Abstract
Background: Prolongation of the QT interval of the electrocardiogram (ECG), underlain by prolongation of the action potential duration (APD) at the cellular level, is linked to increased vulnerability to cardiac arrhythmia. Pharmacological management of arrhythmia associated with QT prolongation is typically achieved through attempting to restore APD to control ranges, reversing the enhanced vulnerability to Ca2+-dependent afterdepolarisations (arrhythmia triggers) and increased transmural dispersion of repolarisation (arrhythmia substrate) associated with APD prolongation. However, such pharmacological modulation has been demonstrated to have limited effectiveness. Understanding the integrative functional impact of pharmacological modulation requires simultaneous investigation of both the trigger and substrate.Methods: We implemented a multi-scale (cell and tissue) in silico approach using a model of the human ventricular action potential, integrated with a model of stochastic 3D spatiotemporal Ca2+ dynamics, and parameter modification to mimic prolonged QT conditions. We used these models to examine the efficacy of the hERG activator MC-II-157c in restoring APD to control ranges, examined its effects on arrhythmia triggers and substrates, and the interaction of these arrhythmia triggers and substrates.Results: QT prolongation conditions promoted the development of spontaneous release events underlying afterdepolarisations during rapid pacing. MC-II-157c applied to prolonged QT conditions shortened the APD, inhibited the development of afterdepolarisations and reduced the probability of afterdepolarisations manifesting as triggered activity in single cells. In tissue, QT prolongation resulted in an increased transmural dispersion of repolarisation, which manifested as an increased vulnerable window for uni-directional conduction block. In some cases, MC-II-157c further increased the vulnerable window through its effects on INa. The combination of stochastic release event modulation and transmural dispersion of repolarisation modulation by MC-II-157c resulted in an integrative behavior wherein the arrhythmia trigger is reduced but the arrhythmia substrate is increased, leading to variable and non-linear overall vulnerability to arrhythmia.Conclusion: The relative balance of reduced trigger and increased substrate underlies a multi-dimensional role of MC-II-157c in modulation of cardiac arrhythmia vulnerability associated with prolonged QT interval.
Highlights
Conditions in which the QT interval of the electrocardiogram (ECG) is prolonged, such as heart failure (Hart, 1994) and inherited or acquired long QT syndromes (LQTS) (Schwartz et al, 2012), are associated with an increased risk of ventricular arrhythmias (Tomaselli and Zipes, 2004; Moss and Kass, 2005)
The combination of stochastic release event modulation and transmural dispersion of repolarisation modulation by MC-II-157c resulted in an integrative behavior wherein the arrhythmia trigger is reduced but the arrhythmia substrate is increased, leading to variable and non-linear overall vulnerability to arrhythmia
The relative balance of reduced trigger and increased substrate underlies a multi-dimensional role of MC-II-157c in modulation of cardiac arrhythmia vulnerability associated with prolonged QT interval
Summary
Conditions in which the QT interval of the electrocardiogram (ECG) is prolonged, such as heart failure (Hart, 1994) and inherited or acquired long QT syndromes (LQTS) (Schwartz et al, 2012), are associated with an increased risk of ventricular arrhythmias (Tomaselli and Zipes, 2004; Moss and Kass, 2005). An increase in the tissue-level substrates for arrhythmias (that is, the necessary conditions for triggered activity to propagate and develop into arrhythmias) arise because APD prolongation is rarely homogenous in and between the different regions of the ventricles (e.g., transmurally, or from base to apex) (Antzelevitch, 2005; Glukhov et al, 2010) This heterogeneous APD prolongation increases the spatial dispersion of repolarisation, potentially leading to regions of recovered (i.e., excitable) tissue partially bordered by still refractory (i.e., unexcitable) tissue. The spatiotemporal region where such partial conduction block could occur is termed the “vulnerable window” (VW) (Starmer et al, 1993; Shaw and Rudy, 1995; Benson et al, 2008, 2011a) It follows that heterogeneous APD prolongation increases the spatial dispersion of repolarisation, and the VW, i.e., the arrhythmia substrate. Understanding the integrative functional impact of pharmacological modulation requires simultaneous investigation of both the trigger and substrate
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
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 call
