Inhibition of the voltage-gated potassium channel Kv1.5 by hydrogen sulfide attenuates remodeling through S-nitrosylation-mediated signaling.

The voltage-gated K+ channel plays a key role in atrial excitability, conducting the ultra-rapid rectifier K+ current (IKur) and contributing to the repolarization of the atrial action potential. In this study, we examine its regulation by hydrogen sulfide (H2S) in HL-1 cardiomyocytes and in HEK293 cells expressing human Kv1.5. Pacing induced remodeling resulted in shorting action potential duration, enhanced both Kv1.5 channel and H2S producing enzymes protein expression in HL-1 cardiomyocytes. H2S supplementation reduced these remodeling changes and restored action potential duration through inhibition of Kv1.5 channel. H2S also inhibited recombinant hKv1.5, lead to nitric oxide (NO) mediated S-nitrosylation and activated endothelial nitric oxide synthase (eNOS) by increased phosphorylation of Ser1177, prevention of NO formation precluded these effects. Regulation of Ikur by H2S has important cardiovascular implications and represents a novel and potential therapeutic target.

Reverse RAMP (REVRAMP) pacing: A novel anti tachycardia pacing technique.

Anti-tachycardia pacing (ATP) is frequently used to terminate ventricular tachycardia (VT), however it is not always successful and may accelerate VT requiring defibrillation. REVRAMP is a novel concept of ATP that involves delivering pacing at a faster rate than VT, but instead of abruptly terminating pacing after eight beats, pacing is gradually slowed until VT continues or normal rhythm is restored. In a pilot study we show that REVRAMP can restore normal rhythm, and that if REVRAMP is unsuccessful, VT is not accelerated.

Deterministic and Stochastic Cellular Mechanisms Contributing to Carbon Monoxide Induced Ventricular Arrhythmias.

Chronic exposure to low levels of Carbon Monoxide is associated with an increased risk of cardiac arrhythmia. Microelectrode recordings from rat and guinea pig single isolated ventricular myocytes exposed to CO releasing molecule CORM-2 and excited at 0.2/s show repolarisation changes that develop over hundreds of seconds: action potential prolongation by delayed repolarisation, EADs, multiple EADs and oscillations around the plateau, leading to irreversible repolarisation failure. The measured direct effects of CO on currents in these cells, and ion channels expressed in mammalian systems showed an increase in prolonged late Na+, and a decrease in the maximal T- and L-type Ca++. peak and late Na+, ultra-rapid delayed, delayed rectifier, and the inward rectifier K+ currents. Incorporation of these CO induced changes in maximal currents in ventricular cell models; (Gattoni et al., J. Physiol., 2016, 594, 4193-4224) (rat) and (Luo and Rudy, Circ. Res., 1994, 74, 1071-1096) (guinea-pig) and human endo-, mid-myo- and epi-cardial (O'Hara et al., PLoS Comput. Biol., 2011, 7, e1002061) models, by changes in maximal ionic conductance reproduces these repolarisation abnormalities. Simulations of cell populations with Gaussian distributions of maximal conductance parameters predict a CO induced increase in APD and its variability. Incorporation of these predicted CO induced conductance changes in human ventricular cell electrophysiology into ventricular tissue and wall models give changes in indices for the probability of the initiation of re-entrant arrhythmia.

Imaging, biomarker and invasive assessment of diffuse left ventricular myocardial fibrosis in atrial fibrillation.

BACKGROUND: Using cardiovascular magnetic resonance imaging (CMR), it is possible to detect diffuse fibrosis of the left ventricle (LV) in patients with atrial fibrillation (AF), which may be independently associated with recurrence of AF after ablation. By conducting CMR, clinical, electrophysiology and biomarker assessment we planned to investigate LV myocardial fibrosis in patients undergoing AF ablation. METHODS: LV fibrosis was assessed by T1 mapping in 31 patients undergoing percutaneous ablation for AF. Galectin-3, coronary sinus type I collagen C terminal telopeptide (ICTP), and type III procollagen N terminal peptide were measured with ELISA. Comparison was made between groups above and below the median for LV extracellular volume fraction (ECV), followed by regression analysis. RESULTS: On linear regression analysis LV ECV had significant associations with invasive left atrial pressure (Beta 0.49, P = 0.008) and coronary sinus ICTP (Beta 0.75, P < 0.001), which remained significant on multivariable regression. CONCLUSION: LV fibrosis in patients with AF is associated with left atrial pressure and invasively measured levels of ICTP turnover biomarker.

