Influence of I(Ks) heterogeneities on the genesis of the T-wave: a computational evaluation.

Despite the commonly accepted notion that action potential duration (APD) is distributed heterogeneously throughout the ventricles and that the associated dispersion of repolarization is mainly responsible for the shape of the T-wave, its concordance and exact morphology are still not completely understood. This paper evaluated the T-waves for different previously measured heterogeneous ion channel distributions. To this end, cardiac activation and repolarization was simulated on a high resolution and anisotropic biventricular model of a volunteer. From the same volunteer, multichannel ECG data were obtained. Resulting transmembrane voltage distributions for the previously measured heterogeneous ion channel expressions were used to calculate the ECG and the simulated T-wave was compared to the measured ECG for quantitative evaluation. Both exclusively transmural (TM) and exclusively apico-basal (AB) setups produced concordant T-waves, whereas interventricular (IV) heterogeneities led to notched T-wave morphologies. The best match with the measured T-wave was achieved for a purely AB setup with shorter apical APD and a mix of AB and TM heterogeneity with M-cells in midmyocardial position and shorter apical APD. Finally, we probed two configurations in which the APD was negatively correlated with the activation time. In one case, this meant that the repolarization directly followed the sequence of activation. Still, the associated T-waves were concordant albeit of low amplitude.

Modeling of cardiac ischemia in human myocytes and tissue including spatiotemporal electrophysiological variations.

Cardiac tissue exhibits spatially heterogeneous electrophysiological properties. In cardiac diseases, these properties also change in time. This study introduces a framework to investigate their role in cardiac ischemia using mathematical modeling and computational simulations at cellular and tissue level. Ischemia was incorporated by reproducing effects of hyperkalemia, acidosis, and hypoxia with a human electrophysiological model. In tissue, spatial heterogeneous ischemia was described by central ischemic (CIZ) and border zone. Anisotropic conduction was simulated with a bidomain approach in an anatomical ventricle model including realistic fiber orientation and transmural, apico-basal, and interventricular electrophysiological heterogeneities. A model of electrical conductivity in a human torso served for ECG calculations. Ischemia increased resting but reduced peak voltage, action potential duration, and upstroke velocity. These effects were strongest in subepicardial cells. In tissue, conduction velocity decreased towards CIZ but effective refractory period increased. At 10 min of ischemia 19% of subepi- and 100% of subendocardial CIZ cells activated with a delay of 34.6+/-7.8 ms and 55.9+/-18.8 ms, respectively, compared to normal. Significant ST elevation and premature T wave end appeared only with the subepicardial CIZ. The model reproduced effects of ischemia at cellular and tissue level. The results suggest that the presented in silico approach can complement experimental studies, e.g., in understanding the role of ischemia or the onset of arrhythmia.

Deficient zebrafish ether-à-go-go-related gene channel gating causes short-QT syndrome in zebrafish reggae mutants.

BACKGROUND: Genetic predisposition is believed to be responsible for most clinically significant arrhythmias; however, suitable genetic animal models to study disease mechanisms and evaluate new treatment strategies are largely lacking. METHODS AND RESULTS: In search of suitable arrhythmia models, we isolated the zebrafish mutation reggae (reg), which displays clinical features of the malignant human short-QT syndrome such as accelerated cardiac repolarization accompanied by cardiac fibrillation. By positional cloning, we identified the reg mutation that resides within the voltage sensor of the zebrafish ether-à-go-go-related gene (zERG) potassium channel. The mutation causes premature zERG channel activation and defective inactivation, which results in shortened action potential duration and accelerated cardiac repolarization. Genetic and pharmacological inhibition of zERG rescues recessive reg mutant embryos, which confirms the gain-of-function effect of the reg mutation on zERG channel function in vivo. Accordingly, QT intervals in ECGs from heterozygous and homozygous reg mutant adult zebrafish are considerably shorter than in wild-type zebrafish. CONCLUSIONS: With its molecular and pathophysiological concordance to the human arrhythmia syndrome, zebrafish reg represents the first animal model for human short-QT syndrome.

Large scale cardiac modeling on the Blue Gene supercomputer.

