title: mHCN4 genetically modified canine mesenchymal stem cells provide biological pacemaking function in complete dogs with atrioventricular block.
abstract: BACKGROUND
  The study was undertaken to assess the properties of mouse HCN4 (mHCN4)-modified canine mesenchymal stem cells (cMSCs) in dogs with experimentally induced complete atrioventricular (AV) block and electronic pacing.
  
  
  METHODS
  Complete AV block was induced in adult dogs who had undergone implantation of backup electronic pacemakers. cMSCs were transfected with mHCN4 genes. Evidence of successful IHCN4 expression was provided by patch-clamp detection. mHCN4-cMSCs or normal cMSCs were injected subepicardially into the left ventricular anterior wall of the dogs. Cardiac parameters were monitored for 6 weeks. Heart rate variability (HRV) was evaluated using quantitative Poincaré plots of R-RN against R-RN+1 intervals. cMSCs survival and expression of HCN4 in vivo were examined by histological studies and Western blot.
  
  
  RESULTS
  In 2 weeks, the maximum heart rate and the number of impulses generated from the injection sites were much higher in dogs injected with HCN4-modified MSCs than in control dogs.  Basal heart rate increased in the HCN4 group and became fully stabilized by Week 4, evidenced by markedly reduced numbers of electronic pacemaker beats. At Week 2, HRV during exercise was significantly higher in HCN4 dogs than in controls as shown by descriptors of both instantaneous (SD1) and longer term (SD2) beat-to-beat deviations (P < 0.05). Hematoxylin-eosin staining and Western blot proved that cMSCs survive and express HCN4 protein in situ in heart of HCN4 dog.
  
  
  CONCLUSIONS
  Transplantation of mHCN4-modified cMSCs provided a stable biological pacemaking function that allowed an appropriate chronotropic response to physical exercise for up to 6 weeks.
authors.affiliation: Department of Cardiology, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
authors.forename: Nong
authors.initials: N
authors.lastname: Yaoming
authors.forename: Ran
authors.initials: R
authors.lastname: Boli
authors.forename: Cheng
authors.initials: C
authors.lastname: Jun
authors.forename: Zhang
authors.initials: Z
authors.lastname: Changhai
authors.forename: Zhou
authors.initials: Z
authors.lastname: Yang
authors.forename: Song
authors.initials: S
authors.lastname: Zhiyuan
mesh_terms: D000818:Animals; D054537:Atrioventricular Block / Q000503:physiopathology* / Q000601:surgery*; D001683:Biological Clocks; D004285:Dogs; D005260:Female; D005818:Genetic Engineering / Q000379:methods; D006329:Heart Conduction System / Q000503:physiopathology* / Q000601:surgery; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000235:genetics*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D014162:Transfection / Q000379:methods; D016896:Treatment Outcome
chemical_list: C578706:Hcn4 protein, mouse; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
keywords: HCN4 gene; biological pacemaker; cell therapy; gene therapy; heart rate variability; stem cells