Phase Entrainment of Induced Ventricular Fibrillation: A Human Feasibility and Proof of Concept Study.

Cardioversion and defibrillation by a single high energy shock applied by myocardial or body surface electrodes is painful, causes long term tissue damage, and is associated with worsening long term outcomes, but is almost always required for treatment of ventricular fibrillation . As a initial step towards developing methods that can terminate ventricular arrhythmias painlessly, we aim to determine if pacing stimuli at a rate of 5/s applied via an implantable cardiac defibrillator (ICD) can modify human ventricular fibrillation. In 8 patients undergoing defibrillation testing of a new/exchanged intracardiac defibrillator, five seconds of pacing at five stimuli per second was applied during the 10-20 seconds of induced ventricular fibrillation before the defibrillation shock was automatically applied, and the cardiac electrograms recorded and analyzed. The high frequency pacing did not entrain the ventricular fibrillation, but altered the dominant frequency in all 8 patients, and modulated the phase computed via the Hilbert Transform, in four of the patients. In this pilot study we demonstrate that high frequency pacing applied via ICD electrodes during VF can alter the dominant frequency and modulate the probability density of the phase of the electrogram of the ventricular fibrillation.

The developmental transcriptome of the human heart.

The human heart develops through complex mechanisms producing morphological and functional changes during gestation. We have recently demonstrated using diffusion tensor MRI that over the relatively short space of 40 days, between 100-140 days gestational age, the ventricular myocardium transforms from a disorganised tissue to the ordered structure characteristic of mature cardiac tissue. However, the genetic basis underpinning this maturation is unclear. Herein, we have used RNA-Seq to establish the developmentally-regulated transcriptome of gene expression in the developing human heart across three gestational ages in the first and second trimester. By comparing 9 weeks gestational age (WGA) with 12 WGA, we find 288 genes show significant differential expression. 305 genes were significantly altered comparing 12 and 16 WGA, and 806 genes differentially expressed between 9 and 16 WGA. Network analysis was used to identify genetic interactions, node properties and gene ontology categories. In summary, we present a comprehensive transcriptomic analysis of human heart development during early gestation, and identify differentially expressed genes during heart development between 9 and 16 weeks, overlapping the first and early second trimester.

A computational model of excitation and contraction in uterine myocytes from the pregnant rat.

Aberrant uterine myometrial activities in humans are major health issues. However, the cellular and tissue mechanism(s) that maintain the uterine myometrium at rest during gestation, and that initiate and maintain long-lasting uterine contractions during delivery are incompletely understood. In this study we construct a computational model for describing the electrical activity (simple and complex action potentials), intracellular calcium dynamics and mechanical contractions of isolated uterine myocytes from the pregnant rat. The model reproduces variant types of action potentials - from spikes with a smooth plateau, to spikes with an oscillatory plateau, to bursts of spikes - that are seen during late gestation under different physiological conditions. The effects of the hormones oestradiol (via reductions in calcium and potassium selective channel conductance), oxytocin (via an increase in intracellular calcium release) and the tocolytic nifedipine (via a block of L-type calcium channels currents) on action potentials and contractions are also reproduced, which quantitatively match to experimental data. All of these results validated the cell model development. In conclusion, the developed model provides a computational platform for further investigations of the ionic mechanism underlying the genesis and control of electrical and mechanical activities in the rat uterine myocytes.

Left atrial voltage, circulating biomarkers of fibrosis, and atrial fibrillation ablation. A prospective cohort study.

