Abstract 10129: Differential Effectiveness of HCN Isoforms as a Biopacemaker in a Model of Sick Sinus Syndrome
Sick sinus syndrome (SSS) is common, often requiring electronic pacemaker implantation. Gene therapy (biopacemaking) may be an alternative and has been tried in atrial and ventricular myocardium by other groups. For sinus node (SAN) disease repair may be better than expression in the working myocardium due to the complex nature of the SAN. We hypothesised that expression of a pacemaker channel (HCN) in a model of SSS may accelerate pacing. The effect of different HCN isoforms in working myocardium has been unpredictable; therefore we assessed the effect of different isoforms in the subsidiary right atrial pacemaker tissue of our model. The upper 2/3 of a rat right atrium was removed in vitro, the leading pacemaker sites of these preparations (SSS) were identified by activation mapping then characterised. Further SSS preparations were injected in this region with recombinant adenovirus causing expression of a control protein (GFP or non-functional HCN4Δ) or a functional HCN channel (HCN2, 4 or chimaeric 212). During tissue culture electrical activity was monitored and the spontaneous pacing rates were compared to the SSS by 2-way ANOVA. The spontaneous pacing rate was not affected by expression of GFP (n=7) or HCN4Δ (n=5 Fig 1A). Expression of HCN4 (n=4) or HCN2 (n=4) did not significantly affect the pacing rate (Figure 1B +, p>0.05). Expression of HCN212 (n=6) significantly increased the pacing rate towards that of the control (Figure 1C, *** p<0.001). These results demonstrate that the pacemaker activity of HCN 2 and 4 display significant context dependence even in subsidiary pacemaker tissue. The pacing rate was increased by HCN212 that has faster kinetics and enhanced cAMP sensitivity. The role of HCN channels in pacemaking is controversial, some suggest that they provide a ‘depolarisation reserve’ rather than driving the speed of diastolic depolarisation. Thus the effect of a biopacemaker target for SSS must be carefully assessed before in vivo experimentation.
- © 2011 by American Heart Association, Inc.