N-Acetylcysteine Suppresses the Progression of Ventricular Remodeling in Acute Myocarditis - Studies in an Experimental Autoimmune Myocarditis (EAM) Model -

Abstract

Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp lectrical and structural remodeling of the heart can develop in various pathological conditions, such as myocardial ischemia, 1-3 cardiomyopathy, 4,5 congestive heart failure, 3,6 hypertension 7 as well as myocarditis. 8, 9 In previous reports, we documented ventricular electrical and structural remodeling in an experimental autoimmune myocarditis (EAM) model in rats, 8,9 and it was characterized by prolongation in the effective refractory period (ERP) and monophasic action potential duration (MAPD) and downregulated expressions of the Kv4.2, Kv1.5, potassium channel interacting protein-2 (KChIP2) and sarcoplasmic reticulum Ca 2+ -ATPase 2a (SERCa2a). In this model, the overexpression of inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) or interferon-γ (IFN-γ) induces myocardial damage and possibly causes ventricular remodeling. 10, 11 We have also reported that TNF-α stimulation induces cellular hypertrophy as well as suppression of the Ito current and Kv4.2 expression in cultured neonatal rat myocytes. 12 Because TNF-α is a strong inducer of nitric oxide (NO) or reactive oxygen species (ROS), this inflammatory process may promote cardiac injury and electrical remodeling through a hyper-oxidative condition. Several studies have documented that antioxidant treatment using N-acetylcysteine (NAC), a thiol-containing radical scavenger and glutathione precursor, may attenuate the myocardial damage through in vitro and in vivo models of heart diseases, 13-15 so that the anti-remodeling effect of antioxidant therapy might be expected in myocarditis. In the present study, we evaluated the expression of inflammatory cytokines and ROS generation through the development of cardiac remodeling in an EAM rat model, and also evaluated the effect of NAC as an antioxidative therapy for ventricular electrical and structural remodeling. Background: Electrical and structural remodeling, characterized by prolonged action potential duration (APD), Kv4.2 downregulation and cellular infiltration were studied in rat experimental autoimmune myocarditis (EAM). Because the reactive oxygen species (ROS) has been speculated to play a role in the promotion of such remodeling, the effect of N-acetylcysteine (NAC) on the progression of ventricular remodeling was evaluated.

Increased Phosphorylation of Ca²⁺ Handling Proteins as a Proarrhythmic Mechanism in Myocarditis

“…6, 35 Niwano et al reported that the N-acetylcysteine treatment suppressed ventricular remodeling in myocarditis rats. 36 This study consistently showed that steroid pretreatment was related to improved survival and suppression of arrhythmias in the rats with myocarditis. Therefore, the prevention of inflammation might suppress arrhythmia by preventing either remodeling or myocarditis itself.…”

Cardiomyocyte-Derived Mitochondrial Superoxide Causes Myocardial Electrical Remodeling by Downregulating Potassium Channels and Related Molecules

“…In our report using an experimental model of autoimmune myocarditis in rats, we have emphasized the role of oxidative stress in the electrical and structural remodeling in the acute phase of myocarditis, but the effect of oxidative stress could not be separated from various stimulations during immune and inflammatory processes. 19 Our previous study using BSO-treated glutathione-depleted rats was the first to evaluate the effect of primary oxidative stress on cardiac remodeling in vivo, and revealed no structural change but there were electrophysiological changes, that is, ERP shortening and MAPD prolongation, and the downregulated expression of erg and sarcoendoplasmic reticulum Ca 2+ -ATPase 2 (SERCA2). 7 In contrast, in the present study, BSO-treated H/M-Sod2 +/-mice exhibited ERP prolongation, MAPD prolongation and the downregulated expression of Kv4.2 and KChIP2 in comparison with the WT control, but no significant difference was observed in the expression of erg, at least not at the protein level.…”

Progression of Ventricular Remodeling and Arrhythmia in the Primary Hyperoxidative State of Glutathione-Depleted Rats

“…We have documented that N-acetylcysteine, a precursor of glutathione, suppressed ventricular remodeling and arrhythmia in experimental autoimmune myocarditis of rats. 7 Therefore, oxidative stress played a key role in promoting electrical and structural remodeling in a model of myocarditis. Similarly, several reports have demonstrated electrophysiological changes that might be caused by oxidative stress in disease-model animals.…”