TBX18 overexpression enhances pacemaker function in a rat subsidiary atrial pacemaker model of sick sinus syndrome
Key points The sinoatrial node (SAN) is the primary pacemaker of the heart. SAN dysfunction, or ‘sick sinus syndrome’, can cause excessively slow heart rates and pauses, leading to exercise limitation and syncope, currently treated by implantation of an electronic pacemaker. ‘Biopacemaking’ utilises...
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| Veröffentlicht in: | The Journal of physiology 2018-12, Vol.596 (24), p.6141-6155 |
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| creator | Choudhury, M. Black, N. Alghamdi, A. D'Souza, A. Wang, R. Yanni, J. Dobrzynski, H. Kingston, P. A. Zhang, H. Boyett, M. R. Morris, G. M. |
| description | Key points
The sinoatrial node (SAN) is the primary pacemaker of the heart. SAN dysfunction, or ‘sick sinus syndrome’, can cause excessively slow heart rates and pauses, leading to exercise limitation and syncope, currently treated by implantation of an electronic pacemaker.
‘Biopacemaking’ utilises gene therapy to restore pacemaker activity by manipulating gene expression. Overexpressing the HCN pacemaker ion channel has been widely used with limited success.
We utilised bradycardic rat subsidiary atrial pacemaker tissue to evaluate alternative gene targets: the Na+/Ca2+ exchanger NCX1, and the transcription factors TBX3 and TBX18 known to be involved in SAN embryonic development.
TBX18 overexpression restored normal SAN function, as assessed by increased rate, improved heart rate stability and restoration of isoprenaline response. TBX3 and NCX1 were not effective in accelerating the rate of subsidiary atrial pacemaker tissue.
Gene therapy targeting TBX18 could therefore have the potential to restore pacemaker function in human sick sinus syndrome obviating electronic pacemakers.
The sinoatrial node (SAN) is the primary pacemaker of the heart. Disease of the SAN, sick sinus syndrome, causes heart rate instability in the form of bradycardia and pauses, leading to exercise limitation and syncope. Biopacemaking aims to restore pacemaker activity by manipulating gene expression, and approaches utilising HCN channel overexpression have been widely used. We evaluated alternative gene targets for biopacemaking to restore normal SAN pacemaker physiology within bradycardic subsidiary atrial pacemaker (SAP) tissue, using the Na+/Ca2+ exchanger NCX1, and the transcription factors TBX3 and TBX18. TBX18 expression in SAP tissue restored normal SAN function, as assessed by increased rate (SAN 267.5 ± 13.6 bpm, SAP 144.1 ± 8.6 bpm, SAP‐TBX18 214.4 ± 14.4 bpm; P |
| doi_str_mv | 10.1113/JP276508 |
| format | Article |
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The sinoatrial node (SAN) is the primary pacemaker of the heart. SAN dysfunction, or ‘sick sinus syndrome’, can cause excessively slow heart rates and pauses, leading to exercise limitation and syncope, currently treated by implantation of an electronic pacemaker.
‘Biopacemaking’ utilises gene therapy to restore pacemaker activity by manipulating gene expression. Overexpressing the HCN pacemaker ion channel has been widely used with limited success.
We utilised bradycardic rat subsidiary atrial pacemaker tissue to evaluate alternative gene targets: the Na+/Ca2+ exchanger NCX1, and the transcription factors TBX3 and TBX18 known to be involved in SAN embryonic development.
TBX18 overexpression restored normal SAN function, as assessed by increased rate, improved heart rate stability and restoration of isoprenaline response. TBX3 and NCX1 were not effective in accelerating the rate of subsidiary atrial pacemaker tissue.
Gene therapy targeting TBX18 could therefore have the potential to restore pacemaker function in human sick sinus syndrome obviating electronic pacemakers.
