Down-Regulation of Connexin43 in Heart Failure Is Reversed by Beta Blocker Therapy

Abstract

Background: Connexin43 (Cx43) is the primary subunit of inter-cellular gap junctions in the human ventricle. It is down-regulated in heart failure and associated with increased arrhythmogenesis. Recent animal studies suggest that beta-blockers may increase Cx43 expression. We hypothesized that metoprolol succinate would upregulate Cx43 gene expression in the intact failing human heart over time. Methods: Seven patients with idiopathic dilated cardiomyopathy, LVEF <40%, NYHA II-IV, age= 44.5±15.5, cardiac index 2.3±0.59 were treated with metoprolol succinate. Each patient had endomyocardial biopsies at baseline, 3 months and 12 months for serial analysis of myocardial gene expression. Myocardial tissues from twelve nonfailing explanted human hearts were analyzed as controls. Cx43 expression was measured utilizing microarrays (Affymetrix U133 Plus2). Differential changes in gene expression were then analyzed using GeneSifter software. Results: Expression of Cx43 was measured with a mean intensity of 17.0±1.2 in the control group compared to 12.4±0.3in the treatment arm at baseline, p<0.05. This is a net decline of 27% in failing hearts compared to nonfailing hearts. After 3 and 12 months of treatment with metoprolol succinate, Cx43 expression increased to 13.3±0.3, p<0.01 and 14.7±0.5, p<0.01, respectively compared to baseline. This is a net 12-month increase of 18%. Conclusions: Cx43 expression is down-regulated in heart failure. This down-regulation is partially reversed by beta-blocker therapy with metoprolol succinate. Background: Connexin43 (Cx43) is the primary subunit of inter-cellular gap junctions in the human ventricle. It is down-regulated in heart failure and associated with increased arrhythmogenesis. Recent animal studies suggest that beta-blockers may increase Cx43 expression. We hypothesized that metoprolol succinate would upregulate Cx43 gene expression in the intact failing human heart over time. Methods: Seven patients with idiopathic dilated cardiomyopathy, LVEF <40%, NYHA II-IV, age= 44.5±15.5, cardiac index 2.3±0.59 were treated with metoprolol succinate. Each patient had endomyocardial biopsies at baseline, 3 months and 12 months for serial analysis of myocardial gene expression. Myocardial tissues from twelve nonfailing explanted human hearts were analyzed as controls. Cx43 expression was measured utilizing microarrays (Affymetrix U133 Plus2). Differential changes in gene expression were then analyzed using GeneSifter software. Results: Expression of Cx43 was measured with a mean intensity of 17.0±1.2 in the control group compared to 12.4±0.3in the treatment arm at baseline, p<0.05. This is a net decline of 27% in failing hearts compared to nonfailing hearts. After 3 and 12 months of treatment with metoprolol succinate, Cx43 expression increased to 13.3±0.3, p<0.01 and 14.7±0.5, p<0.01, respectively compared to baseline. This is a net 12-month increase of 18%. Conclusions: Cx43 expression is down-regulated in heart failure. This down-regulation is partially reversed by beta-blocker therapy with metoprolol succinate.