Table 3.
Gene-based biopacemaking approaches.
| Genetic engineering | Methodology and experimental details | References |
|---|---|---|
| Dominant-negative inhibition of Kir2-encoded inward-rectifier potassium channels | In vivo viral gene transfer to transform quiescent heart-muscle cells into PCs was performed. After the construct injection into the left ventricular cavity of guinea pigs, successful generation of spontaneous, rhythmic electrical activity in the ventricle was achieved. | Miake et al., 2002 |
| Human β2-adrenergic receptor transfection | The effects of β2-adrenergic receptor transfer were studied: in vitro (murine embryonic cardiac myocytes transient transfection with plasmid constructs), ex vivo (murine neonatal cardiac transplantation model), and in vivo (injection into the right atrium of the endogenous heart). | Edelberg et al., 1998 |
| Plasmids encoding human β2-adrenergic receptor were injected into the right atria of native Yorkshire pig hearts. A significant increase of chronotropy compared with control injections was achieved. | Edelberg, 2001 | |
| HCN1 gene overexpression | HCN1 mutant (three deleted residues: HCN1-AAA) showed activation kinetics similar to SAN and induced pacing activity in porcine models. | Tse et al., 2006 |
| HCN2 gene overexpression | HCN2 gene overexpression increased the heart rate and generated biological pacemaker activity in canine models. | Qu et al., 2003 |
| Dual gene constructs HCN2/SkM1 | Dual gene constructs HCN2/SkM1 were transduced into the left bundle branches in the models of complete AVN block dogs. Complete restoration of the heart rate was demonstrated. | Boink et al., 2013 |
| Adenylate cyclase type VI (AC-VI) overexpression | Adenoviral gene transfer of AC-VI induced pacemaker activity in the AVN block model in adult pigs. | Ruhparwar et al., 2010 |
| Adenoviral vector cocktail (K(AAA) + H2), expressing Kir2.1AAA and HCN2 genes | An adenoviral vector cocktail (K(AAA) + H2), expressing Kir2.1AAA and HCN2 genes, was injected into the AV junctional region in a model of AV block in pigs. | Cingolani et al., 2012 |
| AC1 or HCN2/AC1 overexpression | Ca2+-stimulated adenylyl cyclase AC1 or HCN2/AC1 overexpression in left bundle branches provides highly efficient biological pacing and greater sensitivity to autonomic modulation than HCN2 alone. | Boink et al., 2012b |
PCs, pacemaker cells; SAN, sinoatrial node; AVN, atrioventricular node.