Reentrant Wave Research Articles

Computational analysis of the effect of KCNH2 L532P mutation on ventricular electromechanical behaviors

The KCNH2 L532P mutation is an alteration in the IKr channel that is associated with short QT syndrome and atrial fibrillation in zebrafish. In preliminary studies, the electrophysiological effects of the hERG L532P mutation were investigated using a mathematical model in a single-cell and 2D sheet medium. The objective of this study was to quantify the effects of the KCNH2 L532P mutation on the 3D ventricular electrophysiological behavior and the mechanical pumping responses. We used a realistic three-dimensional ventricular electrophysiological–mechanical model, which was adjusted into two conditions: the wild-type (WT) condition, i.e., the original case of the Tusscher et al. model, and the L532P mutation condition, with modification of the original IKr equation. The action potential duration (APD) in the mutant ventricle was reduced by 73% owing to the significant increase of the IKr current density. In the 3D simulation, the L532P mutation maintained the sustainability of reentrant waves; however, the reentry was terminated in the WT condition. The contractility of the ventricle with L532P mutation was significantly reduced compared with that in WT which results in sustain shivering heart during reentry condition. The reduction of the contractility was associated with the shortening APD which simultaneously shortened the duration of the Ca2+ channel opening. In conclusion, the ventricle with KCNH2 L532P mutation is prone to reentry generation with a sustained chaotic condition, and the mutation significantly reduced the pumping performance of the ventricles.

A Simulation Study on the Reentrant Waves in the Pacing Ventricular Tissues

The aim of the study is to investigate the relationship between the reentrant waves and I K1, and probe the effect of I K1 on the reentrant waves. Firstly, based on the TNNP06 model, the single pacing cell is derived by depressing I K1. And then, a 400 cells ×400 cells 2D tissue is developed by coupling the pacing cells together. Thirdly, the S1-S2 protocol is applied to inspire the reentrant waves. Next, the processes of the reentrant waves in the tissue corresponding to different I K1 are analysed. In addition, the action potentials of the cells in special locations are recorded and discussed. With the decrease of the I K1, the reentrant waves spin slowly and the period of reentrant waves increases. Meanwhile, the range of the action potential of the cells becomes larger when I K1 becomes smaller. The results suggest that with the decrease of I K1, the reentrant wave is weakened, and the systolic and diastolic functions of the tissue are enhanced at the same time.

In Silico Investigation of CACNA2D1 S755T Mutation Associated With Short QT Syndrome

Short QT syndrome (SQTS) is a genetic disease characterized by constantly short QT intervals and high risks of sudden death. SQTS6 is one of the identified SQTS genotype variants associated with the CACNA2D1 S755T mutation. However, the pathogenesis of SQTS induced arrhythmias remains unclear. To identify the underlying mechanisms of SQTS6 induced arrhythmias, a multi-scale human ventricle model comprising cell to organ levels was built. Cellular data was fitted at the cell level to reproduce the electrophysiological alterations reported in experiments. The influences were further explored at tissue and organ levels using idealized strand or tissue sheet models, and realistic ventricular slice and three-dimensional organ models. Simulation results suggested that, at the cellular level, the action potential duration (APD) and the effective refractory period (ERP) of myocytes were significantly abbreviated in the mutation condition. The unevenly changed APD and ERP led to transmural heterogeneity remodeling, and resulted in decreased temporal vulnerability. In addition, the S755T mutation shortened the critical length for initiating reentrant spiral waves, which enhanced the spatial vulnerability and provided substrates for reentry arrhythmias. Regarding the sustainability of arrhythmias, the evoked spiral waves or scroll waves persisted in the mutation condition but did not persist in the wild-type condition. The present study clearly suggested that the CACNA1DC S755T mutation can facilitate the initiation and maintenance of ventricular arrhythmias, and therefore contributes to higher risks of ventricular arrhythmias in SQTS6 patients.

Inverse mechano-electrical reconstruction of cardiac excitation wave patterns from mechanical deformation using deep learning.

