title: Effects of candesartan on electrical remodeling in the hearts of inherited dilated cardiomyopathy model mice.
abstract: Inherited dilated cardiomyopathy (DCM) is characterized by dilatation and dysfunction of the ventricles, and often results in sudden death or heart failure (HF). Although angiotensin receptor blockers (ARBs) have been used for the treatment of HF, little is known about the effects on postulated electrical remodeling that occurs in inherited DCM. The aim of this study was to examine the effects of candesartan, one of the ARBs, on cardiac function and electrical remodeling in the hearts of inherited DCM model mice (TNNT2 ΔK210). DCM mice were treated with candesartan in drinking water for 2 months from 1 month of age. Control, non-treated DCM mice showed an enlargement of the heart with prolongation of QRS and QT intervals, and died at t1/2 of 70 days. Candesartan dramatically extended the lifespan of DCM mice, suppressed cardiac dilatation, and improved the functional parameters of the myocardium. It also greatly suppressed prolongation of QRS and QT intervals and action potential duration (APD) in the left ventricular myocardium and occurrence of ventricular arrhythmia. Expression analysis revealed that down-regulation of Kv4.2 (Ito channel protein), KChIP2 (auxiliary subunit of Kv4.2), and Kv1.5 (IKur channel protein) in DCM was partially reversed by candesartan administration. Interestingly, non-treated DCM heart had both normal-sized myocytes with moderately decreased Ito and IKur and enlarged cells with greatly reduced K+ currents (Ito, IKur IK1 and Iss). Treatment with candesartan completely abrogated the emergence of the enlarged cells but did not reverse the Ito, and IKur in normal-sized cells in DCM hearts. Our results indicate that candesartan treatment suppresses structural remodeling to prevent severe electrical remodeling in inherited DCM.
authors.affiliation: Department of Cellular and Molecular Pharmacology, Juntendo University Graduate School of Medicine, Tokyo, Japan; Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Fuminori
authors.initials: F
authors.lastname: Odagiri
authors.affiliation: Department of Physiology, Tokyo Medical University, Tokyo, Japan.
authors.forename: Hana
authors.initials: H
authors.lastname: Inoue
authors.affiliation: Department of Cellular and Molecular Pharmacology, Juntendo University Graduate School of Medicine, Tokyo, Japan; Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Sugihara
authors.affiliation: Department of Cellular and Molecular Pharmacology, Juntendo University Graduate School of Medicine, Tokyo, Japan; Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Department of Cellular and Molecular Pharmacology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Murayama
authors.affiliation: Department of Physiology, Faculty of Medicine, Saga University, Saga, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Shioya
authors.affiliation: Department of Physiology, Tokyo Medical University, Tokyo, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Konishi
authors.affiliation: Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nakazato
authors.affiliation: Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Daida
authors.affiliation: Department of Cellular and Molecular Pharmacology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Sakurai
authors.affiliation: Department of Clinical Pharmacology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Sachio
authors.initials: S
authors.lastname: Morimoto
authors.affiliation: Department of Cellular and Molecular Pharmacology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Nagomi
authors.initials: N
authors.lastname: Kurebayashi
mesh_terms: D057911:Angiotensin Receptor Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D064752:Atrial Remodeling / Q000187:drug effects*; D001562:Benzimidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D001713:Biphenyl Compounds; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D004195:Disease Models, Animal; D004562:Electrocardiography / Q000187:drug effects; D055724:Electrophysiological Phenomena / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D055879:Gene Knock-In Techniques; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D013777:Tetrazoles / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D015221:Potassium Channels; D013777:Tetrazoles; D011188:Potassium; C081643:candesartan