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J Med Biol Eng
2017 Oct 01;375:780-789. doi: 10.1007/s40846-017-0257-x.
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Pro-arrhythmogenic Effects of the V141M KCNQ1 Mutation in Short QT Syndrome and Its Potential Therapeutic Targets: Insights from Modeling.
Lee HC
,
Rudy Y
,
Liang H
,
Chen CC
,
Luo CH
,
Sheu SH
,
Cui J
.
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Gain-of-function mutations in the pore-forming subunit of IKs channels, KCNQ1, lead to short QT syndrome (SQTS) and lethal arrhythmias. However, how mutant IKs channels cause SQTS and the possibility of IKs-specific pharmacological treatment remain unclear. V141M KCNQ1 is a SQTS associated mutation. We studied its effect on IKs gating properties and changes in the action potentials (AP) of human ventricular myocytes. Xenopus oocytes were used to study the gating mechanisms of expressed V141M KCNQ1/KCNE1 channels. Computational models were used to simulate human APs in endocardial, mid-myocardial, and epicardial ventricular myocytes with and without β-adrenergic stimulation. V141M KCNQ1 caused a gain-of-function in IKs characterized by increased current density, faster activation, and slower deactivation leading to IKs accumulation. V141M KCNQ1 also caused a leftward shift of the conductance-voltage curve compared to wild type (WT) IKs (V1/2 = 33.6 ± 4.0 mV for WT, and 24.0 ± 1.3 mV for heterozygous V141M). A Markov model of heterozygous V141M mutant IKs was developed and incorporated into the O'Hara-Rudy model. Compared to the WT, AP simulations demonstrated marked rate-dependent shortening of AP duration (APD) for V141M, predicting a SQTS phenotype. Transmural electrical heterogeneity was enhanced in heterozygous V141M AP simulations, especially under β-adrenergic stimulation. Computational simulations identified specific IK1 blockade as a beneficial pharmacologic target for reducing the transmural APD heterogeneity associated with V141M KCNQ1 mutation. V141M KCNQ1 mutation shortens ventricular APs and enhances transmural APD heterogeneity under β-adrenergic stimulation. Computational simulations identified IK1 blockers as a potential antiarrhythmic drug of choice for SQTS.
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???displayArticle.pmcLink???PMC5714284 ???displayArticle.link???J Med Biol Eng ???displayArticle.grants???[+]
Fig. 1. V141M KCNQ1 affects activation kinetics and voltage dependence of IKs. a Currents of WT KCNQ1/KCNE1 channels (WT IKs) and heterozygous V141M KCNQ1/KCNE1 channels (V141M IKs) expressed in Xenopus oocytes (left panels). The currents were elicited by test pulses to +60 mV from a holding potential of â100 mV. Tail currents were measured at â40 mV for WT and V141M IKs. The WT and V141M IKs were simulated using a Markov model (right panels; see supplementary materials). b V141M KCNQ1 mutation caused a leftward shift of the conductanceâvoltage curve (V1/2 = 33.6 ± 4.0 mV for WT, 24.0 ± 1.3 mV for heterozygous V141M; n = 5 for each). Simulation results (solid lines) are consistent with the experimental data (dashed lines). c Voltage dependence of activation and deactivation time constants (Ï) of WT and heterozygous V141M IKs (n = 5 for each). Ï activation was obtained from fitting the activating current traces with a double exponential function. V141M KCNQ1 causes faster activation of IKs (*p < 0.05 for Ï1 and #p < 0.05 for Ï2; V141M vs WT; n = 3 for each). d V141M KCNQ1 causes slower deactivation of IKs (*p value <0.05 for Ïs; V141M (n = 5) versus WT (n = 3). Ï deactivation was obtained from fitting the deactivating current traces with a double exponential function. Lines indicate specific Ï values for simulations
Fig. 2. Simulated WT and heterozygous V141M KCNQ1 action potentials (AP) and the IKs and ICaL during the AP in endocardial (Endo), epicardial (Epi) and midmyocardial (Mid) myocytes with and without isoproterenol (ISO). A modified OâHara-Rudy (ORd) human ventricular myocyte model was used in the simulations. The cycle length was 1000 ms. Baseline APs (in grey) and APs with ISO challenge (in black) were simulated for WT (dash lines) and V141M KCNQ1 (solid lines) respectively. APs were shortened significantly by the V141M KCNQ1 mutation with and without ISO. In all V141M cases, IKs and ICaL increased relative to WT during the AP
Fig. 3. AP simulations show blunted APD rate adaptation and increased transmural heterogeneity of APD associated with the V141M KCNQ1 mutation. At fast cycle lengths of 500 ms and slow cycle lengths of 2000 ms, WT KCNQ1 APD increased 52.0, 77.6, and 43.5 ms in Endo, Mid and Epi, respectively, but V141M KCNQ1 mutation APD increased 28.3, 43.7, and 21.5 ms respectively (upper panel). At cycle lengths of 500 and 2000 ms, APD heterogeneity diminished from 30.0 to 26.7% and from 32.7 to 28.9% respectively in the presence of isoproterenol (ISO) challenge in WT. In contrast, the heterogeneity of APD was augmented with ISO in V141M KCNQ1. In the presence of ISO, APD heterogeneity increased from 22.4 to 33.1%, from 27.9 to 36.4%, and from 32.6 to 34.4%, at cycle lengths of 500, 2000, or 1000 ms, respectively. The heterogeneity increase was due to preferential abbreviation of epicardial (Epi) and endocardial (Endo) cells as compared with mid-myocardial (Mid) cells
Fig. 4. Effects of different anti-arrhythmic agents or channel blockers on the V141M KCNQ1-augmented transmural heterogeneity of APD. At a cycle length of 1000 ms with isoproterenol (ISO) (upper panel), amiodarone, sotalol, quinidine and IKs block (either at 50 or 90% block) all failed to reduce the mutation-augmented transmural heterogeneity of APD (upper panel). Only the IK1 block (with 90% block) improved APD heterogeneity at both long and short cycle lengths under ISO challenge (lower panel)
Fig. 5. Effects of IK1 blockade on the pseudo-ECG and QT interval. a Pseudo-ECGs at a cycle length of 1000 ms for WT and V41M KCNQ1 mutation, at baseline and with isoproterenol, and with 90% IK1 block. b QT interval measurements for each pseudo-ECG are indicated. c QT intervals on the pseudo-ECG are plotted against the cycle length. In the case of V141M, the QT interval was abnormally shortened with ISO; the shortening of the QT interval was corrected by specific IK1 blockade. ECG electrocardiogram, WT wild type, V141M V141M KCNQ1 mutation
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