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The role of ICAM-1 in myocardial dysfunction during sepsis and ischemia-reperfusion injury Yousefzadeh-Davani, Ehsan


Intramyocardial inflammation occurs in various types of cardiovascular diseases including ischemia-reperfusion, myocarditis, during orthotopic heart transplant rejection, and during sepsis-induced myocardial dysfunction. Intramyocardial inflammation results in increased expression of ICAM-1 on cardiac tissue. ICAM-1 can interact with its ligands including CD11/CD14 receptors on inflammatory cells, and fibrinogen leading to activation of intracellular signaling cascades. To test this hypothesis that ICAM-1 activation on cardiac tissue can trigger signaling which leads to decreased cardiac contractility we used three different in vitro (cardiomyocytes, polymorphonuclear leukocytes (PMN) and fibrinogen co-culture), in vivo (cardiac contractility measurement using micro-catheter) and ex vivo (reperfusion of isolated heart) methods. Cardiomyocyte ICAM-1 -binding by activated PMN, by activated and killed PMNs, and by ICAM-1 cross-linking antibodies decreased cardiomyocytes contractility. In vivo, inducing severe cardiac inflammation by LPS injection decreases cardiac contractility by 58 ± 4% (using end systolic elastance) and increases ICAM-1 expression on cardiac tissue by 2.35 fold compared to control. Morphometery of cardiac vessels indicated increased intravascular PMNs after LPS injection but the number of interstitial PMNs were not different compared to control excluding the role of PMN adhesion in ICAM-1 activation in sepsis. This led to the next hypothesis that fibrinogen can interact with ICAM-1 after LPS injection. Immunohistochemistry staining indicates increased interstitial fibrinogen infiltration six hours after LPS injection supporting the interaction of ICAM-1 and fibrinogen during sepsis. Incubation of cardiomyocytes with fibrinogen decreased cardiomyocytes contractility. This effect of fibrinogen was abolished in the presence of anti ICAM-1 antibody. Treatment of isolated heart with IGF-1 decreases ICAM-1 expression by 2 fold (p<0.01), increases cardiac contractility and heart rate, and decreases CPK during reperfusion compared to TNFα. We conclude that PMN and fibrinogen interact with cardiomyocytes ICAM-1. Fibrinogen infiltrates into the myocardial interstitial space during sepsis and decreases cardiac contractility through adhesion to ICAM-1 receptor on the cardiomyocyte membrane. IGF-1 can be used as a therapeutic intervention to decrease ICAM-1 expression thereby protecting the heart from further injury during cardiac inflammation.

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