Biopacemaking: New Targets and New Mechanisms

Abstract

BACKGROUND: Biopacemaking is the attempt to replicate sinoatrial node (SAN)-like pacemaker activity in other areas of the heart by manipulating genes involved in pacemaking. Application of this could emulate the electronic pacemaker without the need for implantation of permanent hardware, or directly repair dysfunctional SAN tissue in human disease. We upregulated the transcription factors Tbx18, Tbx3 and the membrane ion exchanger NCX1 in bradycardic subsidiary atrial pacemaker (SAP) tissue which we used as a model of SAN dysfunction. We aimed to show that one or more of these gene targets could improve pacemaker function and alter the molecular character of SAP tissue and thus could potentially be used for the repair of dysfunctional SAN tissue.METHODS: SAP tissue was isolated from the right atria of rats and kept beating in culture at 37°C for 48 hours. Recombinant adenoviruses were injected into SAP preparations to upregulate Tbx18, Tbx3 and NCX1 individually. Beating rate, overdrive suppression and pharmacological response to If blockade and β-adrenergic stimulation were measured along with molecular changes in pacemaker and atrial genes and proteins using RT-qPCR and immunohistochemistry.RESULTS: Tbx18 upregulation significantly increased SAP beating rate after 48 hours of culture (a final rate of 141 ± 9 bpm in uninfected SAP tissue versus 215 ± 16 bpm in Ad-Tbx18 infected SAP tissue, p

Date of Award	1 Aug 2017
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Mark Boyett (Supervisor), Paul Kingston (Supervisor), Halina Dobrzynski (Supervisor) & Gwilym Morris (Supervisor)