BACKGROUND: A potential concern about biological pacemakers is their possible malfunction, which might create ventricular tachycardias (VTs). OBJECTIVE: The purpose of this study was to test our hypothesis that should VTs complicate implantation of HCN-channel-based biological pacemakers, they would be suppressed by inhibitors of the pacemaker current, I(f). METHODS: We created a chimeric channel (HCN212) containing the N- and C-termini of mouse HCN2 and the transmembrane region of mouse HCN1 and implanted it in HEK293 cells. Forty-eight hours later, in whole-cell patch clamp recordings, mean steady state block induced by 3 microM ivabradine (IVB) showed HCN1 = HCN212 > HCN2 currents. The HCN212 adenoviral construct was then implanted into the canine left bundle branch in 11 dogs. Complete AV block was created via radiofrequency ablation, and a ventricular demand electronic pacemaker was implanted (VVI 45 bpm). Electrocardiogram, 24-hour Holter monitoring, and pacemaker log record check were performed for 11 days. RESULTS: All dogs developed rapid VT (>120 bpm, maximum rate = 285 +/- 37 bpm) at 0.9 +/- 0.3 days after implantation that persisted through 5 +/- 1 days. IVB, 1 mg/kg over 5 minutes, was administered during rapid VT, and three dogs received a second dose 24 hours later. While VT terminated with IBV in all instances within 3.4 +/- 0.6 minutes, no effect of IVB on sinus rate was noted. CONCLUSION: We conclude that (1) I(f)-associated tachyarrhythmias-if they occur with HCN-based biological pacemakers-can be controlled with I(f)-inhibiting drugs such as IVB; (2) in vitro, IVB appears to have a greater steady state inhibiting effect on HCN1 and HCN212 isoforms than on HCN4; and (3) VT originating from the HCN212 injection site is suppressed more readily than sinus rhythm. This suggests a selectivity of IVB at the concentration attained for ectopic over HCN4-based pacemaker function. This might confer a therapeutic benefit.
BACKGROUND: A potential concern about biological pacemakers is their possible malfunction, which might create ventricular tachycardias (VTs). OBJECTIVE: The purpose of this study was to test our hypothesis that should VTs complicate implantation of HCN-channel-based biological pacemakers, they would be suppressed by inhibitors of the pacemaker current, I(f). METHODS: We created a chimeric channel (HCN212) containing the N- and C-termini of mouseHCN2 and the transmembrane region of mouseHCN1 and implanted it in HEK293 cells. Forty-eight hours later, in whole-cell patch clamp recordings, mean steady state block induced by 3 microM ivabradine (IVB) showed HCN1 = HCN212 > HCN2 currents. The HCN212 adenoviral construct was then implanted into the canine left bundle branch in 11 dogs. Complete AV block was created via radiofrequency ablation, and a ventricular demand electronic pacemaker was implanted (VVI 45 bpm). Electrocardiogram, 24-hour Holter monitoring, and pacemaker log record check were performed for 11 days. RESULTS: All dogs developed rapid VT (>120 bpm, maximum rate = 285 +/- 37 bpm) at 0.9 +/- 0.3 days after implantation that persisted through 5 +/- 1 days. IVB, 1 mg/kg over 5 minutes, was administered during rapid VT, and three dogs received a second dose 24 hours later. While VT terminated with IBV in all instances within 3.4 +/- 0.6 minutes, no effect of IVB on sinus rate was noted. CONCLUSION: We conclude that (1) I(f)-associated tachyarrhythmias-if they occur with HCN-based biological pacemakers-can be controlled with I(f)-inhibiting drugs such as IVB; (2) in vitro, IVB appears to have a greater steady state inhibiting effect on HCN1 and HCN212 isoforms than on HCN4; and (3) VT originating from the HCN212 injection site is suppressed more readily than sinus rhythm. This suggests a selectivity of IVB at the concentration attained for ectopic over HCN4-based pacemaker function. This might confer a therapeutic benefit.
Authors: Sei Iwai; Steven M Markowitz; Kenneth M Stein; Suneet Mittal; David J Slotwiner; Mithilesh K Das; Jennifer D Cohen; Steven C Hao; Bruce B Lerman Journal: Circulation Date: 2002-11-26 Impact factor: 29.690
Authors: C Thollon; S Bedut; N Villeneuve; F Cogé; L Piffard; J-P Guillaumin; C Brunel-Jacquemin; P Chomarat; J-A Boutin; J-L Peglion; J-P Vilaine Journal: Br J Pharmacol Date: 2006-11-27 Impact factor: 8.739
Authors: Alexei N Plotnikov; Iryna Shlapakova; Matthias J Szabolcs; Peter Danilo; Beverly H Lorell; Irina A Potapova; Zhongju Lu; Amy B Rosen; Richard T Mathias; Peter R Brink; Richard B Robinson; Ira S Cohen; Michael R Rosen Journal: Circulation Date: 2007-07-23 Impact factor: 29.690
Authors: Ning Li; Thomas A Csepe; Brian J Hansen; Halina Dobrzynski; Robert S D Higgins; Ahmet Kilic; Peter J Mohler; Paul M L Janssen; Michael R Rosen; Brandon J Biesiadecki; Vadim V Fedorov Journal: Circ Arrhythm Electrophysiol Date: 2015-08-24