Aims Short QT syndrome (SQTS) is an inherited disorder associated with abnormally abbreviated QT ... more 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, I Kr) 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 I Kr Markov chain (MC) formulations based on experimental data of the kinetics of the N588K mutation of the KCNH2-encoded subunit of the I Kr channels. The modified ventricular cell model was then integrated into one-dimensional (1D) strand, 2D regular and realistic tissues with transmural heterogeneities. The channelblocking effect of the drugs on ion currents in healthy and SQT1 cells was modeled using half-maximal inhibitory concentration (IC 50) 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 (APD 90), whereas quinidine caused a significant prolongation of APD 90. Quinidine prolonged and decreased the maximal transmural AP
Pacemaking dysfunction (PD) may result in heart rhythm disorders, syncope or even death. Current ... more Pacemaking dysfunction (PD) may result in heart rhythm disorders, syncope or even death. Current treatment of PD using implanted electronic pacemaker has some limitations, such as finite battery life and the risk of repeated surgery. As such, the biological pacemaker has been proposed as a potential alternative to the electronic pacemaker for PD treatment. Experimentally it has been shown that bio-engineered pacemaker cells can be generated from non-rhythmic ventricular myocytes (VMs) by knocking down genes related to the inward rectifier potassium channel current (IK1) or by overexpressing hyperpolarization-activated cyclic nucleotide gated channel genes responsible for the “funny” current (If). Such approaches can turn the VM cells into rhythmic pacemaker cells. However, it is unclear if a bio-engineered pacemaker based on the modification of IK1- and If-related channels simultaneously would enhance the ability and stability of bio-engineered pacemaking action potentials (APs). Th...
2016 Computing in Cardiology Conference (CinC), Sep 14, 2016
Heart failure (HF) is a particularly prevalent clinical condition promoting atrial arrhythmias. H... more Heart failure (HF) is a particularly prevalent clinical condition promoting atrial arrhythmias. However, the underlying mechanism is rarely studied. In this study, using a GPU-based simulation, a biophysically detailed computational model of the three-dimensional (3D) sheep atria was implemented to investigate the mechanism by which HF-induced electrical remodeling promoting atrial arrhythmia. At both the single cell and the 3D levels of the sheep atrial model, effects of such HF-induced electrical remodeling on the electrical properties were evaluated. At the cellular level, simulation results demonstrated that the action potential duration (APD) and the amplitude of systolic Ca 2+ transient were decreased in all cell types except the PV cell in the HF condition. At the 3D whole organ level, simulation results showed that though localized APDs were shortened, the spatial electrical heterogeneity was maintained in the HF condition, resulting in an increased vulnerability of the tissue for the initiation of the conduction block in response to a premature stimulus. This study provided new insights into understanding the mechanism by which HF promoted atrial arrhythmias.
A gain-of-function KCNJ2 D172N mutation in KCNJ2-encoded Kir2.1 channels underlies one form of sh... more A gain-of-function KCNJ2 D172N mutation in KCNJ2-encoded Kir2.1 channels underlies one form of short QT syndrome (SQT3), which is associated with increased susceptibility to arrhythmias and sudden death. Anti-malarial drug chloroquine was reported as an effective inhibitor of Kir2.1 channels. Using biophysically-detailed human ventricle computer models, this study assessed the effects of chloroquine on SQT3. The ten Tusscher et al. model of human ventricular cell action potential was modified to recapitulate functional changes in the inward rectifier K + current (I K1) due to heterozygous and homozygous forms of the D172N mutation. Mutant formulations were incorporated into multi-scale models. The blocking effects of chloroquine on ionic currents were modelled using IC 50 and Hill coefficient values from literatures. Effects of chloroquine on action potential duration (APD), effective refractory period (ERP) and pseudo-ECGs were quantified. It was shown that chloroquine caused a dose-dependent reduction in I K1 , prolonged APD, and decreased the maximum voltage heterogeneity. Chloroquine prolonged QT interval and declined the T-wave amplitude. Although chloroquine reduced tissue's temporal vulnerability, it increased the minimum substrate size necessary for sustaining re-entry. The actions of chloroquine decreased arrhythmia risk, due to the reduced tissue vulnerability, prolonged ERP and wavelength of re-entrant excitation waves, which in combination prevented and terminated re-entry in the tissue models. In conclusion, the results of this study provide new evidence that the anti-arrhythmic effects of chloroquine on SQT3 and, by extension, to the possibility that chloroquine may be a potential therapeutic agent for SQT3 treatment.