AIMS: To test the ability of four circulating biomarkers of fibrosis, and of low left atrial voltage, to predict recurrence of atrial fibrillation after catheter ablation. BACKGROUND: Circulating biomarkers potentially may be used to improve patient selection for atrial fibrillation ablation. Low voltage areas in the left atrium predict arrhythmia recurrence when mapped in sinus rhythm. This study tested type III procollagen N terminal peptide (PIIINP), galectin-3 (gal-3), fibroblast growth factor 23 (FGF-23), and type I collagen C terminal telopeptide (ICTP), and whether low voltage areas in the left atrium predicted atrial fibrillation recurrence, irrespective of the rhythm during mapping. METHODS: 92 atrial fibrillation ablation patients were studied. Biomarker levels in peripheral and intra-cardiac blood were measured with enzyme-linked immunosorbent assay. Low voltage (<0.5mV) was expressed as a proportion of the mapped left atrial surface area. Follow-up was one year. The primary endpoint was recurrence of arrhythmia. The secondary endpoint was a composite of recurrence despite two procedures, or after one procedure if no second procedure was undertaken. RESULTS: The biomarkers were not predictive of either endpoint. After multivariate Cox regression analysis, high proportion of low voltage area in the left atrium was found to predict the primary endpoint in sinus rhythm mapping (hazard ratio 4.323, 95% confidence interval 1.337-13.982, p = 0.014) and atrial fibrillation mapping (hazard ratio 5.195, 95% confidence interval 1.032-26.141, p = 0.046). This effect was also apparent for the secondary endpoint. CONCLUSION: The studied biomarkers do not predict arrhythmia recurrence after catheter ablation. Left atrial voltage is an independent predictor of recurrence, whether the left atrium is mapped in atrial fibrillation or sinus rhythm.

Multichannel electrocardiogram diagnostics for the diagnosis of arrhythmogenic right ventricular dysplasia.

Aims: The identification of arrhythmogenic right ventricular dysplasia (ARVD) from 12-channel standard electrocardiogram (ECG) is challenging. High density ECG data may identify lead locations and criteria with a higher sensitivity. Methods and results: Eighty-channel ECG recording from patients diagnosed with ARVD and controls were quantified by magnitude and integral measures of QRS and T waves and by a measure (the average silhouette width) of differences in the shapes of the normalized ECG cycles. The channels with the best separability between ARVD patients and controls were near the right ventricular wall, at the third intercostal space. These channels showed pronounced differences in P waves compared to controls as well as the expected differences in QRS and T waves. Conclusion: Multichannel recordings, as in body surface mapping, add little to the reliability of diagnosing ARVD from ECGs. However, repositioning ECG electrodes to a high anterior position can improve the identification of ECG variations in ARVD. Additionally, increased P wave amplitude appears to be associated with ARVD.

Trigger vs. Substrate: Multi-Dimensional Modulation of QT-Prolongation Associated Arrhythmic Dynamics by a hERG Channel Activator.

Background: Prolongation of the QT interval of the electrocardiogram (ECG), underlain by prolongation of the action potential duration (APD) at the cellular level, is linked to increased vulnerability to cardiac arrhythmia. Pharmacological management of arrhythmia associated with QT prolongation is typically achieved through attempting to restore APD to control ranges, reversing the enhanced vulnerability to Ca2+-dependent afterdepolarisations (arrhythmia triggers) and increased transmural dispersion of repolarisation (arrhythmia substrate) associated with APD prolongation. However, such pharmacological modulation has been demonstrated to have limited effectiveness. Understanding the integrative functional impact of pharmacological modulation requires simultaneous investigation of both the trigger and substrate. Methods: We implemented a multi-scale (cell and tissue) in silico approach using a model of the human ventricular action potential, integrated with a model of stochastic 3D spatiotemporal Ca2+ dynamics, and parameter modification to mimic prolonged QT conditions. We used these models to examine the efficacy of the hERG activator MC-II-157c in restoring APD to control ranges, examined its effects on arrhythmia triggers and substrates, and the interaction of these arrhythmia triggers and substrates. Results: QT prolongation conditions promoted the development of spontaneous release events underlying afterdepolarisations during rapid pacing. MC-II-157c applied to prolonged QT conditions shortened the APD, inhibited the development of afterdepolarisations and reduced the probability of afterdepolarisations manifesting as triggered activity in single cells. In tissue, QT prolongation resulted in an increased transmural dispersion of repolarisation, which manifested as an increased vulnerable window for uni-directional conduction block. In some cases, MC-II-157c further increased the vulnerable window through its effects on INa. The combination of stochastic release event modulation and transmural dispersion of repolarisation modulation by MC-II-157c resulted in an integrative behavior wherein the arrhythmia trigger is reduced but the arrhythmia substrate is increased, leading to variable and non-linear overall vulnerability to arrhythmia. Conclusion: The relative balance of reduced trigger and increased substrate underlies a multi-dimensional role of MC-II-157c in modulation of cardiac arrhythmia vulnerability associated with prolonged QT interval.

