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Direct thrombin inhibition with dabigatran attenuates pressure overload-induced cardiac fibrosis and dysfunction in
Anping Dong1, Paul Mueller2, Fanmuyi Yang2
1Division of Cardiovascular Medicine, The Gill Heart Institute, 741 S. Limestone Street, 252 BBSRB, Lexington, KY 40536-0509, United States; Lexington VA Medical Center, 1101 Veterans Drive, Lexington, KY 40502, United States.
Insights
Direct thrombin inhibition with dabigatran attenuated cardiac fibrosis and improved cardiac function in pressure overload heart failure. Dabigatran reduced fibrosis markers and improved coronary flow reserve without affecting cardiac hypertrophy.
Area of Science:
- Cardiology
- Pharmacology
Background:
- Thrombin, a serine protease, promotes inflammation and fibrosis, contributing to cardiac remodeling in heart failure.
- Pressure overload-induced heart failure is a significant clinical concern associated with adverse cardiac remodeling.
Purpose of the Study:
- To investigate the efficacy of direct thrombin inhibition using dabigatran in attenuating myocardial injury and fibrosis in a mouse model of pressure overload-induced heart failure.
Main Methods:
- Cardiac hypertrophy was induced in male C57Bl/6J mice via transverse aortic constriction (TAC).
- Mice received either dabigatran etexilate or placebo in their chow following TAC or sham surgery.
Main Results:
- Dabigatran significantly reduced perivascular (25%) and interstitial (54%) cardiac fibrosis, along with key fibrosis markers (collagen I & III, MMP9, SMA, PAR-1).
- Improvements were observed in coronary flow reserve and global left ventricular function.
- In vitro, dabigatran decreased thrombin and PAR-1-mediated collagen deposition in cardiac fibroblasts.
Conclusions:
- Dabigatran effectively attenuates cardiac fibrosis in pressure overload heart failure, potentially by inhibiting thrombin and down-regulating PAR-1.
- The drug improved cardiac function and coronary flow reserve, independent of effects on cardiomyocyte hypertrophy.
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.
