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Stanley Nattel - One of the best experts on this subject based on the ideXlab platform.
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arrhythmogenic left Atrial cellular electrophysiology in a murine genetic long qt syndrome model
Cardiovascular Research, 2011Co-Authors: Marc D Lemoine, Stanley Nattel, Larissa Fabritz, Denis Chartier, James Elber Duverger, Patrice Naud, Philippe Comtois, Paulus KirchhofAbstract:Aims Increasing evidence indicates that congenital long QT syndromes (LQTSs) promote Atrial fibrillation. The Atrial Action Potential (AP) has a short plateau, and whether LQTS Atrial cardiomyocytes generate triggered activity via early afterdepolarizations (EADs) is unclear. Atrial cellular arrhythmia mechanisms have not been defined in congenital LQTS. Therefore, we studied Atrial cardiomyocyte electrophysiology in mice with an LQTS3 SCN5A inactivation-impairing mutation (ΔKPQ heterozygotes). Methods and results Peak and late Na+ current ( I NaP and I NaL) were measured with whole-cell patch clamp in left Atrial (LA) cardiomyocytes. APs were recorded in multicellular LA preparations with floating microelectrodes. I NaL was increased by 110% in LA cardiomyocytes of ΔKPQ mice, whereas I NaP was unchanged. AP duration (APD) was prolonged over all frequencies in ΔKPQ mice, but particularly at lower frequencies [e.g. APD90 at 0.5 Hz: 197 ± 8 ms vs. wild-type (WT) 82 ± 2 ms, P < 0.001]. EADs occurred at 0.5 Hz in 10/18 ΔKPQ (56%) vs. 1/10 WT (10%) atria ( P < 0.05). EADs immediately preceded premature APs in other LA regions, suggesting triggered activity. Ranolazine preferentially inhibited I NaL (50% inhibitory concentration: 12.5 vs. 151.8 µM for I NaP) in ΔKPQ myocytes. At 10 µM, ranolazine shortened APD (e.g. APD90 at 0.5 Hz to 122 ± 4 ms, P = 0.01) without changing APD in WT and suppressed EAD occurrence and triggered activity (from 10/18 to 1/9 preparations, 11%, P < 0.05). Conclusion This study implicates increased I NaL in excessive Atrial APD prolongation and arrhythmic EAD occurrence in a congenital LQTS3 mouse model. Our observations provide the first direct demonstration of Atrial EADs and triggered activity in a genetically defined animal model of human LQTS and have Potential clinically-relevant mechanistic and therapeutic implications.
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knock in gain of function sodium channel mutation prolongs Atrial Action Potentials and alters Atrial vulnerability
Heart Rhythm, 2010Co-Authors: Andreas Blana, Sven Kaese, Lisa Fortmuller, Sandra Laakmann, Dierk Damke, Kelly A Van Bragt, Jens Eckstein, Ilaria Piccini, Uwe Kirchhefer, Stanley NattelAbstract:Background Patients with long QT syndrome (LQTS) are at increased risk not only for ventricular arrhythmias but also for Atrial pathology including Atrial fibrillation (AF). Some patients with "lone" AF carry Na + -channel mutations. Objective The purpose of this study was to determine the mechanisms underlying Atrial pathology in LQTS. Methods In mice with a heterozygous knock-in long QT syndrome type 3 (LQT3) mutant of the cardiac Na + channel (ΔKPQ-SCN5A) and wild-type (WT) littermates, Atrial size, function, and electrophysiologic parameters were measured in intact Langendorff-perfused hearts, and histologic analysis was performed. Results Atrial Action Potential duration, effective refractory period, cycle length, and PQ interval were prolonged in ΔKPQ-SCN5A hearts (all P P P 5 months old without increase in fibrotic tissue. Conclusion Murine hearts bearing an LQT3 mutation show abnormalities in Atrial electrophysiology and subtle changes in Atrial dimension, including an Atrial arrhythmogenic phenotype on provocation. These results support clinical data suggesting that LQTS mutations can cause Atrial pathology and arrhythmogenesis and indicate that murine sodium channel LQTS models may be useful for exploring underlying mechanisms.
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calcium handling abnormalities underlying Atrial arrhythmogenesis and contractile dysfunction in dogs with congestive heart failure
Circulation-arrhythmia and Electrophysiology, 2008Co-Authors: Yunghsin Yeh, Denis Chartier, Dobromir Dobrev, Ursula Ravens, Pierre Coutu, Reza Wakili, Peter Boknik, Stefan Kaab, Stanley NattelAbstract:Background— Congestive heart failure (CHF) is a common cause of Atrial fibrillation. Focal sources of unknown mechanism have been described in CHF-related Atrial fibrillation. The authors hypothesized that abnormal calcium (Ca2+) handling contributes to the CHF-related Atrial arrhythmogenic substrate. Methods and Results— CHF was induced in dogs by ventricular tachypacing (240 bpm ×2 weeks). Cellular Ca2+-handling properties and expression/phosphorylation status of key Ca2+ handling and myofilament proteins were assessed in control and CHF atria. CHF decreased cell shortening but increased left Atrial diastolic intracellular Ca2+ concentration ([Ca2+]i), [Ca2+]i transient amplitude, and sarcoplasmic reticulum (SR) Ca2+ load (caffeine-induced [Ca2+]i release). SR Ca2+ overload was associated with spontaneous Ca2+ transient events and triggered ectopic activity, which was suppressed by the inhibition of SR Ca2+ release (ryanodine) or Na+/Ca2+ exchange. Mechanisms underlying abnormal SR Ca2+ handling were then studied. CHF increased Atrial Action Potential duration and Action Potential voltage clamp showed that CHF-like Action Potentials enhance Ca2+i loading. CHF increased calmodulin-dependent protein kinase II