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Setting the pace

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The possibility of gene therapy to treat cardiac chronotropic incompetence took a step forward with the successful, if transient, enhancement of heart rate in a large animal model by human gene transfer.

Having already established the principle in a mouse model, with transfer of constructs encoding the β2 human adrenergic receptor resulting in enhanced heart rate, Edelberg and colleagues repeated the process in a Yorkshire pig model — chosen for its similarity to the human cardiovascular system. Plasmids encoding either human β2 adrenergic receptor (pBR322-β actin promoter-β2 adrenergic receptor) or control constructs (pBR322-β actin promoter-β galactosidase) and a co-injection vector (plasmid construct encoding humanised green fluorescent protein with a cytomegalovirus promoter) were injected by cardiac catheterisation into the right atrial myocardium (six pigs for β2 adrenergic receptor and five for controls) in a randomised double blind procedure.

Two days later the average heart rate before injection (108 (SD 16) beats/min) was significantly increased in pigs receiving the β2 adrenergic receptor construct (163 (33) beats/min; p<0.05 compared with preinjection) compared with those receiving control constructs (127(25) beats/min; p>0.3 compared with preinjection). The increase before and after injection was almost a 50% increase in heart rate (p<0.01 compared with that for the controls). After sacrifice sections of the injection sites of the excised hearts were stained with immunofluorescent stain specific for the human β2 adrenergic receptor. Dual fluorescence microscopy showed specific staining only in those hearts injected with the β2 adrenergic receptor construct, indicating expression of the encoded genes.

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