Expression and function of a biological pacemaker in canine heart

Background-We hypothesized that localized overexpression of the hyperpolarization-activated, cyclic nucleotide-gated (HCN2) pacemaker current isoform in canine left atrium (LA) would constitute a novel biological pacemaker. Methods and Results-Adenoviral constructs of mouse HCN2 and green fluorescent protein (GFP) or GFP alone were injected into LA, terminal studies performed 3 to 4 days later, hearts removed, and myocytes examined for native and expressed pacemaker current (I-f). Spontaneous LA rhythms occurred after vagal stimulation-induced sinus arrest in 4 of 4 HCN2+GFP dogs and 0 of 3 GFP dogs (P<0.05). Native I-f in nonexpressed atrial myocytes was 7±4 pA at -130 mV (n=5), whereas HCN2+GFP LA had expressed pacemaker current (I-HCN2) of 3823±713 pA at -125 mV (n=10) and 768±365 pA at -85 mV. Conclusions-HCN2 overexpression provides an I-f-based pacemaker sufficient to drive the heart when injected into a localized region of atrium, offering a promising gene therapy for pacemaker disease.