phosphorylation of phospholamban by 120%, Potentially enhancing SR Ca2+ uptake by reducing phospholamban inhibition of SR Ca2+ ATPase, but it did not affect phosphorylation of SR Ca2+-release channels (RyR2). Total RyR2 and calsequestrin (main SR Ca2+-binding protein) expression were significantly reduced, by 65% and 15%, Potentially contributing to SR dysfunction. CHF decreased expression of total and protein kinase A–phosphorylated myosin-binding protein C (a key contractile filament regulator) by 27% and 74%, Potentially accounting for decreased contractility despite increased Ca2+ transients. Complex phosphorylation changes were explained by enhanced calmodulin-dependent protein kinase IIδ expression and function and type-1 protein-phosphatase activity but downregulated regulatory protein kinase A subunits. Conclusions— CHF causes profound changes in Ca2+-handling and -regulatory proteins that produce Atrial fibrillation–promoting Atrial cardiomyocyte Ca2+-handling abnormalities, arrhythmogenic triggered activity, and contractile dysfunction. Received November 22, 2007; accepted February 29, 2008. # CLINICAL PERSPECTIVE {#article-title-2}
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Atrial fibrillation associated mink38g s polymorphism modulates delayed rectifier current and membrane localization
Cardiovascular Research, 2005Co-Authors: Joachim R Ehrlich, Stanley Nattel, Stephen Zicha, Pierre Coutu, Terence E HebertAbstract:Background : Atrial fibrillation (AF) is a common acquired arrhythmia with multi-factorial pathogenesis. Recently, a single nucleotide polymorphism (SNP, A/G) at position 112 in the KCNE1 gene, resulting in a glycine/serine amino acid substitution at position 38 of the minK peptide, was associated with AF occurrence (AF more frequent with minK38G); however, the functional effect of this SNP is unknown. Methods and Results : We used patch clamp recording, confocal microscopy and protein biochemistry to study the effect of this SNP on delayed-rectifier current expression and mathematical simulation to identify Potential functional consequences. The density of slow delayed rectifier current ( I Ks) resulting from co-expression with KvLQT1 was smaller with minK38G (e.g. at +10 mV: 50 ± 7 pA/pF in Chinese hamster ovary (CHO) cells, 45 ± 14 pA/pF for COS-7 cells) compared to minK38S (93 ± 17 pA/pF, 104 ± 23 pA/pF, respectively, P <0.05 for each). I Ks kinetics and voltage-dependence were unaffected. Currents resulting from co-expression of human ether-a-go-go -related gene ( HERG ) were similar for minK38G and minK38S, e.g. upon repolarization from +10 to −50 mV: tail currents 23 ± 4 pA/pF versus 22 ± 5 pA/pF ( P = ns). KvLQT1 membrane immunofluorescence was less in CHO cells co-expressing minK38G versus minK38S, and surface expression of KvLQT1, as determined by labelling with streptavidin/biotin, was increased with minK38S co-expression. Computer simulations with a human Atrial Action Potential model predicted that the minK38G SNP would slightly prolong the Atrial Action Potential and reduce the frequency for alternans behaviour. In the presence of reduced repolarization reserve, these effects were enhanced and under specific conditions early afterdepolarizations occurred. Conclusions : The minK38G isoform is associated with reduced I Ks, likely due to decreased KvLQT1 membrane expression. This study reveals a novel amino acid determinant of the minK-KvLQT1 interAction, and if the role of minK38G in AF is confirmed, would suggest mechanistic heterogeneity in genetic determinants of AF.
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ionic determinants of functional reentry in a 2 d model of human Atrial cells during simulated chronic Atrial fibrillation
Biophysical Journal, 2005Co-Authors: Sandeep V Pandit, Stanley Nattel, Omer Berenfeld, Justus M B Anumonwo, Roman M Zaritski, James Kneller, Jose JalifeAbstract:Recent studies suggest that Atrial fibrillation (AF) is maintained by fibrillatory conduction emanating from a small number of high-frequency reentrant sources (rotors). Our goal was to study the ionic correlates of a rotor during simulated chronic AF conditions. We utilized a two-dimensional (2-D), homogeneous, isotropic sheet (5 3 5c m 2 ) of human Atrial cells to create a chronic AF substrate, which was able to sustain a stable rotor (dominant frequency ;5.7 Hz, rosette-like tip meander ;2.6 cm). Doubling the magnitude of the inward rectifier K 1 current (IK1) increased rotor frequency (;8.4 Hz), and reduced tip meander (;1.7 cm). This rotor stabilization was due to a shortening of the Action Potential duration and an enhanced cardiac excitability. The latter was caused by a hyperpolarization of the diastolic membrane Potential, which increased the availability of the Na 1 current (INa). The rotor was terminated by reducing the maximum conductance (by 90%) of the Atrial-specific ultrarapid delayed rectifier K 1 current (IKur), or the transient outward K 1 current (Ito), but not the fast or slow delayed rectifier K 1 currents (IKr/IKs). Importantly, blockade of IKur/Ito prolonged the Atrial Action Potential at the plateau, but not at the terminal phase of repolarization, which led to random tip meander and wavebreak, resulting in rotor termination. Altering the rectification profile of IK1 also slowed down or abolished reentrant activity. In combination, these simulation results provide novel insights into the ionic bases of a sustained rotor in a 2-D chronic AF substrate.
Henggui Zhang - One of the best experts on this subject based on the ideXlab platform.