Background: Short QT syndrome (SQTS) is a newly identified clinical disorder associated with atri... more Background: Short QT syndrome (SQTS) is a newly identified clinical disorder associated with atrial and/or ventricular arrhythmias and increased risk of sudden cardiac death (SCD). The SQTS variant 3 is linked to D172N mutation to the KCNJ2 gene that causes a gain-of-function to the inward rectifier potassium channel current (I K1), which shortens the ventricular action potential duration (APD) and effective refractory period (ERP). Pro-arrhythmogenic effects of SQTS have been characterized, but less is known about the possible pharmacological treatment of SQTS. Therefore, in this study, we used computational modeling to assess the effects of amiodarone, class III anti-arrhythmic agent, on human ventricular electrophysiology in SQT3. Methods: The ten Tusscher et al. model for the human ventricular action potentials (APs) was modified to incorporate I K1 formulations based on experimental data of Kir2.1 channels (including WT, WT-D172N and D172N conditions). The modified cell model was then implemented to construct one-dimensional (1D) and 2D tissue models. The blocking effects of amiodarone on ionic currents were modeled using IC 50 and Hill coefficient values from literatures. Effects of amiodarone on APD, ERP and pseudo-ECG traces were computed. Effects of the drug on the temporal and spatial vulnerability of ventricular tissue to genesis and maintenance of re-entry were measured, as well as on the dynamic behavior of re-entry. Results: Amiodarone prolonged the ventricular cell APD and decreased the maximal voltage heterogeneity (δV) among three difference cells types across transmural ventricular wall, leading to a decreased transmural heterogeneity of APD along a 1D model of ventricular transmural strand. Amiodarone increased cellular ERP, prolonged QT interval and decreased the T-wave amplitude. It reduced tissue's temporal susceptibility to the initiation of re-entry and increased the minimum substrate size necessary to sustain re-entry in the 2D tissue. Conclusions: At the therapeutic-relevant concentration of amiodarone, the APD and ERP at the single cell level were increased significantly. The QT interval in pseudo-ECG was prolonged and the re-entry in tissue was prevented. This study provides further evidence that amiodarone may be a potential pharmacological agent for preventing arrhythmogenesis for SQT3 patients.
Cardiac arrhythmias and conduction disturbances are accompanied by structural remodelling of the ... more Cardiac arrhythmias and conduction disturbances are accompanied by structural remodelling of the specialised cardiomyocytes known collectively as the cardiac conduction system. Here, using contrast enhanced micro-computed tomography, we present, in attitudinally appropriate fashion, the first 3-dimensional representations of the cardiac conduction system within the intact human heart. We show that cardiomyocyte orientation can be extracted from these datasets at spatial resolutions approaching the single cell. These data show that commonly accepted anatomical representations are oversimplified. We have incorporated the high-resolution anatomical data into mathematical simulations of cardiac electrical depolarisation. The data presented should have multidisciplinary impact. Since the rate of depolarisation is dictated by cardiac microstructure, and the precise orientation of the cardiomyocytes, our data should improve the fidelity of mathematical models. By showing the precise 3-dime...
Electrophysiological behavior is of great importance for analyzing the cardiac functional mechani... more Electrophysiological behavior is of great importance for analyzing the cardiac functional mechanism under cardiac physiological and pathological condition. Due to the complexity of cardiac structure and biophysiological function, visualization of a cardiac electrophysiological model compositively is still a challenge. The lack of either modality of the whole organ structure or cardiac electrophysiological behaviors makes analysis of the intricate mechanisms of cardiac dynamic function a difficult task. This study aims at exploring 3D conduction of stimulus and electrical excitation reactivity on the level of organ with the authentic fine cardiac anatomy structure. In this paper, a cardiac electrical excitation propagation model is established based on the human cardiac cross-sectional data to explore detailed cardiac electrical activities. A novel biophysical merging visualization method is then presented for biophysical integration of cardiac anatomy and electrophysiological proper...
Insights from echocardiography, magnetic resonance imaging and micro-computed tomography relative... more Insights from echocardiography, magnetic resonance imaging and micro-computed tomography relative to the mid-myocardial left ventricular echogenic zone
Cardiac conduction disorders are common diseases which cause slow heart rate and syncope. The bes... more Cardiac conduction disorders are common diseases which cause slow heart rate and syncope. The best way to treat these diseases by now is to implant electronic pacemakers, which, yet, have many disadvantages, such as the limited battery life and infection. Biopacemaker has been expected to replace the electronic devices. Automatic ventricular myocytes (VMs) could show pacemaker activity, which was induced by depressing inward-rectifier K(+) current (I K1). In this study, a 2D model of human biopacemaker was created from the ventricular endocardial myocytes. We examined the stability of the created biopacemaker and investigated its driving capability by finding the suitable size and spatial distribution of the pacemaker for robust pacing and driving the surrounding quiescent cardiomyocytes. Our results suggest that the rhythm of the pacemaker is similar to that of the single cell at final stable state. The driving force of the biopacemaker is closely related to the pattern of spatial ...