The sinoatrial node (SAN) is the primary pacemaker of the heart. Disease of the SAN, sick sinus syndrome, causes heart rate instability in the form of bradycardia and pauses, leading to exercise limitation and syncope. Biopacemaking aims to restore pacemaker activity by manipulating gene expression, and approaches utilising HCN channel overexpression have been widely used. We evaluated alternative gene targets for biopacemaking to restore normal SAN pacemaker physiology within bradycardic subsidiary atrial pacemaker (SAP) tissue, using the Na+/Ca2+ exchanger NCX1, and the transcription factors TBX3 and TBX18. TBX18 expression in SAP tissue restored normal SAN function, as assessed by increased rate (SAN 267.5 ± 13.6 bpm, SAP 144.1 ± 8.6 bpm, SAP‐TBX18 214.4 ± 14.4 bpm; P < 0.001), improved heart rate stability (standard deviation of RR intervals fell from 39.3 ± 7.2 ms to 6.9 ± 0.8 ms, P < 0.01; root mean square of successive differences of RR intervals fell from 41.7 ± 8.2 ms to 6.1 ± 1.2 ms, P < 0.01; standard deviation of points perpendicular to the line of identity of Poincaré plots (SD1) fell from 29.5 ± 5.8 ms to 7.9 ± 2.0 ms, P < 0.05) and restoration of isoprenaline response (increases in rates of SAN 65.5 ± 1.3%, SAP 28.4 ± 3.4% and SAP‐TBX18 103.3 ± 10.2%; P < 0.001). These changes were driven by a TBX18‐induced switch in the dominant HCN isoform in SAP tissue, with a significant upregulation of HCN2 (from 1.01 × 10−5 ± 2.2 × 10−6 to 2.8 × 10−5 ± 4.3 × 10−6 arbitrary units, P < 0.001). Biophysically detailed computer modelling incorporating isoform‐specific HCN channel electrophysiology confirmed that the measured changes in HCN abundance could account for the observed changes in beating rates. TBX3 and NCX1 were not effective in accelerating the rate of SAP tissue.
Key points
The sinoatrial node (SAN) is the primary pacemaker of the heart. SAN dysfunction, or ‘sick sinus syndrome’, can cause excessively slow heart rates and pauses, leading to exercise limitation and syncope, currently treated by implantation of an electronic pacemaker.
‘Biopacemaking’ utilises gene therapy to restore pacemaker activity by manipulating gene expression. Overexpressing the HCN pacemaker ion channel has been widely used with limited success.
We utilised bradycardic rat subsidiary atrial pacemaker tissue to evaluate alternative gene targets: the Na+/Ca2+ exchanger NCX1, and the transcription factors TBX3 and TBX18 known to be involved in SAN embryonic development.
TBX18 overexpression restored normal SAN function, as assessed by increased rate, improved heart rate stability and restoration of isoprenaline response. TBX3 and NCX1 were not effective in accelerating the rate of subsidiary atrial pacemaker tissue.
Gene therapy targeting TBX18 could therefore have the potential to restore pacemaker function in human sick sinus syndrome obviating electronic pacemakers.]]></description><identifier>ISSN: 0022-3751</identifier><identifier>EISSN: 1469-7793</identifier><identifier>DOI: 10.1113/JP276508</identifier><identifier>PMID: 30259525</identifier><language>eng</language><publisher>England: Wiley Subscription Services, Inc</publisher><subject>Animals ; biopacemaking ; Bradycardia ; Calcium ; Cardiovascular ; Computer Simulation ; Coronary artery disease ; Electrophysiology ; Gene expression ; Gene Expression Regulation ; gene therapy ; Heart Atria ; Heart Conduction System - metabolism ; Heart