Inhibition of the atrial ultra-rapid delayed rectifier potassium current (I Kur) represents a promising therapeutic strategy in the therapy of atrial fibrillation. However, experimental and clinical data on the antiarrhythmic efficacy remain controversial. We tested the hypothesis that antiarrhythmic effects of I Kur inhibitors are dependent on kinetic properties of channel blockade. A mathematical description of I Kur blockade was introduced into Courtemanche-Ramirez-Nattel models of normal and remodeled atrial electrophysiology. Effects of five model compounds with different kinetic properties were analyzed. Although a reduction of dominant frequencies could be observed in two dimensional tissue simulations for all compounds, a reduction of spiral wave activity could be only be detected in two cases. We found that an increase of the percent area of refractory tissue due to a prolongation of the wavelength seems to be particularly important. By automatic tracking of spiral tip movement we find that increased refractoriness resulted in rotor extinction caused by an increased spiral-tip meandering. We show that antiarrhythmic effects of I Kur inhibitors are dependent on kinetic properties of blockade. We find that an increase of the percent area of refractory tissue is the underlying mechanism for an increased spiral-tip meandering, resulting in the extinction of re-entrant circuits.
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 IC50 of 0.85 μM 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
PURPOSE: There is controversy about relevant EEG signal changes indicating adequate or inadequate anaesthesia. Differences of drug-induced and nociceptive mediated signal changes have not been studied in detail. The present study investigates whether signal changes during decreases of depth of anaesthesia due to surgical stimulation depend on different isoflurane concentrations during sufentanil anaesthesia. METHODS: Following IRB approval and written informed consent 28 patients (ASA: I; age 43 +/- 11 y) scheduled for elective abdominal surgery were included in the study. Anaesthesia: propofol (2.0 mg/kg) and sufentanil (1.0 micrograms/kg). Following endotracheal intubation (vecuronium 0.1 mg/kg) patients were normoventilated (P(ET)CO2: 36-38 mmHg). Randomly assigned to steady-state anaesthesia (group 1: P(ET)Isoflurane 0.2%, (14n); group 2: P(ET)Isoflurane 0.6%, (14n) during the start of surgery. Monitoring: heart rate (HF), mean arterial blood pressure (MAP), P(ET)CO2, arterial oxygen saturation and rectal temperature. EEG (16 channels referenced to Cz; CATEEM, Medisyst, Linden) recorded 5 min before until 10 min after the start of surgery. EEG-analysis (FFT: 4s, 256/s, 0.45-35.0 Hz): topographical distribution of power spectral densities (delta, theta, alpha 1, and alpha 2). Artifact control: ECG and EOG. RESULTS: Surgical stimulation resulted in increases of MAP in both groups (p < 0.05 vs BL), whereas HR was only slightly affected in group 2 when compared with BL. Other variables except of EEG data did not change over time. In group 1 (0.2% isoflurane) surgical stimulation resulted in decreases of delta over the whole cortex (F2, C3, P3, O1) and in marked increases of alpha predominantly at central leads (C3)(p < 0.05 vs BL). In group 2 (0.6% isoflurane) nociceptive stimulation was associated with decreases of faster waves (alpha: F3)(p < 0.05 vs BL) and increases in delta at fronto-central areas (F3, C3)(p < 0.05 vs BL). CONCLUSIONS: EEG recordings are useful in assessing pharmacodynamic drug effects. In contrast, intraoperative EEG recordings have a low correlation to clinical signs of changes in the anaesthetic state. Previous studies demonstrate paradoxical EEG-arousal reactions during isoflurane anaesthesia. The present data suggest that classical or even paradoxical EEG arousal due to nociceptive stimulation may depend on the isoflurane concentration. It seems reasonable that the ascending reticular formation is functionally blocked by isoflurane in a dose-dependent manner.
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.
