title: Characterization of a right atrial subsidiary pacemaker and acceleration of the pacing rate by HCN over-expression.
abstract: OBJECTIVE
  Although the right atrium (RA contains subsidiary atrial pacemaker (SAP) tissue that can take over from the sinoatrial node (SAN) in sick sinus syndrome (SSS), SAP tissue is bradycardic. Little is known about SAP tissue and one aim of the study was to characterize ion channel expression to obtain insight into SAP pacemaker mechanisms. A second aim was to determine whether HCN over-expression (a 'biopacemaker'-like strategy) can accelerate the pacemaker rate producing a pacemaker that is similar in nature to the SAN.
  
  
  RESULTS
  SAP tissue was isolated from the rat and the leading pacemaker site was characterized. Cell size at the leading pacemaker site in the SAP was smaller than in the RA and comparable to that in the SAN. mRNA levels showed the SAP to be similar to, but distinct from, the SAN. For example, in the SAN and SAP, expression of Tbx3 and HCN1 was higher and Nav1.5 and Cx43 lower than in the RA. Organ-cultured SAP tissue beat spontaneously, but at a slower rate than the SAN. Adenovirus-mediated gene transfer of HCN2 and the chimeric protein HCN212 significantly increased the pacemaker rate of the SAP close to that of the native SAN, but HCN4 was ineffective.
  
  
  CONCLUSIONS
  SAP tissue near the inferior vena cava is bradycardic, but shares characteristics with the SAN. Pacing can be accelerated by the over-expression of HCN2 or HCN212. This provides proof of concept for the use of SAP tissue as a substrate for biopacemaking in the treatment of SSS.
authors.affiliation: Institute of Cardiovascular Sciences, University of Manchester, Core Technology Facility, 46 Grafton Street, Manchester M13 9NT, UK.
authors.forename: Gwilym M
authors.initials: GM
authors.lastname: Morris
authors.forename: Alicia
authors.initials: A
authors.lastname: D'Souza
authors.forename: Halina
authors.initials: H
authors.lastname: Dobrzynski
authors.forename: Ming
authors.initials: M
authors.lastname: Lei
authors.forename: Moinuddin
authors.initials: M
authors.lastname: Choudhury
authors.forename: Rudi
authors.initials: R
authors.lastname: Billeter
authors.forename: Yelena
authors.initials: Y
authors.lastname: Kryukova
authors.forename: Richard B
authors.initials: RB
authors.lastname: Robinson
authors.forename: Paul A
authors.initials: PA
authors.lastname: Kingston
authors.forename: Mark R
authors.initials: MR
authors.lastname: Boyett
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000502:physiology*; D002304:Cardiac Pacing, Artificial; D006325:Heart Atria; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000235:genetics / Q000502:physiology*; D008297:Male; D010138:Pacemaker, Artificial; D015221:Potassium Channels / Q000235:genetics / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D015222:Sodium Channels / Q000502:physiology; D019076:Transgenes
chemical_list: D015220:Calcium Channels; C513836:HCN4 protein, rat; C578667:Hcn1 protein, rat; C578712:Hcn2 protein, rat; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D015221:Potassium Channels; D012333:RNA, Messenger; D015222:Sodium Channels
keywords: Biopacemaker; Gene therapy; Sick sinus syndrome; Sinus node; Subsidiary atrial pacemaker