Selective Targeting of Gain-of-Function KCNQ1 Mutations Predisposing to Atrial Fibrillation

Background Atrial fibrillation is the most common sustained cardiac arrhythmia in adults. We hypothesized that gain-of-function KCNQ1 mutations previously associated with familial atrial fibrillation have distinct pharmacological properties that may enable targeted inhibition. Methods and Results Wild-type (WT) KCNQ1 or the familial atrial fibrillation mutation KCNQ1-S140G was heterologously coexpressed with KCNE1 to enable electrophysiological recording of the slow delayed rectifier current (I-Ks) and investigation of pharmacological effects of the I-Ks selective blocker HMR-1556. Coexpression of KCNQ1-S140G with KCNE1 generated potassium currents (S140G-I-Ks) that exhibited greater sensitivity to HMR-1556 than WT-I-Ks. Enhanced HMR-1556 sensitivity was also observed for another gain-of-function atrial fibrillation mutation, KCNQ1-V141M. Heteromeric expression of KCNE1 with both KCNQ1-WT and KCNQ1-S140G generated currents (HET-I-Ks) with gain-of-function features, including larger amplitude, a constitutively active component, hyperpolarized voltage dependence of activation, and extremely slow deactivation. A low concentration of HMR-1556, which had little effect on WT-I-Ks but was capable of inhibiting the mutant channel, reduced both instantaneous and steady state HET-I-Ks to levels that were not significantly different from WT-I-Ks and attenuated use-dependent accumulation of the current. In cultured adult rabbit left atrial myocytes, expression of S140G-I-Ks shortened action potential duration compared with WT-I-Ks. Application of HMR-1556 mitigated S140G-I-Ks-induced action potential duration shortening and did not alter action potential duration in cells expressing WT-I-Ks. Conclusions The enhanced sensitivity of KCNQ1 gain-of-function mutations for HMR-1556 suggests the possibility of selective therapeutic targeting, and, therefore, our data illustrate a potential proof of principle for genotype-specific treatment of this heritable arrhythmia.