AIMS: The clinical efficacy in preventing the recurrence of atrial fibrillation (AF) is higher for amiodarone than for dronedarone. Moreover, pharmacotherapy with these drugs is less successful in patients with remodelled substrate induced by chronic AF (cAF) and patients suffering from familial AF. To date, the reasons for these phenomena are only incompletely understood. We analyse the effects of the drugs in a computational model of atrial electrophysiology. METHODS AND RESULTS: The Courtemanche-Ramirez-Nattel model was adapted to represent cAF remodelled tissue and hERG mutations N588K and L532P. The pharmacodynamics of amiodarone and dronedarone were investigated with respect to their dose and heart rate dependence by evaluating 10 descriptors of action potential morphology and conduction properties. An arrhythmia score was computed based on a subset of these biomarkers and analysed regarding circadian variation of drug concentration and heart rate. Action potential alternans at high frequencies was observed over the whole dronedarone concentration range at high frequencies, while amiodarone caused alternans only in a narrow range. The total score of dronedarone reached critical values in most of the investigated dynamic scenarios, while amiodarone caused only minor score oscillations. Compared with the other substrates, cAF showed significantly different characteristics resulting in a lower amiodarone but higher dronedarone concentration yielding the lowest score. CONCLUSION: Significant differences exist in the frequency and concentration-dependent effects between amiodarone and dronedarone and between different atrial substrates. Our results provide possible explanations for the superior efficacy of amiodarone and may aid in the design of substrate-specific pharmacotherapy for AF.
AIMS: Human ether-a-go-go-related gene (hERG) missense mutations N588K and L532P are both associated with atrial fibrillation (AF). However, the underlying gain-of-function mechanism is different. The aim of this computational study is to assess and understand the arrhythmogenic mechanisms of these genetic disorders on the cellular and tissue level as a basis for the improvement of therapeutic strategies. METHODS AND RESULTS: The IKr formulation of an established model of human atrial myocytes was adapted by using the measurement data of wild-type and mutant hERG channels. Restitution curves of the action potential duration and its slope, effective refractory period (ERP), conduction velocity, reentry wavelength (WL), and the vulnerable window (VW) were determined in a one-dimensional (1D) tissue strand. Moreover, spiral wave inducibility and rotor lifetime in a 2D tissue patch were evaluated. The two mutations caused an increase in IKr regarding both peak amplitude and current integral, whereas the duration during which IKr is active was decreased. The WL was reduced due to a shorter ERP. Spiral waves could be initiated by using mutation models as opposed to the control case. The frequency dependency of the VW was reversed. CONCLUSION: Both mutations showed an increased arrhythmogenicity due to decreased refractory time in combination with a more linear repolarization phase. The effects were more pronounced for mutation L532P than for N588K. Furthermore, spiral waves presented higher stability and a more regular pattern for L532P. These in silico investigations unveiling differences of mutations affecting the same ion channel may help to advance genotype-guided AF prevention and therapy strategies.
Computational models of cardiac electrophysiology provided insights into arrhythmogenesis and paved the way toward tailored therapies in the last years. To fully leverage in silico models in future research, these models need to be adapted to reflect pathologies, genetic alterations, or pharmacological effects, however. A common approach is to leave the structure of established models unaltered and estimate the values of a set of parameters. Today's high-throughput patch clamp data acquisition methods require robust, unsupervised algorithms that estimate parameters both accurately and reliably. In this work, two classes of optimization approaches are evaluated: gradient-based trust-region-reflective and derivative-free particle swarm algorithms. Using synthetic input data and different ion current formulations from the Courtemanche et al. electrophysiological model of human atrial myocytes, we show that neither of the two schemes alone succeeds to meet all requirements. Sequential combination of the two algorithms did improve the performance to some extent but not satisfactorily. Thus, we propose a novel hybrid approach coupling the two algorithms in each iteration. This hybrid approach yielded very accurate estimates with minimal dependency on the initial guess using synthetic input data for which a ground truth parameter set exists. When applied to measured data, the hybrid approach yielded the best fit, again with minimal variation. Using the proposed algorithm, a single run is sufficient to estimate the parameters. The degree of superiority over the other investigated algorithms in terms of accuracy and robustness depended on the type of current. In contrast to the non-hybrid approaches, the proposed method proved to be optimal for data of arbitrary signal to noise ratio. The hybrid algorithm proposed in this work provides an important tool to integrate experimental data into computational models both accurately and robustly allowing to assess the often non-intuitive consequences of ion channel-level changes on higher levels of integration.
