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

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 (I/sub K/). 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 /spl sim/10% compared to baseline. E3-transduced cells had an APD/sub 90/ of 87 /spl plusmn/ 8 vs. 298 /spl plusmn/ 19 ms in control cells, while E-4031-insensitive I/sub K/ 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).