diseases ; Heart rate ; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels - genetics ; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels - metabolism ; Ion channels (cyclic nucleotide-gated) ; Male ; Models, Biological ; Na+/Ca2+ exchanger ; NCX1 protein ; Pacemakers ; Protein Isoforms - genetics ; Protein Isoforms - metabolism ; Rats ; Research Paper ; sick sinus syndrome ; Sick Sinus Syndrome - therapy ; Sinoatrial Node - physiology ; Sodium-Calcium Exchanger - metabolism ; Standard deviation ; subsidiary atrial pacemaker tissue ; Syncope ; T-Box Domain Proteins - genetics ; T-Box Domain Proteins - metabolism ; TBX18 ; Tissue Culture Techniques ; Transcription factors</subject><ispartof>The Journal of physiology, 2018-12, Vol.596 (24), p.6141-6155</ispartof><rights>2018 The Authors. published by John Wiley & Sons Ltd on behalf of The Physiological Society</rights><rights>2018 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.</rights><rights>Journal compilation © 2018 The Physiological Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5445-bf91cce4780f728bfdaf2aa2cb7ecf60e9dabf8eaafcf5b90a0ded25ef79728c3</citedby><cites>FETCH-LOGICAL-c5445-bf91cce4780f728bfdaf2aa2cb7ecf60e9dabf8eaafcf5b90a0ded25ef79728c3</cites><orcidid>0000-0001-9893-6648 ; 0000-0003-3795-8178</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6292813/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6292813/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,1411,1427,27903,27904,45553,45554,46387,46811,53769,53771</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30259525$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Choudhury, M.</creatorcontrib><creatorcontrib>Black, N.</creatorcontrib><creatorcontrib>Alghamdi, A.</creatorcontrib><creatorcontrib>D'Souza, A.</creatorcontrib><creatorcontrib>Wang, R.</creatorcontrib><creatorcontrib>Yanni, J.</creatorcontrib><creatorcontrib>Dobrzynski, H.</creatorcontrib><creatorcontrib>Kingston, P. A.</creatorcontrib><creatorcontrib>Zhang, H.</creatorcontrib><creatorcontrib>Boyett, M. R.</creatorcontrib><creatorcontrib>Morris, G. M.</creatorcontrib><title>TBX18 overexpression enhances pacemaker function in a rat subsidiary atrial pacemaker model of sick sinus syndrome</title><title>The Journal of physiology</title><addtitle>J Physiol</addtitle><description><![CDATA[Key points
The sinoatrial node (SAN) is the primary pacemaker of the heart. SAN dysfunction, or ‘sick sinus syndrome’, can cause excessively slow heart rates and pauses, leading to exercise limitation and syncope, currently treated by implantation of an electronic pacemaker.
‘Biopacemaking’ utilises gene therapy to restore pacemaker activity by manipulating gene expression. Overexpressing the HCN pacemaker ion channel has been widely used with limited success.
We utilised bradycardic rat subsidiary atrial pacemaker tissue to evaluate alternative gene targets: the Na+/Ca2+ exchanger NCX1, and the transcription factors TBX3 and TBX18 known to be involved in SAN embryonic development.
TBX18 overexpression restored normal SAN function, as assessed by increased rate, improved heart rate stability and restoration of isoprenaline response. TBX3 and NCX1 were not effective in accelerating the rate of subsidiary atrial pacemaker tissue.
Gene therapy targeting TBX18 could therefore have the potential to restore pacemaker function in human sick sinus syndrome obviating electronic pacemakers.