BACKGROUND AND PURPOSE: Atomoxetine is a selective noradrenaline reuptake inhibitor, recently approved for the treatment of attention-deficit/hyperactivity disorder. So far, atomoxetine has been shown to be well tolerated, and cardiovascular effects were found to be negligible. However, two independent cases of QT interval prolongation, associated with atomoxetine overdose, have been reported recently. We therefore analysed acute and subacute effects of atomoxetine on cloned human Ether-a-Go-Go-Related Gene (hERG) channels. EXPERIMENTAL APPROACH: hERG channels were heterologously expressed in Xenopus oocytes and in a human embryonic kidney cell line and hERG currents were measured using voltage clamp and patch clamp techniques. Action potential recordings were made in isolated guinea-pig cardiomyocytes. Gene expression and channel surface expression were analysed using quantitative reverse transcriptase polymerase chain reaction, Western blot and the patch clamp techniques. KEY RESULTS: In human embryonic kidney cells, atomoxetine inhibited hERG current with an IC(50) of 6.3 micromol.L(-1). Development of block and washout were fast. Channel activation and inactivation were not affected. Inhibition was state-dependent, suggesting an open channel block. No use-dependence was observed. Inhibitory effects of atomoxetine were attenuated in the pore mutants Y652A and F656A. In guinea-pig cardiomyocytes, atomoxetine lengthened action potential duration without inducing action potential triangulation. Overnight incubation with high atomoxetine concentrations resulted in a decrease of channel surface expression. CONCLUSIONS AND IMPLICATIONS: Whereas subacute effects of atomoxetine seem negligible under therapeutically relevant concentrations, hERG channel block should be considered in cases of atomoxetine overdose and when administering atomoxetine to patients at increased risk for the development of acquired long-QT syndrome.
Aims Amiodarone and cisapride are both known to prolong the QT interval, yet the two drugs have different effects on arrhythmia. Cisapride can cause torsades de pointes while amiodarone is found to be anti-arrhythmic. A computational model was used to investigate the action of these two drugs.Methods and results In a biophysically detailed model, the ion current conductivities affected by both drugs were reduced in order to simulate the pharmacological effects in healthy and ischaemic cells. Furthermore, restitution curves of the action potential duration (APD), effective refractory period, conduction velocity, wavelength, and the vulnerable window were determined in a one-dimensional (1D) tissue strand. Moreover, cardiac excitation propagation was computed in a 3D model of healthy ventricles. The corresponding body surface potentials were calculated and standard 12-lead electrocardiograms were derived. Both cisapride and amiodarone caused a prolongation of the QT interval and the refractory period. However, cisapride did not significantly alter the conduction-related properties, such as e.g. the wavelength or vulnerable window, whereas amiodarone had a larger impact on them. It slightly flattened the APD restitution slope and furthermore reduced the conduction velocity and wavelength.Conclusion Both drugs show similar prolongation of the QT interval, although they present different electrophysiological properties in the single-cell as well as in tissue simulations of cardiac excitation propagation. These computer simulations help to better understand the underlying mechanisms responsible for the initiation or termination of arrhythmias caused by amiodarone and cisapride.
Book Chapters (1)
M. Daumer, W. Nahm, M. Scholz, and F. Danneger. Online Monitoring mit virtuellen Instrumenten. In Virtuelle Instrumente in der Praxis - Meßtechnik, R. Jamal, H. Jaschinski (eds), VDE-Verlag, pp. 265-270, 1998
Conference Contributions (16)
P. Carrillo, G. Seemann, E. Scholz, D. L. Weiss, and O. Dössel. Impact of the hERG Channel Mutation N588K on the Electrical Properties of the Human Atrium. In 4th European Conference of the International Federation for Medical and Biological Engineering, IFMBE Proc., vol. 22(22) , pp. 2583-2586, 2009
Atrial fibrillation is the most common cardiac arrhythmia in humans. The precise cellular mechanisms underlying atrial fibrillation are still poorly understood. Recent studies have identified several genetic defects as predisposing factors for this pathology. One of the identified genetic defects is the mutation N588K, which affects the cardiac IKr channel. Genetic variants in this channel have been identified to modify ventricular repolarization. The aim of this work is to investigate the effect of this mutation on atrial repolarization and the predisposition to atrial fibrillation.Measured data obtained with whole cell voltage clamp technique of wild-type and mutated hERG channel were implemented in the Courtemanche et al. ionic model. For this purpose, channel kinetics and density of the model were adjusted using parameter fitting to the measured data. By this way, the effects of the mutation in the hERG channel could be analyzed in the whole cell and in tissue, as well. The channel mutation N588K showed a gain of function effect, causing a rapid repolarization and consequently, a shortening of the action potential duration. Computer simulations of a schematic anatomical model of the right atrium were then carried out to investigate the excitation propagation and the repolarization.The action potential duration of the mutant cell was reduced to 116 ms and the effective refractory period to 220 ms. Both factors are linked to a shortening of the wavelength, indicating that the mutation N588K predisposes the initiation and perpetuation of atrial fibrillation.
