Abstract 10260: Thrombin is a Novel Target of the Treatment of Dilated Cardiomyopathy

Abstract

Introduction: A state of hypercoagulability has been observed in patients with dilated cardiomyopathy (DCM) compared to healthy subjects. In addition to being found in blood, thrombin is also expressed in the heart. Hypothesis: We hypothesize that thrombin in the heart tissue may contribute to the pathology of DCM and thrombin inhibition may be beneficial for the development of DCM. Methods: We evaluated the expression of thrombin by immunohistochemical analysis in the left ventricle of 5 patients with DCM undergoing Batista operation and that of 4 patients without heart disease serving as controls. The immunohistochemical staining was scored subjectively on a semi-quantitative scale of 0-4. We investigated the effects of the direct thrombin inhibitor, dabigatran, in the development of DCM in a mouse model carrying a deletion mutant of cardiac troponin T (DCM mouse) which causes human DCM, by using echocardiography and Kaplan-Meier method. We also estimated the apoptotic index using the terminal dUTP nick-end labeling (TUNEL) assay using the heart tissue from DCM mouse. Results: Immunohistochemical analysis showed strong thrombin expression in DCM patients compared to patients without heart disease [3.60 in DCM (n=5), 1.25 in control (n=4), p<0.001]. Dabigatran significantly improved impaired left ventricular function of DCM mouse by echocardiographic examination; fractional shortening was 15.6±5.7 % in DCM mouse and was 42.7±7.3 % in DCM with dabigatran (p=0.03, n=4). Dabigatran also significantly improved the poor outcome of DCM mouse (p=0.02, n=7) (Figure1). Although there were no significant differences, dabigatran tended to reduce the apoptotic index; the percentage of TUNEL-positive nuclei was 0.20±0.04 % in DCM mouse and was 0.08±0.05 % in DCM with dabigatran (p=0.11, n=4). Conclusion: Upregulation of tissue thrombin may be involved in the pathogenesis of DCM. The direct thrombin inhibitor, dabigatran, may be a possible treatment option against DCM.