Effects of propafenone on KCNH2-linked short QT syndrome: A modelling study

The identified genetic short QT syndrome (SQTS) is associated with an increased risk of arrhythmia and sudden death. This study was to investigate the potential effects of propafenone on KCNH2-linked short QT syndrome (SQT1) using a multi-scale biophysically detailed model of the heart developed by ten Tusscher and Panfilov. The ion electrical conductivities were reduced by propafenone in order to simulate the pharmacological effects in healthy and SQT1 cells. Based on the experimental data of McPate et al., the pharmacological effect of propafenone was modelled by dose-dependent IKr blocking. Action potential (AP) profiles and 1D tissue level were analyzed to predict the effects of propafenone on SQT1. Both low- and high- dose of propafenone prolonged APD and QT interval in SQT1 cells. It suggests the superior efficacy of high dose of propafenone on SQT1. However, propafenone did not significantly alter the healthy APD or QT interval at low dose, whereas markedly shortened them at high dose. Our simulation data show that propafenone has a dose-dependently anti-arrhythmic effect on SQT1, and a pro-arrhythmic effect on healthy cells. These computer simulations help to better understand the underlying mechanisms responsible for the initiation or termination of arrhythmias in healthy or SQT1 patients using propafenone.

[1]  K. T. ten Tusscher,et al.  Alternans and spiral breakup in a human ventricular tissue model. , 2006, American journal of physiology. Heart and circulatory physiology.

[2]  R Dumaine,et al.  Modulation of I(Kr) inactivation by mutation N588K in KCNH2: a link to arrhythmogenesis in short QT syndrome. , 2005, Cardiovascular research.

[3]  Martin Borggrefe,et al.  Congenital Short QT Syndrome and Implantable Cardioverter Defibrillator Treatment: , 2003, Journal of cardiovascular electrophysiology.

[4]  Cunjin Luo,et al.  The virtual heart as a platform for screening drug cardiotoxicity , 2015, British journal of pharmacology.

[5]  P. Lercher,et al.  Propafenone shows class Ic and class II antiarrhythmic effects. , 2016, Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology.

[6]  Henggui Zhang,et al.  In silico investigation of the short QT syndrome, using human ventricle models incorporating electromechanical coupling , 2013, Front. Physiol..

[7]  J. Hancox,et al.  Proarrhythmia in KCNJ2-linked short QT syndrome: insights from modelling. , 2012, Cardiovascular research.

[8]  B. Kaye,et al.  Termination of malignant ventricular arrhythmias with an implanted automatic defibrillator in human beings , 1981 .

[9]  Martin Borggrefe,et al.  Blocking effects of the antiarrhythmic drug propafenone on the HERG potassium channel , 2001, Naunyn-Schmiedeberg's Archives of Pharmacology.

[10]  G. Breithardt,et al.  Propafenone--a new antiarrhythmic drug. , 1980, European heart journal.

[11]  J. Brugada,et al.  Idiopathic Short QT Interval:A New Clinical Syndrome? , 2001, Cardiology.

[12]  O. Dössel,et al.  Impact of amiodarone and cisapride on simulated human ventricular electrophysiology and electrocardiograms. , 2012, Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology.

[13]  Henggui Zhang,et al.  Repolarisation and vulnerability to re-entry in the human heart with short QT syndrome arising from KCNQ1 mutation--a simulation study. , 2008, Progress in biophysics and molecular biology.

[14]  Jules C. Hancox,et al.  The N588K-HERG K+ channel mutation in the ‘short QT syndrome’: Mechanism of gain-in-function determined at 37 °C , 2005 .

[15]  Henggui Zhang,et al.  Effects of amiodarone on ventricular excitation associated with the KCNJ2-linked short QT syndrome: Insights from a modelling study , 2015, 2015 Computing in Cardiology Conference (CinC).

[16]  S. Priori,et al.  A Novel Form of Short QT Syndrome (SQT3) Is Caused by a Mutation in the KCNJ2 Gene , 2005, Circulation research.

[17]  S Nattel,et al.  Differential distribution of inward rectifier potassium channel transcripts in human atrium versus ventricle. , 1998, Circulation.

[18]  J. Hancox,et al.  Pharmacology of the short QT syndrome N588K‐hERG K+ channel mutation: differential impact on selected class I and class III antiarrhythmic drugs , 2008, British journal of pharmacology.

[19]  Y. Rudy,et al.  Ionic Current Basis of Electrocardiographic Waveforms: A Model Study , 2002, Circulation research.

[20]  Gary R. Mirams,et al.  Computational assessment of drug-induced effects on the electrocardiogram: from ion channel to body surface potentials , 2013, British journal of pharmacology.

[21]  Michel Haïssaguerre,et al.  Loss-of-Function Mutations in the Cardiac Calcium Channel Underlie a New Clinical Entity Characterized by ST-Segment Elevation, Short QT Intervals, and Sudden Cardiac Death , 2007, Circulation.

[22]  J. Brugada,et al.  Sudden Death Associated With Short-QT Syndrome Linked to Mutations in HERG , 2003, Circulation.

[23]  Jonathan M. Cordeiro,et al.  Modulation of IKr inactivation by mutation N588K in KCNH2: A link to arrhythmogenesis in short QT syndrome , 2005 .

[24]  Martin Borggrefe,et al.  Short QT Syndrome: A Familial Cause of Sudden Death , 2003, Circulation.

[25]  Martin Borggrefe,et al.  Short QT syndrome. , 2005, Cardiovascular research.

[26]  A. V. van Ginneken,et al.  Mutation in the KCNQ1 Gene Leading to the Short QT-Interval Syndrome , 2004, Circulation.