M. Daumer, W. Nahm, M. Scholz, F. Dannegger, G. Morfill, E. Kochs, and A. Neiss. Konzept für eine Internet-basierte Datenbank zur Unterstützung von Projekten auf dem Gebiet der Biosignalanalys - Concept for an internet-based databank for supporting projects in the area of biosignal analysis. In Biomedizinische Technik. Biomedical Engineering, vol. 43 s3, pp. 23-26, 1998
Pharmacological therapy of atrial fibrillation (AF) is still a major clinical challenge. Particularly AF of early onset has a significant familiar component and was asso- ciated with various gene mutations. In this study, we de- signed and optimized antiarrhythmic agents for atrial sub- strates affected by human ether-a`-go-go-related gene mu- tations L532P and N588K. A virtual multichannel blocker was designed aiming at a restoration of the wild-type (WT) action potential (AP) on the single cell and tissue level. Furthermore, the amiodarone and dronedarone concen- trations yielding the smallest difference between WT and mutated APs were identified. The WT AP at a basic cy- cle length (BCL) of 1000 ms could be restored by signifi- cant block of IK r and IK ur (\039%) and less pronounced block of IKs, ICa,L, Ib,Na, and Ib,Ca (17%) for both mutations. Effective dronedarone concentrations of 88 nM for L532P and 40 nM for N588K yielded matches almost as good while amiodarone could not sufficiently restore the WT AP. APD90 restitution was effectively restored by the tuned N588K agent whereas differences of up to 34 ms were observed for low BCLs using the tuned L532P agent. Our results provide insight into the pharmacodynamic re- sponse of mutated myocytes and may aid in the optimiza- tion of patient group-specific therapeutic approaches.
The clinical efficacy in preventing the recurrence of atrial fibrillation (AF) is higher for amiodarone than for dronedarone. Moreover, pharmacotherapy with these drugs is less successful in patients with remodeled substrate induced by chronic AF (cAF) and patients suffering from familial AF. To date, the reasons for these phenomena are only incompletely understood. We analyzed the effects of these two drugs in a computational model of atrial electrophysiology. The Courtemanche-Ramirez-Nattel model was adapted to represent cAF remodeled tissue and hERG mutations N588K and L532P. The pharmacodynamics of amiodarone and dronedarone were investigated with respect to their dose and heart rate dependence by evaluating 10 descriptors of action potential morphology and conduction properties. An arrhythmia score was computed based on a subset of these biomarkers and analyzed regarding circadian variation of drug concentration and heart rate. Action potential alternans at high frequencies was observed over the whole dronedarone concentration range at high frequencies, while amiodarone caused alternans only in a narrow range. The total score of dronedarone reached critical values in most of the investigated dynamic scenarios, while amiodarone caused only minor score oscillations. Compared with the other substrates, cAF showed significantly different characteristics resulting in a lower amiodarone but higher dronedarone concentration yielding the lowest score. Significant differences exist in the frequency and concentration-dependent effects between amiodarone and dronedarone and between different atrial substrates. Our results provide possible explanations for the superior efficacy of amiodarone and may aid in the design of substrate-specific pharmacotherapy for AF.
While human ether-à-go-go-related gene (hERG) mutations N588K and K897T are associated with atrial fib- rillation (AF), the underlying arrhythmogenic mechanisms are understood only incompletely. In this work, an ap- proach integrating IKr measurement data from transgenic Xenopus oocytes into established computational models of cardiac electrophysiology is presented. Parameters are es- timated using a minimization formulation, which is handled by a hybrid particle swarm optimization (PSO) and trust- region-reflective (TRR) algorithm. Cell models adapted to the mutation measurements show a significantly shorter ac- tion potential (AP) with less pronounced spike-and-dome morphology. Results of single cell simulations compare with myocytes in chronic AF.
A. Loewe, Y. Xu, E. P. Scholz, O. Dössel, and G. Seemann. Understanding the cellular mode of action of vernakalant using a computational model: answers and new questions. In Current Directions in Biomedical Engineering, vol. 1(1) , pp. 418422, 2015
Vernakalant is a new antiarrhythmic agent for the treatment of atrial fibrillation. While it has proven to be effective in a large share of patients in clinical studies, its underlying mode of action is not fully understood. In this work, we aim to link experimental data from the subcellular, tissue, and system level using an in-silico approach. A Hills equation-based drug model was extended to cover the frequency dependence of sodium channel block. Two model variants were investigated: M1 based on subcellular data and M2 based on tissue level data. 6 action potential (AP) markers were evaluated regarding their dose, frequency and substrate dependence. M1 comprising potassium, sodium, and calcium channel block reproduced the reported prolongation of the refractory period. M2 not including the effects on potassium channels reproduced reported AP morphology changes on the other hand. The experimentally observed increase of ERP accompanied by a shortening of APD90 was not reproduced. Thus, explanations for the drug-induced changes are provided while none of the models can explain the effects in their entirety. These results foster the understanding of vernakalants cellular mode of action and point out relevant gaps in our current knowledge to be addressed in future in-silico and experimental research on this aspiring antiarrhythmic agent.