The sinoatrial node (SAN) is the primary pacemaker of the heart. Disease of the SAN, sick sinus syndrome, causes heart rate instability in the form of bradycardia and pauses, leading to exercise limitation and syncope. Biopacemaking aims to restore pacemaker activity by manipulating gene expression, and approaches utilising HCN channel overexpression have been widely used. We evaluated alternative gene targets for biopacemaking to restore normal SAN pacemaker physiology within bradycardic subsidiary atrial pacemaker (SAP) tissue, using the Na+/Ca2+ exchanger NCX1, and the transcription factors TBX3 and TBX18. TBX18 expression in SAP tissue restored normal SAN function, as assessed by increased rate (SAN 267.5 ± 13.6 bpm, SAP 144.1 ± 8.6 bpm, SAP‐TBX18 214.4 ± 14.4 bpm; P < 0.001), improved heart rate stability (standard deviation of RR intervals fell from 39.3 ± 7.2 ms to 6.9 ± 0.8 ms, P < 0.01; root mean square of successive differences of RR intervals fell from 41.7 ± 8.2 ms to 6.1 ± 1.2 ms, P < 0.01; standard deviation of points perpendicular to the line of identity of Poincaré plots (SD1) fell from 29.5 ± 5.8 ms to 7.9 ± 2.0 ms, P < 0.05) and restoration of isoprenaline response (increases in rates of SAN 65.5 ± 1.3%, SAP 28.4 ± 3.4% and SAP‐TBX18 103.3 ± 10.2%; P < 0.001). These changes were driven by a TBX18‐induced switch in the dominant HCN isoform in SAP tissue, with a significant upregulation of HCN2 (from 1.01 × 10−5 ± 2.2 × 10−6 to 2.8 × 10−5 ± 4.3 × 10−6 arbitrary units, P < 0.001). Biophysically detailed computer modelling incorporating isoform‐specific HCN channel electrophysiology confirmed that the measured changes in HCN abundance could account for the observed changes in beating rates. TBX3 and NCX1 were not effective in accelerating the rate of SAP tissue.
Key points
The sinoatrial node (SAN) is the primary pacemaker of the heart. SAN dysfunction, or ‘sick sinus syndrome’, can cause excessively slow heart rates and pauses, leading to exercise limitation and syncope, currently treated by implantation of an electronic pacemaker.
‘Biopacemaking’ utilises gene therapy to restore pacemaker activity by manipulating gene expression. Overexpressing the HCN pacemaker ion channel has been widely used with limited success.
We utilised bradycardic rat subsidiary atrial pacemaker tissue to evaluate alternative gene targets: the Na+/Ca2+ exchanger NCX1, and the transcription factors TBX3 and TBX18 known to be involved in SAN embryonic development.
TBX18 overexpression restored normal SAN function, as assessed by increased rate, improved heart rate stability and restoration of isoprenaline response. TBX3 and NCX1 were not effective in accelerating the rate of subsidiary atrial pacemaker tissue.
Gene therapy targeting TBX18 could therefore have the potential to restore pacemaker function in human sick sinus syndrome obviating electronic pacemakers.]]></description><subject>Animals</subject><subject>biopacemaking</subject><subject>Bradycardia</subject><subject>Calcium</subject><subject>Cardiovascular</subject><subject>Computer Simulation</subject><subject>Coronary artery disease</subject><subject>Electrophysiology</subject><subject>Gene expression</subject><subject>Gene Expression Regulation</subject><subject>gene therapy</subject><subject>Heart Atria</subject><subject>Heart Conduction System - metabolism</subject><subject>Heart diseases</subject><subject>Heart rate</subject><subject>Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels - genetics</subject><subject>Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels - metabolism</subject><subject>Ion channels (cyclic nucleotide-gated)</subject><subject>Male</subject><subject>Models, Biological</subject><subject>Na+/Ca2+ exchanger</subject><subject>NCX1 protein</subject><subject>Pacemakers</subject><subject>Protein Isoforms - genetics</subject><subject>Protein Isoforms - metabolism</subject><subject>Rats</subject><subject>Research Paper</subject><subject>sick sinus syndrome</subject><subject>Sick Sinus Syndrome - therapy</subject><subject>Sinoatrial Node - physiology</subject><subject>Sodium-Calcium Exchanger - metabolism</subject><subject>Standard deviation</subject><subject>subsidiary atrial pacemaker tissue</subject><subject>Syncope</subject><subject>T-Box Domain Proteins - genetics</subject><subject>T-Box Domain Proteins - metabolism</subject><subject>TBX18</subject><subject>Tissue Culture Techniques</subject><subject>Transcription factors</subject><issn>0022-3751</issn><issn>1469-7793</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>EIF</sourceid><recordid>eNp1kU1rFTEUhoMo9loFf4EE3LiZmo_JZLIRtFi1FOziCu7CmcyJTTuTXJM7tfffm9IPq-DmZHEeHt6Tl5CXnB1wzuXb41OhO8X6R2TF2840Whv5mKwYE6KRWvE98qyUc8a4ZMY8JXuSCWWUUCuS1x--856mS8x4tclYSkiRYjyD6LDQDTic4QIz9Ut02-tdiBRohi0ty1DCGCDvKGxzgOkBPacRJ5o8LcFd1BGXQssujjnN-Jw88TAVfHH77pNvRx_Xh5-bk6-fvhy-P2mcalvVDN5w57DVPfNa9IMfwQsA4QaNzncMzQiD7xHAO68Gw4CNOAqFXpvKO7lP3t14N8sw4-gwbjNMdpPDXDPbBMH-vYnhzP5Il7YTRvRcVsGbW0FOPxcsWzuH4nCaIGJaihX164XmQvUVff0Pep6WHOt5lVKqlZ3U7I_Q5VRKRn8fhjN7XaS9K7Kirx6GvwfvmqvAwQ3wK0y4-6_Iro9Pa0ql5G-0sqn-</recordid><startdate>201812</startdate><enddate>201812</enddate><creator>Choudhury, M.</creator><creator>Black, N.</creator><creator>Alghamdi, A.</creator><creator>D'Souza, A.</creator><creator>Wang, R.</creator><creator>Yanni, J.</creator><creator>Dobrzynski, H.</creator><creator>Kingston, P. A.</creator><creator>Zhang, H.</creator><creator>Boyett, M. R.</creator><creator>Morris, G. M.</creator><general>Wiley Subscription Services, Inc</general><general>John Wiley and Sons Inc</general><scope>24P</scope><scope>WIN</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>7TS</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-9893-6648</orcidid><orcidid>https://orcid.org/0000-0003-3795-8178</orcidid></search><sort><creationdate>201812</creationdate><title>TBX18 overexpression enhances pacemaker function in a rat subsidiary atrial pacemaker model of sick sinus syndrome</title><author>Choudhury, M. ; Black, N. ; Alghamdi, A. ; D'Souza, A. ; Wang, R. ; Yanni, J. ; Dobrzynski, H. ; Kingston, P. A. ; Zhang, H. ; Boyett, M. R. ; Morris, G. M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5445-bf91cce4780f728bfdaf2aa2cb7ecf60e9dabf8eaafcf5b90a0ded25ef79728c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Animals</topic><topic>biopacemaking</topic><topic>Bradycardia</topic><topic>Calcium</topic><topic>Cardiovascular</topic><topic>Computer Simulation</topic><topic>Coronary artery disease</topic><topic>Electrophysiology</topic><topic>Gene expression</topic><topic>Gene Expression Regulation</topic><topic>gene therapy</topic><topic>Heart Atria</topic><topic>Heart Conduction System - metabolism</topic><topic>Heart diseases</topic><topic>Heart rate</topic><topic>Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels - genetics</topic><topic>Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels - metabolism</topic><topic>Ion channels (cyclic nucleotide-gated)</topic><topic>Male</topic><topic>Models, Biological</topic><topic>Na+/Ca2+ exchanger</topic><topic>NCX1 protein</topic><topic>Pacemakers</topic><topic>Protein Isoforms - genetics</topic><topic>Protein Isoforms - metabolism</topic><topic>Rats</topic><topic>Research Paper</topic><topic>sick sinus syndrome</topic><topic>Sick Sinus Syndrome - therapy</topic><topic>Sinoatrial Node - physiology</topic><topic>Sodium-Calcium Exchanger - metabolism</topic><topic>Standard deviation</topic><topic>subsidiary atrial pacemaker tissue</topic><topic>Syncope</topic><topic>T-Box Domain Proteins - genetics</topic><topic>T-Box Domain Proteins - metabolism</topic><topic>TBX18</topic><topic>Tissue Culture Techniques</topic><topic>Transcription factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Choudhury, M.</creatorcontrib><creatorcontrib>Black, N.</creatorcontrib><creatorcontrib>Alghamdi, A.</creatorcontrib><creatorcontrib>D'Souza, A.</creatorcontrib><creatorcontrib>Wang, R.</creatorcontrib><creatorcontrib>Yanni, J.</creatorcontrib><creatorcontrib>Dobrzynski, H.