Cardiac virtual tissues are biophysically, histologically and anatomically detailed computational... more Cardiac virtual tissues are biophysically, histologically and anatomically detailed computational models that are sufficiently well validated to be used as a predictive tool, are currently used in basic research, and are beginning to be applied to clinical problems. Virtual cardiac cells and tissues are stiff, high order ordinary and partial differential equations. While 1- and 2-D tissues can be run
2014 IEEE International Conference on Bioinformatics and Biomedicine (BIBM), 2014
Atrial fibrillation (AF) is the most common cardiac arrhythmias causing morbidity and mortality. ... more Atrial fibrillation (AF) is the most common cardiac arrhythmias causing morbidity and mortality. Current treatment of AF is unsatisfactory as the mechanisms underlying the genesis and control of AF are not yet understood. Given the complexity of cardiac nonlinear dynamics, it is a grand challenge to underpin such mechanisms by classic bio-medical research. Recent advances in bio-systems engineering and sciences that uses multidisciplinary approaches shed light to study the functions of the heart. In this talk, I shall review recent progresses in the development of virtual physiological heart (e-Heart) and demonstrate its great potentials to investigate the functional impacts of some gene mutations in genesis of AF.
Sheng wu yi xue gong cheng xue za zhi = Journal of biomedical engineering = Shengwu yixue gongchengxue zazhi, 2011
In this paper, to analyze the functional influence of ischemia on cardiac cell electrical activit... more In this paper, to analyze the functional influence of ischemia on cardiac cell electrical activity and subsequently on ventricular electrical wave conduction, a human ventricular ischemic model was developed, which took into account three major pathophysiological components of ischemias hyperkalaemia, acidosis, and anoxia. This model simulated the action potential (AP) propagations of endocardial, midmycardial and epicardial cells with different levels of ischemia, and the influence of each factor on cell AP was analyzed. Finally the ECG waveform under ischemia was quantified by using a 2D model of human left ventricular tissue based on the anatomical structure of human heart. The experimental results showed that under ischemia action potential durations (APD) were reduced. In most cases, the larger the size of ischemic region or the more severe the ischemic level, the more dramatic the changes in the amplitude of ST-T wave were observed. For the three components of ischemia, hyperk...
The sinoatrial node (SAN) is heterogeneous in terms of cell size, ion channels, current densities... more The sinoatrial node (SAN) is heterogeneous in terms of cell size, ion channels, current densities, connexins and electrical coupling. For example, Na v 1.5 (responsible for I Na) and Cx43 (responsible for electrical coupling) are absent from the centre of the SAN (normally the leading pacemaker site), but present in the periphery (at SAN-atrial muscle junction). To test whether the heterogeneity is important for the functioning of the SAN, one-and two-dimensional models of the SAN and surrounding atrial muscle were created. Normal functioning of the SAN (in terms of cycle length, position of leading pacemaker site, conduction times, activation and repolarization sequences and space constants) was observed when, from the centre to the periphery, (i) cell characteristics (cell size and ionic current densities) were changed in a gradient fashion from a central-type (lacking I Na) to a peripheral-type (possessing I Na) and (ii) coupling conductance was increased in a gradient fashion. We conclude that the heterogeneous nature of the node is important for its normal functioning. The presence of Na v 1.5 and Cx43 in the periphery may be essential for the node to be able to drive the atrial muscle: Na v 1.5 provides the necessary depolarizing current and Cx43 delivers it to the atrial muscle.
Sheep are often used as animal models for experimental studies into the underlying mechanisms of ... more Sheep are often used as animal models for experimental studies into the underlying mechanisms of cardiac arrhythmias. Previous studies have shown that biophysically detailed computer models of the heart provide a powerful alternative to experimental animal models for underpinning such mechanisms. In this study, we have developed a family of mathematical models for the electrical action potentials of various sheep atrial cell types. The developed cell models were then incorporated into a three-dimensional anatomical model of the sheep atria, which was recently reconstructed and segmented based on anatomical features within different regions. This created a novel biophysically detailed computational model of the three-dimensional sheep atria. Using the model, we then investigated the mechanisms by which paroxysmal rapid focal activity in the pulmonary veins can transit to sustained atrial fibrillation. It was found that the anisotropic property of the atria arising from the fibre stru...
