Abstract 720: “Runaway” Biological Pacemaker Function Induced by HCN212 is Controlled by If Blockade with Ivabradine
A concern regarding biological pacemakers has been the potential for “runaway pacemakers” seen as rapid ventricular tachycardia (VT) originating at the implant site. We have not seen this with the HCN2 gene or E324A mutant, but in preliminary experiments found an adenoviral construct of the HCN212 chimera (whose transmembrane channel domain derives from HCN1), induces rapid VT after implantation into the canine left bundle branch system (LBB).
Hypothesis: Runaway pacemaker function induced by HCN212 can be controlled by the If-blocking drug ivabradine (IVB).
Methods: HCN2, HCN1 and HCN212 channels were expressed in HEK293 cells and pacemaker current recorded via whole cell patch clamp. In vivo, HCN212 in an adenoviral vector was injected into the LBB and 24h ECG monitoring was performed. IVB 1mg/kg was administered IV during rapid VT and ECG response evaluated.
Results. In HEK293 cells mean steady-state current block induced by 3 μM IVB (activation/deactivation protocol, −100 mV/+5 mV) was: HCN2, 63.4% (n = 5), HCN1, 83.1 % (n = 5) HCN212 82.4% (n = 5), indicating steady-state HCN212 block similar to HCN1. However, for state dependence of IVB block, HCN212 differed from HCN1 and approximated HCN2 in lacking closed state block. In experiments in vivo, post-LBB implantation, 5/6 dogs developed fast, bursting VT whose QRS configuration pace-mapped to the injection site. In all 5 the initial QRS configuration differed from that of VT, suggesting a site of origin other than the injection site. VT maximal rate = 285 ± 37 bpm (X+/-SEM), starting on day 0.9 ± 0.3 and persisting 5 ± 1days. IVB was given to and terminated VT in 3 dogs in 3.2 ± 0.6 min. The pace-mapped VT terminated first and the initial QRS complex originating from another site terminated last.
IVB terminated VT induced by a runaway HCN212 pacemaker, suggesting If associated arrhythmias which may occur with biological pacemakers can be controlled with If blocking drugs;
In vitro, IVB has a greater steady-state effect on HCN1 and HCN212 isoforms than HCN2.
This is consistent with the finding in vivo that VT originating from the HCN212 injection site was suppressed more readily than the first VT complex which was likely of HCN2 origin.