Abstract
AimsShort QT syndrome (SQTS) is an inherited disorder associated with abnormally abbreviated QT intervals and an increased incidence of atrial and ventricular arrhythmias. SQT1 variant (linked to the rapid delayed rectifier potassium channel current, IKr) of SQTS, results from an inactivation-attenuated, gain-of-function mutation (N588K) in the KCNH2-encoded potassium channels. Pro-arrhythmogenic effects of SQT1 have been well characterized, but less is known about the possible pharmacological antiarrhythmic treatment of SQT1. Therefore, this study aimed to assess the potential effects of E-4031, disopyramide and quinidine on SQT1 using a mathematical model of human ventricular electrophysiology.MethodsThe ten Tusscher et al. biophysically detailed model of the human ventricular action potential (AP) was modified to incorporate IKr Markov chain (MC) formulations based on experimental data of the kinetics of the N588K mutation of the KCNH2-encoded subunit of the IKr channels. The modified ventricular cell model was then integrated into one-dimensional (1D) strand, 2D regular and realistic tissues with transmural heterogeneities. The channel-blocking effect of the drugs on ion currents in healthy and SQT1 cells was modeled using half-maximal inhibitory concentration (IC50) and Hill coefficient (nH) values from literatures. Effects of drugs on cell AP duration (APD), effective refractory period (ERP) and pseudo-ECG traces were calculated. Effects of drugs on the ventricular temporal and spatial vulnerability to re-entrant excitation waves were measured. Re-entry was simulated in both 2D regular and realistic ventricular tissue.ResultsAt the single cell level, the drugs E-4031 and disopyramide had hardly noticeable effects on the ventricular cell APD at 90% repolarization (APD90), whereas quinidine caused a significant prolongation of APD90. Quinidine prolonged and decreased the maximal transmural AP heterogeneity (δV); this led to the decreased transmural heterogeneity of APD across the 1D strand. Quinidine caused QT prolongation and a decrease in the T-wave amplitude, and increased ERP and decreased temporal susceptibility of the tissue to the initiation of re-entry and increased the minimum substrate size necessary to prevent re-entry in the 2D regular model, and further terminated re-entrant waves in the 2D realistic model. Quinidine exhibited significantly better therapeutic effects on SQT1 than E-4031 and disopyramide.ConclusionsThe simulated pharmacological actions of quinidine exhibited antiarrhythmic effects on SQT1. This study substantiates a causal link between quinidine and QT interval prolongation in SQT1 and suggests that quinidine may be a potential pharmacological agent for treating SQT1 patients.
Highlights
Short QT syndrome (SQTS) is a cardiac disorder associated with abnormally abbreviated QT intervals and an increased incidence of atrial and ventricular arrhythmias or sudden cardiac death (SCD) [1,2,3,4]
At the single cell level, the drugs E-4031 and disopyramide had hardly noticeable effects on the ventricular cell AP duration (APD) at 90% repolarization (APD90), whereas quinidine caused a significant prolongation of APD90
Disopyramide and E-4031 on short QT syndrome variant 1 heterogeneity; this led to the decreased transmural heterogeneity of APD across the 1D strand
Summary
Short QT syndrome (SQTS) is a cardiac disorder associated with abnormally abbreviated QT intervals and an increased incidence of atrial and ventricular arrhythmias or sudden cardiac death (SCD) [1,2,3,4]. The familial nature and characteristics of this sudden death syndrome were demonstrated by Gaita et al [2] in 2003. These reports led to the recognition of SQTS as a new, distinct disease and have been quickly followed by additional human case reports over the past decade. The corresponding short QT syndrome has been termed from SQT1 to SQT6 depending on the chronological order of discovery Among these dominant mutations, either a gain-in-function of the potassium channel (linked to KCNH2, KCNQ1 and KCNJ2 gene) or a loss-in-function of the calcium channel (linked to CACNA1C, CACNB2b and CACNA2D1 gene) across the membrane of cardiac muscle cells has been observed
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
