An FFR ≥ 0.80 in patients presenting with symptomatic CAD predicts an excellent longer term mortality outcome at 3 years with conservative management. Recurrent chest discomfort is noted in one in four patients with revascularisation however undertaken infrequently.
Assessment of FFR may prevent unnecessary interventions in equivocal lesions. doi:10.1016/j.hlc.2010.06.734 68 Macrophage Migration Inhibitory Factor (MIF) Regulates Inflammatory Mediators and MMP-9 Levels in Ischemic Hearts and Peripheral Blood Mononuclear Cells D. White 1,∗ , K. Lu Fang 2 , Y. Liu 1 , Y. Su 1 , X. Du 1 , A. Dart 2 , X. Gao 1 1 Baker 2 Alfred
IDI Heart and Diabetes Institute, Australia Hospital Heart Centre, Australia
Inflammatory responses following ischemic injury result in the activation of matrix metalloproteinase9 (MMP-9), which is crucial for cardiac remodelling. Demonstration of set-point mediators that influence inflammatory response is vital for better therapies. Methods: First, we studied the role of MIF in regulating levels of MMP-9 and inflammatory mediators in mouse hearts following ischemia/reperfusion (I/R). Wild-type (WT) and MIF knockout (MIFKO) mice were subjected to I/R (1 h/24 h) or sham operation. Gene expression of MMP9, and other inflammatory cytokines and mediators were examined by qRT-PCR. MMP9 levels were tested by gelatin zymography. Second, the influence of MIF in MMP9 production/activation from human peripheral blood mononuclear cells (PBMCs) was examined. PBMCs from healthy human were prepared and cultured for 24 h, and then stimulated with interleukin-1 (IL-1, 10n g/mL) with or without the MIF antagonist COR100140 (at 10, 25, 50 and 100 M). MMP9 levels were determined by zymography. Results: Compared with the baseline level, I/R in WT mice resulted in an increase in gene expression of MMP-9 (76-folds), TNF␣ (2.6-folds), IL-1 56-folds), IL-6 (129-folds), MCP-1 (104-folds), ICAM-1 (3-folds), VCAM1 (2.3-folds) and MIF (1.3-folds). All these changes were significantly suppressed in MIFKO mice (all p < 0.05–0.01). IL-1 stimulation to human PBMCs elevated MMP-9 release while MIF-inhibitor COR100140 at 50 and 100 M significantly reduced MMP-9 activity and gene expression of TNF␣ (both p < 0.05). Conclusion: Disruption of MIF gene halted the expression of MMP-9 and pro-inflammatory cytokines in the heart following IR injury. Pharmacological inhibition of MIF in human PBMCs similarly suppressed IL-1 stimulated MMP-9 synthesis. Thus, MIF likely functions as a master cytokine in promoting inflammatory responses. doi:10.1016/j.hlc.2010.06.735