Abstract
ObjectiveThrombin, the final coagulation product of the coagulation cascade, has been demonstrated to have many physiological effects, including pro-fibrotic actions via protease-activated receptor (PAR)-1. Recent investigations have demonstrated that activation of the cardiac local coagulation system was associated with atrial fibrillation. However, the distribution of thrombin in the heart, especially difference between the atria and the ventricle, remains to be clarified. We herein investigated the expression of thrombin and other related proteins, as well as tissue fibrosis, in the human left atria and left ventricle.MethodsWe examined the expression of thrombin and other related molecules in the autopsied hearts of patients with and without atrial fibrillation. An immunohistochemical analysis was performed in the left atria and the left ventricle.ResultsThe thrombin was immunohistologically detected in both the left atria and the left ventricles. Other than in the myocardium, the expression of thrombin was observed in the endocardium and the subendocardium of the left atrium. Thrombin was more highly expressed in the left atrium compared to the left ventricle, which was concomitant with more tissue fibrosis and inflammation, as detected by CD68 expression, in the left atrium. We also confirmed the expression of prothrombin in the left atrium. The expression of PAR-1 was observed in the endocardium, subendocardium and myocardium in the left atrium. In patients with atrial fibrillation, strong thrombin expression was observed in the left atrium.ConclusionsThe strong expression levels of thrombin, prothrombin and PAR-1 were demonstrated in the atrial tissues of human autopsied hearts.
Highlights
Thrombin, the final coagulation product of the coagulation cascade, plays various physiological roles, including pro-fibrotic actions via protease-activated receptor (PAR)-1, PAR-2 and PAR4 [1]
Thrombin was more highly expressed in the left atrium compared to the left ventricle, which was concomitant with more tissue fibrosis and inflammation, as detected by CD68 expression, in the left atrium
An 85-year-old male who died of hepatocellular carcinoma caused by hepatitis C virus infection and had no history of atrial fibrillation, patient 3: a 67-year-old male who died of chronic lymphocytic lymphoma and had no history of atrial fibrillation, patient 4: a 77-year-old male who died of pneumonia and had no history of atrial fibrillation, patient 5: a 50-year-old male who died of acute myeloid leukemia and had no history of atrial fibrillation, patient 6: a 75-year-old male who died of intrahepatic bile duct carcinoma who had a history of paroxysmal atrial fibrillation, patient 7: a 69-year-old male who died of pneumonia and had a history of ventricular tachycardia and atrial fibrillation)
Summary
The final coagulation product of the coagulation cascade, plays various physiological roles, including pro-fibrotic actions via protease-activated receptor (PAR)-1, PAR-2 and PAR4 [1]. The induction of myofibroblasts occurs primarily via the actions of PAR-1 [5], [6], and a recent study demonstrated the importance of PAR-1 in the pathogenesis of fibrosis in cardiac fibroblasts [7]. Recent clinical investigations have demonstrated that the local coagulation system in the heart is activated in patients with atrial fibrillation [8], [9], [10]. There have been few reports that have immunohistologically analyzed the distribution of thrombin in the heart, or the roles of tissue thrombin in the inflammatory process and fibrosis, which is a substrate of atrial tachyarrhythmias [13]
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