</creatorcontrib><creatorcontrib>Kingston, P. A.</creatorcontrib><creatorcontrib>Zhang, H.</creatorcontrib><creatorcontrib>Boyett, M. R.</creatorcontrib><creatorcontrib>Morris, G. M.</creatorcontrib><collection>Wiley Online Library Open Access</collection><collection>Wiley Free Content</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Physical Education Index</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of physiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Choudhury, M.</au><au>Black, N.</au><au>Alghamdi, A.</au><au>D'Souza, A.</au><au>Wang, R.</au><au>Yanni, J.</au><au>Dobrzynski, H.</au><au>Kingston, P. A.</au><au>Zhang, H.</au><au>Boyett, M. R.</au><au>Morris, G. M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>TBX18 overexpression enhances pacemaker function in a rat subsidiary atrial pacemaker model of sick sinus syndrome</atitle><jtitle>The Journal of physiology</jtitle><addtitle>J Physiol</addtitle><date>2018-12</date><risdate>2018</risdate><volume>596</volume><issue>24</issue><spage>6141</spage><epage>6155</epage><pages>6141-6155</pages><issn>0022-3751</issn><eissn>1469-7793</eissn><abstract><![CDATA[Key points
The sinoatrial node (SAN) is the primary pacemaker of the heart. SAN dysfunction, or ‘sick sinus syndrome’, can cause excessively slow heart rates and pauses, leading to exercise limitation and syncope, currently treated by implantation of an electronic pacemaker.
‘Biopacemaking’ utilises gene therapy to restore pacemaker activity by manipulating gene expression. Overexpressing the HCN pacemaker ion channel has been widely used with limited success.
We utilised bradycardic rat subsidiary atrial pacemaker tissue to evaluate alternative gene targets: the Na+/Ca2+ exchanger NCX1, and the transcription factors TBX3 and TBX18 known to be involved in SAN embryonic development.
TBX18 overexpression restored normal SAN function, as assessed by increased rate, improved heart rate stability and restoration of isoprenaline response. TBX3 and NCX1 were not effective in accelerating the rate of subsidiary atrial pacemaker tissue.
Gene therapy targeting TBX18 could therefore have the potential to restore pacemaker function in human sick sinus syndrome obviating electronic pacemakers.
The sinoatrial node (SAN) is the primary pacemaker of the heart. Disease of the SAN, sick sinus syndrome, causes heart rate instability in the form of bradycardia and pauses, leading to exercise limitation and syncope. Biopacemaking aims to restore pacemaker activity by manipulating gene expression, and approaches utilising HCN channel overexpression have been widely used. We evaluated alternative gene targets for biopacemaking to restore normal SAN pacemaker physiology within bradycardic subsidiary atrial pacemaker (SAP) tissue, using the Na+/Ca2+ exchanger NCX1, and the transcription factors TBX3 and TBX18. TBX18 expression in SAP tissue restored normal SAN function, as assessed by increased rate (SAN 267.5 ± 13.6 bpm, SAP 144.1 ± 8.6 bpm, SAP‐TBX18 214.4 ± 14.4 bpm; P < 0.001), improved heart rate stability (standard deviation of RR intervals fell from 39.3 ± 7.2 ms to 6.9 ± 0.8 ms, P < 0.01; root mean square of successive differences of RR intervals fell from 41.7 ± 8.2 ms to 6.1 ± 1.2 ms, P < 0.01; standard deviation of points perpendicular to the line of identity of Poincaré plots (SD1) fell from 29.5 ± 5.8 ms to 7.9 ± 2.0 ms, P < 0.05) and restoration of isoprenaline response (increases in rates of SAN 65.5 ± 1.3%, SAP 28.4 ± 3.4% and SAP‐TBX18 103.3 ± 10.2%; P < 0.001). These changes were driven by a TBX18‐induced switch in the dominant HCN isoform in SAP tissue, with a significant upregulation of HCN2 (from 1.01 × 10−5 ± 2.2 × 10−6 to 2.8 × 10−5 ± 4.3 × 10−6 arbitrary units, P < 0.001). Biophysically detailed computer modelling incorporating isoform‐specific HCN channel electrophysiology confirmed that the measured changes in HCN abundance could account for the observed changes in beating rates. TBX3 and NCX1 were not effective in accelerating the rate of SAP tissue.