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in silico assessment of pharmacotherapy for human Atrial patho electrophysiology associated with herg linked short qt syndrome
Frontiers in Physiology, 2019Co-Authors: Jules C Hancox, Dominic G Whittaker, Henggui ZhangAbstract:Short QT syndrome variant 1 (SQT1) arises due to gain-of-function mutations to the human Ether-a-go-go-Related Gene (hERG), which encodes the α subunit of channels carrying rapid delayed rectifier potassium current, IKr. In addition to QT interval shortening and ventricular arrhythmias, SQT1 is associated with increased risk of Atrial fibrillation (AF), which is often the only clinical presentation. However, the underlying basis of AF and its pharmacological treatment remain incompletely understood in the context of SQT1. In this study, computational modelling was used to investigate mechanisms of human Atrial arrhythmogenesis consequent to a SQT1 mutation, as well as pharmacotherapeutic effects of selected class I drugs – disopyramide, quinidine, and propafenone. A Markov chain formulation describing wild type (WT) and N588K-hERG mutant IKr was incorporated into a contemporary human Atrial Action Potential (AP) model, which was integrated into one-dimensional (1D) tissue strands, idealised 2D sheets, and a 3D heterogeneous, anatomical human atria model. Multi-channel pharmacological effects of disopyramide, quinidine, and propafenone, including binding kinetics for IKr/hERG and sodium current, INa, were considered. Heterozygous and homozygous formulations of the N588K-hERG mutation shortened the AP duration (APD) by 53 and 86 ms, respectively, which abbreviated the effective refractory period (ERP) and excitation wavelength in tissue, increasing the lifespan and dominant frequency (DF) of scroll waves in the 3D anatomical human atria. At the concentrations tested in this study, quinidine most effectively prolonged the APD and ERP in the setting of SQT1, followed by disopyramide and propafenone. In 2D simulations, disopyramide and quinidine promoted re-entry termination by increasing the re-entry wavelength, whereas propafenone induced secondary waves which destabilised the re-entrant circuit. In 3D simulations, the DF of re-entry was reduced in a dose-dependent manner for disopyramide and quinidine, and propafenone to a lesser extent. All of the anti-arrhythmic agents promoted pharmacological conversion, most frequently terminating re-entry in the order quinidine > propafenone = disopyramide. Our findings provide further insight into mechanisms of SQT1-related AF and a rational basis for the pursuit of combined IKr and INa block based pharmacological strategies in the treatment of SQT1-linked AF.
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Data_Sheet_1_In silico Assessment of Pharmacotherapy for Human Atrial Patho-Electrophysiology Associated With hERG-Linked Short QT Syndrome.pdf
2019Co-Authors: Dominic G Whittaker, Jules C Hancox, Henggui ZhangAbstract:Short QT syndrome variant 1 (SQT1) arises due to gain-of-function mutations to the human Ether-à-go-go-Related Gene (hERG), which encodes the α subunit of channels carrying rapid delayed rectifier potassium current, IKr. In addition to QT interval shortening and ventricular arrhythmias, SQT1 is associated with increased risk of Atrial fibrillation (AF), which is often the only clinical presentation. However, the underlying basis of AF and its pharmacological treatment remain incompletely understood in the context of SQT1. In this study, computational modeling was used to investigate mechanisms of human Atrial arrhythmogenesis consequent to a SQT1 mutation, as well as pharmacotherapeutic effects of selected class I drugs–disopyramide, quinidine, and propafenone. A Markov chain formulation describing wild type (WT) and N588K-hERG mutant IKr was incorporated into a contemporary human Atrial Action Potential (AP) model, which was integrated into one-dimensional (1D) tissue strands, idealized 2D sheets, and a 3D heterogeneous, anatomical human atria model. Multi-channel pharmacological effects of disopyramide, quinidine, and propafenone, including binding kinetics for IKr/hERG and sodium current, INa, were considered. Heterozygous and homozygous formulations of the N588K-hERG mutation shortened the AP duration (APD) by 53 and 86 ms, respectively, which abbreviated the effective refractory period (ERP) and excitation wavelength in tissue, increasing the lifespan and dominant frequency (DF) of scroll waves in the 3D anatomical human atria. At the concentrations tested in this study, quinidine most effectively prolonged the APD and ERP in the setting of SQT1, followed by disopyramide and propafenone. In 2D simulations, disopyramide and quinidine promoted re-entry termination by increasing the re-entry wavelength, whereas propafenone induced secondary waves which destabilized the re-entrant circuit. In 3D simulations, the DF of re-entry was reduced in a dose-dependent manner for disopyramide and quinidine, and propafenone to a lesser extent. All of the anti-arrhythmic agents promoted pharmacological conversion, most frequently terminating re-entry in the order quinidine > propafenone = disopyramide. Our findings provide further insight into mechanisms of SQT1-related AF and a rational basis for the pursuit of combined IKr and INa block based pharmacological strategies in the treatment of SQT1-linked AF.
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Video_1_In silico Assessment of Pharmacotherapy for Human Atrial Patho-Electrophysiology Associated With hERG-Linked Short QT Syndrome.AVI
2019Co-Authors: Dominic G Whittaker, Jules C Hancox, Henggui ZhangAbstract:Short QT syndrome variant 1 (SQT1) arises due to gain-of-function mutations to the human Ether-à-go-go-Related Gene (hERG), which encodes the α subunit of channels carrying rapid delayed rectifier potassium current, IKr. In addition to QT interval shortening and ventricular arrhythmias, SQT1 is associated with increased risk of Atrial fibrillation (AF), which is often the only clinical presentation. However, the underlying basis of AF and its pharmacological treatment remain incompletely understood in the context of SQT1. In this study, computational modeling was used to investigate mechanisms of human Atrial arrhythmogenesis consequent to a SQT1 mutation, as well as pharmacotherapeutic effects of selected class I drugs–disopyramide, quinidine, and propafenone. A Markov chain formulation describing wild type (WT) and N588K-hERG mutant IKr was incorporated into a contemporary human Atrial Action Potential (AP) model, which was integrated into one-dimensional (1D) tissue strands, idealized 2D sheets, and a 3D heterogeneous, anatomical human atria model. Multi-channel pharmacological effects of disopyramide, quinidine, and propafenone, including binding kinetics for IKr/hERG and sodium current, INa, were considered. Heterozygous and homozygous formulations of the N588K-hERG mutation shortened the AP duration (APD) by 53 and 86 ms, respectively, which abbreviated the effective refractory period (ERP) and excitation wavelength in tissue, increasing the lifespan and dominant frequency (DF) of scroll waves in the 3D anatomical human atria. At the concentrations tested in this study, quinidine most effectively prolonged the APD and ERP in the setting of SQT1, followed by disopyramide and propafenone. In 2D simulations, disopyramide and quinidine promoted re-entry termination by increasing the re-entry wavelength, whereas propafenone induced secondary waves which destabilized the re-entrant circuit. In 3D simulations, the DF of re-entry was reduced in a dose-dependent manner for disopyramide and quinidine, and propafenone to a lesser extent. All of the anti-arrhythmic agents promoted pharmacological conversion, most frequently terminating re-entry in the order quinidine > propafenone = disopyramide. Our findings provide further insight into mechanisms of SQT1-related AF and a rational basis for the pursuit of combined IKr and INa block based pharmacological strategies in the treatment of SQT1-linked AF.
