Effects of Angiotensin II Receptor Blocker on the Progression of Electrical Remodeling in Hearts of Inherited DCM Model Mice

Abstract

Inherited dilated cardiomyopathy (DCM), characterized by dilation and impaired systolic function of ventricle, is a progressive disease often resulting in death with congestive heart failure (CHF) or sudden death (SD). It remains unclear how electrical remodeling proceed in inherited DCM. Furthermore, although angiotensin II receptor blockers (ARBs) is known to have beneficial effects on HF in general, little is known about the effects of ARB on the electrical remodeling in inherited DCM. The aim of our study was to investigate effects of ARB on the remodeling in inherited DCM hearts using a knock-in mouse model of DCM (TNNT2 ΔK210). In DCM mice at 2 months of age when mortality rate abruptly increased, myocardium showed a significant reduction in K+ current density with substantial decreases in expression of Kv4.2, Kv1.5 and KChIP2. In contrast, at 1 month, down-regulation of Kv1.5 or KChIP2 was not observed, but up-regulation of Cav3.1 was detected. At 3 months, some of DCM mice showed a lung edema, a sign of CHF. CHF myocardium showed further decrease in expression of the various K+ channels. Treatment with ARB, candesartan, started at 1 months, considerably extended lifespan of DCM mice. Interestingly, expression changes that occurred in later phase were inhibited by ARB whereas changes occurred at early stage were not affected. Our results indicate that the electrical remodeling at later stage of DCM is critical for survival of this mouse model and the remodeling is controllable by ARB.