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 (IKs). A Markov chain (MC) model recapitulating wild type (WT) and V307L mutant IKs 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 IKs 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 IKs 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. IKs 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 IKs as a potential anti-arrhythmic strategy in SQT2.
Highlights
The short QT syndrome (SQTS) was first published as a distinct clinical entity in 20001
We conducted the present study in order to: (i) develop a novel biophysically-accurate and validated Markov chain (MC) model to recapitulate the kinetic changes to IKs in the SQT2 V307L KCNQ1 mutation based on available experimental data at physiological temperature; (ii) determine the functional consequences of the SQT2 V307L mutation on action potential (AP) repolarisation and the QT interval by incorporating it into a well-established human ventricular cell model[20]; (iii) explore the arrhythmogenic substrate in the SQT2 V307L mutation by using “realistic” 2D tissue and 3D organ-scale simulations; and, ; (iv) investigate theoretically the degree of IKs inhibition required to normalise the QT interval as a pseudo-pharmacological therapeutic intervention
We tested the ability of the IKs MC model to reproduce the previously published experimental data[17] on the voltage dependence of wild type (WT) and V307L KCNQ1+KCNE1 IKs at physiological temperature
Summary
The short QT syndrome (SQTS) was first published as a distinct clinical entity in 20001. That study[16] had some intrinsic limitations: (i) the developed HH model of SQT2 did not incorporate slow deactivation of the IKs with the V307L KCNQ1 mutation that was subsequently identified[17]; (ii) it did not consider possible functional www.nature.com/scientificreports/. We conducted the present study in order to: (i) develop a novel biophysically-accurate and validated Markov chain (MC) model to recapitulate the kinetic changes to IKs in the SQT2 V307L KCNQ1 mutation based on available experimental data at physiological temperature; (ii) determine the functional consequences of the SQT2 V307L mutation on AP repolarisation and the QT interval by incorporating it into a well-established human ventricular cell model[20]; (iii) explore the arrhythmogenic substrate in the SQT2 V307L mutation by using “realistic” 2D tissue and 3D organ-scale simulations; and, ; (iv) investigate theoretically the degree of IKs inhibition required to normalise the QT interval as a pseudo-pharmacological therapeutic intervention
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