The inverse mechano-electrical problem in cardiac electrophysiology is the attempt to reconstruct electrical excitation or action potential wave patterns from the heart's mechanical deformation that occurs in response to electrical excitation. Because heart muscle cells contract upon electrical excitation due to the excitation-contraction coupling mechanism, the resulting deformation of the heart should reflect macroscopic action potential wave phenomena. However, whether the relationship between macroscopic electrical and mechanical phenomena is well-defined and unique enough to be utilized for an inverse imaging technique in which mechanical activation mapping is used as a surrogate for electrical mapping has yet to be determined. Here, we provide a numerical proof-of-principle that deep learning can be used to solve the inverse mechano-electrical problem in phenomenological two- and three-dimensional computer simulations of the contracting heart wall, or in elastic excitable media, with muscle fiber anisotropy. We trained a convolutional autoencoder neural network to learn the complex relationship between electrical excitation, active stress, and tissue deformation during both focal or reentrant chaotic wave activity and, consequently, used the network to successfully estimate or reconstruct electrical excitation wave patterns from mechanical deformation in sheets and bulk-shaped tissues, even in the presence of noise and at low spatial resolutions. We demonstrate that even complicated three-dimensional electrical excitation wave phenomena, such as scroll waves and their vortex filaments, can be computed with very high reconstruction accuracies of about 95% from mechanical deformation using autoencoder neural networks, and we provide a comparison with results that were obtained previously with a physics- or knowledge-based approach.

Abstract 14201: The Application of Hipsc-derived Cardiomyocytes Paced by Re-entrant Waves for Drug Assessment

Introduction: How to precisely evaluate response in newly developed medications in vitro may be a great concern in drug screening. We modified normal low-attachment culture dish and created closed-loop tissue ring from single hiPSC-CMs. We hypothesized that the re-entrant wave (ReW) could originate and pace the cardiac tissue ring, and the CMs under pacing could be matured and used for drug assessment. Methods: PDMS wells and pillars were mounted in low-attachment petri dishes (Figure 1A). 4 х 10 5 hiPSC-CMs were plated into the wells to form tissue ring where the ReW could spontaneously originate. After cultivation for 14 days, the hiPSC-CMs were evaluated by immunostaining and gene expression. Micro electrode array (MEA) were used to evaluating the CM response to different drugs. Results: The electrical signal recorded by MEA indicated that the ReWs could make the CMs beat at a much higher rate than the Control group (Figure 1B, 123.26 ± 10.36 bpm vs. 14.08 ± 4.53 bpm, p<0.0001). After 14 day culture, the ReW group demonstrated significantly higher expression of Troponin T (TnT2), myosin heavy chain 7 (β-MHC), and α-actinin. Interestingly, the α-actinin staining indicated alignment of CMs within the ReW group (Figure 1C). The CMs under ReW pacing showed robust response to several cardiac compounds including E4031, (hERG K+ channel blocker, Figure 1D and E), isoproterenol (β adrenoceptor agonist) and propranolol (beta-blocker). Both the field potential as well as the Ca 2+ transients showed correlated dose-dependent change and the recovering after washout of the drugs. Conclusions: The ReWs could spontaneously originate in the cultured cardiac tissue ring with enhancement of the maturation in the hiPSC-CMs and robust response to various drugs, indicating the system as a robust drug assessment system with multiple read-out methods.

Right Atrial Collision Time (RACT): a novel marker of propensity for typical atrial flutter

Abstract Background The risk of typical atrial flutter (AFL) is increased by factors that increase right atrial (RA) size or cause scarring to reduce conduction velocity. These characteristics ensure the macro re-entrant wave front does not meet its refractory tail. The time taken to traverse the circuit would take account of both of these characteristics (being equal to distance divided by velocity), and may provide a superior marker of propensity to develop AFL. Purpose To investigate right atrial collision time (RACT) as a marker of typical AFL. Methods This single centre, prospective study recruited consecutive typical AFL ablation cases that were in sinus rhythm. Controls were consecutive cases other than atrial fibrillation and >50 years of age. Exclusion criteria for both groups were a prior ablation in the RA and class I and III antiarrhythmics. While pacing the coronary sinus ostium at 600 ms, a local activation time map was created to locate the latest collision point on the anterolateral wall, excluding the RA appendage (Figure 1). This RACT approximates half a revolution. Results The AFL group's (n=34) mean RACT was 132.5±15.06 vs 98.7±12.23ms in the controls (n=40) (p<0.01). No significant difference was observed for age (mean 65.6 vs 62.6 (p=0.18)), male (68.8% vs 60% (p=0.59)), body surface area (mean 2.1 vs 2.03 m2 (p=0.24)). The RACT also proved to be a superior marker than the echocardiographic measurement of right atrial area in an apical four chamber view (mean 17.8 vs 16.3 cm2 (p=0.21).A ROC curve indicated an AUC of 0.97 (95% CI: 0.93–1.0, p<0.01). A RACT cut-off of 120 ms had a specificity of 99% and a sensitivity of 75%. Conclusion RACT is a novel and promising marker of propensity for typical AFL. The ability to predict AFL would be of significant clinical value given the risk of stroke and frequent need for ablation. Funding Acknowledgement Type of funding source: None

