Multistep Electrical Remodeling and Sudden Death Precede Heart Failure in a Mouse Model of Inherited Dilated Cardiomyopathy

Abstract

Patients 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 patients. 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. DCM mice at 1 month had already enlarged hearts, but showed no symptoms of HF and much lower mortality than at 2 months or later. At 2 months they often die suddenly without clear symptoms of HF, whereas at 3 months, many of them showed evident symptoms of HF. In isolated left ventricular myocardium (LV) from 2 month-mice, spontaneous activity frequently occurred and action potential duration was prolonged. Transient outward (Ito) and ultrarapid delayed rectifier K+ currents (IKur) were significantly reduced in DCM myocytes. Correspondingly, down-regulation of Kv4.2, Kv1.5 and KChIP2 was evident in mRNA and protein levels. In 3 month-LV, more frequent spontaneous activity and further down-regulation in above K+ channels were observed. 1 month mice, on the contrary, showed infrequent spontaneous activity in LV, in which Kv4.2 but not Kv1.5 or KChIP2 was down-regulated. Because they are at low risk of death in spite of enlarged hearts, reduction in Kv4.2 is not sufficient for sudden death (SD). Our results suggest 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 SD in this DCM model.