Multi-scale, multi-physical heart models have not yet been able to include a high degree of accuracy and resolution with respect to model detail and spatial resolution due to computational limitations of current systems. We propose a framework to compute large scale cardiac models. Decomposition of anatomical data in segments to be distributed on a parallel computer is carried out by optimal recursive bisection (ORB). The algorithm takes into account a computational load parameter which has to be adjusted according to the cell models used. The diffusion term is realized by the monodomain equations. The anatomical data-set was given by both ventricles of the Visible Female data-set in a 0.2 mm resolution. Heterogeneous anisotropy was included in the computation. Model weights as input for the decomposition and load balancing were set to (a) 1 for tissue and 0 for non-tissue elements; (b) 10 for tissue and 1 for non-tissue elements. Scaling results for 512, 1024, 2048, 4096 and 8192 computational nodes were obtained for 10 ms simulation time. The simulations were carried out on an IBM Blue Gene/L parallel computer. A 1 s simulation was then carried out on 2048 nodes for the optimal model load. Load balances did not differ significantly across computational nodes even if the number of data elements distributed to each node differed greatly. Since the ORB algorithm did not take into account computational load due to communication cycles, the speedup is close to optimal for the computation time but not optimal overall due to the communication overhead. However, the simulation times were reduced form 87 minutes on 512 to 11 minutes on 8192 nodes. This work demonstrates that it is possible to run simulations of the presented detailed cardiac model within hours for the simulation of a heart beat.

The influence of fibre orientation, extracted from different segments of the human left ventricle, on the activation and repolarization sequence: a simulation study.

AIMS: This computational study examined the influence of fibre orientation on the electrical processes in the heart. In contrast to similar previous studies, human diffusion tensor magnetic resonance imaging measurements were used. METHODS: The fibre orientation was extracted from distinctive regions of the left ventricle. It was incorporated in a single tissue segment having a fixed geometry. The electrophysiological model applied in the computational units considered transmural heterogeneities. Excitation was computed by means of the monodomain model; the accompanying pseudo-electrocardiograms (ECGs) were calculated. RESULTS: The distribution of fibre orientation extracted from the same transversal section showed only small variations. The fibre information extracted from the equal circumferential but different longitudinal positions showed larger differences, mainly in the imbrication angle. Differences of the endocardial myocyte orientation mainly affected the beginning of the activation sequence. The transmural propagation was faster in areas with larger imbrication angles leading to a narrower QRS complex in pseudo-ECGs. CONCLUSION: The model can be expanded to simulate electrophysiology and contraction in the whole heart geometry. Embedded in a torso model, the impact of fibre orientation on body surface ECGs and their relation to local pseudo-ECGs can be identified.

A framework for modeling of mechano-electrical feedback mechanisms of cardiac myocytes and tissues.

The term cardiac mechano-electrical feedback precis the various phenomena related to modulation of electrophysiology by mechanical deformation of cells and tissues of the heart. The significance of mechano-electrical feedback and the underlying mechanisms are still poorly understood despite intense experimental research. We introduce and discuss a framework for computational modeling and simulation of mechano-electrical feedback at ion channel, cell and tissue level. The framework consists of modules to reconstruct electrical currents through mechano-sensitive ion channels, their effect on myocytes' electrophysiology, strain-modulation of tissue conductivities and electrical conduction in myocyte clusters and myocardium. We applied the framework to study the effect of strain on conduction velocity in papillary muscle. The simulations reconstructed strain-conduction velocity relationships as reported in experimental studies. Furthermore, the computational studies indicated that increased stimulus frequency aggravated the reduction of conduction velocity for larger strains. Mathematical modeling of mechano-electrical feedback will help to integrate experimental data and predict behavior at system level. Computational simulations might give otherwise unavailable insights, particularly with respect to clinical relevance of mechano-electrical feedback.

Computer based modeling of the congenital long-QT 2 syndrome in the Visible Man torso: from genes to ECG.

The congenital long-QT syndrome is commonly associated with a high risk for polymorphic ventricular tachy-cardia and sudden cardiac death. This is probably due to an intensification of the intrinsic heterogeneities present in ventricular myocardium. Increasing the electrophysiological heterogeneities amplifies the dispersion of repolarization which directly affects the morphology of the T wave in the ECG. The aim of this work is to investigate the effects of LQT2, a specific subtype of the long-QT syndrome (LQTS), on the Body Surface Potential Maps (BSPM) and the ECG. In this context a three-dimensional, heterogeneous model of the human ventricles is used to simulate both physiological and pathological excitation propagation. The results are used as input for the forward calculation of the BSPM and ECG. Characteristic QT prolongation is simulated correctly. The main goal of this study is to prepare and evaluate a simulation environment that can be used prospectivley to find features in the ECG or the BSPM that are characteristic for the LQTS. Such features might be used to facilitate the identification of LQTS patients.

Anticholinergic antiparkinson drug orphenadrine inhibits HERG channels: block attenuation by mutations of the pore residues Y652 or F656.