Ventricular myocardium development and the role of connexins in the human fetal heart.

The developmental timeline of the human heart remains elusive. The heart takes on its characteristic four chambered appearance by ~56 days gestational age (DGA). However, owing to the complexities (both technical and logistical) of exploring development in utero, we understand little of how the ventricular walls develop. To address this, we employed diffusion tensor magnetic resonance imaging to explore the architecture and tissue organization of the developing heart aged 95-143 DGA. We show that fractional anisotropy increases (from ~0.1 to ~0.5), diffusion coefficients decrease (from ~1 × 10-3mm2/sec to ~0.4 × 10-3mm2/sec), and fiber paths, extracted by tractography, increase linearly with gestation, indicative of the increasing organization of the ventricular myocytes. By 143 DGA, the developing heart has the classical helical organization observed in mature mammalian tissue. This was accompanied by an increase in connexin 43 and connexin 40 expression levels, suggesting their role in the development of the ventricular conduction system and that electrical propagation across the heart is facilitated in later gestation. Our findings highlight a key developmental window for the structural organization of the fetal heart.

Intra-cardiac and peripheral levels of biochemical markers of fibrosis in patients undergoing catheter ablation for atrial fibrillation.

AIMS: Measurement of circulating biomarkers of fibrosis may have a role in selecting patients and treatment strategy for catheter ablation. Pro-collagen type III N-terminal pro-peptide (PIIINP), C-telopeptide of type I collagen (ICTP), fibroblast growth factor 23 (FGF-23), and galectin 3 (gal-3) have all been suggested as possible biomarkers for this indication, but studies assessing whether peripheral levels reflect intra-cardiac levels are scarce. METHODS AND RESULTS: We studied 93 patients undergoing ablation for paroxysmal atrial fibrillation (AF) (n = 63) or non-paroxysmal AF (n = 30). Femoral venous, left and right atrial, and coronary sinus blood were analysed using ELISA to determine biomarker levels. Levels were compared with control patients (n = 36) and baseline characteristics, including left atrial voltage mapping data. C-telopeptide of type I collagen levels were higher in AF than in non-AF patients (P = 0.007). Peripheral ICTP levels were higher than all intra-cardiac levels (P < 0.001). Peripheral gal-3 levels were higher than left atrial levels (P = 0.001). Peripheral levels of FGF-23 and PIIINP were not significantly different from intra-cardiac levels. CS levels of ICTP were higher than right and left atrial levels (P < 0.001). gal-3 was higher in women vs. men (P ≤ 0.001) and with higher body mass index (P ≤ 0.001). ICTP levels increased with reducing ejection fraction (P ≤ 0.012). CONCLUSIONS: Atrial fibrillation patients have higher levels of circulating ICTP than matched non-AF controls. In AF ablation patients, intra-cardiac sampling of FGF-23 or PIIINP gives no further information over peripheral sampling. For gal-3 and ICTP, intra-cardiac sampling may be necessary to assess their association with intra-cardiac processes. None of the biomarkers is related to fibrosis assessed by left atrial voltage.

Assessment of atrial fibrosis for the rhythm control of atrial fibrillation.

