Direct thrombin inhibition with dabigatran attenuates pressure overload-induced cardiac fibrosis and dysfunction in mice

Abstract

Introduction The multifunctional serine protease thrombin exerts proinflammatory and profibrotic cellular effects that may contribute to cardiac remodeling. This study was designed to investigate whether direct thrombin inhibition with dabigatran attenuates myocardial injury in the setting of pressure overload-induced heart failure. Material and Methods Transverse aortic constriction (TAC) surgery was performed on C57Bl/6J male mice to elicit cardiac hypertrophy. TAC, or sham, mice were randomly assigned to receive chow supplemented with the oral anticoagulant, dabigatran etexilate, or placebo. Results Dabigatran did not affect cardiac hypertrophy, as measured by heart weight-to-body weight or the heart weight-to-tibia length, although a non-significant reduction in myocardial hypertrophic markers (ANP, BNP and MHC) occurred. Dabigatran reduced perivascular fibrosis by 25%, interstitial fibrosis by 54%, and the expression of myocardial fibrosis markers collagen I & III, MMP9, SMA, and PAR-1. These changes were associated with significant improvement in both coronary flow reserve and global left ventricular function. In cultured cardiac fibroblasts, dabigatran decreased thrombin and PAR-1-mediated collagen deposition by 30% and 37%, respectively. Conclusions Dabigatran attenuates cardiac fibrosis in the setting of pressure overload and improves coronary flow reserve and global cardiac function possibly by inhibiting thrombin activity and down-regulating PAR-1 expression in the absence of an effect on cardiomyocyte hypertrophy.

Short‐Term Cessation of Dabigatran Causes a Paradoxical Prothrombotic State

“…We estimated blood concentration of dabigatran based on measurements of dabigatran‐calibrated dTT (Fig 3A). 28,29 Calculated dabigatran concentrations in the blood (Fig 3B) ranged from 61.0 to 96.0 ng/mL at 7 days after dabigatran administration and dropped to levels similar to those of the vehicle group (8.2 ± 2.3 ng/mL) after dabigatran cessation for 1 day (10.3 ± 1.6 ng/mL; MD [95% CI] 2.1 ng/mL [−8.5–12.8]; p = 0.98), which is in line with the known rapid clearance rate of dabigatran 30,31 …”

The Biological Role of Nestin(+)-Cells in Physiological and Pathological Cardiovascular Remodeling

“…In contrast to reparative fibrosis, reactive fibrosis reduces ventricular compliance thereby exacerbating systolic/diastolic dysfunction (Creemers and Pinto, 2011 ; Chen and Frangogiannis, 2013 ; Prabhu and Frangogiannis, 2016 ). An additional pathological feature of the pressure-overloaded heart is perivascular fibrosis characterized by the deposition of collagen type I within the adventitial region of the coronary vasculature leading to vascular stiffness (Dong et al, 2017 ). In the hypertrophied/fibrotic left ventricle of the rat heart secondary to pressure-overload, nestin protein levels were upregulated and attributed in part to the increased density of collagen type I-immunoreactive mesenchymal cells co-expressing the intermediate filament protein (Hertig et al, 2017 ).…”

Therapeutic molecular targets of SSc-ILD

“…25 Dabigatran also attenuated cardiac fibrosis induced by transverse aortic constriction (TAC) surgery. 26 Moreover, treatment with thrombin antagonism SSR182289 reduced hepatic fibrogenesis in CCl 4 -induced murine liver fibrosis. 27…”