Molecular dissection of cardiac repolarization by in vivo Kv4.3 gene transfer
Uta C. Hoppe, … , Eduardo Marbán, David C. Johns
Uta C. Hoppe, … , Eduardo Marbán, David C. Johns
Published April 15, 2000
Citation Information: J Clin Invest. 2000;105(8):1077-1084. https://doi.org/10.1172/JCI8757.
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Article

Molecular dissection of cardiac repolarization by in vivo Kv4.3 gene transfer

Abstract

Heart failure leads to marked suppression of the Ca2+-independent transient outward current (Ito1), but it is not clear whether Ito1 downregulation suffices to explain the concomitant action potential prolongation. To investigate the role of Ito1 in cardiac repolarization while circumventing culture-related action potential alterations, we injected adenovirus vectors in vivo to overexpress or to suppress Ito1 in guinea pigs and rats, respectively. Myocytes were isolated 72 hours after intramyocardial injection and stimulation of the ecdysone-inducible vectors with intraperitoneal injection of an ecdysone analog. Kv4.3-infected guinea pig myocytes exhibited robust transient outward currents. Increasing density of Ito1 progressively depressed the plateau potential in Kv4.3-infected guinea pig myocytes and abbreviated action potential duration (APD). In vivo infection with a dominant-negative Kv4.3-W362F construct suppressed peak Ito1 in rat ventriculocytes, elevated the plateau height, significantly prolonged the APD, and resulted in a prolongation by about 30% of the QT interval in surface electrocardiogram recordings. These results indicate that Ito1 plays a crucial role in setting the plateau potential and overall APD, supporting a causative role for suppression of this current in the electrophysiological alterations of heart failure. The electrocardiographic findings indicate that somatic gene transfer can be used to create gene-specific animal models of the long QT syndrome.

Authors

Uta C. Hoppe, Eduardo Marbán, David C. Johns

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Figure 4

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Effect of Ito1 current size on the height of the action potential platea...
Effect of Ito1 current size on the height of the action potential plateau in guinea pig myocytes infected in vivo with AdCGI-DBEcR and AdE8I-Kv4.3. (a) Introduction of Ito1 (50.1 pA/pF) into a guinea pig myocyte depressed the voltage of the early plateau phase measured at d2V/dt2=0 (arrow) (at the transition from early repolarization to final repolarization; ref. 27). (b) The suppression of the action potential plateau correlated well with the introduced Ito1 density (n = 10).