Zhilin Qu

Computational models replicated the characteristic electrocardiogram patterns and modes of VA onset observed in human patients with JWS, including “short-long-normal-short” sequence to VA, “short-long-short” sequence to VA, and sudden onset of VA. Mechanisms of these rate-dependent onset of VA and the potential ionic causes were revealed by the computer simulations. This study not only provides mechanistic insights into spontaneous genesis of VA in JWS but also important information for identifying therapeutic targets.

Alternating (temporally period-2) stripes, clusters, and labyrinths have been observed in chemical and biochemical reactions, in Min-protein dynamics in and systems, and in calcium alternans in cardiac myocytes. However, the mechanisms underlying the formation of these spatiotemporal patterns and the transitions among them remain incompletely understood. In this article, we use an amplitude-equation (AE) approach to perform theoretical analysis and numerical simulations to elucidate the mechanisms of the alternating pattern formation and selection, and we then use reaction-diffusion models to validate the predictions of the AE model. It was shown previously that in chemical reactions and cardiac myocytes, a global feedback loop plays a key role in the formation of alternating clusters. Based on previous AE models developed to describe cardiac alternans dynamics, we first develop an AE model that incorporates either a spatially uniform global feedback (UGF) loop or a spatially nonuniform global feedback (NUGF) loop. The NUGF is represented by a spatially Gaussian-weighted function. We then use the AE model to conduct nonlinear stability analysis to reveal the mechanisms underlying the emergence of alternating patterns under different feedback conditions. Under positive UGF, no patterns can form. When the UGF is negative, the stable patterns are only multiple stripes and circular clusters. For stripe patterns, they may be spatially periodic or random as long as they satisfy the requirements for pattern selection. For circular clusters, a medium can support one or multiple circular alternating clusters of the same radius depending on the size of the medium. Under NUGF, in addition to stripe and circular-cluster patterns, lateral instability arises when the width of the Gaussian function falls within an intermediate range, leading to transitions from stripes or circular clusters to labyrinths. Other initial-condition-dependent patterns are also observed under NUGF. Under UGF, the width of the stripe can be periodic or random, but under NUGF, the patterns become less random in space as the feedback strength increases. Finally, we incorporate the UGF and NUGF loops into several reaction-diffusion models, including the Belousov-Zhabotinsky reaction model, the carbon monoxide oxidation model, and the periodically paced FitzHugh-Nagumo model. These models successfully reproduce the alternating pattern dynamics predicted by the AE model, validating the theoretical predictions.

As a result of the electrotonic effect, under gap junction coupling, a critical number of excited cells is needed to elicit electrical conduction in cardiac tissue, a phenomenon called the source–sink effect. However, it is unclear how ephaptic coupling affects the source–sink effect. To address this issue, we carry out computer simulations to investigate the effects of ephaptic coupling and its interaction with gap junction coupling on conduction triggered by the following types of depolarization: (i) an external stimulation; (ii) a delayed afterdepolarization; and (iii) automaticity. Simulations were carried out using a one‐dimensional cable with the presence of a cleft between two adjacent myocytes and junctional ion channel distributions. We show that: (i) under pure ephaptic coupling, only one stimulated cell is needed to elicit conduction, implying that there is no source–sink effect; (i) the minimum number of stimulated (or delayed afterdepolarization or oscillatory) cells needed to elicit a conduction increases as gap junction conductance increases, as predicted by the gap junction coupling theory; and (iii) the dependence of the source–sink effect on the cleft width exhibits complex behaviours, which are mainly caused by self‐attenuation of the junctional sodium current as a result of the ephaptic effect and self‐enhancement of the junctional inward rectifier potassium current as a result of an increase of potassium concentration in the cleft. In conclusion, ephaptic coupling and cleft width play non‐trivial roles in the source–sink effect of cardiac conduction and thus may be non‐trivial for arrhythmogenesis under disease conditions in which gap junctions and cleft structure are altered. image Key points: Gap junction coupling is recognized as the primary mechanism of cardiac conduction, but ephaptic coupling may also play a non‐trivial role. Source–sink effects are a key feature of cardiac conduction, and it is unclear how they are affected by ephaptic coupling. Computer simulations are used to investigate how source–sink effects are altered by ephaptic coupling and its interaction with gap junction coupling. Under pure ephaptic coupling, only one stimulated cell is needed to elicit conduction, implying that there is no source–sink effect. The minimum number of depolarized cells needed to elicit a conduction exhibits complex behaviours and depends on the manner of depolarization. These effects are mainly caused by self‐attenuation of the junctional sodium current as a result of the ephaptic effect and self‐enhancement of the inward rectifier potassium current as a result of increase of potassium concentration in the cleft.

BACKGROUND: Cardiovascular disease is the number 1 killer in industrialized countries, with sudden cardiac death due to ventricular arrhythmias representing a major component. To reduce sudden cardiac death, accurate risk prediction and development of effective preventive treatments remain major challenges. In this study, we explored the possibility of using a population-based computational modeling approach to perform virtual clinical trials for antiarrhythmic drug discovery and drug safety testing. METHODS: We developed genetically diverse populations of 1-dimensional cardiac tissue models for both normal hearts and hearts with long QT syndromes (LQT1, LQT2, and LQT3) based on matching the models to the clinically measured distributions of corrected QT intervals for each condition. RESULTS: Using a doubling of the L-type calcium current to mimic sympathetic stress, the population models exhibited a similar incidence of arrhythmias as observed in corresponding clinical studies for each condition. We demonstrated that the model populations (1) accurately predicted arrhythmia risk under normal and diseased conditions; (2) could be used to assess the effectiveness of a therapeutic strategy, namely shifting the steady-state inactivation curve of the L-type calcium current; and (3) accurately predicted the cardiotoxicity of a series of drugs when compared with their known clinical profiles. CONCLUSIONS: The population-based modeling approach outlined here shows promise as a computational platform that can directly take advantage of data from human clinical studies to improve arrhythmia risk prediction, test antiarrhythmic therapies, and assess cardiotoxicity of drugs.

