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.
Highlights
Inherited dilated cardiomyopathy (DCM) is a progressive disease characterized by dilatation and dysfunction of the ventricles, and often results in heart failure (HF) or sudden cardiac death (SCD) from lethal arrhythmia [1,2]
Our results indicate that early initiation of candesartan treatment dramatically expands lifespan, preserves cardiac function, suppresses cardiac enlargement as well as cellular enlargement, and attenuate electrical remodeling
In the group treated with 3 mg/ kg/day, about 8% of mice died within 1 month after initiation of the treatment, but thereafter they rarely died until 6 months of age
Summary
Inherited dilated cardiomyopathy (DCM) is a progressive disease characterized by dilatation and dysfunction of the ventricles, and often results in heart failure (HF) or sudden cardiac death (SCD) from lethal arrhythmia [1,2]. In addition to HF development, electrical remodeling, which is accompanied by prolongation of the action potential duration (APD), can be observed in DCM hearts and is thought to be related to increased arrhythmogenicity [4,5]. A growing body of evidence shows that ARBs inhibit cardiac hypertrophy, structural remodeling and ventricular arrhythmias in HF and thereby reduce cardiac morbidity and mortality [6,7,8,9]. Their effects on inherited DCM are not well known. Because data in humans are confounded by various environmental and genetic factors, investigations with animal models of inherited DCM are required
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