Key points
The sinoatrial node (SAN) is the primary pacemaker of the heart. SAN dysfunction, or ‘sick sinus syndrome’, can cause excessively slow heart rates and pauses, leading to exercise limitation and syncope, currently treated by implantation of an electronic pacemaker.
‘Biopacemaking’ utilises gene therapy to restore pacemaker activity by manipulating gene expression. Overexpressing the HCN pacemaker ion channel has been widely used with limited success.
We utilised bradycardic rat subsidiary atrial pacemaker tissue to evaluate alternative gene targets: the Na+/Ca2+ exchanger NCX1, and the transcription factors TBX3 and TBX18 known to be involved in SAN embryonic development.
TBX18 overexpression restored normal SAN function, as assessed by increased rate, improved heart rate stability and restoration of isoprenaline response. TBX3 and NCX1 were not effective in accelerating the rate of subsidiary atrial pacemaker tissue.
Gene therapy targeting TBX18 could therefore have the potential to restore pacemaker function in human sick sinus syndrome obviating electronic pacemakers.]]></abstract><cop>England</cop><pub>Wiley Subscription Services, Inc</pub><pmid>30259525</pmid><doi>10.1113/JP276508</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0001-9893-6648</orcidid><orcidid>https://orcid.org/0000-0003-3795-8178</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0022-3751 |
| ispartof | The Journal of physiology, 2018-12, Vol.596 (24), p.6141-6155 |
| issn | 0022-3751 1469-7793 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6292813 |
| source | MEDLINE; Wiley Online Library Journals Frontfile Complete; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Wiley Free Content; PubMed Central |
| subjects | Animals biopacemaking Bradycardia Calcium Cardiovascular Computer Simulation Coronary artery disease Electrophysiology Gene expression Gene Expression Regulation gene therapy Heart Atria Heart Conduction System - metabolism Heart diseases Heart rate Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels - genetics Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels - metabolism Ion channels (cyclic nucleotide-gated) Male Models, Biological Na+/Ca2+ exchanger NCX1 protein Pacemakers Protein Isoforms - genetics Protein Isoforms - metabolism Rats Research Paper sick sinus syndrome Sick Sinus Syndrome - therapy Sinoatrial Node - physiology Sodium-Calcium Exchanger - metabolism Standard deviation subsidiary atrial pacemaker tissue Syncope T-Box Domain Proteins - genetics T-Box Domain Proteins - metabolism TBX18 Tissue Culture Techniques Transcription factors |
| title | TBX18 overexpression enhances pacemaker function in a rat subsidiary atrial pacemaker model of sick sinus syndrome |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-23T23%3A24%3A13IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=TBX18%20overexpression%20enhances%20pacemaker%20function%20in%20a%20rat%20subsidiary%20atrial%20pacemaker%20model%20of%20sick%20sinus%20syndrome&rft.jtitle=The%20Journal%20of%20physiology&rft.au=Choudhury,%20M.&rft.date=2018-12&rft.volume=596&rft.issue=24&rft.spage=6141&rft.epage=6155&rft.pages=6141-6155&rft.issn=0022-3751&rft.eissn=1469-7793&rft_id=info:doi/10.1113/JP276508&rft_dat=%3Cproquest_pubme%3E2113271258%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2155436370&rft_id=info:pmid/30259525&rfr_iscdi=true |