Results Effects of Acute Pressure Overload on Endocardial Thrombomodulin Expression

Background—Patients with heart failure are at increased risk for thromboembolic events, including stroke. Historically attributed to blood stasis, little is known about the adverse effects of elevated chamber filling pressure on endocardial function, which could predispose to intracardiac thrombus formation. Methods and Results—We investigated changes in the expression of thrombomodulin, a key component of the anticoagulant protein C pathway, in rats subjected to acute atrial pressure overload caused by aortic banding. Acute elevation of left atrial filling pressure, without an associated decline in ventricular systolic function, caused a 70% inhibition of atrial endocardial thrombomodulin expression and resulted in increased local thrombin generation. Targeted restoration of atrial thrombomodulin expression with adenovirus-mediated gene transfer successfully reduced thrombin generation to baseline levels. In vitro co-culture studies revealed that thrombomodulin downregulation is caused by the paracrine release of transforming growth factorfrom cardiac connective tissue in response to mechanical stretch. This was confirmed in vivo by administration of a neutralizing transforming growth factorantibody, which effectively prevented thrombomodulin downregulation during acute pressure overload. Conclusions—These findings suggest that increased hemodynamic load adversely affects endocardial function and is a potentially important contributor to thromboembolus formation in heart failure. (Circulation. 2007;115:67-75.)