Abstract 1660: Amiodarone Inihibits Tissue Factor and Arterial Thrombus Formation
In patients with coronary artery disease and reduced ejection fraction, amiodarone reduces mortality by decreasing sudden cardiac death. Since the latter may be triggered by coronary artery thrombosis as much as ventricular arrhythmias, amiodarone might interfere with tissue factor (TF) expression and thrombus formation. Clinically relevant plasma concentrations of amiodarone inhibited TF activity and carotid artery thrombus formation in a mouse photo-chemical injury model in vivo (n = 5; p < 0.035; Figure 1). In human endothelial and vascular smooth muscle cells, amiodarone inhibited tumor necrosis factor-α and thrombin induced TF protein expression (n = 4; p < 0.001) as well as surface activity (n = 4; p < 0.0001). Tissue factor pathway inhibitor was not affected (n = 5; p = NS). Amiodarone lacking iodine as well as the main metabolite of amiodarone, N-monodesethylamiodarone, inhibited TF expression (n = 4; p< 0.01). Amiodarone did not affect mitogen activated protein kinase activation(n = 3; p = NS), TF mRNA expression (n = 5; p = NS), and TF protein degradation (n = 4; p = NS). Metabolic labelling by [35S]-methionine/cysteine confirmed that amiodarone inhibited TF protein translation (n = 4; p < 0.001). Amiodarone impairs arterial TF activity and thrombus formation in vivo; in line with this, it inhibits TF protein expression and surface activity in human vascular cells. These pleiotropic actions occur within the range of amiodarone concentrations measured in patients, and thus may account at least in part for its beneficial effects in patients with coronary artery disease.