title: Tissue thrombin is associated with the pathogenesis of dilated cardiomyopathy.
abstract: BACKGROUND
  Thrombin is a serine protease known to be the final product of the coagulation cascade. However, thrombin plays other physiological roles in processes such as gastric contractions and vessel wound healing, and a state of coagulability is increased in patients with dilated cardiomyopathy (DCM). In this study, we investigate the role of thrombin in the pathogenesis of DCM. The purpose of this study is to clarify the role of thrombin in the pathogenesis of DCM and investigate the possibility of treatment against DCM by thrombin inhibition.
  
  
  METHODS
  We investigated the expression of thrombin in the left ventricles of five patients with DCM who underwent the Batista operation and four patients without heart disease. Furthermore, we investigated the involvement of thrombin in the development of DCM using knock-in mice with a deletion mutation of cardiac troponin T that causes human DCM (∆K210 knock-in mouse) (B6;129-Tnnt2tm2Mmto) and assessed the effects of a direct thrombin inhibitor, dabigatran on ∆K210 knock-in mice using echocardiographic examinations, the Kaplan-Meier method and Western blotting.
  
  
  RESULTS
  The immunohistochemical analysis showed a strong thrombin expression in the DCM patients compared to the patients without heart disease. In immunohistochemical analysis, a strong thrombin expression was observed in the heart tissues analysis in the ∆K210 knock-in mice. Dabigatran administration significantly improved fractional shortening according to the echocardiographic examination and the survival outcomes in ∆K210 knock-in mice.
  
  
  CONCLUSIONS
  Tissue thrombin is involved in the pathogenesis of DCM and thrombin inhibition can be beneficial for the treatment of DCM.
authors.affiliation: Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan. Electronic address: keke-ito@jikei.ac.jp.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Ito
authors.affiliation: Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Hongo
authors.affiliation: Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Date
authors.affiliation: Department of Pathology, The Jikei University School of Medicine, 3-25-8, Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ikegami
authors.affiliation: Department of Pathology, The Jikei University School of Medicine, 3-25-8, Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hano
authors.affiliation: Department of Pathology, The Jikei University School of Medicine, 3-25-8, Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan.
authors.forename: Mamiko
authors.initials: M
authors.lastname: Owada
authors.affiliation: Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Morimoto
authors.affiliation: Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kashiwagi
authors.affiliation: Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Katoh
authors.affiliation: Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Yoshino
authors.affiliation: Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Yoshii
authors.affiliation: Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan.
authors.forename: Haruka
authors.initials: H
authors.lastname: Kimura
authors.affiliation: Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan.
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Nagoshi
authors.affiliation: Department of Cell Physiology, The Jikei University School of Medicine, 3-25-8, Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan.
authors.forename: Ichige
authors.initials: I
authors.lastname: Kajimura
authors.affiliation: Department of Cell Physiology, The Jikei University School of Medicine, 3-25-8, Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Kusakari
authors.affiliation: Department of Cell Physiology, The Jikei University School of Medicine, 3-25-8, Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Akaike
authors.affiliation: Department of Cell Physiology, The Jikei University School of Medicine, 3-25-8, Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Minamisawa
authors.affiliation: Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Ogawa
authors.affiliation: Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Minai
authors.affiliation: Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ogawa
authors.affiliation: Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kawai
authors.affiliation: Department of Cardiovascular Medicine, The Cardiovascular Institute, 3-2-19, Nishiazabu, Minato-ku, Tokyo 106-0031, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Yajima
authors.affiliation: Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan.
authors.forename: Seiichiro
authors.initials: S
authors.lastname: Matsuo
authors.affiliation: Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan.
authors.forename: Teiichi
authors.initials: T
authors.lastname: Yamane
authors.affiliation: Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Taniguchi
authors.affiliation: Department of Clinical Pharmacology, Kyushu University Graduate School of Medicine, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Sachio
authors.initials: S
authors.lastname: Morimoto
authors.affiliation: Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan.
authors.forename: Michihiro
authors.initials: M
authors.lastname: Yoshimura
mesh_terms: D000818:Animals; D000991:Antithrombins / Q000627:therapeutic use; D002311:Cardiomyopathy, Dilated / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D000069604:Dabigatran / Q000627:therapeutic use; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D013917:Thrombin / Q000378:metabolism*
chemical_list: D000991:Antithrombins; D013917:Thrombin; D000069604:Dabigatran
keywords: Dilated cardiomyopathy; Direct thrombin inhibitor; Thrombin