Characterization of a right atrial subsidiary pacemaker and acceleration of the pacing rate by HCN over-expression

Gwilym M. Morris, Alicia D'Souza, Halina Dobrzynski, Ming Lei, Moinuddin Choudhury, Rudi Billeter, Yelena Kryukova, Richard B. Robinson, Paul A. Kingston, Mark R. Boyett

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Aims: 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. Methods and results: SAP tissue was isolated from the rat and the leading pacemaker site was characterized. Cell size at the leading pacemaker sitein the SAP was smaller than in the RA and comparableto that in the SAN. mRNA levels showed the SAPto besimilar 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 spontaneousl, but at a slower rate than the SAN. Adeno-virus-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. Conclusion: SAP tissue near the inferior vena cava is bradycardic, but shares characteristics with the SAN. Pacing canbe 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. © The Author 2013.
Original languageUndefined
Pages (from-to)160-169
Number of pages10
JournalCardiovascular research
Issue number1
Publication statusPublished - 19 Jun 2013


  • Biopacemaker
  • Gene therapy
  • Sick sinus syndrome
  • Sinus node
  • Subsidiary atrial pacemaker

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