Multistep Ion Channel Remodeling and Lethal Arrhythmia Precede Heart Failure in a Mouse Model of Inherited Dilated Cardiomyopathy

Abstract

BackgroundPatients with inherited dilated cardiomyopathy (DCM) frequently die with severe heart failure (HF) or die suddenly with arrhythmias, although these symptoms are not always observed at birth. It remains unclear how and when HF and arrhythmogenic changes develop in these DCM mutation carriers. In order to address this issue, properties of the myocardium and underlying gene expressions were studied using a knock-in mouse model of human inherited DCM caused by a deletion mutation ΔK210 in cardiac troponinT.Methodology/Principal FindingsBy 1 month, DCM mice had already enlarged hearts, but showed no symptoms of HF and a much lower mortality than at 2 months or later. At around 2 months, some would die suddenly with no clear symptoms of HF, whereas at 3 months, many of the survivors showed evident symptoms of HF. In isolated left ventricular myocardium (LV) from 2 month-mice, spontaneous activity frequently occurred and action potential duration (APD) was prolonged. Transient outward (Ito) and ultrarapid delayed rectifier K+ (IKur) currents were significantly reduced in DCM myocytes. Correspondingly, down-regulation of Kv4.2, Kv1.5 and KChIP2 was evident in mRNA and protein levels. In LVs at 3-months, more frequent spontaneous activity, greater prolongation of APD and further down-regulation in above K+ channels were observed. At 1 month, in contrast, infrequent spontaneous activity and down-regulation of Kv4.2, but not Kv1.5 or KChIP2, were observed.Conclusions/SignificanceOur results suggest that at least three steps of electrical remodeling occur in the hearts of DCM model mice, and that the combined down-regulation of Kv4.2, Kv1.5 and KChIP2 prior to the onset of HF may play an important role in the premature sudden death in this DCM model. DCM mice at 1 month or before, on the contrary, are associated with low risk of death in spite of inborn disorder and enlarged heart.

Effects of Candesartan on Electrical Remodeling in the Hearts of Inherited Dilated Cardiomyopathy Model Mice

“…APD has been reported to be influenced by I to , I Kur , I K1 and I ss [19], and we have previously found that the expression of I to - and I Kur -related molecules is considerably decreased in DCM mice at 2 months [13]. In this study, we analyzed the expression levels of genes encoding the various ion channels that carry I K1 (Kir2.1 and Kir2.2), I ss (Kv2.1), I to (Kv4.2 and the accessory subunit KChIP2), and I Kur (Kv1.5) in WT and DCM mice at 3 months.…”

“…A knock-in mouse model carrying this mutation was created by Morimoto and colleagues [12]–[14]. These mice closely recapitulate the phenotypes of human DCM, and previous study of this DCM model mouse indicated that down-regulation of various K + channels is one of the causes of lethal arrhythmia and SCD [13].…”

Torasemide reduces dilated cardiomyopathy, complication of arrhythmia, and progression to heart failure

“…Similar measurements were determined in the right ventricle and left atrial muscles. Myocardial automaticity appears to be considerably enhanced in the left ventricle (Suzuki et al, 2012).…”

“…Elucidation of the genetic basis of familial DCM can enable effective gene-targeted therapy to be implemented. Also, multiple types of progressive electrical remodeling, such as ion channel reduction in Ito and Kv4.2 transcription and concurrent upregulation of Na + -Ca 2+ exchanger-1, occur and the action potential duration is prolonged (Suzuki et al, 2012), thus the reason for arrhythmogenesis being complex.…”

The potential role of Kv4.3 K+channel in heart hypertrophy

“…35 In addition, the downregulation of KChIP2 mRNA and/or protein expressions has also been shown in heart failure mice models. 36,37 Grubb et al reported that, compared with the wild type mice with heart failure, KChIP2-/-heart failure mice showed a larger reduction of K + -current density. 38 These results suggest that the reduction of KChIP2 may contribute to the downregulation of Kv4.3 K + channels in heart diseases.…”