To predict the safety of a drug at an early stage in its development is a major challenge as ther... more To predict the safety of a drug at an early stage in its development is a major challenge as there is a lack of in vitro heart models that correlate data from preclinical toxicity screening assays with clinical results. A biophysically detailed computer model of the heart, the virtual heart, provides a powerful tool for simulating drug-ion channel interactions and cardiac functions during normal and disease conditions and, therefore, provides a powerful platform for drug cardiotoxicity screening. In this article, we first review recent progress in the development of theory on drug-ion channel interactions and mathematical modelling. Then we propose a family of biomarkers that can quantitatively characterize the actions of a drug on the electrical activity of the heart at multi-physical scales including cellular and tissue levels. We also conducted some simulations to demonstrate the application of the virtual heart to assess the pro-arrhythmic effects of cisapride and amiodarone. Us...
Left ventricular hypertrophy induces remodeling for various ion channels. We modified a model of ... more Left ventricular hypertrophy induces remodeling for various ion channels. We modified a model of electrical activity of rat ventricular cell by incorporating available experimental data on the kinetics and conductances of various currents. We simulated hypertrophy by incorporating experimental data of changes in channel kinetics, cell size and Ca 2+ handling. The simulated action potentials (AP) and calcium transients consistent with experimental data. We developed virtual ventricular strands to investigate the rate dependent propagation in homogenous tissue under normal and hypertrophic conditions. A continuous increase in APD and corresponding decrease in conduction velocity (CV) with subsequent beats was observed, resulting in irregular conduction block at low values of stimulus intervals (SI), for which the simulated action potential duration (APD) restitution of the cell models has negative slope.
Background-Mutations in the cardiac Na ϩ channel gene (SCN5A) can adversely affect electric funct... more Background-Mutations in the cardiac Na ϩ channel gene (SCN5A) can adversely affect electric function in the heart, but effects can be age dependent. We explored the interacting effects of Scn5a disruption and aging on the pathogenesis of sinus node dysfunction in a heterozygous Scn5a knockout (Scn5a ϩ/Ϫ) mouse model. Methods and Results-We compared functional, histological, and molecular features in young (3 to 4 month) and old (1 year) wild type and Scn5a ϩ/Ϫ mice. Both Scn5a disruption and aging were associated with decreased heart rate variability, reduced sinoatrial node automaticity, and slowed sinoatrial conduction. They also led to increased collagen and fibroblast levels and upregulated transforming growth factor- 1 (TGF- 1) and vimentin transcripts, providing measures of fibrosis and reduced Nav1.5 expression. All these effects were most noticeable in old Scn5a ϩ/Ϫ mice. Na ϩ channel inhibition by Nav1.5-E3 antibody directly increased TGF- 1 production in both cultured human cardiac myocytes and fibroblasts. Finally, aging was associated with downregulation of a wide range of ion channel and related transcripts and, again, was greatest in old Scn5a ϩ/Ϫ mice. The quantitative results from these studies permitted computer simulations that successfully replicated the observed sinoatrial node phenotypes shown by the different experimental groups. Conclusions-These results implicate a tissue degeneration triggered by Nav1.5 deficiency manifesting as a TGF- 1mediated fibrosis accompanied by electric remodeling in the sinus node dysfunction associated with Scn5a disruption or aging. The latter effects interact to produce the most severe phenotype in old Scn5a ϩ/Ϫ mice. In demonstrating this, our findings suggest a novel regulatory role for Nav1.5 in cellular biological processes in addition to its electrophysiologic function.
In order to better understand biatrial conduction, investigate various conduction pathways, and c... more In order to better understand biatrial conduction, investigate various conduction pathways, and compare the differences between isotropic and anisotropic conductions in human atria, we present a simulation study of biatrial conduction with known/assumed conduction pathways using a recently developed human atrial model. In addition to known pathways: (1) Bachmann's bundle (BB), (2) limbus of fossa ovalis (LFO), and (3) coronary sinus (CS), we also hypothesize that there exist two fast conduction bundles that connect the crista terminalis (CT), LFO, and CS. Our simulation demonstrates that use of these fast conduction bundles results in a conduction pattern consistent with experimental data. The comparison of isotropic and anisotropoic conductions in the BB case showed that the atrial working muscles had small effect on conduction time and conduction speed, although the conductivities assigned in anisotropic conduction were two to four times higher than the isotropic conduction. In conclusion, we suggest that the hypothesized intercaval bundles play a significant role in the biatrial conduction and that myofiber orientation has larger effects on the conduction system than the atrial working muscles. This study presents readers with new insights into human atrial conduction.
