Abstract 15845: Biological Pacemaker Induced in vivo by Focal Tbx18 Gene Transfer in the Guinea-Pig Left Ventricle
Cardiac rhythm disorders due to disease and aging of the sinoatrial node (SAN) can lead to malfunction in the generation of the electrical impulses that initiate the heartbeat. While state-of-the-art electronic pacemakers adequately maintain cardiac function, the cost of implantation/maintenance, combined with the risk of hardware infection, has driven the search for viable biological alternatives. Early efforts have focused on gene therapy to generate biological pacemakers by modulation of ionic currents (IK1, If) or cell therapy by delivering engineered pacemaker cells to the working myocardium. However, transdifferentiation of chamber cardiomyocytes to pacemaker cells by re-expression of embryonic transcription factors that shape the SAN has not been explored as an alternative. In an effort to generate biological pacemakers via reprogramming of ventricular myocytes to the pacemaker phenotype, Tbx18, a transcription factor required for delineation and determination of the SAN, was delivered to the apex of the left ventricle of guinea pigs using adenoviral vectors. 5-10 days post adenoviral delivery, downward deflections in electrocardiogram (ECG) recordings after methacholine injection (0.05mg/ml) revealed ectopic pacemaker activity from the ventricle, with a wider QRS complex than that of native beats and a rhythm of 40±20 beats/min in Tbx18-injected guinea pigs (n=5/7). No such ectopic activity was observed in control, Ad-GFP injected guinea pigs (n=0/7). Additionally, vectorcardiography indicated that the ectopic beats originated from the site of injection (apex) and propagated towards the base in Tbx18-injected guinea pig hearts. In contrast, controls exhibited only occasional escape rhythms arising from the secondary conduction system, with ECG vectors that began at the AV junction and spread towards the apex. Histological analysis revealed recapitulation of key features of the SAN in Tbx18-transduced tissue: suppression of connexin 43 and atrial natriuretic peptide expression, myofibrillar disorganization, HCN4 upregulation and diminished cell size. In summary, the expression of a single transcription factor, Tbx18, suffices to create induced biopacemaker activity in vivo, by reprogramming ventricular tissue.
- © 2011 by American Heart Association, Inc.