December 27, 2006Open Access
View Full PaperHemodynamic Modulation of Endocardial Thromboresistance
Key Result
Acute elevation of left atrial filling pressure caused a 70% inhibition of atrial endocardial thrombomodulin expression and increased local thrombin generation, mediated by transforming growth factor-beta.
Structured PICO
P
Population
Rats subjected to acute atrial pressure overload caused by aortic banding, and in vitro co-culture models
I
Intervention
Adenovirus-mediated gene transfer for targeted restoration of atrial thrombomodulin expression, and administration of a neutralizing transforming growth factor-beta antibody
C
Comparator
Acute pressure overload without targeted intervention
O
Outcome
Changes in the expression of thrombomodulin and local thrombin generationsurrogate
Increased hemodynamic load downregulates endocardial thrombomodulin via TGF-beta, suggesting a mechanism for increased thromboembolic risk in heart failure independent of blood stasis.
Abstract
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 factor-beta from cardiac connective tissue in response to mechanical stretch. This was confirmed in vivo by administration of a neutralizing transforming growth factor-beta antibody, 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.