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modelling the effects of propafenone on human Atrial patho electrophysiology associated with herg linked short qt syndrome
Computing in Cardiology Conference, 2018Co-Authors: Dominic G Whittaker, Jules C Hancox, Henggui ZhangAbstract:The N588K mutation to the human Ether-a-go-go-Related Gene (hERG) underlies short QT syndrome variant 1 (SQT1), which is associated with Atrial fibrillation (AF). However, mechanisms and management of AF in the context of SQT1 remain poorly understood. In this study, multi-scale computational modelling was used to investigate pharmacotherapeutic effects of the class Ic drug propafenone for SQT1-mediated human Atrial patho-electrophysiology. A Markov chain formulation of rapid delayed rectifier potassium current, I Kr , describing wild type (WT) and N588K mutant currents was incorporated into a recent model of the human Atrial Action Potential (AP), which was integrated into multi-scale tissue models. Effects of multi-channel block by propafenone were simulated on single- and multi-cellular electrophysiology models. At the single cell level, propafenone prolonged the AP duration under SQT1 (heterozygous N588K) conditions in a dose-dependent manner. In tissue, propafenone prolonged the effective refractory period and excitation wavelength, whilst reducing the conduction velocity. In 2D sheet simulations, propafenone demonstrated efficacy in pharmacological conversion of re-entry. Our findings suggest that propafenone shows efficacy in reversing AF associated with hERG-linked short QT syndrome.
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In silico assessment of genetic variation in KCNA5 reveals multiple mechanisms of human Atrial arrhythmogenesis.
PLoS computational biology, 2017Co-Authors: Michael A. Colman, Bo Liang, Nicole Schmitt, Henggui ZhangAbstract:A recent experimental study investigating patients with lone Atrial fibrillation identified six novel mutations in the KCNA5 gene. The mutants exhibited both gain- and loss-of-function of the Atrial specific ultra-rapid delayed rectifier K+ current, IKur. The aim of this study is to elucidate and quantify the functional impact of these KCNA5 mutations on Atrial electrical activity. A multi-scale model of the human atria was updated to incorporate detailed experimental data on IKur from both wild-type and mutants. The effects of the mutations on human Atrial Action Potential and rate dependence were investigated at the cellular level. In tissue, we assessed the effects of the mutations on the vulnerability to unidirectional conduction patterns and dynamics of re-entrant excitation waves. Gain-of-function mutations shortened the Action Potential duration in single cells, and stabilised and accelerated re-entrant excitation in tissue. Loss-of-function mutations had heterogeneous effects on Action Potential duration and promoted early-after-depolarisations following beta-adrenergic stimulation. In the tissue model, loss-of-function mutations facilitated breakdown of excitation waves at more physiological excitation rates than the wild-type, and the generation of early-after-depolarisations promoted unidirectional patterns of excitation. Gain- and loss-of-function IKur mutations produced multiple mechanisms of Atrial arrhythmogenesis, with significant differences between the two groups of mutations. This study provides new insights into understanding the mechanisms by which mutant IKur contributes to Atrial arrhythmias. In addition, as IKur is an Atrial-specific channel and a number of IKur-selective blockers have been developed as anti-AF agents, this study also helps to understand some contradictory results on both pro- and anti-arrhythmic effects of blocking IKur.
W R Giles - One of the best experts on this subject based on the ideXlab platform.
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mathematical model of an adult human Atrial cell the role of k currents in repolarization
Circulation Research, 1998Co-Authors: A Nygren, J W Clark, C Fiset, L Firek, D S Lindblad, R Clark, W R GilesAbstract:Abstract—We have developed a mathematical model of the human Atrial myocyte based on averaged voltage-clamp data recorded from isolated single myocytes. Our model consists of a Hodgkin-Huxley–type equivalent circuit for the sarcolemma, coupled with a fluid compartment model, which accounts for changes in ionic concentrations in the cytoplasm as well as in the sarcoplasmic reticulum. This formulation can reconstruct Action Potential data that are representative of recordings from a majority of human Atrial cells in our laboratory and therefore provides a biophysically based account of the underlying ionic currents. This work is based in part on a previous model of the rabbit Atrial myocyte published by our group and was motivated by differences in some of the repolarizing currents between human and rabbit atrium. We have therefore given particular attention to the sustained outward K+ current (Isus), which putatively has a prominent role in determining the duration of the human Atrial Action Potential. Our...
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mathematical model of an adult human Atrial cell the role of k currents in repolarization
Circulation Research, 1998Co-Authors: A Nygren, J W Clark, C Fiset, L Firek, D S Lindblad, R B Clark, W R GilesAbstract:We have developed a mathematical model of the human atria myocyte based on averaged voltage-clamp data recorded from isolated single myocytes. Our model consists of a Hodgkin-Huxley-type equivalent circuit for the sarcolemma, coupled with a fluid compartment model, which accounts for changes in ionic concentrations in the cytoplasm as well as in the sarcoplasmic reticulum. This formulation can reconstruct Action Potential data that are representative of recordings from a majority of human Atrial cells in our laboratory and therefore provides a biophysically based account of the underlying ionic currents. This work is based in part on a previous model of the rabbit Atrial myocyte published by our group and was motivated by differences in some of the repolarizing currents between human and rabbit atrium. We have therefore given particular attention to the sustained outward K+ current (I[sus]), which putatively has a prominent role in determining the duration of the human Atrial Action Potential. Our results demonstrate that the Action Potential shape during the peak and plateau phases is determined primarily by transient outward K+ current, I(sus) and L-type Ca2+ current (I[Ca,L]) and that the role of I(sus) in the human Atrial Action Potential can be modulated by the baseline sizes of I(Ca,L), I(sus) and the rapid delayed rectifier K+ current. As a result, our simulations suggest that the functional role of I(sus) can depend on the physiological/disease state of the cell.