Aims Short QT syndrome (SQTS) is an inherited disorder associated with abnormally abbreviated QT ... more 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, I Kr) 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 I Kr Markov chain (MC) formulations based on experimental data of the kinetics of the N588K mutation of the KCNH2-encoded subunit of the I Kr channels. The modified ventricular cell model was then integrated into one-dimensional (1D) strand, 2D regular and realistic tissues with transmural heterogeneities. The channelblocking effect of the drugs on ion currents in healthy and SQT1 cells was modeled using half-maximal inhibitory concentration (IC 50) 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 (APD 90), whereas quinidine caused a significant prolongation of APD 90. Quinidine prolonged and decreased the maximal transmural AP
Pacemaking dysfunction (PD) may result in heart rhythm disorders, syncope or even death. Current ... more Pacemaking dysfunction (PD) may result in heart rhythm disorders, syncope or even death. Current treatment of PD using implanted electronic pacemaker has some limitations, such as finite battery life and the risk of repeated surgery. As such, the biological pacemaker has been proposed as a potential alternative to the electronic pacemaker for PD treatment. Experimentally it has been shown that bio-engineered pacemaker cells can be generated from non-rhythmic ventricular myocytes (VMs) by knocking down genes related to the inward rectifier potassium channel current (IK1) or by overexpressing hyperpolarization-activated cyclic nucleotide gated channel genes responsible for the “funny” current (If). Such approaches can turn the VM cells into rhythmic pacemaker cells. However, it is unclear if a bio-engineered pacemaker based on the modification of IK1- and If-related channels simultaneously would enhance the ability and stability of bio-engineered pacemaking action potentials (APs). Th...
2016 Computing in Cardiology Conference (CinC), Sep 14, 2016
Heart failure (HF) is a particularly prevalent clinical condition promoting atrial arrhythmias. H... more Heart failure (HF) is a particularly prevalent clinical condition promoting atrial arrhythmias. However, the underlying mechanism is rarely studied. In this study, using a GPU-based simulation, a biophysically detailed computational model of the three-dimensional (3D) sheep atria was implemented to investigate the mechanism by which HF-induced electrical remodeling promoting atrial arrhythmia. At both the single cell and the 3D levels of the sheep atrial model, effects of such HF-induced electrical remodeling on the electrical properties were evaluated. At the cellular level, simulation results demonstrated that the action potential duration (APD) and the amplitude of systolic Ca 2+ transient were decreased in all cell types except the PV cell in the HF condition. At the 3D whole organ level, simulation results showed that though localized APDs were shortened, the spatial electrical heterogeneity was maintained in the HF condition, resulting in an increased vulnerability of the tissue for the initiation of the conduction block in response to a premature stimulus. This study provided new insights into understanding the mechanism by which HF promoted atrial arrhythmias.
A gain-of-function KCNJ2 D172N mutation in KCNJ2-encoded Kir2.1 channels underlies one form of sh... more A gain-of-function KCNJ2 D172N mutation in KCNJ2-encoded Kir2.1 channels underlies one form of short QT syndrome (SQT3), which is associated with increased susceptibility to arrhythmias and sudden death. Anti-malarial drug chloroquine was reported as an effective inhibitor of Kir2.1 channels. Using biophysically-detailed human ventricle computer models, this study assessed the effects of chloroquine on SQT3. The ten Tusscher et al. model of human ventricular cell action potential was modified to recapitulate functional changes in the inward rectifier K + current (I K1) due to heterozygous and homozygous forms of the D172N mutation. Mutant formulations were incorporated into multi-scale models. The blocking effects of chloroquine on ionic currents were modelled using IC 50 and Hill coefficient values from literatures. Effects of chloroquine on action potential duration (APD), effective refractory period (ERP) and pseudo-ECGs were quantified. It was shown that chloroquine caused a dose-dependent reduction in I K1 , prolonged APD, and decreased the maximum voltage heterogeneity. Chloroquine prolonged QT interval and declined the T-wave amplitude. Although chloroquine reduced tissue's temporal vulnerability, it increased the minimum substrate size necessary for sustaining re-entry. The actions of chloroquine decreased arrhythmia risk, due to the reduced tissue vulnerability, prolonged ERP and wavelength of re-entrant excitation waves, which in combination prevented and terminated re-entry in the tissue models. In conclusion, the results of this study provide new evidence that the anti-arrhythmic effects of chloroquine on SQT3 and, by extension, to the possibility that chloroquine may be a potential therapeutic agent for SQT3 treatment.