Rhythm control of atrial fibrillation (AF) remains challenging, with modest long-term success rates. Atrial fibrosis has been associated with AF, but the clinical utility of assessment of this fibrosis has yet to be fully elucidated. In this paper we review the current state of understanding of the pathophysiology of atrial fibrosis in AF, and its impact upon the instigation and propagation of the arrhythmia. Fibrosis causes an increase in volume of dysfunctional extracellular matrix, and is associated with cellular alterations such as hypertrophy, apoptosis and membrane dysfunction within the atrial myocardium. In turn, these cause pathological alterations to atrial conduction, such as increased anisotropy, conduction block and re-entry, which can lead to AF. We review current methods of assessing atrial fibrosis and their impact upon the prediction of success of interventional rhythm control strategies such as ablation and cardioversion. We focus particularly on circulating biomarkers of fibrosis and scar formation; their role in the fibrotic process, and their value in the prediction of rhythm control success. We also review imaging and invasive electrocardiographic mapping techniques that may identify fibrosis, and again assess their potential predictive value. In this area there exist many unanswered questions, but further work will help to refine techniques to reliably identify and treat those patients who are most likely to benefit from rhythm control treatment strategies.

Effects of human atrial ionic remodelling by ß-blocker therapy on mechanisms of atrial fibrillation: a computer simulation.

AIMS: Atrial anti-arrhythmic effects of ß-adrenoceptor antagonists (ß-blockers) may involve both a suppression of pro-arrhythmic effects of catecholamines, and an adaptational electrophysiological response to chronic ß-blocker use; so-called 'pharmacological remodelling'. In human atrium, such remodelling decreases the transient outward (Ito) and inward rectifier (IK1) K(+) currents, and increases the cellular action potential duration (APD) and effective refractory period (ERP). However, the consequences of these changes on mechanisms of genesis and maintenance of atrial fibrillation (AF) are unknown. Using mathematical modelling, we tested the hypothesis that the long-term adaptational decrease in human atrial Ito and IK1 caused by chronic ß-blocker therapy, i.e. independent of acute electrophysiological effects of ß-blockers, in an otherwise un-remodelled atrium, could suppress AF. METHODS AND RESULTS: Contemporarily, biophysically detailed human atrial cell and tissue models were used to investigate effects of the ß-blocker-based pharmacological remodelling. Chronic ß-blockade remodelling prolonged atrial cell APD and ERP. The incidence of small amplitude APD alternans in the CRN model was reduced. At the 1D tissue level, ß-blocker remodelling decreased the maximum pacing rate at which APs could be conducted. At the three-dimensional organ level, ß-blocker remodelling reduced the life span of re-entry scroll waves. CONCLUSION: This study improves our understanding of the electrophysiological mechanisms of AF suppression by chronic ß-blocker therapy. Atrial fibrillation suppression may involve a reduced propensity for maintenance of re-entrant excitation waves, as a consequence of increased APD and ERP.

Towards computational modelling of the human foetal electrocardiogram: normal sinus rhythm and congenital heart block.

AIMS: We aim to engineer a computational model of propagation during normal sinus rhythm in the foetal human heart, by modifying models for adult cardiac tissue to match foetal electrocardiogram (fECG) characteristics. The model will be partially validated by fECG data, and applied to explore possible mechanisms of arrhythmogenesis in the foetal heart. METHODS AND RESULTS: Foetal electrocardiograms have been recorded during pregnancy, with P- and T-waves, and the QRS complex, identified by averaging and signal processing. Intervals of the fECG are extracted and used to modify currently available human adult cardiomyocyte models. RR intervals inform models of the pacemaking cells by constraining their rate, the QT interval and its rate dependence constrain models of ventricular cells, and the width of the P-wave, the QR and PR intervals constrain propagation times, conduction velocities, and intercellular coupling. These cell models are coupled into a one-dimensional (1D) model of propagation during normal sinus rhythm in the human foetal heart. We constructed a modular, heterogeneous 1D model for propagation in the foetal heart, and predicted the effects of reduction in L-type Ca(++) current. These include bradycardia and atrioventricular conduction blocks. These may account quantitatively for congenital heart block produced by positive IgG antibodies. CONCLUSION: The fECG can be interpreted mechanistically and quantitatively by using a simple computational model for propagation. After further validation, by clinical recordings of the fECG and the electrophysiological experiments on foetal cardiac cells and tissues, the model may be used to predict the effects of maternally administered pharmaceuticals on the fECG.