The anticholinergic antiparkinson drug orphenadrine is an antagonist at central and peripheral muscarinic receptors. Orphenadrine intake has recently been linked to QT prolongation and Torsade-de-Pointes tachycardia. So far, inhibitory effects on I (Kr) or cloned HERG channels have not been examined. HERG channels were heterologously expressed in a HEK 293 cell line and in Xenopus oocytes and HERG current was measured using the whole cell patch clamp and the double electrode voltage clamp technique. Orphenadrine inhibits cloned HERG channels in a concentration dependent manner, yielding an IC(50) of 0.85 microM in HEK cells. Onset of block is fast and reversible upon washout. Orphenadrine does not alter the half-maximal activation voltage of HERG channels. There is no shift of the half-maximal steady-state-inactivation voltage. Time constants of direct channel inactivation are not altered significantly and there is no use-dependence of block. HERG blockade is attenuated significantly in mutant channels lacking either of the aromatic pore residues Y652 and F656. In conclusion, we show that the anticholinergic agent orphenadrine is an antagonist at HERG channels. These results provide a novel molecular basis for the reported proarrhythmic side effects of orphenadrine.

Modeling of IK1 mutations in human left ventricular myocytes and tissue.

Elucidation of the cellular basis of arrhythmias in ion channelopathy disorders is complicated by the inherent difficulties in studying human cardiac tissue. Thus we used a computer modeling approach to study the mechanisms of cellular dysfunction induced by mutations in inward rectifier potassium channel (K(ir))2.1 that cause Andersen-Tawil syndrome (ATS). ATS is an autosomal dominant disorder associated with ventricular arrhythmias that uncommonly degenerate into the lethal arrhythmia torsade de pointes. We simulated the cellular and tissue effects of a potent disease-causing mutation D71V K(ir)2.1 with mathematical models of human ventricular myocytes and a bidomain model of transmural conduction. The D71V K(ir)2.1 mutation caused significant action potential duration prolongation in subendocardial, midmyocardial, and subepicardial myocytes but did not significantly increase transmural dispersion of repolarization. Simulations of the D71V mutation at shorter cycle lengths induced stable action potential alternans in midmyocardial, but not subendocardial or subepicardial cells. The action potential alternans was manifested as an abbreviated QRS complex in the transmural ECG, the result of action potential propagation failure in the midmyocardial tissue. In addition, our simulations of D71V mutation recapitulate several key ECG features of ATS, including QT prolongation, T-wave flattening, and QRS widening. Thus our modeling approach faithfully recapitulates several features of ATS and provides a mechanistic explanation for the low frequency of torsade de pointes arrhythmia in ATS.

Modelling of short QT syndrome in a heterogeneous model of the human ventricular wall.

AIMS: A percentage of sudden cardiac death events occur in individuals with structurally normal hearts due to an abnormality in the ion channel activity. While the majority of these hereditary syndromes are well-established, little is known about the significance of the short QT syndrome. METHODS: This study is based on discovered insights into the molecular basis of the originally described form of this disease. A biophysically detailed model of cellular electrophysiology was adapted to emulate the behaviour of cells affected by the short QT syndrome. Simulations were performed in single cell and homogeneous as well as heterogeneous anisotropic multi-cellular environment describing the human left ventricle. RESULTS: The short QT mutation increased the activity of the repolarizing outward potassium current I(Kr). The heterogeneous abbreviation of the action potential duration decreased the dispersion of repolarization in heterogeneous tissue. Repolarization was homogenized and the final repolarization was shifted to epicardial sites. The transmural ECG showed a shortened QT interval and a T wave with reduced amplitude. CONCLUSION: The altered characteristics of the mutant I(Kr) current were consistent with experimental findings. The heterogeneous reduction of the action potential duration and the reduced T wave amplitude need to be verified by measurements.

Quantitative reconstruction of cardiac electromechanics in human myocardium: regional heterogeneity.

INTRODUCTION: Regional heterogeneity of electrophysiologic properties within the human ventricles is based on changes in ion channel kinetics and density inside the wall. The heterogeneity not only influences the electrophysiologic properties but also cellular force development. In this study, the influence of heterogeneity was investigated using mathematical models. METHODS AND RESULTS: An overview of measurements of the heterogeneity of electrophysiology and force development is presented. This knowledge is transferred to an electromechanical heart model composed of a human ionic cell model describing electrophysiologic properties and a model for the development of forces. Heterogeneity is included in the ionic model by changing ion channel kinetics and density. The characteristics and dependencies of the electromechanical model are demonstrated in a single-cell environment and a multicell environment. In the single-cell environment, the effects of heterogeneity on electrical activity are demonstrated. The notch in the action potential decreases from epicardium to endocardium, and action potential duration is longest in the mid-myocardium. The developed forces are largest in the subendocardial cells and decrease continuously toward the epicardium. The multicell environment describes a transmural line of cells in the left ventricular free wall using a bidomain approach. The transmural ECG shows typical characteristics with a positive monophasic T wave. CONCLUSIONS: This work demonstrates the need to incorporate regional heterogeneity in order to model human cardiac electromechanics. The results of electrophysiologic simulations correspond to measured data. The dependencies of regional heterogeneity on force development need to be validated in experiments, because little is known about the influence of heterogeneity on electromechanical coupling.