Background: Short QT syndrome (SQTS) is a newly identified clinical disorder associated with atri... more Background: Short QT syndrome (SQTS) is a newly identified clinical disorder associated with atrial and/or ventricular arrhythmias and increased risk of sudden cardiac death (SCD). The SQTS variant 3 is linked to D172N mutation to the KCNJ2 gene that causes a gain-of-function to the inward rectifier potassium channel current (I K1), which shortens the ventricular action potential duration (APD) and effective refractory period (ERP). Pro-arrhythmogenic effects of SQTS have been characterized, but less is known about the possible pharmacological treatment of SQTS. Therefore, in this study, we used computational modeling to assess the effects of amiodarone, class III anti-arrhythmic agent, on human ventricular electrophysiology in SQT3. Methods: The ten Tusscher et al. model for the human ventricular action potentials (APs) was modified to incorporate I K1 formulations based on experimental data of Kir2.1 channels (including WT, WT-D172N and D172N conditions). The modified cell model was then implemented to construct one-dimensional (1D) and 2D tissue models. The blocking effects of amiodarone on ionic currents were modeled using IC 50 and Hill coefficient values from literatures. Effects of amiodarone on APD, ERP and pseudo-ECG traces were computed. Effects of the drug on the temporal and spatial vulnerability of ventricular tissue to genesis and maintenance of re-entry were measured, as well as on the dynamic behavior of re-entry. Results: Amiodarone prolonged the ventricular cell APD and decreased the maximal voltage heterogeneity (δV) among three difference cells types across transmural ventricular wall, leading to a decreased transmural heterogeneity of APD along a 1D model of ventricular transmural strand. Amiodarone increased cellular ERP, prolonged QT interval and decreased the T-wave amplitude. It reduced tissue's temporal susceptibility to the initiation of re-entry and increased the minimum substrate size necessary to sustain re-entry in the 2D tissue. Conclusions: At the therapeutic-relevant concentration of amiodarone, the APD and ERP at the single cell level were increased significantly. The QT interval in pseudo-ECG was prolonged and the re-entry in tissue was prevented. This study provides further evidence that amiodarone may be a potential pharmacological agent for preventing arrhythmogenesis for SQT3 patients.
Cardiac arrhythmias and conduction disturbances are accompanied by structural remodelling of the ... more Cardiac arrhythmias and conduction disturbances are accompanied by structural remodelling of the specialised cardiomyocytes known collectively as the cardiac conduction system. Here, using contrast enhanced micro-computed tomography, we present, in attitudinally appropriate fashion, the first 3-dimensional representations of the cardiac conduction system within the intact human heart. We show that cardiomyocyte orientation can be extracted from these datasets at spatial resolutions approaching the single cell. These data show that commonly accepted anatomical representations are oversimplified. We have incorporated the high-resolution anatomical data into mathematical simulations of cardiac electrical depolarisation. The data presented should have multidisciplinary impact. Since the rate of depolarisation is dictated by cardiac microstructure, and the precise orientation of the cardiomyocytes, our data should improve the fidelity of mathematical models. By showing the precise 3-dime...
Electrophysiological behavior is of great importance for analyzing the cardiac functional mechani... more Electrophysiological behavior is of great importance for analyzing the cardiac functional mechanism under cardiac physiological and pathological condition. Due to the complexity of cardiac structure and biophysiological function, visualization of a cardiac electrophysiological model compositively is still a challenge. The lack of either modality of the whole organ structure or cardiac electrophysiological behaviors makes analysis of the intricate mechanisms of cardiac dynamic function a difficult task. This study aims at exploring 3D conduction of stimulus and electrical excitation reactivity on the level of organ with the authentic fine cardiac anatomy structure. In this paper, a cardiac electrical excitation propagation model is established based on the human cardiac cross-sectional data to explore detailed cardiac electrical activities. A novel biophysical merging visualization method is then presented for biophysical integration of cardiac anatomy and electrophysiological proper...
Insights from echocardiography, magnetic resonance imaging and micro-computed tomography relative... more Insights from echocardiography, magnetic resonance imaging and micro-computed tomography relative to the mid-myocardial left ventricular echogenic zone
Cardiac conduction disorders are common diseases which cause slow heart rate and syncope. The bes... more Cardiac conduction disorders are common diseases which cause slow heart rate and syncope. The best way to treat these diseases by now is to implant electronic pacemakers, which, yet, have many disadvantages, such as the limited battery life and infection. Biopacemaker has been expected to replace the electronic devices. Automatic ventricular myocytes (VMs) could show pacemaker activity, which was induced by depressing inward-rectifier K(+) current (I K1). In this study, a 2D model of human biopacemaker was created from the ventricular endocardial myocytes. We examined the stability of the created biopacemaker and investigated its driving capability by finding the suitable size and spatial distribution of the pacemaker for robust pacing and driving the surrounding quiescent cardiomyocytes. Our results suggest that the rhythm of the pacemaker is similar to that of the single cell at final stable state. The driving force of the biopacemaker is closely related to the pattern of spatial ...