Elucidating the relationship between arrhythmia and ischemic heterogeneity: an in silico study.

Dialysis causes blood flow defects in the heart that may augment electrophysiological heterogeneity in the form of increased number of ischemic zones in the human left ventricle. We computationally tested whether a larger number of ischemic zones aggravate arrhythmia using a 2D electrophysiological model of the human ventricle.A human ventricle cardiomyocyte model capable of simulating ischemic action potentials was adapted in this study. The cell model was incorporated into a spatial 2D model consisting of known number of ischemic zones. Inter-cellular gap junction coupling within ischemic zones was reduced to simulate slow conduction. Arrhythmia severity was assessed by inducing a re-entry, and quantifying the ensuing breakup and tissue pacing rates.Ischemia elevated the isolated cardiomyocyte's resting potential and reduced its action potential duration. In the absence of ischemic zones, the propensity in the 2D model to induce multiple re-entrant waves was low. The inclusion of ischemic zones provided the substrate for initiation of re-entrant waves leading to fibrillation. Dominant frequency, which measured the highest rate of pacing in the tissue, increased drastically with the inclusion of multiple ischemic zones. Re-entrant wave tip maximum numbers increased from 1 tip (no ischemic zone) to 34 tips when a large number (20) of ischemic zones were included. Computational limiting factors of our platform were identified using software profiling.Clinical significance. Dialysis may promote deleterious arrhythmias by increasing tissue level action potential dispersion.

Effect of Percentage Reduction in Action Potential Duration of M-cells on Re-entry in Short QT Syndrome.

Increase in transmural dispersion of repolarisation along with a diminished QT interval have been known to aid in the development of arrhythmia during KCNQ1-linked short QT syndrome type 2 (SQTS2). However, the percentage by which action potential duration (APD) shortens in the different cell types that make up the ventricular wall are not fully understood. In this study, the percentage of APD shortening of M-cells was varied to determine the conditions under which re-entry occurs during SQTS2. A 2D transmural section of the heart with anisotropic properties is considered. Slight modifications to the TP06 equations are used to simulate the electrophysiology of the endocardial (endo), midmyocardial (M) and epicardial (epi) cells. A discrete network of 250×100 cells are interconnected using gap junction conductances and from this, a pseudo ECG is generated. On pacing the tissue with premature beats in the midst of normal pacing pulses and on including SQTS, it is observed that re-entry is sustained for a longer duration when the APD shortening in M-cells is more compared to the epi or endo cells while the percentage reduction in APD of M-cells is about 5% to 7% lesser than that in epi and endo cells. Further, when the percentage reduction in APD of M-cells is similar to epi or endo cells, no re-entry is generated. This analysis highlights the key role of percentage reduction in APD of M-cells compared to epi and endo cells in maintaining the re-entrant waves.

Optogenetic approaches for termination of ventricular tachyarrhythmias after myocardial infarction in rats in vivo.

Cardiac optogenetics facilitates the painless manipulation of the heart with optical energy and was recently shown to terminate ventricular tachycardia (VT) in explanted mice heart. This study aimed to evaluate the optogenetic-based termination of induced VT under ischemia in an open-chest rat model and to develop an optimal, optical-manipulation procedure. VT was induced by burst stimulation after ligation of the left anterior descending coronary artery, and the termination effects of the optical manipulation, including electrical anti-tachycardia pacing (ATP) and spontaneous recovery, were tested. Among different multisegment optical modes, four repeated illuminations of 1000 ms in duration with 1-second interval at a 20-times intensity threshold on the right ventricle achieved the highest termination rate of 86.14% ± 4.145%, higher than that achieved by ATP and spontaneous termination. We demonstrated that optogenetic-based cardioversion is feasible and effective in vivo, with the underlying mechanism involving the light-triggered, ChR2-induced depolarization of the illuminated myocardium, in turn generating an excitation that disrupts the preexisting reentrant wave front.

