Published Online
on November 10, 2003

A more recent version of this article appeared on November 18, 2003

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Submitted on June 6, 2003
Revised on September 26, 2003
Accepted on September 26, 2003

Thrombomodulin and Tissue Factor Pathway Inhibitor in Endocardium of Rapidly Paced Rat Atria

Takeshi Yamashita MD, PhD^*, Akiko Sekiguchi PhD, Yu-ki Iwasaki MD, PhD, Kouichi Sagara MD, Seiji Hatano MD, PhD, Hiroyuki Iinuma MD, Tadanori Aizawa MD, PhD, and Long-Tai Fu MD, PhD

From The Cardiovascular Institute, Tokyo, Japan.

^* To whom correspondence should be addressed. E-mail: yamt-tky{at}umin.ac.jp.

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.

Key words: fibrillation • anticoagulants • endocardium

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