Effects of candesartan on electrical remodeling in the hearts of inherited dilated cardiomyopathy model mice

• Published in: PloS one Vol. 9; no. 7; p. e101838
• Main Authors: Odagiri, Fuminori, Inoue, Hana, Sugihara, Masami, Suzuki, Takeshi, Murayama, Takashi, Shioya, Takao, Konishi, Masato, Nakazato, Yuji, Daida, Hiroyuki, Sakurai, Takashi, Morimoto, Sachio, Kurebayashi, Nagomi
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 07-07-2014; Public Library of Science (PLoS)
• Subjects: Action potential; Analysis; Angiotensin; Angiotensin Receptor Antagonists - pharmacology; Angiotensin Receptor Antagonists - therapeutic use; Animals; Arrhythmia; Atrial Remodeling - drug effects; Benzimidazoles - pharmacology; Benzimidazoles - therapeutic use; Biology and Life Sciences; Candesartan; Cardiac arrhythmia; Cardiomyopathy; Cardiomyopathy, Dilated; Cardiomyopathy, Dilated - drug therapy; Cardiomyopathy, Dilated - genetics; Cardiomyopathy, Dilated - pathology; Cardiomyopathy, Dilated - physiopathology; Dilated cardiomyopathy; Disease Models, Animal; Down-regulation; Drinking water; Electrocardiography; Electrocardiography - drug effects; Electrophysiological Phenomena - drug effects; Enlargement; Expansion; Gene Expression Regulation - drug effects; Gene Knock-In Techniques; Heart; Heart - drug effects; Heart - physiopathology; Heart diseases; Heart Ventricles - drug effects; Heart Ventricles - pathology; Intervals; Life span; Medicine and Health Sciences; Mice; Mice, Inbred C57BL; Mutation; Myocardium; Myocytes; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - pathology; Potassium - metabolism; Potassium channels (voltage-gated); Potassium Channels - genetics; Potassium Channels - metabolism; Potassium currents; Prolongation; Research and Analysis Methods; Rodents; Survival Analysis; Tetrazoles - pharmacology; Tetrazoles - therapeutic use; Ventricle; Water treatment; United States > US; Japan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0101838

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.