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a model of the Action Potential and underlying membrane currents in a rabbit Atrial cell
American Journal of Physiology-heart and Circulatory Physiology, 1996Co-Authors: Douglas Lindblad, C R Murphey, J W Clark, W R GilesAbstract:We have developed a mathematical model of the rabbit Atrial myocyte and have used it in an examination of the ionic basis of the Atrial Action Potential. Available biophysical data have been incorp...
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a model of the Action Potential and underlying membrane currents in a rabbit Atrial cell
American Journal of Physiology-heart and Circulatory Physiology, 1996Co-Authors: Douglas Lindblad, C R Murphey, J W Clark, W R GilesAbstract:We have developed a mathematical model of the rabbit Atrial myocyte and have used it in an examination of the ionic basis of the Atrial Action Potential. Available biophysical data have been incorporated into the model to quantify the specific ultrastructural morphology, intracellular ion buffering, and time- and voltage-dependent currents and transport mechanisms of the rabbit Atrial cell. When possible, mathematical expressions describing ionic currents identified in rabbit atrium are based on whole cell voltage-clamp data from enzymatically isolated rabbit Atrial myocytes. This membrane model is coupled to equations describing Na+, K+, and Ca2+ homeostasis, including the uptake and release of Ca2+ by the sarcoplasmic reticulum and Ca2+ buffering. The resulting formulation can accurately simulate the whole cell voltage-clamp data on which it is based and provides fits to a family of rabbit Atrial cell Action Potentials obtained at 35 degrees C over a range of stimulus rates (0.2–3.0 Hz). The model is utilized to provide a qualitative prediction of the intracellular Ca2+ concentration transient during the Action Potential and to illustrate the interActions between membrane currents that underlie repolarization in the rabbit Atrial myocyte.
Dominic G Whittaker - One of the best experts on this subject based on the ideXlab platform.
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in silico assessment of pharmacotherapy for human Atrial patho electrophysiology associated with herg linked short qt syndrome
Frontiers in Physiology, 2019Co-Authors: Jules C Hancox, Dominic G Whittaker, Henggui ZhangAbstract:Short QT syndrome variant 1 (SQT1) arises due to gain-of-function mutations to the human Ether-a-go-go-Related Gene (hERG), which encodes the α subunit of channels carrying rapid delayed rectifier potassium current, IKr. In addition to QT interval shortening and ventricular arrhythmias, SQT1 is associated with increased risk of Atrial fibrillation (AF), which is often the only clinical presentation. However, the underlying basis of AF and its pharmacological treatment remain incompletely understood in the context of SQT1. In this study, computational modelling was used to investigate mechanisms of human Atrial arrhythmogenesis consequent to a SQT1 mutation, as well as pharmacotherapeutic effects of selected class I drugs – disopyramide, quinidine, and propafenone. A Markov chain formulation describing wild type (WT) and N588K-hERG mutant IKr was incorporated into a contemporary human Atrial Action Potential (AP) model, which was integrated into one-dimensional (1D) tissue strands, idealised 2D sheets, and a 3D heterogeneous, anatomical human atria model. Multi-channel pharmacological effects of disopyramide, quinidine, and propafenone, including binding kinetics for IKr/hERG and sodium current, INa, were considered. Heterozygous and homozygous formulations of the N588K-hERG mutation shortened the AP duration (APD) by 53 and 86 ms, respectively, which abbreviated the effective refractory period (ERP) and excitation wavelength in tissue, increasing the lifespan and dominant frequency (DF) of scroll waves in the 3D anatomical human atria. At the concentrations tested in this study, quinidine most effectively prolonged the APD and ERP in the setting of SQT1, followed by disopyramide and propafenone. In 2D simulations, disopyramide and quinidine promoted re-entry termination by increasing the re-entry wavelength, whereas propafenone induced secondary waves which destabilised the re-entrant circuit. In 3D simulations, the DF of re-entry was reduced in a dose-dependent manner for disopyramide and quinidine, and propafenone to a lesser extent. All of the anti-arrhythmic agents promoted pharmacological conversion, most frequently terminating re-entry in the order quinidine > propafenone = disopyramide. Our findings provide further insight into mechanisms of SQT1-related AF and a rational basis for the pursuit of combined IKr and INa block based pharmacological strategies in the treatment of SQT1-linked AF.
