Abstract 15671: Direct Thrombin Inhibition with Dabigatran Attenuates Pressure Overload-Induced Cardiac Fibrosis and Diastolic Dysfunction in Mice
Introduction: Thrombin, a multifunctional serine protease, exerts proinflammatory and profibrotic cellular effects that may contribute to cardiac remodeling and hypertrophy mediated by its high-affinity protease-activated receptor-1 (PAR-1). The aim of the present study was to investigate whether direct thrombin inhibition with dabigatran attenuates myocardial injury in the setting of pressure overload-induced heart failure.
Methods: Transverse aortic constriction (TAC) surgery was performed in C57/BL6J male mice (10-12 weeks old) to generate pressure overload and cardiac hypertrophy. TAC or sham mice were randomly assigned receive chow supplemented with dabigatran etexilate (10 mg/gm) or placebo (TAC+dabigatran, TAC+placebo, sham+dabigatran, sham+placebo).
Results: Dabigatran treatment significantly extend thrombin clotting time by 3.2 fold (p<0.001) independently of TAC or sham surgery, corresponding to plasma concentrations of approximately 0.4 ng/ml. Similarly, dabigatran reduced plasma thrombin activity by 39% (p<0.001). Five weeks after TAC, dabigatran treatment did not affect cardiac hypertrophy, as measured by heart weight-to-body weight or the heart weight-to-tibia, although a non-significant reduction in myocardial hypertrophic markers (ANP, BNP and MHC) occurred. Dabigatran treatment attenuated cardiac fibrosis (fibrotic area 4859 µm2 ± 523 in placebo-fed TAC mice vs. 2176 µm2 ± 309 in dabigatran-fed TAC mice, p<0.05) and expression of myocardial collagen type I (5.59 ± 0.35 vs. 1.15 ± 0.18, p<0.01), collagen type III (4.47 ± 0.38 vs. 1.22 ± 0.21, p<0.01), and MMP9 (4.79± 0.15 vs. 1.05 ± 0.09, p<0.01). Dabigatran also significantly decreased PAR-1 expression (4.62± 0.24 vs. 1.44 ± 0.09, p<0.05). Finally, pre-treatment with dabigatran significantly improved myocardial function measured by tissue doppler imaging Tei index (0.66 ± 0.06 in placebo-fed TAC mice vs. 0.26 ± 0.04 in dabigatran-fed TAC mice, p<0.001).
Conclusion: Our results indicate that dabigatran attenuated cardiac fibrosis in the setting of pressure overload and improved diastolic function by inhibiting thrombin activity and possibly through down-regulation of PAR-1 expression without effects on cardiomyocyte hypertrophy.
- © 2012 by American Heart Association, Inc.