In silico assessment of the effects of quinidine, disopyramide and E-4031 on short QT syndrome variant 1 in the human ventricles.

Aims Short 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. Methods The 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. Results At 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. Conclusions The 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

Kv1.4 channel block by quinidine: evidence for a drug-induced allosteric effect

We studied quinidine block of Kv1.4ΔN, a K+ channel lacking N-type inactivation, expressed in Xenopus ooctyes. Initially, quinidine intracellularly blocked the open channel so rapidly it overlapped with activation. This rapid open channel block was reduced (non-additively) by interventions that slow C-type inactivation: [K+]o elevation and an extracellular lysine to tyrosine mutation (K532Y). These manipulations reduced the affinity of rapid open channel block ≈10-fold, but left the effective electrical distance unchanged at ≈0.15. Following rapid open channel block, there were time-dependent quinidine effects: the rate of inactivation during a single depolarisation was increased, and repetitive pulsing showed use dependence. The rate of recovery from the time-dependent aspect of quinidine block was similar to recovery from normal C-type inactivation. Manipulations that prevented the channel from entering the C-type inactivated state (i.e. high [K+]o or the K532Y mutation) prevented the development of the time-dependent quinidine-induced inactivation. The concentration dependence of the rapid block and the time-dependent quinidine-induced inactivation were similar, but the time-dependent component was strongly voltage sensitive, with an effective electrical distance of 2. Clearly, this cannot reflect the permeation of quinidine through the electric field, but must be the result of some other voltage-sensitive change in the channel. We propose that quinidine promotes the entry of the channel into a C-type inactivated state in a time- and voltage-dependent manner. We developed a mathematical model based on these results to test the hypothesis that, following rapid open channel block, quinidine promotes development of the C-type inactivated state through a voltage-dependent conformational change