In silico investigation of a KCNQ1 mutation associated with short QT syndrome

Abstract

Short QT syndrome (SQTS) is a rare condition characterized by abnormally 'short' QT intervals on the ECG and increased susceptibility to cardiac arrhythmias and sudden death. This simulation study investigated arrhythmia dynamics in multi-scale human ventricle models associated with the SQT2-related V307L KCNQ1 'gain-of-function' mutation, which increases slow-delayed rectifier potassium current (I_Ks). A Markov chain (MC) model recapitulating wild type (WT) and V307L mutant I_Ks kinetics was incorporated into a model of the human ventricular action potential (AP) for investigation of QT interval changes and arrhythmia substrates. In addition, the degree of simulated I_Ks inhibition necessary to normalize the QT interval and terminate re-entry in SQT2 conditions was quantified. The developed MC model accurately reproduced AP shortening and reduced effective refractory period associated with altered I_Ks kinetics in homozygous (V307L) and heterozygous (WT-V307L) mutation conditions, which increased the lifespan and dominant frequency of re-entry in 3D human ventricle models. I_Ks reductions of 58% and 65% were sufficient to terminate re-entry in WT-V307L and V307L conditions, respectively. This study further substantiates a causal link between the V307L KCNQ1 mutation and pro-arrhythmia in human ventricles, and establishes partial inhibition of I_Ks as a potential anti-arrhythmic strategy in SQT2.

Figure 1

Simulated voltage and AP clamp experiments for I_Ks. Current traces for WT (Ai) and V307L (Bi) KCNQ1 I_Ks at step potentials of −60 mV (blue), −30 mV (green), 0 mV (red) and 30 mV (cyan) using the voltage clamp protocol shown in (Aii,Bii). Comparison of simulated and experimental I-V relationship for I_Ks under WT (Aiii) and V307L (Biii) conditions. I_Ks profile during AP clamp using a ventricular AP waveform voltage command in WT (Aiv) and V307L (Biv) conditions. All experimental data, including insets shown in panels Ai and Bi, are taken from El Harchi et al..

Figure 2

Action potentials and I_Ks profiles. Steady state APs (i) for EPI (A), MIDDLE (B), and ENDO (C) cells in WT (blue), WT-V307L (green), and V307L (red) conditions at a pacing rate of 1 Hz. Corresponding I_Ks profiles (ii) and I-V relationships (iii) for EPI (A), MIDDLE (B), and ENDO (C) cells.

Figure 3

Restitution curves for APD and ERP. APD₉₀ restitution curves for EPI (A), MIDDLE (B), and ENDO (C) cells in WT (red), WT-V307L (green), and V307L (red) conditions, with corresponding maximal slope of APD restitution (D). ERP restitution curves for EPI (E), MIDDLE (F), and ENDO (G) cells in WT (red), WT-V307L (green), and V307L (red) conditions, with corresponding maximal slope of ERP restitution (H).

Figure 4

Pseudo-ECG measured in 1D strand. Space-time plot of AP propagation in a 1D transmural strand in WT (A), WT-V307L (B), and V307L (C) conditions, with membrane potential colour mapped from blue (−100 mV) to red (+60 mV). Space runs vertically from the endocardial (ENDO) end (bottom) to epicardial (EPI) end of the strand (top), and time runs horizontally. Pseudo-ECGs measured in WT (D), WT-V307L (E), and V307L (F) conditions. Superimposed pseudo-ECGs for the WT, WT-V307L, and V307L conditions, with associated QT intervals (G).

Figure 5

Snapshots of re-entry in 2D cross-section of ventricles. (A) Application of a premature S2 stimulus into the refractory and partially recovered tissue following excitation after a delay of 370 ms for WT (i), 310 ms for WT-V307L (ii), and 230 ms for V307L (iii) conditions. Snapshots of developed spiral waves at time, t = 800 ms (B), t = 1000 ms (C), and t = 1500 ms (D) in WT (i), WT-V307L (ii), and V307L (iii) conditions. (E) Time series of cellular APs recorded in the left ventricle in WT (i), WT-V307L (ii), and V307L (iii) conditions. Measured lifespan (F) and dominant frequency (G) of re-entrant spiral waves. Computed dominant frequencies are 1.96 Hz, 3.32 Hz, and 4.30 Hz for WT, WT-V307L, and V307L conditions, respectively.

Figure 6

Snapshots of re-entry in 3D anatomical model of ventricles. (A) Application of a premature S2 stimulus in a local region during the refractory period of a previous excitation wave after a time delay of 355 ms for WT (i), 315 ms for WT-V307L (ii), and 260 ms for V307L (iii) conditions. Snapshots of developed scroll waves at time, t = 500 ms (B), t = 750 ms (C), and t = 1000 ms (D) in WT (i), WT-V307L (ii), and V307L (iii) conditions. (E) Time series of cellular APs recorded in the left ventricle in WT (i), WT-V307L (ii), and V307L (iii) conditions. Measured lifespan (F) and dominant frequency (G) of re-entrant spiral waves. Computed dominant frequencies of electrical activity recorded in the left ventricle are 2.34 Hz, 3.13 Hz, and 7.42 Hz for WT, WT-V307L, and V307L conditions, respectively.

Figure 7

I_Ks blockade in single cell and 1D simulations. Action potentials in WT-V307L (A) and V307L (D) conditions under varying degrees of I_Ks blockade. The dashed line represents the WT and the boxed percentage represents the degree of I_Ks block required to normalize the APD under the respective mutation condition. I_Ks profiles corresponding to the APs shown in (A) and (D) are shown for WT-V307L (B) and V307L (E) conditions, respectively. Pseudo-ECGs corresponding to varying degrees of I_Ks blockade are shown in WT-V307L (C) and V307L (F) conditions. The blue line represents the WT and the boxed percentage represents the degree of I_Ks block required to normalize the QT interval under the respective mutation condition.

Figure 8

Termination of re-entry in 3D ventricle model by I_Ks blockade. (A) Application of a premature S2 stimulus in a local region of WT tissue during the refractory period (355 ms) leads to the development of a scroll wave (500 ms) that terminates in under 1000 ms. (Bi) Application of a premature S2 stimulus in a local region of WT-V307L tissue during the refractory period (315 ms) leads to the development of a scroll wave (500 ms) which persists beyond 1000 ms. (Bii) Application of a premature S2 stimulus in a local region of WT-V307L tissue with 58% I_Ks blockade during the refractory period (355 ms) leads to the development of a scroll wave (500 ms) that terminates in under 1000 ms. (Ci) Application of a premature S2 stimulus in a local region of V307L tissue during the refractory period (260 ms) leads to the development of a scroll wave (500 ms) which persists beyond 1000 ms. (Cii) Application of a premature S2 stimulus in a local region of V307L tissue with 65% I_Ks blockade during the refractory period (355 ms) leads to the development of a scroll wave (500 ms) that terminates in under 750 ms.