title: Therapeutic effect of {beta}-adrenoceptor blockers using a mouse model of dilated cardiomyopathy with a troponin mutation.
abstract: OBJECTIVE
  Extensive clinical studies have demonstrated that beta-adrenoceptor blocking agents (beta-blockers) are beneficial in the treatment of chronic heart failure, which is due to various aetiologies, including idiopathic dilated cardiomyopathy (DCM) and ischaemic heart disease. However, little is known about the therapeutic efficacy of beta-blockers in the treatment of the inherited form of DCM, of which causative mutations have recently been identified in various genes, including those encoding cardiac sarcomeric proteins. Using a mouse model of inherited DCM with a troponin mutation, we aim to study the treatment benefits of beta-blockers.
  
  
  RESULTS
  Three different types of beta-blockers, carvedilol, metoprolol, and atenolol, were orally administered to a knock-in mouse model of inherited DCM with a deletion mutation DeltaK210 in the cardiac troponin T gene (TNNT2). Therapeutic effects were examined on the basis of survival and myocardial remodelling. The lipophilic beta(1)-selective beta-blocker metoprolol was found to prevent cardiac dysfunction and remodelling and extend the survival of knock-in mice. Conversely, both the non-selective beta-blocker carvedilol and the hydrophilic beta(1)-selective beta-blocker atenolol had no beneficial effects on survival and myocardial remodelling in this mouse model of inherited DCM.
  
  
  CONCLUSIONS
  The highly lipophilic beta(1)-selective beta-blocker metoprolol, known to prevent ventricular fibrillation via central nervous system-mediated vagal activation, may be especially beneficial to DCM patients showing a family history of frequent sudden cardiac death, such as those with a deletion mutation DeltaK210 in the TNNT2 gene.
authors.affiliation: Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Dong-Yun
authors.initials: DY
authors.lastname: Zhan
authors.forename: Sachio
authors.initials: S
authors.lastname: Morimoto
authors.forename: Cheng-Kun
authors.initials: CK
authors.lastname: Du
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Wang
authors.forename: Qun-Wei
authors.initials: QW
authors.lastname: Lu
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tanaka
authors.forename: Tomomi
authors.initials: T
authors.lastname: Ide
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Miwa
authors.forename: Fumi
authors.initials: F
authors.lastname: Takahashi-Yanaga
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sasaguri
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000818:Animals; D001262:Atenolol / Q000627:therapeutic use; D002227:Carbazoles / Q000627:therapeutic use; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D000077261:Carvedilol; D004195:Disease Models, Animal; D004562:Electrocardiography; D008790:Metoprolol / Q000627:therapeutic use; D051379:Mice; D009154:Mutation; D011412:Propanolamines / Q000627:therapeutic use; D020107:Troponin T / Q000235:genetics*; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D011412:Propanolamines; D020107:Troponin T; D000077261:Carvedilol; D001262:Atenolol; D008790:Metoprolol