Spatiotemporal patterning of uterine excitation patterns in human labour.

The mechanisms leading to the initiation of normal, premature or dysfunctional human labour are poorly understood, as animal models are inappropriate, and experimental studies are limited. Computational modelling provides a means of linking non-invasive clinical data with the results of in vitro cell and tissue physiology. Nonlinear wave processes - propagation in an excitable medium - provides a quantitatively testable description of mechanisms of premature and full term labour, and a view of changes in uterine electrophysiology during gestation as a trajectory in excitation and intercellular coupling parameter space. Propagation phenomena can account for both premature and full term labour.

Application of micro-computed tomography with iodine staining to cardiac imaging, segmentation, and computational model development.

Micro-computed tomography (micro-CT) has been widely used to generate high-resolution 3-D tissue images from small animals nondestructively, especially for mineralized skeletal tissues. However, its application to the analysis of soft cardiovascular tissues has been limited by poor inter-tissue contrast. Recent ex vivo studies have shown that contrast between muscular and connective tissue in micro-CT images can be enhanced by staining with iodine. In the present study, we apply this novel technique for imaging of cardiovascular structures in canine hearts. We optimize the method to obtain high-resolution X-ray micro-CT images of the canine atria and its distinctive regions-including the Bachmann's bundle, atrioventricular node, pulmonary arteries and veins-with clear inter-tissue contrast. The imaging results are used to reconstruct and segment the detailed 3-D geometry of the atria. Structure tensor analysis shows that the arrangement of atrial fibers can also be characterized using the enhanced micro-CT images, as iodine preferentially accumulates within the muscular fibers rather than in connective tissues. This novel technique can be particularly useful in nondestructive imaging of 3-D cardiac architectures from large animals and humans, due to the combination of relatively high speed ( ~ 1 h/per scan of the large canine heart) and high voxel resolution (36 µm) provided. In summary, contrast micro-CT facilitates fast and nondestructive imaging and segmenting of detailed 3-D cardiovascular geometries, as well as measuring fiber orientation, which are crucial in constructing biophysically detailed computational cardiac models.

Antenatal architecture and activity of the human heart.

We construct the components for a family of computational models of the electrophysiology of the human foetal heart from 60 days gestational age (DGA) to full term. This requires both cell excitation models that reconstruct the myocyte action potentials, and datasets of cardiac geometry and architecture. Fast low-angle shot and diffusion tensor magnetic resonance imaging (DT-MRI) of foetal hearts provides cardiac geometry with voxel resolution of approximately 100 µm. DT-MRI measures the relative diffusion of protons and provides a measure of the average intravoxel myocyte orientation, and the orientation of any higher order orthotropic organization of the tissue. Such orthotropic organization in the adult mammalian heart has been identified with myocardial sheets and cleavage planes between them. During gestation, the architecture of the human ventricular wall changes from being irregular and isotropic at 100 DGA to an anisotropic and orthotropic architecture by 140 DGA, when it has the smooth, approximately 120° transmural change in myocyte orientation that is characteristic of the adult mammalian ventricle. The DT obtained from DT-MRI provides the conductivity tensor that determines the spread of potential within computational models of cardiac tissue electrophysiology. The foetal electrocardiogram (fECG) can be recorded from approximately 60 DGA, and RR, PR and QT intervals between the P, R, Q and T waves of the fECG can be extracted by averaging from approximately 90 DGA. The RR intervals provide a measure of the pacemaker rate, the QT intervals an index of ventricular action potential duration, and its rate-dependence, and so these intervals constrain and inform models of cell electrophysiology. The parameters of models of adult human sinostrial node and ventricular cells that are based on adult cell electrophysiology and tissue molecular mapping have been modified to construct preliminary models of foetal cell electrophysiology, which reproduce these intervals from fECG recordings. The PR and QR intervals provide an index of conduction times, and hence propagation velocities (approx. 1-10 cm s(-1), increasing during gestation) and so inform models of tissue electrophysiology. Although the developing foetal heart is small and the cells are weakly coupled, it can support potentially lethal re-entrant arrhythmia.