Circulating re-entrant waves promote maturation of hiPSC-derived cardiomyocytes in self-organized tissue ring

Directed differentiation methods allow acquisition of high-purity cardiomyocytes differentiated from human induced pluripotent stem cells (hiPSCs); however, their immaturity characteristic limits their application for drug screening and regenerative therapy. The rapid electrical pacing of cardiomyocytes has been used for efficiently promoting the maturation of cardiomyocytes, here we describe a simple device in modified culture plate on which hiPSC-derived cardiomyocytes can form three-dimensional self-organized tissue rings (SOTRs). Using calcium imaging, we show that within the ring, reentrant waves (ReWs) of action potential spontaneously originated and ran robustly at a frequency up to 4 Hz. After 2 weeks, SOTRs with ReWs show higher maturation including structural organization, increased cardiac-specific gene expression, enhanced Ca2+-handling properties, an increased oxygen-consumption rate, and enhanced contractile force. We subsequently use a mathematical model to interpret the origination, propagation, and long-term behavior of the ReWs within the SOTRs.

Anisotropic shortening in the wavelength of electrical waves promotes onset of electrical turbulence in cardiac tissue: An in silico study

Several pathological conditions introduce spatial variations in the electrical properties of cardiac tissue. These variations occur as localized or distributed gradients in ion-channel functionality over extended tissue media. Electrical waves, propagating through such affected tissue, demonstrate distortions, depending on the nature of the ionic gradient in the diseased substrate. If the degree of distortion is large, reentrant activity may develop, in the form of rotating spiral (2d) and scroll (3d) waves of electrical activity. These reentrant waves are associated with the occurrence of lethal cardiac rhythm disorders, known as arrhythmias, such as ventricular tachycardia (VT) and ventricular fibrillation (VF), which are believed to be common precursors of sudden cardiac arrest. By using state-of-the-art mathematical models for generic, and ionically-realistic (human) cardiac tissue, we study the detrimental effects of these ionic gradients on electrical wave propagation. We propose a possible mechanism for the development of instabilities in reentrant wave patterns, in the presence of ionic gradients in cardiac tissue, which may explain how one type of arrhythmia (VT) can degenerate into another (VF). Our proposed mechanism entails anisotropic reduction in the wavelength of the excitation waves because of anisotropic variation in its electrical properties, in particular the action potential duration (APD). We find that the variation in the APD, which we induce by varying ion-channel conductances, imposes a spatial variation in the spiral- or scroll-wave frequency ω. Such gradients in ω induce anisotropic shortening of wavelength of the spiral or scroll arms and eventually leads to instabilitites.

Study on the coolant pressure of internal combustion engines through vibro-acoustical analysis of a real cylinder block structure

Liner cavitation is caused by water pressure fluctuation in the water coolant passage of internal combustion engines. The high-speed re-entrant jet and shock wave following the implosion of cavitation bubbles cause cavitation erosion on the wet cylinder liner surface. The present work proposes a numerical method to predict the water pressure fluctuation of engine systems considering acoustic features of water coolant passage. The effect of the geometry modification of water coolant passage is evaluated. The water coolant passage acoustic field is introduced into the engine system containing a crankcase, a gear case, a cylinder head and an injection pump. The water coolant pressure fluctuation and engine vibration are calculated for engine systems with different exciting forces. The cross-sectional pressure distribution of water coolant passage and the longitudinal pressure distribution along thrust side of liner at top dead center are discussed. It is revealed that the pressure distribution is influenced by certain acoustic modes. The pressure fluctuates strongly at the top dead center, which is conductive to bubble formation and explosion.

Proarrhythmogenic Effect of the L532P and N588K KCNH2 Mutations in the Human Heart Using a 3D Electrophysiological Model.