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Video_1_In silico Assessment of Pharmacotherapy for Human Atrial Patho-Electrophysiology Associated With hERG-Linked Short QT Syndrome.AVI
2019Co-Authors: Dominic G Whittaker, Jules C Hancox, Henggui ZhangAbstract:Short QT syndrome variant 1 (SQT1) arises due to gain-of-function mutations to the human Ether-à-go-go-Related Gene (hERG), which encodes the α subunit of channels carrying rapid delayed rectifier potassium current, IKr. In addition to QT interval shortening and ventricular arrhythmias, SQT1 is associated with increased risk of Atrial fibrillation (AF), which is often the only clinical presentation. However, the underlying basis of AF and its pharmacological treatment remain incompletely understood in the context of SQT1. In this study, computational modeling was used to investigate mechanisms of human Atrial arrhythmogenesis consequent to a SQT1 mutation, as well as pharmacotherapeutic effects of selected class I drugs–disopyramide, quinidine, and propafenone. A Markov chain formulation describing wild type (WT) and N588K-hERG mutant IKr was incorporated into a contemporary human Atrial Action Potential (AP) model, which was integrated into one-dimensional (1D) tissue strands, idealized 2D sheets, and a 3D heterogeneous, anatomical human atria model. Multi-channel pharmacological effects of disopyramide, quinidine, and propafenone, including binding kinetics for IKr/hERG and sodium current, INa, were considered. Heterozygous and homozygous formulations of the N588K-hERG mutation shortened the AP duration (APD) by 53 and 86 ms, respectively, which abbreviated the effective refractory period (ERP) and excitation wavelength in tissue, increasing the lifespan and dominant frequency (DF) of scroll waves in the 3D anatomical human atria. At the concentrations tested in this study, quinidine most effectively prolonged the APD and ERP in the setting of SQT1, followed by disopyramide and propafenone. In 2D simulations, disopyramide and quinidine promoted re-entry termination by increasing the re-entry wavelength, whereas propafenone induced secondary waves which destabilized the re-entrant circuit. In 3D simulations, the DF of re-entry was reduced in a dose-dependent manner for disopyramide and quinidine, and propafenone to a lesser extent. All of the anti-arrhythmic agents promoted pharmacological conversion, most frequently terminating re-entry in the order quinidine > propafenone = disopyramide. Our findings provide further insight into mechanisms of SQT1-related AF and a rational basis for the pursuit of combined IKr and INa block based pharmacological strategies in the treatment of SQT1-linked AF.
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Data_Sheet_1_In silico Assessment of Pharmacotherapy for Human Atrial Patho-Electrophysiology Associated With hERG-Linked Short QT Syndrome.pdf
2019Co-Authors: Dominic G Whittaker, Jules C Hancox, Henggui ZhangAbstract:Short QT syndrome variant 1 (SQT1) arises due to gain-of-function mutations to the human Ether-à-go-go-Related Gene (hERG), which encodes the α subunit of channels carrying rapid delayed rectifier potassium current, IKr. In addition to QT interval shortening and ventricular arrhythmias, SQT1 is associated with increased risk of Atrial fibrillation (AF), which is often the only clinical presentation. However, the underlying basis of AF and its pharmacological treatment remain incompletely understood in the context of SQT1. In this study, computational modeling was used to investigate mechanisms of human Atrial arrhythmogenesis consequent to a SQT1 mutation, as well as pharmacotherapeutic effects of selected class I drugs–disopyramide, quinidine, and propafenone. A Markov chain formulation describing wild type (WT) and N588K-hERG mutant IKr was incorporated into a contemporary human Atrial Action Potential (AP) model, which was integrated into one-dimensional (1D) tissue strands, idealized 2D sheets, and a 3D heterogeneous, anatomical human atria model. Multi-channel pharmacological effects of disopyramide, quinidine, and propafenone, including binding kinetics for IKr/hERG and sodium current, INa, were considered. Heterozygous and homozygous formulations of the N588K-hERG mutation shortened the AP duration (APD) by 53 and 86 ms, respectively, which abbreviated the effective refractory period (ERP) and excitation wavelength in tissue, increasing the lifespan and dominant frequency (DF) of scroll waves in the 3D anatomical human atria. At the concentrations tested in this study, quinidine most effectively prolonged the APD and ERP in the setting of SQT1, followed by disopyramide and propafenone. In 2D simulations, disopyramide and quinidine promoted re-entry termination by increasing the re-entry wavelength, whereas propafenone induced secondary waves which destabilized the re-entrant circuit. In 3D simulations, the DF of re-entry was reduced in a dose-dependent manner for disopyramide and quinidine, and propafenone to a lesser extent. All of the anti-arrhythmic agents promoted pharmacological conversion, most frequently terminating re-entry in the order quinidine > propafenone = disopyramide. Our findings provide further insight into mechanisms of SQT1-related AF and a rational basis for the pursuit of combined IKr and INa block based pharmacological strategies in the treatment of SQT1-linked AF.
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modelling the effects of propafenone on human Atrial patho electrophysiology associated with herg linked short qt syndrome
Computing in Cardiology Conference, 2018Co-Authors: Dominic G Whittaker, Jules C Hancox, Henggui ZhangAbstract:The N588K mutation to the human Ether-a-go-go-Related Gene (hERG) underlies short QT syndrome variant 1 (SQT1), which is associated with Atrial fibrillation (AF). However, mechanisms and management of AF in the context of SQT1 remain poorly understood. In this study, multi-scale computational modelling was used to investigate pharmacotherapeutic effects of the class Ic drug propafenone for SQT1-mediated human Atrial patho-electrophysiology. A Markov chain formulation of rapid delayed rectifier potassium current, I Kr , describing wild type (WT) and N588K mutant currents was incorporated into a recent model of the human Atrial Action Potential (AP), which was integrated into multi-scale tissue models. Effects of multi-channel block by propafenone were simulated on single- and multi-cellular electrophysiology models. At the single cell level, propafenone prolonged the AP duration under SQT1 (heterozygous N588K) conditions in a dose-dependent manner. In tissue, propafenone prolonged the effective refractory period and excitation wavelength, whilst reducing the conduction velocity. In 2D sheet simulations, propafenone demonstrated efficacy in pharmacological conversion of re-entry. Our findings suggest that propafenone shows efficacy in reversing AF associated with hERG-linked short QT syndrome.
