Abstract 2282: Adrenergic Deficiency Leads to Slowed Ventricular Conduction and Increased Arrhythmias in Embryonic Mouse Hearts
Adrenergic hormones of cardiac origin are necessary for embryonic survival. For unknown reasons, norephinephrine- and epinephrine-deficient (dopamine β-hydroylase knock-out, Dbh−/−) mice die of apparent heart failure beginning embryonic day 10.5 (E10.5). To examine possible changes to the cardiac conduction system at E10.5, immunofluorescent staining for the pacemaker channel HCN4 and major gap junction protein connexin 43 (Cx43) was performed on hearts from Dbh+/+ and Dbh+/− (adrenergic competent, AC) and Dbh−/− embryos. Dbh−/− hearts displayed no change in HCN4 expression but greatly reduced Cx43 expression throughout the myocardium. To evaluate conduction velocity, extracellular field potentials were measured from hearts on microelectrode arrays (8×8, 200 μm apart). Atrial conduction speed (sinoatrial region to atrioventricular junction (AVJ)) was not different in Dbh−/− hearts, but ventricular septal conduction (AVJ to apex) was significantly slowed (AC: 15.4±1.7 n=6 vs. Dbh−/−: 31.4±6.4 ms n=5, p<0.05). To evaluate sinus rhythmicity, hearts were filmed in culture dishes and cycle lengths measured using LabView software. Heart rates were not different. Arrhythmias were more frequent and severe in Dbh−/− hearts than AC by cycle length variation (AC: 0.057±0.017 n=20 vs. Dbh−/−: 0.166±0.043 n=10, p<0.01, Figure⇓). These results are characteristic of Cx43-deficient mouse models and indicate that Cx43 insufficiency is a probable contributor to embryonic Dbh−/− lethality. This report provides novel physiological evidence suggesting that adrenergic hormones play a key role in development of the cardiac conduction system.
This research has received full or partial funding support from the American Heart Association, Greater Southeast Affiliate (Alabama, Florida, Georgia, Louisiana, Mississippi, Puerto Rico & Tennessee).