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Thrombomodulin and tissue factor pathway inhibitor in endocardium of rapidly paced rat atria
Takeshi Yamashita1, Akiko Sekiguchi, Yu-ki Iwasaki
1The Cardiovascular Institute, Roppongi 7-3-10, Minato-ku, Tokyo 106-0032, Japan. yamt-tky@umin.ac.jp
Insights
Atrial fibrillation (AF) disrupts atrial endocardial function, decreasing anticoagulant factors like thrombomodulin (TM) and tissue factor pathway inhibitor (TFPI). This imbalance promotes blood clot formation in the atria.
Area of Science:
- Cardiovascular Research
- Thrombosis and Hemostasis
Background:
- Atrial fibrillation (AF) is a primary cardiogenic cause of thromboembolism.
- Existing theories focus on reduced blood flow and hypercoagulability in AF.
- Endocardial dysfunction's role in AF-related thrombogenesis is less understood.
Purpose of the Study:
- To investigate if AF induces local coagulation imbalance by affecting atrial endocardial function.
- To examine the expression of key anticoagulant factors, thrombomodulin (TM) and tissue factor pathway inhibitor (TFPI), in an AF model.
Main Methods:
- A rat model of paroxysmal atrial fibrillation (AF) was induced via rapid atrial pacing.
- Gene expression of TM and TFPI was quantified using ribonuclease protection assay.
- Protein levels and localization were assessed via Western blotting and immunohistochemistry.
Main Results:
- Rapid atrial pacing for 8 hours significantly decreased TM and TFPI mRNA and protein levels in the left atrium, but not the ventricle.
- Immunohistochemistry showed a loss of TM and TFPI expression in the atrial endocardium following pacing.
- This downregulation creates a deficiency in the anticoagulant barrier within the atrial cavity.
Conclusions:
- Acute AF induction via rapid pacing downregulates TM and TFPI gene expression in the atrial endocardium.
- This leads to a local coagulation imbalance on the atrial endocardial surface.
- Findings support the potential therapeutic benefit of supplementing deficient anticoagulant molecules in AF.
Background:
Atrial fibrillation (AF) is well known as one of the cardiogenic causes for thromboembolism. Although decreased flow and hypercoagulable state of the blood in the fibrillating atrium have been emphasized as the underlying mechanisms, endocardial dysfunction in maintaining the local coagulation balance could also contribute to the thrombogenesis in AF.
Methods And Results:
The paroxysmal AF model was created by rapid atrial pacing in anesthetized rats. To test the hypothesis that AF induces local coagulation imbalance by disturbing the atrial endocardial function, the gene expression of intrinsic anticoagulant factors, thrombomodulin (TM) and tissue factor pathway inhibitor (TFPI), were determined by means of ribonuclease protection assay, Western blotting, and immunohistochemistry. Rapid atrial pacing for 8 hours significantly decreased TM and TFPI mRNA levels in the left atrium but not in the ventricle, leading to the downregulation of their immunoreactive proteins. Immunohistochemical analysis revealed that TM and TFPI were expressed predominantly in the endocardial cells of the normal atrium, presumably preventing local blood coagulation, and that rapid atrial pacing induced the loss of TM and TFPI expression in the endocardium, leading to deficiency in anticoagulant barriers between the atria and the blood.
Conclusions:
Rapid atrial pacing acutely downregulated the gene expression of TM and TFPI in the atrial endocardium, thereby inducing local coagulation imbalance on the internal surface of the atrial cavity. These results would support the validity of supplement of anticoagulant molecules deficient in AF.
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