Therapeutic effect of {beta}-adrenoceptor blockers using a mouse model of dilated cardiomyopathy with a troponin mutation.
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.
Zhan
Dong-Yun
DY
Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Morimoto
Sachio
S
Du
Cheng-Kun
CK
Wang
Yuan-Yuan
YY
Lu
Qun-Wei
QW
Tanaka
Atsushi
A
Ide
Tomomi
T
Miwa
Yoshikazu
Y
Takahashi-Yanaga
Fumi
F
Sasaguri
Toshiyuki
T
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
D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D011412:Propanolamines; D020107:Troponin T; D000077261:Carvedilol; D001262:Atenolol; D008790:Metoprolol