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mHCN4 Genetically Modified Canine Mesenchymal Stem Cells Provide Biological Pacemaking Function in Complete Dogs with Atrioventricular Block
Author(s) -
LU WEI,
YAOMING G,
BOLI RAN,
JUN CHENG,
CHANGHAI ZHANG,
YANG ZHOU,
ZHIYUAN SONG
Publication year - 2013
Publication title -
pacing and clinical electrophysiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.686
H-Index - 101
eISSN - 1540-8159
pISSN - 0147-8389
DOI - 10.1111/pace.12154
Subject(s) - medicine , atrioventricular block , western blot , cardiology , heart rate , andrology , pathology , biology , gene , biochemistry , blood pressure
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 I HCN4 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‐R N against R‐R N+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. Conclusion 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.