title: Biological pacemaker engineered by nonviral gene transfer in a mouse model of complete atrioventricular block.
abstract: We hypothesized that a nonviral gene delivery of the hyperpolarization-activated HCN2 channel combined with the beta(2)-adrenergic receptor (ADRB2) would generate a functional pacemaker in a mouse model of complete atrioventricular block (CAVB) induced by radiofrequency ablation of the His bundle. Plasmids encoding HCN2 and ADRB2 mixed with tetronic 304, a poloxamine block copolymer, were injected in the left ventricular free wall (HCN2-ADRB2 mice). Sham mice received a noncoding plasmid. CAVB was induced 5 days later. Ventricular escape rhythms in HCN2-ADRB2 mice were significantly faster than in sham mice at day 15 after ablation and later. In HCN2-ADRB2 mice, QRS complexes were larger than in sham mice and characterized by abnormal axes. Immunostaining of GFP-HCN2 fusion protein showed an expression of HCN2 channel in left ventricular myocardium for at least 45 days after injection. In the mouse, CAVB induces progressive hypertrophy and heart failure leading to 50% mortality after 110 days. HCN2-ADRB2 mice survived 3 weeks longer than sham mice. Finally, beta-adrenergic input increased ventricular escape rhythms significantly more in HCN2-ADRB2 mice than in sham mice. In conclusion, nonviral gene transfer can produce a functional cardiac biological pacemaker regulated by sympathetic input, which improves life expectancy in a mouse model of CAVB.
authors.affiliation: INSERM, UMR915, l'institut du thorax, Nantes, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Piron
authors.forename: Khai Le
authors.initials: KL
authors.lastname: Quang
authors.forename: François
authors.initials: F
authors.lastname: Briec
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Amirault
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Leoni
authors.forename: Léa
authors.initials: L
authors.lastname: Desigaux
authors.forename: Denis
authors.initials: D
authors.lastname: Escande
authors.forename: Bruno
authors.initials: B
authors.lastname: Pitard
authors.forename: Flavien
authors.initials: F
authors.lastname: Charpentier
mesh_terms: D000818:Animals; D054537:Atrioventricular Block / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D001683:Biological Clocks; D002908:Chronic Disease; D004195:Disease Models, Animal; D004562:Electrocardiography; D005500:Follow-Up Studies; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D008297:Male; D051379:Mice; D011943:Receptors, Adrenergic, beta / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate; D019076:Transgenes / Q000235:genetics*
chemical_list: D011943:Receptors, Adrenergic, beta