Molecular enhancement of porcine cardiac chronotropy

Objective-To test the potential of gene transfer approaches to enhance card iac chronotropy in a porcine system as a model of the human heart. Methods-Plasmids encoding either the human beta (2) adrenergic receptor or control constructs were injected into the right atria of native Yorkshire p ig hearts. Percutaneous electrophysiological recording catheters equipped w ith 33 gauge circular injection needles were positioned in the mid-lateral right atrium. At the site of the earliest atrial potential the circular inj ection needles were rotated into the myocardium and the beta (2) adrenergic receptor (n = 6) or control plasmid constructs (n = 5) were injected. Results-Injection of the beta (2) adrenergic receptor construct significant ly enhanced chronotropy compared with control injections. The average (SD) heart rate of the pigs was 108 (16) beats/min before injection. Two days af ter injection with control plasmids the heart rate was 127 (25) beats/min ( NS compared with preinjection rates). After injection with plasmid encoding the beta (2) adrenergic receptor the heart rate increased by 50% to 163 (3 3) beats/min (p < 0.05 compared with preinjection and postinjection control rates). Conclusions-The present studies showed in a large animal model that local t argeting of gene expression may be a feasible modality to regulate cardiac pacemaking activity. In addition, these investigations provide an experimen tal basis for developing future clinical gene transfer approaches to upregu late heart rate and modulate cardiac conduction.