title: Biological pacemaker created by minimally invasive somatic reprogramming in pigs with complete heart block.
abstract: Somatic reprogramming by reexpression of the embryonic transcription factor T-box 18 (TBX18) converts cardiomyocytes into pacemaker cells. We hypothesized that this could be a viable therapeutic avenue for pacemaker-dependent patients afflicted with device-related complications, and therefore tested whether adenoviral TBX18 gene transfer could create biological pacemaker activity in vivo in a large-animal model of complete heart block. Biological pacemaker activity, originating from the intramyocardial injection site, was evident in TBX18-transduced animals starting at day 2 and persisted for the duration of the study (14 days) with minimal backup electronic pacemaker use. Relative to controls transduced with a reporter gene, TBX18-transduced animals exhibited enhanced autonomic responses and physiologically superior chronotropic support of physical activity. Induced sinoatrial node cells could be identified by their distinctive morphology at the site of injection in TBX18-transduced animals, but not in controls. No local or systemic safety concerns arose. Thus, minimally invasive TBX18 gene transfer creates physiologically relevant pacemaker activity in complete heart block, providing evidence for therapeutic somatic reprogramming in a clinically relevant disease model.
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, CA 90048, USA. Division of Cardiology, Department of Internal Medicine, Taipei Veterans General Hospital and National Yang-Ming University, Taipei 112, Taiwan.
authors.forename: Yu-Feng
authors.initials: YF
authors.lastname: Hu
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, CA 90048, USA.
authors.forename: James Frederick
authors.initials: JF
authors.lastname: Dawkins
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, CA 90048, USA.
authors.forename: Hee Cheol
authors.initials: HC
authors.lastname: Cho
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, CA 90048, USA. eugenio.cingolani@csmc.edu eduardo.marban@csmc.edu.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Marbán
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, CA 90048, USA. eugenio.cingolani@csmc.edu eduardo.marban@csmc.edu.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Cingolani
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001145:Arrhythmias, Cardiac / Q000473:pathology; D001683:Biological Clocks; D065150:Cellular Reprogramming; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006327:Heart Block / Q000473:pathology*; D006801:Humans; D009043:Motor Activity; D032383:Myocytes, Cardiac / Q000473:pathology; D034421:Sus scrofa; D020825:T-Box Domain Proteins / Q000235:genetics; D014018:Tissue Distribution; D014161:Transduction, Genetic
chemical_list: D020825:T-Box Domain Proteins; C523796:Tbx18 protein, human; D049452:Green Fluorescent Proteins