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. 2001 Nov;86(5):559–562. doi: 10.1136/heart.86.5.559

Molecular enhancement of porcine cardiac chronotropy

J Edelberg 1, D Huang 1, M Josephson 1, R Rosenberg 1
PMCID: PMC1729967  PMID: 11602553

Abstract

OBJECTIVE—To test the potential of gene transfer approaches to enhance cardiac chronotropy in a porcine system as a model of the human heart.
METHODS—Plasmids encoding either the human β2 adrenergic receptor or control constructs were injected into the right atria of native Yorkshire pig hearts. Percutaneous electrophysiological recording catheters equipped with 33 gauge circular injection needles were positioned in the mid-lateral right atrium. At the site of the earliest atrial potential the circular injection needles were rotated into the myocardium and the β2 adrenergic receptor (n = 6) or control plasmid constructs (n = 5) were injected.
RESULTS—Injection of the β2 adrenergic receptor construct significantly enhanced chronotropy compared with control injections. The average (SD) heart rate of the pigs was 108 (16) beats/min before injection. Two days after injection with control plasmids the heart rate was 127 (25) beats/min (NS compared with preinjection rates). After injection with plasmid encoding the β2 adrenergic receptor the heart rate increased by 50% to 163 (33) beats/min (p < 0.05 compared with preinjection and postinjection control rates).
CONCLUSIONS—The present studies showed in a large animal model that local targeting of gene expression may be a feasible modality to regulate cardiac pacemaking activity. In addition, these investigations provide an experimental basis for developing future clinical gene transfer approaches to upregulate heart rate and modulate cardiac conduction.


Keywords: sinus node; adrenergic receptor; chronotropic agents; conduction system; gene therapy

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Figure 1  .

Figure 1  

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Cine of electrophysiological recording and injection catheter (arrow head) during injection of complementary DNA in to the porcine lateral right atrium (A). Two examples are shown of surface and intracardiac ECGs recorded before injection into the right atrium (B).

Figure 2  .

Figure 2  

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(A) Representative surface ECGs recorded 48 hours after injection of either control constructs or constructs encoding β2 adrenergic receptor. (B) The average percentage change in heart rate (HR) after injection of control construct or β2 adrenergic receptor (β2 AR) encoding plasmids (*p < 0.01 versus control). Dual fluorescence micrographs of sections of right atrial tissue co-injected with plasmids encoding green fluorescent protein and control constructs (C) and with the human β2 adrenergic receptor (D). Green fluorescent protein was visualised directly (green), and the human β2 adrenergic receptor was detected by immunostaining (red). Bar 32 µm.

Selected References

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