Study of factors affecting the progression and termination of drug induced Torsade de pointes in two dimensional cardiac tissue
Introduction
Torsade de pointes (TdP) is a deadly arrhythmia characterized by QRS complexes that “twist” around the isoelectric line in an electrocardiogram. Antiarrhythmic drugs like quinidine, sotalol etc. as well as a variety of non-cardiac medications have been known to cause drug induced TdP. It is thus essential for testing of TdP and long QT syndrome (LQTS) during preclinical drug development. LQTS is a prolongation of the QT interval on the electrocardiogram and is characterized by a QT interval greater than 450 ms and an abnormal T wave. At the cellular level, LQTS occurs because of either a reduction in the net repolarizing current or prolonged depolarization due to the presence of a late sodium component. LQTS may be congenital due to mutations in the genes encoding these ionic currents or acquired by response to various drugs. The drugs inducing LQTS and TdP mostly act by inhibiting the functioning of the IKr channel otherwise known as hERG channel [1].
Reduction in the repolarizing potassium current causes early after depolarizations (EADs) to occur in single cells. EAD is a slowing or reversal of repolarization during phase 2 or phase 3 of the AP. Though EADs may occur at cellular level, at the tissue level its effect is neutralized due to propagation through conductive gap junctions. TdP is sustained either by EADs arising simultaneously from a group of cells that act as an ectopic source or by reentry around an ionic heterogeneity [2]. TdP has a typical initiating short–long–short (SLS) pattern of R-R cycles consisting of a short-coupled premature ventricular complex (PVC) followed by a compensatory pause and then another PVC that falls close to or on the T wave peak [3]. TdP usually terminates spontaneously or degenerates into a more fatal ventricular fibrillation.
A 2D transmural cardiac tissue is considered for this study. Differences in action potential duration (APD) exist along the transmural layer giving rise to a positive T wave [4]. This gradient is caused by ion channel variations between epicardial (epi), midmyocardial (mid) and endocardial (endo) myocytes as well as reduced intercellular coupling at the epi–mid interface. Thus, depolarization occurs from the endo to mid to epi. However, the epi and endo cells repolarize first followed by mid cells. The repolarization end of the epi cells coincides with the peak of the normal T wave while that of the mid cells indicates the end of the T wave. The repolarization end of the endo cells falls in between the peak and end of the T wave. The interval between the time instants at which the earliest epi cell and the last mid cell reach resting potential after repolarization is defined as transmural dispersion of repolarization (TDR) and can be approximately estimated as the interval between the peak and the end of the T wave (Tend–Tpeak). LQTS and an increase in TDR creates a substrate for re-entry and is vulnerable to the development of TdP [5].
Multiple risk factors like bradycardia, electrolyte imbalance (hypokalemia, hypomagnesemia, hypocalcemia), underlying heart disease etc. that elevate predisposition to TdP are listed in Ref. [6]. Drugs like dofetilide and d-Sotalol induce TdP in chronic AV block dogs in the presence of ventricular electrical remodeling [7], [8]. This remodeling increased AP dispersion and readily induced EADs. Beat to beat variability of ventricular repolarization (BVR) in CAVB hypertrophied dog myocytes was observed to be dependent on SR calcium release, which may have acted through modulation of ICaL current [9].
In this paper, this ventricular remodeling has been implemented in a two dimensional grid of human ventricular myocardial cells by increasing the ICaL current of each cell thereby making them inducible to EADs. Acquired LQTS caused by drugs is incorporated by reducing IKr current. The objective is to study the level of remodeling required to induce TdP at a percentage reduction of IKr in addition to predisposing factors like bradycardia and timely applied ectopic stimuli. Further, we analyze the effect of hypokalemia along with the above mentioned conditions on TdP induction.
When TdP does not terminate spontaneously or degenerate into ventricular fibrillation, it is treated by many ways [10]. The most popular method is intravenous magnesium. It prevents future occurrence of ectopic beats and TdP by decreasing the influx of calcium current and thereby lowering the amplitude of EADs. Experimental studies of Kuryshev et al. [11] showed that a gap junction enhancer suppressed ibutilide induced TdP under conditions of hypokalemia and hypomagnesemia by decreasing TDR. In our study once TdP is initiated, the possibility of TdP termination is examined by increasing the gap junction conductance in between all cells and decreasing the ICaL current of all cells.
Section snippets
Cell model
The mathematical cell model developed by Ten Tusscher (TP06) [12] is used to describe the electrophysiological properties of the human ventricular transmural cells. The ionic currents of this model is described using the equations shown below.
The following differential equation describes the electrophysiological activity of a cellwhere Vm is the transmembrane potential, t is time, Cm is the membrane capacitance, Iion
Results
On exciting the tissue at a CL of 1200 ms, the normalized pseudo-ECG for different percentage reduction of GKr is recorded in Fig. 2(i). Reduction in GKr causes greater APD prolongation in mid cells compared to other cell types and this appears as a widening of the T wave in the ECG. When the GKr is reduced to 50%, 25% and 0%, the QT interval is prolonged from 350 ms in control condition to 380 ms, 405 ms and 445 ms and TDR also increases from 35 ms under a control condition to 45 ms, 60 ms and 80 ms
Discussion
Drug induced QT prolongation mainly occurs due to block of the rapid delayed rectifier potassium current (IKr) [6]. Our simulation studies on blocking IKr to different percentages show a pseudo-ECG pattern with prolongation of QT interval and increase in TDR which creates a substrate for genesis of TdP. Drugs which do not increase TDR do not pose much of a risk for inducing TdP. However, on pacing the tissue with a bradycardiac SLS triggering sequence in presence of reduced GKr alone does not
Conclusion
A drug induced TdP arrhythmic pseudo-ECG pattern was thus simulated in a remodeled cardiac ventricular 2D grid using the classic clinical scenarios of decreased potassium current, bradycardia and SLS initiating pattern. Additional factors like hypokalemia and increased calcium current predispose the tissue to development of TdP. A non-terminating TdP can be stopped by drugs that increase GJC or decrease the calcium current in all cells. This study shows that ICal has a major role in initiating
Acknowledgments
This work was supported by the Indian Institute of Technology Madras.
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Simulation study of the ionic mechanisms underlying Torsade de Pointes in a 2D cardiac tissue
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