Cardiac virtual tissues are biophysically, histologically and anatomically detailed computational... more Cardiac virtual tissues are biophysically, histologically and anatomically detailed computational models that are sufficiently well validated to be used as a predictive tool, are currently used in basic research, and are beginning to be applied to clinical problems. Virtual cardiac cells and tissues are stiff, high order ordinary and partial differential equations. While 1- and 2-D tissues can be run
2014 IEEE International Conference on Bioinformatics and Biomedicine (BIBM), 2014
Atrial fibrillation (AF) is the most common cardiac arrhythmias causing morbidity and mortality. ... more Atrial fibrillation (AF) is the most common cardiac arrhythmias causing morbidity and mortality. Current treatment of AF is unsatisfactory as the mechanisms underlying the genesis and control of AF are not yet understood. Given the complexity of cardiac nonlinear dynamics, it is a grand challenge to underpin such mechanisms by classic bio-medical research. Recent advances in bio-systems engineering and sciences that uses multidisciplinary approaches shed light to study the functions of the heart. In this talk, I shall review recent progresses in the development of virtual physiological heart (e-Heart) and demonstrate its great potentials to investigate the functional impacts of some gene mutations in genesis of AF.
Sheng wu yi xue gong cheng xue za zhi = Journal of biomedical engineering = Shengwu yixue gongchengxue zazhi, 2011
In this paper, to analyze the functional influence of ischemia on cardiac cell electrical activit... more In this paper, to analyze the functional influence of ischemia on cardiac cell electrical activity and subsequently on ventricular electrical wave conduction, a human ventricular ischemic model was developed, which took into account three major pathophysiological components of ischemias hyperkalaemia, acidosis, and anoxia. This model simulated the action potential (AP) propagations of endocardial, midmycardial and epicardial cells with different levels of ischemia, and the influence of each factor on cell AP was analyzed. Finally the ECG waveform under ischemia was quantified by using a 2D model of human left ventricular tissue based on the anatomical structure of human heart. The experimental results showed that under ischemia action potential durations (APD) were reduced. In most cases, the larger the size of ischemic region or the more severe the ischemic level, the more dramatic the changes in the amplitude of ST-T wave were observed. For the three components of ischemia, hyperk...
The sinoatrial node (SAN) is heterogeneous in terms of cell size, ion channels, current densities... more The sinoatrial node (SAN) is heterogeneous in terms of cell size, ion channels, current densities, connexins and electrical coupling. For example, Na v 1.5 (responsible for I Na) and Cx43 (responsible for electrical coupling) are absent from the centre of the SAN (normally the leading pacemaker site), but present in the periphery (at SAN-atrial muscle junction). To test whether the heterogeneity is important for the functioning of the SAN, one-and two-dimensional models of the SAN and surrounding atrial muscle were created. Normal functioning of the SAN (in terms of cycle length, position of leading pacemaker site, conduction times, activation and repolarization sequences and space constants) was observed when, from the centre to the periphery, (i) cell characteristics (cell size and ionic current densities) were changed in a gradient fashion from a central-type (lacking I Na) to a peripheral-type (possessing I Na) and (ii) coupling conductance was increased in a gradient fashion. We conclude that the heterogeneous nature of the node is important for its normal functioning. The presence of Na v 1.5 and Cx43 in the periphery may be essential for the node to be able to drive the atrial muscle: Na v 1.5 provides the necessary depolarizing current and Cx43 delivers it to the atrial muscle.
Sheep are often used as animal models for experimental studies into the underlying mechanisms of ... more Sheep are often used as animal models for experimental studies into the underlying mechanisms of cardiac arrhythmias. Previous studies have shown that biophysically detailed computer models of the heart provide a powerful alternative to experimental animal models for underpinning such mechanisms. In this study, we have developed a family of mathematical models for the electrical action potentials of various sheep atrial cell types. The developed cell models were then incorporated into a three-dimensional anatomical model of the sheep atria, which was recently reconstructed and segmented based on anatomical features within different regions. This created a novel biophysically detailed computational model of the three-dimensional sheep atria. Using the model, we then investigated the mechanisms by which paroxysmal rapid focal activity in the pulmonary veins can transit to sustained atrial fibrillation. It was found that the anisotropic property of the atria arising from the fibre stru...
