hmr-1556 and Atrial-Fibrillation

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.. 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 (IKs) and investigation of pharmacological effects of the IKs selective blocker HMR-1556. Coexpression of KCNQ1-S140G with KCNE1 generated potassium currents (S140G-IKs) that exhibited greater sensitivity to HMR-1556 than WT-IKs. 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-IKs) 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-IKs but was capable of inhibiting the mutant channel, reduced both instantaneous and steady state HET-IKs to levels that were not significantly different from WT-IKs and attenuated use-dependent accumulation of the current. In cultured adult rabbit left atrial myocytes, expression of S140G-IKs shortened action potential duration compared with WT-IKs. Application of HMR-1556 mitigated S140G-IKs-induced action potential duration shortening and did not alter action potential duration in cells expressing WT-IKs.. 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.

Topics: Animals; Atrial Fibrillation; Cells, Cultured; Chromans; Cricetulus; Genetic Predisposition to Disease; KCNQ1 Potassium Channel; Mutation; Myocytes, Cardiac; Patch-Clamp Techniques; Plasmids; Potassium Channels, Voltage-Gated; Rabbits; Risk Factors; Sulfonamides

We recently reported that an S140G mutation in human KCNQ1, an alpha subunit of potassium channels, was involved in the pathogenesis of familial atrial fibrillation (AF), but it is not clear whether the mutation is associated with other cardiac arrhythmias.. The purpose of this study was to further explore the association of the KCNQ1 S140G mutation with cardiac arrhythmias.. We produced a transgenic mouse model with myocardium-specific expression of the human KCNQ1 S140G mutation under the control of an alpha-cardiac myosin heavy chain promoter by standard transgenic procedure and evaluated the relationship between the KCNQ1 mutation and its phenotypes in a human family.. Four lines of transgenic mice were established with a high level of human KCNQ1 S140G expression in the heart. Frequent episodes of first-, second-, advanced-, or third-degree atrioventricular block (AVB) occurred in at least 65% of transgenic descendants from the four lines. However, none of the five wild-type transgenic lines presented with AVBs. HMR1556, a KCNQ1-specific blocker, can terminate the AVBs. With the exception of at most three AF individuals, at least 13 AF patients were found to show obviously slow ventricular response, which may be one manifestation of AVBs. Interestingly, AF was not detected in these transgenic mice.. The results suggest that human KCNQ1 S140G is also likely to be a causative mutation responsible for AVBs. The transgenic mouse model is a potential tool to explore mechanisms of AVBs.

Topics: Animals; Atrial Fibrillation; Atrioventricular Node; China; Chromans; Electrocardiography; Female; Genetic Predisposition to Disease; Glycine; Heart Block; Heart Rate; Heart Ventricles; Humans; Ion Channel Gating; KCNQ1 Potassium Channel; Male; Mice; Mice, Transgenic; Mutation; Pedigree; Phenotype; Research Design; Reverse Transcriptase Polymerase Chain Reaction; Serine; Severity of Illness Index; Sulfonamides

Antiarrhythmic drugs for treatment of atrial fibrillation in patients with heart failure are limited by proarrhythmia and low efficacy. Experimental studies indicate that the pure I(Ks) blocking agents chromanol 293b and HMR 1556 prolong repolarization more markedly at fast than at slow heart rates and during beta-adrenergic stimulation. These properties may overcome some of the above quoted limitations.. Ten domestic swine underwent pacemaker implantation (PM) and atrial burst pacing to induce persistent AF. Four days after onset of persistent AF, pigs were randomized to HMR 1556 (30 mg/kg, p.o., 10 days) or placebo. All animals receiving HMR 1556 converted to SR (5.2 +/- 1.9 days), whereas placebo pigs remained in AF. Pigs treated with placebo developed high ventricular rates (297 +/- 5 bpm) and severe heart failure, whereas pigs treated with HMR 1556 remained hemodynamically stable. Left ventricular ejection fraction on the day of euthanization was significantly lower in the placebo compared to the HMR 1556 group (30 +/- 4% vs. 69 +/- 5%, p < 0.005). Similar results were seen with epinephrine levels (placebo 1563 +/- 193 pmol/l vs. HMR 613 +/-196 pmol/l, p < 0.05). Right atrial monophasic action potentials were significantly longer in the HMR 1556 compared to the placebo group (230 +/- 7 ms vs. 174 +/- 13 ms, p < 0.05).. The new I(Ks) blocker HMR 1556 efficiently and safely restores SR and prevents CHF in a model of persistent AF. Restoration of SR is most likely linked to a marked prolongation of atrial repolarization even at high heart rates.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Chromans; Disease Models, Animal; Heart Conduction System; Pacemaker, Artificial; Potassium Channels, Voltage-Gated; Sinoatrial Node; Sulfonamides; Sus scrofa