BackgroundAtrial arrhythmia is a cardiac disorder caused by abnormal electrical signaling and transmission, which can result in atrial fibrillation and eventual death. Genetic defects in ion channels can cause myocardial repolarization disorders. Arrhythmia-associated gene mutations, including KCNH2 gene mutations, which are one of the most common genetic disorders, have been reported. This mutation causes abnormal QT intervals by a gain of function in the rapid delayed rectifier potassium channel (IKr). In this study, we demonstrated that mutations in the KCNH2 gene cause atrial arrhythmia.MethodsThe N588K and L532P mutations were induced in the Courtemanche-Ramirez-Nattel (CRN) cell model, which was subjected to two-dimensional and three-dimensional simulations to compare the electrical conduction patterns of the wild-type and mutant-type genes.ResultsIn contrast to the early self-termination of the wild-type conduction waveforms, the conduction waveform of the mutant-type retained the reentrant wave (N588K) and caused a spiral break-up, resulting in irregular wave generation (L532P).ConclusionThe present study confirmed that the KCNH2 gene mutation increases the vulnerability of the atrial tissue for arrhythmia.

The Arrhythmogenic Effect of Protein-Bound Uremic Toxin p-Cresylsulfate: An In Vitro Study.

p-Cresylsulfate (PCS) is a protein-bound uremic toxin that accumulates in patients with chronic kidney disease. Previous studies have indicated that serum total PCS levels are significantly increased in the presence of abnormal corrected QT (QTc) intervals, and that they are associated with QTc prolongation. However, the QTc prolongation effect of PCS remains unclear. The current study aimed to investigate the arrhythmogenic effect of PCS using in vitro experiments and computer simulation. The arrhythmogenic effect of PCS was evaluated by incubating H9c2 rat ventricular cardiomyocytes in vitro with increasing concentrations of PCS. Electrophysiological studies and mathematical computer simulations were performed. in vitro, the delayed rectifier potassium current (IK ) was significantly decreased in a dose-dependent manner after treatment with PCS. The modulation of PCS on IK was through regulation of the phosphorylation of the major potassium ion channel protein Kv2.1. In computer simulations, the decrease in IK induced by PCS prolonged the action potential duration (APD) and sped up the re-entrant wave, which is known to be a trigger mechanism for lethal ventricular arrhythmias. PCS significantly downregulated the phosphorylation of the IK channel protein Kv2.1 and IK current activity, which increased the cardiomyocyte APD. This was observed both in vitro and in the computer O'Hara-Rudy dynamic human ventricular model. These findings suggest that PCS may play a key role in the development of cardiac arrhythmias.

Proarrhythmia in the p.Met207Val PITX2c-Linked Familial Atrial Fibrillation-Insights From Modeling.

Functional analysis has shown that the p.Met207Val mutation was linked to atrial fibrillation and caused an increase in transactivation activity of PITX2c, which caused changes in mRNA synthesis related to ionic channels and intercellular electrical coupling. We assumed that these changes were quantitatively translated to the functional level. This study aimed to investigate the potential impact of the PITX2c p.Met207Val mutation on atrial electrical activity through multiscale computational models. The well-known Courtemanche-Ramirez-Nattel (CRN) model of human atrial cell action potentials (APs) was modified to incorporate experimental data on the expected p.Met207Val mutation-induced changes in ionic channel currents (INaL, IKs, and IKr) and intercellular electrical coupling. The cell models for wild-type (WT), heterozygous (Mutant/Wild type, MT/WT), and homozygous (Mutant, MT) PITX2c cases were incorporated into homogeneous multicellular 1D and 2D tissue models. Effects of this mutation-induced remodeling were quantified as changes in AP profile, AP duration (APD) restitution, conduction velocity (CV) restitution and wavelength (WL). Temporal and spatial vulnerabilities of atrial tissue to the genesis of reentry were computed. Dynamic behaviors of re-entrant excitation waves (Life span, tip trajectory and dominant frequency) in a homogeneous 2D tissue model were characterized. Our results suggest that the PITX2c p.Met207Val mutation abbreviated atrial APD and flattened APD restitution curves. It reduced atrial CV and WL that facilitated the conduction of high rate atrial excitation waves. It increased the tissue's temporal vulnerability by increasing the vulnerable window for initiating reentry and increased the tissue spatial vulnerability by reducing the substrate size necessary to sustain reentry. In the 2D models, the mutation also stabilized and accelerated re-entrant excitation waves, leading to rapid and sustained reentry. In conclusion, electrical and structural remodeling arising from the PITX2c p.Met207Val mutation may increase atrial susceptibility to arrhythmia due to shortened APD, reduced CV and increased tissue vulnerability, which, in combination, facilitate initiation and maintenance of re-entrant excitation waves.

