Age-Dependent Intercalated Disc Perinexal Narrowing Conceals Long-Qt Syndrome Type 3 Phenotype

Abstract

Long-QT Syndrome Type 3 (LQT3) is characterized by cardiac action potential duration (APD) prolongation, which can be exacerbated by widening intercellular nanodomains adjacent to gap junctions in the intercalated disc, termed the perinexus. Previous studies suggest aging is associated with increased late sodium current (INaL), leading to APD prolongation in ventricular myocytes. We previously found that perinexal width correlates with age in surgery patients, but could not exclude disease as a confounding variable. However, it remains unknown if ventricular APD prolongation and perinexal expansion are associated with aging. The purpose of this study was to determine whether ventricular APD and perinexal separation change with age specifically in a model of LQT3. Ventricular APD was obtained from optical maps of Langendorff-perfused young (3 month) and aged (15 month) male guinea pig hearts. LQT3 phenotype was induced with an INaL agonist (ATXII), and perinexal width (Wp) was increased with an intercalated disc adhesion inhibitor (βadp1). Wp in fixed tissues was quantified by transmission electron microscopy. APD was not significantly different between young and aged hearts at baseline, with ATXII, or with ATXII+βadp1. Since we previously demonstrated ATXII does not affect Wp, it was surprising that Wp was significantly narrower in aged relative to young hearts in the presence of ATXII. Although βadp1 widened perinexi and prolonged APD in the presence of ATXII in both age groups, Wp remained significantly narrower in aged relative to young hearts. Correcting for Wp demonstrates that APD was significantly longer in aged relative to young hearts with similar Wp. The data reveal that perinexal separation narrows with aging in this model of drug-induced LQT3 without changing APD, suggesting perinexal narrowing with modest aging may suppress APD prolongation caused by age-dependent increases in INaL in ventricular myocytes.