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Atrial arrhythmogenicity of kcnj2 mutations in short qt syndrome insights from virtual human atria
PLOS Computational Biology, 2017Co-Authors: Dominic G Whittaker, Jules C Hancox, Henggui Zhang, Aziza El HarchiAbstract:Gain-of-function mutations in KCNJ2-encoded Kir2.1 channels underlie variant 3 (SQT3) of the short QT syndrome, which is associated with Atrial fibrillation (AF). Using biophysically-detailed human atria computer models, this study investigated the mechanistic link between SQT3 mutations and Atrial arrhythmogenesis, and Potential ion channel targets for treatment of SQT3. A contemporary model of the human Atrial Action Potential (AP) was modified to recapitulate functional changes in IK1 due to heterozygous and homozygous forms of the D172N and E299V Kir2.1 mutations. Wild-type (WT) and mutant formulations were incorporated into multi-scale homogeneous and heterogeneous tissue models. Effects of mutations on AP duration (APD), conduction velocity (CV), effective refractory period (ERP), tissue excitation threshold and their rate-dependence, as well as the wavelength of re-entry (WL) were quantified. The D172N and E299V Kir2.1 mutations produced distinct effects on IK1 and APD shortening. Both mutations decreased WL for re-entry through a reduction in ERP and CV. Stability of re-entrant excitation waves in 2D and 3D tissue models was mediated by changes to tissue excitability and dispersion of APD in mutation conditions. Combined block of IK1 and IKr was effective in terminating re-entry associated with heterozygous D172N conditions, whereas IKr block alone may be a safer alternative for the E299V mutation. Combined inhibition of IKr and IKur produced a synergistic anti-arrhythmic effect in both forms of SQT3. In conclusion, this study provides mechanistic insights into Atrial proarrhythmia with SQT3 Kir2.1 mutations and highlights possible pharmacological strategies for management of SQT3-linked AF.
Jules C Hancox - One of the best experts on this subject based on the ideXlab platform.
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role of sk channel activation in determining the Action Potential configuration in freshly isolated human Atrial myocytes from the skarf study
Biochemical and Biophysical Research Communications, 2019Co-Authors: Yousif A Shamsaldeen, Lucy Culliford, Madeleine Clout, Andrew F James, Raimondo Ascione, Jules C Hancox, Neil V MarrionAbstract:Abstract Inhibition of SK channel function is being pursued in animal models as a possible therapeutic approach to treat Atrial fibrillation (AF). However, the pharmacology of SK channels in human atria is unclear. SK channel function is inhibited by both apamin and UCL1684, with the former discriminating between SK channel subtypes. In this proof-of-principle study, the effects of apamin and UCL1684 on right Atrial myocytes freshly isolated from patients in sinus rhythm undergoing elective cardiac surgery were investigated. Outward current evoked from voltage clamped human Atrial myocytes was reduced by these two inhibitors of SK channel function. In contrast, membrane current underlying the Atrial Action Potential was affected significantly only by UCL1684 and not by apamin. This pharmacology mirrors that observed in mouse atria, suggesting that mammalian atria possess two populations of SK channels, with only one population contributing to the Action Potential waveform. Immuno-visualization of the subcellular localization of SK2 and SK3 subunits showed a high degree of colocalization, consistent with the formation of heteromeric SK2/SK3 channels. These data reveal that human Atrial myocytes express two SK channel subtypes, one exhibiting an unusual pharmacology. These channels contribute to the Atrial Action Potential waveform and might be a target for novel therapeutic approaches to treat supraventricular arrhythmic conditions such as Atrial fibrillation.
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in silico assessment of pharmacotherapy for human Atrial patho electrophysiology associated with herg linked short qt syndrome
Frontiers in Physiology, 2019Co-Authors: Jules C Hancox, Dominic G Whittaker, Henggui ZhangAbstract:Short QT syndrome variant 1 (SQT1) arises due to gain-of-function mutations to the human Ether-a-go-go-Related Gene (hERG), which encodes the α subunit of channels carrying rapid delayed rectifier potassium current, IKr. In addition to QT interval shortening and ventricular arrhythmias, SQT1 is associated with increased risk of Atrial fibrillation (AF), which is often the only clinical presentation. However, the underlying basis of AF and its pharmacological treatment remain incompletely understood in the context of SQT1. In this study, computational modelling was used to investigate mechanisms of human Atrial arrhythmogenesis consequent to a SQT1 mutation, as well as pharmacotherapeutic effects of selected class I drugs – disopyramide, quinidine, and propafenone. A Markov chain formulation describing wild type (WT) and N588K-hERG mutant IKr was incorporated into a contemporary human Atrial Action Potential (AP) model, which was integrated into one-dimensional (1D) tissue strands, idealised 2D sheets, and a 3D heterogeneous, anatomical human atria model. Multi-channel pharmacological effects of disopyramide, quinidine, and propafenone, including binding kinetics for IKr/hERG and sodium current, INa, were considered. Heterozygous and homozygous formulations of the N588K-hERG mutation shortened the AP duration (APD) by 53 and 86 ms, respectively, which abbreviated the effective refractory period (ERP) and excitation wavelength in tissue, increasing the lifespan and dominant frequency (DF) of scroll waves in the 3D anatomical human atria. At the concentrations tested in this study, quinidine most effectively prolonged the APD and ERP in the setting of SQT1, followed by disopyramide and propafenone. In 2D simulations, disopyramide and quinidine promoted re-entry termination by increasing the re-entry wavelength, whereas propafenone induced secondary waves which destabilised the re-entrant circuit. In 3D simulations, the DF of re-entry was reduced in a dose-dependent manner for disopyramide and quinidine, and propafenone to a lesser extent. All of the anti-arrhythmic agents promoted pharmacological conversion, most frequently terminating re-entry in the order quinidine > propafenone = disopyramide. Our findings provide further insight into mechanisms of SQT1-related AF and a rational basis for the pursuit of combined IKr and INa block based pharmacological strategies in the treatment of SQT1-linked AF.