Background: Methadone blocks several ionic currents with different half‐maximal inhibitory concentrations, including the rapid component of the delayed and inward (I _K1 ) rectifier potassium current, the L‐type calcium current, and the late sodium current. Despite the well‐known proarrhythmic effect of methadone, the underlying mechanisms remain less well understood. Methods: Computer simulations were used to explore the proarrhythmic effects of methadone by investigating how its blocking effects on ionic currents act alone or together in arrhythmogenesis. Results: The major findings are (1) blocking I _K1 potentiates QT prolongation‐related arrhythmogenesis by enhancing a tissue‐scale dynamical instability for the spontaneous genesis of ectopic excitations; blocking I _K1 and the rapid component of the delayed rectifier potassium current together results in a synergistic effect, greatly increasing the arrhythmia propensity, much larger than that of blocking either one alone; (2) blocking I _K1 in combination with lowering L‐type calcium current potentiates phase 2 reentry caused by spike‐and‐dome action potential morphology, an arrhythmia mechanism of early repolarization or Brugada syndrome, whereas blocking the rapid component of the delayed rectifier potassium current exhibits little effect for this mechanism of arrhythmias; and (3) hypoxia, often comorbid in methadone populations, can potentiate QT prolongation‐related arrhythmias at high sympathetic activity and phase 2 reentry at low sympathetic activity, mainly via its effect on the L‐type calcium current. Conclusions: Methadone promotes both early and delayed repolarization arrhythmias. Early repolarization may be responsible for methadone‐related deaths occurring mainly during sleep and occurring more often in men. Blocking I _K1 can work synergistically with other channel blockers to disproportionately increase arrhythmia propensity, greatly increasing methadone's risk when it is combined with other proarrhythmic drugs or under disease conditions.

Alternating (temporally period-2) stripes and labyrinths have been observed in media of chemical and biochemical reactions; however, the mechanisms underlying the formation of these spatiotemporal patterns remain unclear. Here, we conduct computer simulation using a modified model of Belousov-Zhabotinsky reaction that incorporates a global feedback loop with a spatial strength profile of Gaussian distribution. The simulation results demonstrate that the transition from alternating stripes to alternating labyrinths occurs when the feedback is negative with a certain width of the Gaussian function. We add the same Gaussian-weighted feedback loop to an amplitude equation to describe the amplitude dynamics of the period-2 oscillation and show that the pattern dynamics of the Belousov-Zhabotinsky reaction can be well captured by this amplitude equation. Analyses of the amplitude equation demonstrate that the transition from stripes to labyrinths arises from the transverse instabilities of bistable fronts caused by the Gaussian-weighted negative global feedback.

Background: Methadone is widely used for chronic pain relief and in the maintenance therapy of opioid use disorder, however, it also increases the risk of ventricular arrhythmias and sudden cardiac death. Methadone blocks several ionic currents with different half-maximal inhibitory concentrations (IC ₅₀ ), including the rapid component of the delayed rectifier potassium current (I _Kr ), the inward rectifier potassium current (I _K1 ), the L-type calcium current (I _Ca,L ), and the late component of the sodium current (I _NaL ). Despite the well-known proarrhythmic effect of I _Kr blockade, the effects of blocking other ionic currents on arrhythmogenesis remain less well understood. Methods: Computer simulations were used to explore the proarrhythmic effects of methadone by investigating how its blocking effects on ionic currents act alone or together in arrhythmogenesis. Results: The major findings are: 1) blocking I _K1 potentiates QT prolongation-related arrhythmogenesis by enhancing a tissue-scale dynamical instability for the spontaneous genesis of ectopic excitations. Blocking I _K1 and I _Kr together results in a synergistic effect, greatly increasing the arrhythmia propensity, much larger than that of blocking either one alone; 2) blocking I _K1 in combination with lowering I _Ca,L potentiates phase-2 reentry caused by spike-and-dome action potential morphology, an arrhythmia mechanism of Brugada syndrome. Blocking I _Kr exhibits little effect for this mechanism of arrhythmias; and 3) hypoxia, often comorbid in methadone populations, can potentiate QT prolongation-related arrhythmias at high sympathetic activity and phase-2 reentry at low or basal sympathetic activity, mainly via its effect on I _Ca,L. Conclusions: These simulation results provide mechanistic insights into the genesis of QT prolongation-related Torsades de Pointes and Brugada-like ECG related arrhythmias caused by methadone use.

The standard conception of cardiac conduction is based on the cable theory of nerve conduction, which treats cardiac tissue as a continuous syncytium described by the Hodgkin–Huxley equations. However, cardiac tissue is composed of discretized cells with microscopic and macroscopic heterogeneities and discontinuities, such as subcellular localizations of sodium channels and connexins. In addition to this, there are heterogeneities in the distribution of sympathetic and parasympathetic nerves, which powerfully regulate impulse propagation. In the continuous models, the ultrastructural details, i.e. the microscopic heterogeneities and discontinuities, are ignored by ‘coarse graining’ or ‘smoothing’. However, these ultrastructural components may play crucial roles in cardiac conduction and arrhythmogenesis, particularly in disease states. We discuss the current progress of modelling the effects of ultrastructural components on electrical conduction, the issues and challenges faced by the cardiac modelling community, and how to scale up conduction properties at the subcellular (microscopic) scale to the tissue and whole‐heart (macroscopic) scale in future modelling and experimental studies, i.e. how to link the ultrastructure at different scales to impulse conduction and arrhythmogenesis in the heart. image