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Article: Bioartificial sinus node constructed via in vivo gene transfer of an engineered pacemaker HCN channel reduces the dependence on electronic pacemaker in a sick-sinus syndrome model

TitleBioartificial sinus node constructed via in vivo gene transfer of an engineered pacemaker HCN channel reduces the dependence on electronic pacemaker in a sick-sinus syndrome model
Authors
KeywordsChemicals And Cas Registry Numbers
Issue Date2006
PublisherLippincott Williams & Wilkins. The Journal's web site is located at http://circ.ahajournals.org
Citation
Circulation, 2006, v. 114 n. 10, p. 1000-1011 How to Cite?
AbstractBACKGROUND - The normal cardiac rhythm originates in the sinoatrial (SA) node that anatomically resides in the right atrium. Malfunction of the SA node leads to various forms of arrhythmias that necessitate the implantation of electronic pacemakers. We hypothesized that overexpression of an engineered HCN construct via somatic gene transfer offers a flexible approach for fine-tuning cardiac pacing in vivo. METHODS AND RESULTS - Using various electrophysiological and mapping techniques, we examined the effects of in situ focal expression of HCN1-ΔΔΔ, the S3-S4 linker of which has been shortened to favor channel opening, on impulse generation and conduction. Single left ventricular cardiomyocytes isolated from guinea pig hearts preinjected with the recombinant adenovirus Ad-CMV-GFP-IRES-HCN1-ΔΔΔ in vivo uniquely exhibited automaticity with a normal firing rate (237±12 bpm). High-resolution ex vivo optical mapping of Ad-CGI-HCN1-ΔΔΔ- injected Langendorff-perfused hearts revealed the generation of spontaneous action potentials from the transduced region in the left ventricle. To evaluate the efficacy of our approach for reliable atrial pacing, we generated a porcine model of sick-sinus syndrome by guided radiofrequency ablation of the native SA node, followed by implantation of a dual-chamber electronic pacemaker to prevent bradycardia-induced hemodynamic collapse. Interestingly, focal transduction of Ad-CGI-HCN1-ΔΔΔ in the left atrium of animals with sick-sinus syndrome reproducibly induced a stable, catecholamine-responsive in vivo "bioartificial node" that exhibited a physiological heart rate and was capable of reliably pacing the myocardium, substantially reducing electronic pacing. CONCLUSIONS - The results of the present study provide important functional and mechanistic insights into cardiac automaticity and have further refined an HCN gene-based therapy for correcting defects in cardiac impulse generation. © 2006 American Heart Association, Inc.
Persistent Identifierhttp://hdl.handle.net/10722/91529
ISSN
2015 Impact Factor: 17.047
2015 SCImago Journal Rankings: 7.853
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorTse, HFen_HK
dc.contributor.authorXue, Ten_HK
dc.contributor.authorLau, CPen_HK
dc.contributor.authorSiu, CWen_HK
dc.contributor.authorWang, Ken_HK
dc.contributor.authorZhang, QYen_HK
dc.contributor.authorTomaselli, GFen_HK
dc.contributor.authorAkar, FGen_HK
dc.contributor.authorLi, RAen_HK
dc.date.accessioned2010-09-17T10:20:52Z-
dc.date.available2010-09-17T10:20:52Z-
dc.date.issued2006en_HK
dc.identifier.citationCirculation, 2006, v. 114 n. 10, p. 1000-1011en_HK
dc.identifier.issn0009-7322en_HK
dc.identifier.urihttp://hdl.handle.net/10722/91529-