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Data_Sheet_1_In silico Assessment of Pharmacotherapy for Human Atrial Patho-Electrophysiology Associated With hERG-Linked Short QT Syndrome.pdf
2019Co-Authors: Dominic G Whittaker, Jules C Hancox, Henggui ZhangAbstract:Short QT syndrome variant 1 (SQT1) arises due to gain-of-function mutations to the human Ether-à-go-go-Related Gene (hERG), which encodes the α subunit of channels carrying rapid delayed rectifier potassium current, IKr. In addition to QT interval shortening and ventricular arrhythmias, SQT1 is associated with increased risk of Atrial fibrillation (AF), which is often the only clinical presentation. However, the underlying basis of AF and its pharmacological treatment remain incompletely understood in the context of SQT1. In this study, computational modeling was used to investigate mechanisms of human Atrial arrhythmogenesis consequent to a SQT1 mutation, as well as pharmacotherapeutic effects of selected class I drugs–disopyramide, quinidine, and propafenone. A Markov chain formulation describing wild type (WT) and N588K-hERG mutant IKr was incorporated into a contemporary human Atrial Action Potential (AP) model, which was integrated into one-dimensional (1D) tissue strands, idealized 2D sheets, and a 3D heterogeneous, anatomical human atria model. Multi-channel pharmacological effects of disopyramide, quinidine, and propafenone, including binding kinetics for IKr/hERG and sodium current, INa, were considered. Heterozygous and homozygous formulations of the N588K-hERG mutation shortened the AP duration (APD) by 53 and 86 ms, respectively, which abbreviated the effective refractory period (ERP) and excitation wavelength in tissue, increasing the lifespan and dominant frequency (DF) of scroll waves in the 3D anatomical human atria. At the concentrations tested in this study, quinidine most effectively prolonged the APD and ERP in the setting of SQT1, followed by disopyramide and propafenone. In 2D simulations, disopyramide and quinidine promoted re-entry termination by increasing the re-entry wavelength, whereas propafenone induced secondary waves which destabilized the re-entrant circuit. In 3D simulations, the DF of re-entry was reduced in a dose-dependent manner for disopyramide and quinidine, and propafenone to a lesser extent. All of the anti-arrhythmic agents promoted pharmacological conversion, most frequently terminating re-entry in the order quinidine > propafenone = disopyramide. Our findings provide further insight into mechanisms of SQT1-related AF and a rational basis for the pursuit of combined IKr and INa block based pharmacological strategies in the treatment of SQT1-linked AF.
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Video_1_In silico Assessment of Pharmacotherapy for Human Atrial Patho-Electrophysiology Associated With hERG-Linked Short QT Syndrome.AVI
2019Co-Authors: Dominic G Whittaker, Jules C Hancox, Henggui ZhangAbstract:Short QT syndrome variant 1 (SQT1) arises due to gain-of-function mutations to the human Ether-à-go-go-Related Gene (hERG), which encodes the α subunit of channels carrying rapid delayed rectifier potassium current, IKr. In addition to QT interval shortening and ventricular arrhythmias, SQT1 is associated with increased risk of Atrial fibrillation (AF), which is often the only clinical presentation. However, the underlying basis of AF and its pharmacological treatment remain incompletely understood in the context of SQT1. In this study, computational modeling was used to investigate mechanisms of human Atrial arrhythmogenesis consequent to a SQT1 mutation, as well as pharmacotherapeutic effects of selected class I drugs–disopyramide, quinidine, and propafenone. A Markov chain formulation describing wild type (WT) and N588K-hERG mutant IKr was incorporated into a contemporary human Atrial Action Potential (AP) model, which was integrated into one-dimensional (1D) tissue strands, idealized 2D sheets, and a 3D heterogeneous, anatomical human atria model. Multi-channel pharmacological effects of disopyramide, quinidine, and propafenone, including binding kinetics for IKr/hERG and sodium current, INa, were considered. Heterozygous and homozygous formulations of the N588K-hERG mutation shortened the AP duration (APD) by 53 and 86 ms, respectively, which abbreviated the effective refractory period (ERP) and excitation wavelength in tissue, increasing the lifespan and dominant frequency (DF) of scroll waves in the 3D anatomical human atria. At the concentrations tested in this study, quinidine most effectively prolonged the APD and ERP in the setting of SQT1, followed by disopyramide and propafenone. In 2D simulations, disopyramide and quinidine promoted re-entry termination by increasing the re-entry wavelength, whereas propafenone induced secondary waves which destabilized the re-entrant circuit. In 3D simulations, the DF of re-entry was reduced in a dose-dependent manner for disopyramide and quinidine, and propafenone to a lesser extent. All of the anti-arrhythmic agents promoted pharmacological conversion, most frequently terminating re-entry in the order quinidine > propafenone = disopyramide. Our findings provide further insight into mechanisms of SQT1-related AF and a rational basis for the pursuit of combined IKr and INa block based pharmacological strategies in the treatment of SQT1-linked AF.
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modelling the effects of propafenone on human Atrial patho electrophysiology associated with herg linked short qt syndrome
Computing in Cardiology Conference, 2018Co-Authors: Dominic G Whittaker, Jules C Hancox, Henggui ZhangAbstract:The N588K mutation to the human Ether-a-go-go-Related Gene (hERG) underlies short QT syndrome variant 1 (SQT1), which is associated with Atrial fibrillation (AF). However, mechanisms and management of AF in the context of SQT1 remain poorly understood. In this study, multi-scale computational modelling was used to investigate pharmacotherapeutic effects of the class Ic drug propafenone for SQT1-mediated human Atrial patho-electrophysiology. A Markov chain formulation of rapid delayed rectifier potassium current, I Kr , describing wild type (WT) and N588K mutant currents was incorporated into a recent model of the human Atrial Action Potential (AP), which was integrated into multi-scale tissue models. Effects of multi-channel block by propafenone were simulated on single- and multi-cellular electrophysiology models. At the single cell level, propafenone prolonged the AP duration under SQT1 (heterozygous N588K) conditions in a dose-dependent manner. In tissue, propafenone prolonged the effective refractory period and excitation wavelength, whilst reducing the conduction velocity. In 2D sheet simulations, propafenone demonstrated efficacy in pharmacological conversion of re-entry. Our findings suggest that propafenone shows efficacy in reversing AF associated with hERG-linked short QT syndrome.