Adenoviral gene delivery of KCNE3 in guinea pigs significantly reduced the corrected QT interval from 158 ms to 143 ms and abbreviated action potential duration.
Ectopic expression of KCNE3 accelerates cardiac repolarization and shortens the QT interval, suggesting a potential gene therapy approach for long QT syndrome if homogeneous expression can be achieved.
Absolute Event Rate: 143% vs 158%
p-value: p=<0.05
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 (APD) by interacting with Q1 and augmenting the delayed rectifier current (I(K)). Thus, we transiently coexpressed E3 with Q1 and KCNE1 (E1) in Chinese hamster ovary cells and found that E3 coexpression increased outward current at potentials by > or = -80 mV and accelerated activation. We then examined the changes in cardiac electrophysiology following injection of adenovirus-expressed E3 into the left ventricular cavity of guinea pigs. After 72 hours, the corrected QT interval of the electrocardiogram was reduced by approximately 10%. APD was reduced by >3-fold in E3-transduced cells relative to controls, while E-4031-insensitive I(K) and activation kinetics were significantly augmented. Based on quantitative modeling of a transmural cardiac segment, we demonstrate that the degree of QT interval abbreviation observed results from electrotonic interactions in the face of limited transduction efficiency and that heterogeneous transduction of E3 may actually potentiate arrhythmias. Provided that fairly homogeneous ectopic ventricular expression of regulatory subunits can be achieved, this approach may be useful in enhancing repolarization and in treating long QT syndrome.
Mazhari et al. (Mon,) conducted a other in Long QT syndrome (preclinical model). Adenovirus-expressed KCNE3 (AdCGI-KCNE3) vs. Baseline / AdCGI without KCNE3 was evaluated on Corrected QT interval (QTc) in milliseconds (p=<0.05). Adenoviral gene delivery of KCNE3 in guinea pigs significantly reduced the corrected QT interval from 158 ms to 143 ms and abbreviated action potential duration.