Focal modification of electrical conduction in the heart by viral gene transfer

J. Kevin Donahue, Alan W. Heldman, Heather Fraser, Amy D. Mcdonald, Julie M. Miller, Jeffrey J. Rade, Thomas Eschenhagen, Eduardo Marbán

Research output: Contribution to journalArticle

147 Citations (Scopus)

Abstract

Modern treatment of cardiac arrhythmias is limited to pharmacotherapy, radiofrequency ablation, or implantable devices. Antiarrhythmic medications suppress arrhythmias, but their systemic effects are often poorly tolerated and their proarrhythmic tendencies increase mortality. Radiofrequency ablation can cure only a limited number of arrhythmias. Implantable devices can be curative for bradyarrhythmias and lifesaving for tachyarrhythmias, but require a lifetime commitment to repeated procedures, are a significant expense, and may lead to severe complications. One possibility is the use of gene therapy as an antiarrhythmic strategy. As an initial attempt to explore this option, we focused on genetic modification of the atrioventricular node. First, we developed an intracoronary perfusion model for gene delivery, building on our previous work in isolated cardiac myocytes and hearts perfused ex vivo. Using this method, we infected porcine hearts with Adssgal (recombinant adenovirus expressing Escherichia coli β-galactosidase) or with AdG(i) (adenovirus encoding the Gα12 subunit). We hypothesized that excess Gα12 would mimic the effects of β-adreneric antagonists, in effect creating a localized β-blockade. Gα12 overexpression suppressed baseline atrioventricular conduction and slowed the heart rate during atrial fibrillation without producing complete heart block. In contrast, expression of the reporter gene β-galactosidase had no electrophysiological effects. Our results demonstrate the feasibility of using myocardial gene transfer strategies to treat common arrhythmias.

Original languageEnglish
Pages (from-to)1395-1398
Number of pages4
JournalNature Medicine
Volume6
Issue number12
DOIs
StatePublished - Dec 1 2000
Externally publishedYes

Fingerprint

Gene transfer
Viral Genes
Cardiac Arrhythmias
Galactosidases
Ablation
Adenoviridae
Genes
Drug therapy
Gene therapy
Equipment and Supplies
Atrioventricular Node
Heart Block
Bradycardia
Reporter Genes
Cardiac Myocytes
Tachycardia
Genetic Therapy
Atrial Fibrillation
Escherichia coli
Swine

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Kevin Donahue, J., Heldman, A. W., Fraser, H., Mcdonald, A. D., Miller, J. M., Rade, J. J., ... Marbán, E. (2000). Focal modification of electrical conduction in the heart by viral gene transfer. Nature Medicine, 6(12), 1395-1398. https://doi.org/10.1038/82214

Focal modification of electrical conduction in the heart by viral gene transfer. / Kevin Donahue, J.; Heldman, Alan W.; Fraser, Heather; Mcdonald, Amy D.; Miller, Julie M.; Rade, Jeffrey J.; Eschenhagen, Thomas; Marbán, Eduardo.

In: Nature Medicine, Vol. 6, No. 12, 01.12.2000, p. 1395-1398.

Research output: Contribution to journalArticle

Kevin Donahue, J, Heldman, AW, Fraser, H, Mcdonald, AD, Miller, JM, Rade, JJ, Eschenhagen, T & Marbán, E 2000, 'Focal modification of electrical conduction in the heart by viral gene transfer', Nature Medicine, vol. 6, no. 12, pp. 1395-1398. https://doi.org/10.1038/82214
Kevin Donahue J, Heldman AW, Fraser H, Mcdonald AD, Miller JM, Rade JJ et al. Focal modification of electrical conduction in the heart by viral gene transfer. Nature Medicine. 2000 Dec 1;6(12):1395-1398. https://doi.org/10.1038/82214
Kevin Donahue, J. ; Heldman, Alan W. ; Fraser, Heather ; Mcdonald, Amy D. ; Miller, Julie M. ; Rade, Jeffrey J. ; Eschenhagen, Thomas ; Marbán, Eduardo. / Focal modification of electrical conduction in the heart by viral gene transfer. In: Nature Medicine. 2000 ; Vol. 6, No. 12. pp. 1395-1398.
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