P2439Reconstructing electrocardiograms from computational models of infarcted ventricles to determine the location of myocardial infarct scars based on features of the signal

Abstract Myocardial infarction can cause ventricular tachycardia as a result of reentrant electrical activation waves propagating around the infarct scar. The tachycardia can be treated by radiofrequency catheter ablation which requires the cardiologist to deliver radiofrequency, via an intracardiac catheter, to ablate a specific site within the scar, disrupting the reentrant circuit, to terminate the arrhythmia. Therefore, determining the location of the scar is an important step in the procedure. MRI and CT scans can show the region of scar but are costly and are contraindicated in many cases. Cardiologists observe ECG recordings of the patient's tachycardia, looking at the gross characteristics of the signal to determine an approximate location of the scar. However, this technique assumes a recording of the patient's tachycardia is available, and is only able to suggest a gross region of the heart. In addition, the method is based on studies which have identified characteristic features of the ECG using intracardiac mapping to determine the location of the scar, which may be unreliable. This study aims to determine features of the ECG which may be able to predict the location of an infarct scar with more accuracy and specificity than current methods allow. The use of computational models ensures that the true location of the scar is known, unlike in previous studies. Moreover, we aim to determine whether there are any characteristics of resting state ECG which may indicate the location of an infarct scar. An anatomically accurate finite element model of rabbit ventricles in a conductive bath was utilised in order to simulate electrical activation waves and generate ECG signals, by reconstructing the extracellular potentials. Scar regions comprising of non-conducting scar surrounded by tissue with altered electrophysiological properties to represent the borderzone were incorporated into the ventricular model at varying locations across the myocardium. The models were stimulated using an S1S2 protocol to produce wave block and reentry. ECGs were reconstructed and the differences between models were observed. Results suggest that differences in timing and amplitude of the R wave on the ECG could be an indication of scar location. Changes in the repolarisation phase of the ECG were also apparent, suggesting more features which could determine the location of the scar. Importantly, characteristic features of the ECG could also be determined from resting state ECG, generated from models where scar was present but no reentry occurred. Utilising computational models of rabbit ventricles with scars incorporated at a variety of locations around the myocardium, we were able to determine a set of features from the ECG which may be of use in determining the location of an infarct scar. Future validation of this study using patient data could indicate that this methodology may be of use in predicting scar location in ablation procedures. Acknowledgement/Funding YH is funded by the MRC (MR/R024995/1). JT acknowledges the financial support of the EPSRC (EP/N014391/1) and the Wellcome Trust WT105618MA.

The role of the size of infarcted area on two kinds of vulnerable window in two dimension ventricular tissue.

Sudden cardiac death (SCD) is mainly induced by ventricular arrhythmia, especially among patients with myocardial infarction (MI). Previous studies have shown that ventricular tachycardia and fibrillation are thought to be caused by re-entrant waves of excitation. Although in heterogeneous tissue, the traditional vulnerable window of unidirectional block and the vulnerable window when bidirectional propagation was initiated could coexist, little studies are based on effects of infarcted areas on both vulnerable windows. The electrophysiology remodeling was based on TP06 model in the present study. In simulation of two-dimension (2D) ideal models, excitation wave conduction in ventricular tissue was simulated under three different types of stimulus. 2D ideal models of ventricular tissue were constructed as loop areas in the center of a square tissue with the resolution of 600×600 grid points and cell size of 0.35mm. Simulation results showed that the traditional vulnerable window when unidirectional propagation was initiated was consistent no matter where the position of stimulus is and how long and how wide the size of the infarcted area is. However, the vulnerable window when bidirectional propagation was initiated varies in different conditions. The traditional vulnerable window could not reflect the role of the infarcted area on arrhythmogenesis. The vulnerable window when bidirectional propagation was initiated increases with the increasement of the width and the length of the infarcted area with the appropriate position of the stimulus, which could help us to conclude the arrhythmogenesis according to the size of infarcted areas.

