0386 : Direct thrombin inhibitors prevent atrial myocardial hypertrophy and atrial fibrillation susceptibility associated with heart failure in the rat

Atrial fibrillation (AF) is the most frequent cardiac arrhythmia, which is characterized by a high risk of stroke due to increased thrombogenesis and thrombin formation in poorly contractile atria. In addition to its role in the coagulation cascade, thrombin has pleiotropic effects on cardiovascular system through the activation of protease activated receptor 1 (PAR 1). Here we examined whether thrombin contributes to the atrial myocardial remodeling that occurs during heart failure (HF) and whether direct thrombin inhibitors can prevent this remodeling process and AF progression. The study was conducted in a well established rat model of atrial dilation and susceptibility to AF associated with ischemic HF secondary to myocardial infarction (MI). The endogenous thrombin potential increased in plasma after MI, and remained elevated in HF rats. Treating MI rats for one or two months with direct thrombin inhibitors reduced the area and diameter of left atria. After two months, there was also a reduction of the duration of burst pacing induced AF and a downregulation of the expression of hypertrophic markers such as brain natriuretic peptide and β myosin heavy chain. The transcription factor NFATc3, known to be activated in cardiac hypertrophy, and the plasminogen activator inhibitor 1, which has both thrombotic and fibrogenic activities were also downregulated. Treating rats with a PAR 1 antagonist reproduced the effect of thrombin inhibitors. To study the role of thrombin on atrial myocardium in absence of other cardiac stimuli, atrial explant cultures were performed. In cultured atria, thrombin upregulated hypertrophic markers and plasminogen activator inhibitor 1 through PAR 1 and the Rho/Rho kinase pathway. These results indicate that thrombin is a potent hypertrophic factor for atrial myocardium; they point to chronic inhibition of thrombin/PAR1 pathways as a potential therapeutic option to prevent atrial remodeling and AF substrate formation. The author hereby declares no conflict of interest