Regulation of cardiac repolarization by adenoviral gene transfer rationalized by computational modeling

Reza Mazhari, Eduardo Marbán, Raimond L. Winslow

Research output: Contribution to journalConference articlepeer-review

Abstract

Regulatory subunit KCNE3 (E3) interacts with KCNQ1 (Q1) in epithelia, regulating its activation kinetics and augmenting current density. Since E3 is expressed weakly in the heart, we hypothesized that ectopic expression of E3 in cardiac myocytes might abbreviate action potential duration by interacting with Q1 and augmenting the delayed rectifier current (IK). We constructed an adenoviral vector co-expressing GFP and E3, and injected it into the left ventricular cavity of guinea pigs. After 72 hrs, the electrocardiographic QT interval was reduced by ∼10% compared to baseline. E3-transduced cells had an APD90 of 87±8 vs. 298±19 ms in control cells, while E-4031-insensitive IK and activation kinetics were significantly augmented. Quantitative modeling of a transmural cardiac segment rationalized the degree of QT-interval abbreviation as a consequence of electrotonic interactions in the face of limited transduction efficiency and showed that heterogeneous transduction of E3 may actually potentiate arrhythmias. The results provide proof of the principle that ectopic expression of regulatory subunits can be exploited to enhance repolarization, a principle that may be useful in treating long QT syndrome (but only if fairly homogeneous ventricular expression can be achieved).

Original languageEnglish (US)
Pages (from-to)2233-2234
Number of pages2
JournalAnnual International Conference of the IEEE Engineering in Medicine and Biology - Proceedings
Volume3
StatePublished - Dec 1 2002
EventProceedings of the 2002 IEEE Engineering in Medicine and Biology 24th Annual Conference and the 2002 Fall Meeting of the Biomedical Engineering Society (BMES / EMBS) - Houston, TX, United States
Duration: Oct 23 2002Oct 26 2002

Keywords

  • Arrhythmia
  • Electrophysiology
  • Gene therapy
  • Heart
  • Mathematical modeling

ASJC Scopus subject areas

  • Signal Processing
  • Biomedical Engineering
  • Computer Vision and Pattern Recognition
  • Health Informatics

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