Effect of myocardial heterogeneity on ventricular electro-mechanical responses: a computational study

BackgroundThe heart wall exhibits three layers of different thicknesses: the outer epicardium, mid-myocardium, and inner endocardium. Among these layers, the mid-myocardium is typically the thickest. As indicated by preliminary studies, heart-wall layers exhibit various characteristics with regard to electrophysiology, pharmacology, and pathology. Construction of an accurate three-dimensional (3D) model of the heart is important for predicting physiological behaviors. However, the wide variability of myocardial shapes and the unclear edges between the epicardium and soft tissues are major challenges in the 3D model segmentation approach for identifying the boundaries of the epicardium, mid-myocardium, and endocardium. Therefore, this results in possible variations in the heterogeneity ratios between the epicardium, mid-myocardium, and endocardium. The objective of this study was to observe the effects of different thickness ratios of the epicardium, mid-myocardium, and endocardium on cardiac arrhythmogenesis, reentry instability, and mechanical responses during arrhythmia.MethodsWe used a computational method and simulated three heterogeneous ventricular models: Model 1 had the thickest M cell layer and thinnest epicardium and endocardium. Model 2 had intermediate layer thicknesses. Model 3 exhibited the thinnest mid-myocardium and thickest epicardium and endocardium. Electrical and mechanical simulations of the three heterogeneous models were performed under normal sinus rhythm and reentry conditions.ResultsModel 1 exhibited the highest probability of terminating reentrant waves, and Model 3 exhibited to experience greater cardiac arrhythmia. In the reentry simulation, at 8 s, Model 3 generated the largest number of rotors (eight), while Models 1 and 2 produced five and seven rotors, respectively. There was no significant difference in the cardiac output obtained during the sinus rhythm. Under the reentry condition, the highest cardiac output was generated by Model 1 (19 mL/s), followed by Model 2 (9 mL/s) and Model 3 (7 mL/s).ConclusionsA thicker mid-myocardium led to improvements in the pumping efficacy and contractility and reduced the probability of cardiac arrhythmia. Conversely, thinner M cell layers generated more unstable reentrant spiral waves and hindered the ventricular pumping.

Optogenetic Control of Re-Entrant Waves Demonstrated in Human Induced Stem Cell Derived Cardiomyocytes (hiPSC-CMs)

Optogenetic Control of Re-Entrant Waves Demonstrated in Human Induced Stem Cell Derived Cardiomyocytes (hiPSC-CMs)

Human Atrial Arrhythmogenesis and Sinus Bradycardia in KCNQ1-Linked Short QT Syndrome: Insights From Computational Modelling.

Atrial fibrillation (AF) and sinus bradycardia have been reported in patients with short QT syndrome variant 2 (SQT2), which is underlain by gain-of-function mutations in KCNQ1 encoding the α subunit of channels carrying slow delayed rectifier potassium current, IKs. However, the mechanism(s) underlying the increased atrial arrhythmogenesis and impaired cardiac pacemaking activity arising from increased IKs remain unclear. Possible pharmacological interventions of AF in the SQT2 condition also remain to be elucidated. Using computational modelling, we assessed the functional impact of SQT2 mutations on human sinoatrial node (SAN) pacemaking, atrial repolarisation and arrhythmogenesis, and efficacy of the anti-arrhythmic drug quinidine. Markov chain formulations of IKs describing two KCNQ1 mutations – V141M and V307L – were developed from voltage-clamp experimental data and then incorporated into contemporary action potential (AP) models of human atrial and SAN cells, the former of which were integrated into idealised and anatomically detailed tissue models. Both mutations shortened atrial AP duration (APD) through distinct IKs ‘gain-of-function’ mechanisms, whereas SAN pacemaking rate was slowed markedly only by the V141M mutation. Differences in APD restitution steepness influenced re-entry dynamics in tissue – the V141M mutation promoted stationary and stable spiral waves whereas the V307L mutation promoted non-stationary and unstable re-entrant waves. Both mutations shortened tissue excitation wavelength through reduced effective refractory period but not conduction velocity, which served to increase the lifespan of re-entrant excitation in a 3D anatomical human atria model, as well as the dominant frequency (DF), which was higher for the V141M mutation. Quinidine was effective at terminating arrhythmic excitation waves associated with the V307L but not V141M mutation, and reduced the DF in a dose-dependent manner under both mutation conditions. This study provides mechanistic insights into different AF/bradycardia phenotypes in SQT2 and the efficacy of quinidine pharmacotherapy.