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

doi:10.1093/cvr/cvt164

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

Division of Cardiovascular Sciences (L5)

Research output: Contribution to journal › Article › peer-review

Abstract

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 language	Undefined
Pages (from-to)	160-169
Number of pages	10
Journal	Cardiovascular research
Volume	100
Issue number	1
DOIs	https://doi.org/10.1093/cvr/cvt164
Publication status	Published - 19 Jun 2013

Keywords

Biopacemaker
Gene therapy
Sick sinus syndrome
Sinus node
Subsidiary atrial pacemaker

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10.1093/cvr/cvt164

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@article{b7569a5bbfb847e5b78285c3ed02b074,

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

abstract = "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. {\textcopyright} The Author 2013.",

keywords = "Biopacemaker, Gene therapy, Sick sinus syndrome, Sinus node, Subsidiary atrial pacemaker",

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

year = "2013",

month = jun,

day = "19",

doi = "10.1093/cvr/cvt164",

language = "Undefined",

volume = "100",

pages = "160--169",

journal = "Cardiovascular research",

issn = "0008-6363",

publisher = "Oxford University Press",

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TY - JOUR

T1 - Characterization of a right atrial subsidiary pacemaker and acceleration of the pacing rate by HCN over-expression

AU - Morris, Gwilym M.

AU - D'Souza, Alicia

AU - Dobrzynski, Halina

AU - Lei, Ming

AU - Choudhury, Moinuddin

AU - Billeter, Rudi

AU - Kryukova, Yelena

AU - Robinson, Richard B.

AU - Kingston, Paul A.

AU - Boyett, Mark R.

PY - 2013/6/19

Y1 - 2013/6/19

N2 - 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.

AB - 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.

KW - Biopacemaker

KW - Gene therapy

KW - Sick sinus syndrome

KW - Sinus node

KW - Subsidiary atrial pacemaker

UR - http://www.scopus.com/inward/record.url?eid=2-s2.0-84887922535&partnerID=MN8TOARS

U2 - 10.1093/cvr/cvt164

DO - 10.1093/cvr/cvt164

M3 - Article

C2 - 23787003

SN - 0008-6363

VL - 100

SP - 160

EP - 169

JO - Cardiovascular research

JF - Cardiovascular research

IS - 1

ER -

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

Abstract

Keywords

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