Modeling the chronotropic effect of isoprenaline on rabbit sinoatrial node.

INTRODUCTION: ß-adrenergic stimulation increases the heart rate by accelerating the electrical activity of the pacemaker of the heart, the sinoatrial node (SAN). Ionic mechanisms underlying the actions of ß-adrenergic stimulation are not yet fully understood. Isoprenaline (ISO), a ß-adrenoceptor agonist, shifts voltage-dependent I(f) activation to more positive potentials resulting in an increase of I(f), which has been suggested to be the main mechanism underlying the effect of ß-adrenergic stimulation. However, ISO has been found to increase the firing rate of rabbit SAN cells when I(f) is blocked. ISO also increases I(CaL), I(st), I(Kr), and I(Ks); and shifts the activation of I(Kr) to more negative potentials and increases the rate of its deactivation. ISO has also been reported to increase the intracellular Ca(2+) transient, which can contribute to chronotropy by modulating the "Ca(2+) clock." The aim of this study was to analyze the ionic mechanisms underlying the positive chronotropy of ß-adrenergic stimulation using two distinct and well established computational models of the electrical activity of rabbit SAN cells. METHODS AND RESULTS: We modified the Boyett et al. (2001) and Kurata et al. (2008) models of electrical activity for the central and peripheral rabbit SAN cells by incorporating equations for the known dose-dependent actions of ISO on various ionic channel currents (I(CaL), I(st), I(Kr), and I(Ks)), kinetics of I(Kr) and I(f), and the intracellular Ca(2+) transient. These equations were constructed from experimental data. To investigate the ionic basis of the effects of ISO, we simulated the chronotropic effect of a range of ISO concentrations when ISO exerted all its actions or just a subset of them. CONCLUSION: In both the Boyett et al. and Kurata et al. SAN models, the chronotropic effect of ISO was found to result from an integrated action of ISO on I(CaL), I(f), I(st), I(Kr), and I(Ks), among which an increase in the rate of deactivation of I(Kr) plays a prominent role, though the effect of ISO on I(f) and [Ca(2+)](i) also plays a role.

Virtual tissue engineering of the human atrium: modelling pharmacological actions on atrial arrhythmogenesis.

Computational models of human atrial cells, tissues and atria have been developed. Cell models, for atrial wall, crista terminalis, appendage, Bachmann's bundle and pectinate myocytes are characterised by action potentials, ionic currents and action potential duration (APD) restitution. The principal effect of the ion channel remodelling of persistent atrial fibrillation (AF), and a mutation producing familial AF, was APD shortening at all rates. Electrical alternans was abolished by the modelled action of Dronedarone. AF induced gap junctional remodelling slows propagation velocity at all rates. Re-entrant spiral waves in 2-D models are characterised by their frequency, wavelength, meander and stability. For homogenous models of normal tissue, spiral waves self-terminate, due to meander to inexcitable boundaries, and by dissipation of excitation. AF electrical remodelling in these homogenous models led to persistence of spiral waves, and AF fibrotic remodelling to their breakdown into fibrillatory activity. An anatomical model of the atria was partially validated by the activation times of normal sinus rhythm. The use of tissue geometry from clinical MRI, and tissue anisotropy from ex vivo diffusion tensor magnetic resonance imaging is outlined. In the homogenous model of normal atria, a single scroll breaks down onto spatio-temporal irregularity (electrical fibrillation) that is self-terminating; while in the AF remodelled atria the fibrillatory activity is persistent. The persistence of electrical AF can be dissected in the model in terms of ion channel and intercellular coupling processes, that can be modified pharmacologically; the effects of anatomy, that can be modified by ablation; and the permanent effects of fibrosis, that need to be prevented.