dc.description.abstractBACKGROUND - The normal cardiac rhythm originates in the sinoatrial (SA) node that anatomically resides in the right atrium. Malfunction of the SA node leads to various forms of arrhythmias that necessitate the implantation of electronic pacemakers. We hypothesized that overexpression of an engineered HCN construct via somatic gene transfer offers a flexible approach for fine-tuning cardiac pacing in vivo. METHODS AND RESULTS - Using various electrophysiological and mapping techniques, we examined the effects of in situ focal expression of HCN1-ΔΔΔ, the S3-S4 linker of which has been shortened to favor channel opening, on impulse generation and conduction. Single left ventricular cardiomyocytes isolated from guinea pig hearts preinjected with the recombinant adenovirus Ad-CMV-GFP-IRES-HCN1-ΔΔΔ in vivo uniquely exhibited automaticity with a normal firing rate (237±12 bpm). High-resolution ex vivo optical mapping of Ad-CGI-HCN1-ΔΔΔ- injected Langendorff-perfused hearts revealed the generation of spontaneous action potentials from the transduced region in the left ventricle. To evaluate the efficacy of our approach for reliable atrial pacing, we generated a porcine model of sick-sinus syndrome by guided radiofrequency ablation of the native SA node, followed by implantation of a dual-chamber electronic pacemaker to prevent bradycardia-induced hemodynamic collapse. Interestingly, focal transduction of Ad-CGI-HCN1-ΔΔΔ in the left atrium of animals with sick-sinus syndrome reproducibly induced a stable, catecholamine-responsive in vivo "bioartificial node" that exhibited a physiological heart rate and was capable of reliably pacing the myocardium, substantially reducing electronic pacing. CONCLUSIONS - The results of the present study provide important functional and mechanistic insights into cardiac automaticity and have further refined an HCN gene-based therapy for correcting defects in cardiac impulse generation. © 2006 American Heart Association, Inc.en_HK
dc.languageengen_HK
dc.publisherLippincott Williams & Wilkins. The Journal's web site is located at http://circ.ahajournals.orgen_HK
dc.relation.ispartofCirculationen_HK
dc.rightsCirculation. Copyright © Lippincott Williams & Wilkins.-
dc.subjectChemicals And Cas Registry Numbersen_HK
dc.subject.meshAnimalsen_HK
dc.subject.meshArrhythmias, Cardiac - physiopathology - surgeryen_HK
dc.subject.meshBioartificial Organsen_HK
dc.subject.meshCyclic Nucleotide-Gated Cation Channelsen_HK
dc.subject.meshDisease Models, Animalen_HK
dc.subject.meshElectrophysiologyen_HK
dc.subject.meshGene Transfer Techniquesen_HK
dc.subject.meshGuinea Pigsen_HK
dc.subject.meshHeart Rateen_HK
dc.subject.meshIon Channels - geneticsen_HK
dc.subject.meshMiceen_HK
dc.subject.meshPacemaker, Artificialen_HK
dc.subject.meshPotassium Channelsen_HK
dc.subject.meshSick Sinus Syndrome - physiopathology - surgeryen_HK
dc.subject.meshSinoatrial Node - physiologyen_HK
dc.subject.meshSwineen_HK
dc.subject.meshSwine, Miniatureen_HK
dc.titleBioartificial sinus node constructed via in vivo gene transfer of an engineered pacemaker HCN channel reduces the dependence on electronic pacemaker in a sick-sinus syndrome modelen_HK
dc.typeArticleen_HK
dc.identifier.emailTse, HF:hftse@hkucc.hku.hken_HK
dc.identifier.emailSiu, CW:cwdsiu@hkucc.hku.hken_HK
dc.identifier.emailLi, RA:ronaldli@hkucc.hku.hken_HK
dc.identifier.authorityTse, HF=rp00428en_HK
dc.identifier.authoritySiu, CW=rp00534en_HK
dc.identifier.authorityLi, RA=rp01352en_HK
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1161/CIRCULATIONAHA.106.615385en_HK
dc.identifier.pmid16923751-
dc.identifier.scopuseid_2-s2.0-33748508208en_HK
dc.identifier.hkuros183054-
dc.identifier.hkuros126501-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-33748508208&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume114en_HK
dc.identifier.issue10en_HK
dc.identifier.spage1000en_HK
dc.identifier.epage1011en_HK
dc.identifier.eissn1524-4539-
dc.identifier.isiWOS:000240244700004-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridTse, HF=7006070805en_HK
dc.identifier.scopusauthoridXue, T=7005064190en_HK
dc.identifier.scopusauthoridLau, CP=7401968501en_HK
dc.identifier.scopusauthoridSiu, CW=7006550690en_HK
dc.identifier.scopusauthoridWang, K=35286098800en_HK
dc.identifier.scopusauthoridZhang, QY=35331268500en_HK
dc.identifier.scopusauthoridTomaselli, GF=7005223451en_HK
dc.identifier.scopusauthoridAkar, FG=6701446552en_HK
dc.identifier.scopusauthoridLi, RA=7404724466en_HK

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