Roles of aldosterone on ventricular arrhythmias, and associated gap junction and ion channel remodeling in hypertrophic heart

Abstract Background Ventricular arrhythmias are critical causes of death in patients with chronic heart failure (CHF). Aldosterone (Ald) is an exacerbating factor of CHF and mineral corticoid receptor antagonist (MRA) is usual drug for the management of CHF. MRA also suppressed sudden cardiac death, however, mechanisms of these effects remain unknown. We investigated the effects of MRA on ventricular arrhythmias and arrhythmogenic factors using Dahl Salt sensitive (DS) rats. Methods (in vivo) DS rats were divided into three groups; low salt group (LS), high salt group (HS), and eplerenone-, an MRA, treated high salt group (HS+EPL). Low salt (0.3% NaCl) or high salt (8% NaCl) were administrated for 8 weeks and EPL was administrated in the last 4 weeks. Cardiac geometry and function were assessed by echocardiography. Susceptibility of ventricular arrhythmias were assessed using programmed stimulation. Myocyte hypertrophy and cardiac fibrosis were examined by Masson’s trichrome staining. Expression and distribution of connexin43 (Cx43) were examined by immunostaining and western blotting. mRNA expression of Ca transient-related factors, such as phospholamban, SERCA2a, and ryanosin 2, and potassium ion channel-related factors, such as KCNE1 and KCNQ1, was examined by RT-PCR. (in vitro) Ald (1-100 nM) was administrated to cultured rat neonatal cardiomyocytes. Expression of Cx43, Ca transient-related, and potassium ion channel-related factors are also examined as mentioned above. Effects of Src tyrosin kinase inhibitor, PP2, and ERK inhibitor, PD98059, on Ald-induced Cx43 reduction were examined by RT-PCR and immunostaining. Results Systolic blood pressure and Ald concentrations in cardiac tissue were higher in HS group than LS group, and EPL did not affect them. In HS group left ventricular hypertrophy, dilatation and systolic dysfunction were observed in association with myocyte hypertrophy and interstitial fibrosis. EPL significantly recovered cardiac function and histological impairments. In addition, elongation of QTc in ECG and susceptibility of ventricular tachycardia were remarkable in HS group rather than LS and EPL attenuated them. Distribution of Cx43 was scattered in HS group, and EPL attenuated these changes. Decrease in SERCA2a and increase in KCNE1/KCNQ1 mRNA expression were found in HS group, and these changes were attenuated by EPL. In cultured myocytes, Ald decreased Cx43 mRNA and protein expression in a dose dependent fashion. Ald-induced Cx43 reduction was inhibited by PP2 and PD98059. In addition, Ald (100 nM) also decreased SERCA2a and increased KCNE1/KCNQ1 mRNA expression. Conclusion These results indicate that Ald reduced and dispersed the Cx43 expression reduction and dispersion through Src tyrosin kinase and ERK signaling pathways, and also mediated SRECA2A and KCNE1/KCNQ1 expression, which induced QTc prolongation and susceptibility of lethal ventricular arrhythmias in hypertensive cardiac hypertrophy.