AIMS: To assess the efficacy of autologous biological pacing function by autograft of gene-transferred mesenchymal stem cells in a porcine model of complete heart block. METHODS AND RESULTS: Fourteen healthy young male pigs were randomized into active group (n=8) and control group (n=6). Porcine MSCs were transfected with Ad.HCN4 or Ad.Null. The pacemaker function of transfected MSCs was studied by whole-cell patch clamp. The CHB model of porcine was created with transthoracic ablation technique and the transfected MSCs were autografted into the free wall of right ventricle. The pacing function was studied by ECG and ambulatory Holter recording weekly. The adrenergic responsiveness was evaluated by the variation of heart rate after isoprenaline infusion or food provision following an overnight fasting. HCN4-MSCs expressed a robust time-dependent inward current (If) and the current density of If was 4.3±0.6 pA/pF at -105 mV. In week 2 after autograft, the heart rate of active group became significantly higher than control (53±5 bpm vs. 38±4 bpm, P<0.05) and the percent of pacing beats in active group was higher than control (69±10% vs. 28±8%, P<0.05). By infusion of isoprenaline, the heart rate was increased significantly in both groups. However, there was a significant increase of heart rate when presenting food for active group (P<0.05) while not in control. CONCLUSIONS: Our findings demonstrated that autografted HCN4-MSCs could increase the heart rate by providing an adrenergic-responsive biological pacing function, indicating a promising approach without immunological or ethical issues for the treatment of complete heart block.
AIMS: To assess the efficacy of autologous biological pacing function by autograft of gene-transferred mesenchymal stem cells in a porcine model of complete heart block. METHODS AND RESULTS: Fourteen healthy young male pigs were randomized into active group (n=8) and control group (n=6). Porcine MSCs were transfected with Ad.HCN4 or Ad.Null. The pacemaker function of transfected MSCs was studied by whole-cell patch clamp. The CHB model of porcine was created with transthoracic ablation technique and the transfected MSCs were autografted into the free wall of right ventricle. The pacing function was studied by ECG and ambulatory Holter recording weekly. The adrenergic responsiveness was evaluated by the variation of heart rate after isoprenaline infusion or food provision following an overnight fasting. HCN4-MSCs expressed a robust time-dependent inward current (If) and the current density of If was 4.3±0.6 pA/pF at -105 mV. In week 2 after autograft, the heart rate of active group became significantly higher than control (53±5 bpm vs. 38±4 bpm, P<0.05) and the percent of pacing beats in active group was higher than control (69±10% vs. 28±8%, P<0.05). By infusion of isoprenaline, the heart rate was increased significantly in both groups. However, there was a significant increase of heart rate when presenting food for active group (P<0.05) while not in control. CONCLUSIONS: Our findings demonstrated that autografted HCN4-MSCs could increase the heart rate by providing an adrenergic-responsive biological pacing function, indicating a promising approach without immunological or ethical issues for the treatment of complete heart block.