In SQT1 rabbits (gain-of-function KCNH2 N588K mutation), shRNA targeting mutant KCNH2 significantly prolonged QTc from 283 ± 8 ms to 333 ± 9 ms (p < 0.01), approaching wild-type values (342 ± 7 ms). Cardiomyocyte APD90 increased from 267 ± 11 ms to 316 ± 9 ms. Ventricular effective refractory period (VERP) improved from 142 ± 8 ms to 187 ± 11 ms (p < 0.05). Arrhythmia inducibility was significantly reduced (Torsades observed in 5/7 sham vs. 1/8 treated; p = 0.03). No off-target effects or myocardial inflammation were detected. This evidence concerns the gene KCNH2 and cardiac arrhythmia.