To predict the safety of a drug at an early stage in its development is a major challenge as ther... more To predict the safety of a drug at an early stage in its development is a major challenge as there is a lack of in vitro heart models that correlate data from preclinical toxicity screening assays with clinical results. A biophysically detailed computer model of the heart, the virtual heart, provides a powerful tool for simulating drug-ion channel interactions and cardiac functions during normal and disease conditions and, therefore, provides a powerful platform for drug cardiotoxicity screening. In this article, we first review recent progress in the development of theory on drug-ion channel interactions and mathematical modelling. Then we propose a family of biomarkers that can quantitatively characterize the actions of a drug on the electrical activity of the heart at multi-physical scales including cellular and tissue levels. We also conducted some simulations to demonstrate the application of the virtual heart to assess the pro-arrhythmic effects of cisapride and amiodarone. Us...
Left ventricular hypertrophy induces remodeling for various ion channels. We modified a model of ... more Left ventricular hypertrophy induces remodeling for various ion channels. We modified a model of electrical activity of rat ventricular cell by incorporating available experimental data on the kinetics and conductances of various currents. We simulated hypertrophy by incorporating experimental data of changes in channel kinetics, cell size and Ca 2+ handling. The simulated action potentials (AP) and calcium transients consistent with experimental data. We developed virtual ventricular strands to investigate the rate dependent propagation in homogenous tissue under normal and hypertrophic conditions. A continuous increase in APD and corresponding decrease in conduction velocity (CV) with subsequent beats was observed, resulting in irregular conduction block at low values of stimulus intervals (SI), for which the simulated action potential duration (APD) restitution of the cell models has negative slope.
Background-Mutations in the cardiac Na ϩ channel gene (SCN5A) can adversely affect electric funct... more Background-Mutations in the cardiac Na ϩ channel gene (SCN5A) can adversely affect electric function in the heart, but effects can be age dependent. We explored the interacting effects of Scn5a disruption and aging on the pathogenesis of sinus node dysfunction in a heterozygous Scn5a knockout (Scn5a ϩ/Ϫ) mouse model. Methods and Results-We compared functional, histological, and molecular features in young (3 to 4 month) and old (1 year) wild type and Scn5a ϩ/Ϫ mice. Both Scn5a disruption and aging were associated with decreased heart rate variability, reduced sinoatrial node automaticity, and slowed sinoatrial conduction. They also led to increased collagen and fibroblast levels and upregulated transforming growth factor- 1 (TGF- 1) and vimentin transcripts, providing measures of fibrosis and reduced Nav1.5 expression. All these effects were most noticeable in old Scn5a ϩ/Ϫ mice. Na ϩ channel inhibition by Nav1.5-E3 antibody directly increased TGF- 1 production in both cultured human cardiac myocytes and fibroblasts. Finally, aging was associated with downregulation of a wide range of ion channel and related transcripts and, again, was greatest in old Scn5a ϩ/Ϫ mice. The quantitative results from these studies permitted computer simulations that successfully replicated the observed sinoatrial node phenotypes shown by the different experimental groups. Conclusions-These results implicate a tissue degeneration triggered by Nav1.5 deficiency manifesting as a TGF- 1mediated fibrosis accompanied by electric remodeling in the sinus node dysfunction associated with Scn5a disruption or aging. The latter effects interact to produce the most severe phenotype in old Scn5a ϩ/Ϫ mice. In demonstrating this, our findings suggest a novel regulatory role for Nav1.5 in cellular biological processes in addition to its electrophysiologic function.
In order to better understand biatrial conduction, investigate various conduction pathways, and c... more In order to better understand biatrial conduction, investigate various conduction pathways, and compare the differences between isotropic and anisotropic conductions in human atria, we present a simulation study of biatrial conduction with known/assumed conduction pathways using a recently developed human atrial model. In addition to known pathways: (1) Bachmann's bundle (BB), (2) limbus of fossa ovalis (LFO), and (3) coronary sinus (CS), we also hypothesize that there exist two fast conduction bundles that connect the crista terminalis (CT), LFO, and CS. Our simulation demonstrates that use of these fast conduction bundles results in a conduction pattern consistent with experimental data. The comparison of isotropic and anisotropoic conductions in the BB case showed that the atrial working muscles had small effect on conduction time and conduction speed, although the conductivities assigned in anisotropic conduction were two to four times higher than the isotropic conduction. In conclusion, we suggest that the hypothesized intercaval bundles play a significant role in the biatrial conduction and that myofiber orientation has larger effects on the conduction system than the atrial working muscles. This study presents readers with new insights into human atrial conduction.
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Papers by Henggui Zhang