Congenital Long-QT Syndrome (LQTS) is a genetic dis- order affecting the repolarization of the heart. The most prevalent subtypes of LQTS are LQT1-3. In this work, we aim to evaluate the differences in the T-waves of simu- lated LQT1-3 in order to identify markers in the ECG that might help to classify patients solely based on ECG mea- surements. For LQT1, mutation S277L was used to char- acterize IKs and mutation S818L in IKr for LQT2. Volt- age clamp data were used to parametrize the ion channel equations of the ten Tusscher and Panfilov model of hu- man ventricular electrophysiology. LQT3 was integrated using an existing mutant INa model. The monodomain model was used in a transmural and apico-basal heteroge- neous model of the ventricles to calculate ventricular exci- tation propagation. The forward calculation on a torso model was performed to determine body surface ECGs. Compared to the physiological case with a QT-time of 375 ms, this interval was prolonged in all LQTS (LQT1 423 ms; LQT2 394 ms; LQT3 405 ms). The T-wave ampli- tude was changed (Einthoven lead II: LQT1 108%; LQT2 91%; LQT3 103%). Also, the width of the T-wave was en- larged (full width at half maximum: LQT1 111%; LQT2 125%; LQT3 109%). At the current state of modeling and data analysis, the three LQTS have not been distinguish- able solely by ECG data.
Atrial fibrillation (AF) is the most common cardiac arrhythmia in the western world. Genetic variants in the cardiac I Kr channel have been identified to influence ventricular repolarization. The aim of this work is to investigate the effect of the mutation N588K on atrial repolarization and the predisposition to AF. Experimental data of N588K mutated hERG channel were incorporated in an atrial ionic model using parameter fitting. The effects of the mutation were analyzed in cell and tissue. N588K showed a gain of function effect, causing a rapid repolarization and a shortening of the action potential duration. Computer simulations of a schematic right atrial geometry were used to investigate the excitation conduction properties. The effective refractory period of mutant cells were reduced from 317 to 233 ms at 1 Hz. The conduction velocity is not significantly influenced by the mutation. Nevertheless, the wavelength of mutant cells is for all frequencies smaller, indicating that the mutation N588K predisposes the initiation and perpetuation of AF.
Atrial fibrillation (AF) is a common pathology. AF modifies the electrophysiological properties of cells (remodeling) promoting the occurrence and maintenance of AF.Electrical remodeling includes changes in ICa,L, Ito, IK1 and IK,ACh. These effects were integrated in a human atrial computer model. Gap junction remodeling was considered in the conductivity of the monodomain equation calculating excitation. Specific features were calculated to determine the risk of AF initiation and perpetuation.ERP was reduced from 330ms to 103ms. CV was lowered from 755mm/s to 608mm/s. The WL reduction was even higher (from 249mm to 63mm) leading to a higher probability of occurrence and maintenance of AF. A maximum of 7 spirals waves were initiated leading to a peak in the power spectrum at 10.32Hz.The computer model underlines the relevance of remodeling in AF chronification. The results add to the knowledge of AF maintenance. Our model might prove to be a tool for the development of novel therapeutic strategies.
Electrophysiological modeling of the heart enable quantitative description of electrical processes during normal and abnormal excitation. Cell models describe e.g. the properties of the cell membrane and the gating process of ionic channels. New measurement data is available for these channels for physiological and some pathological states. These data should be included in the models to enhance their features. In this work we describe a framework adapting ion channel models to measurement data by using a particle swarm optimization (PSO). Models of ion channels can be described by Hogdkin-Huxley equations or by Markovian models. They consider rate constants that are complex functions depending on the transmembrane voltage. Each transition has two rate constants described by several parameters. These parameters need to be varied in order to minimize the difference between measured and simulated ion channel kinetics. Since this minimization procedure is multidimensional and the function can have several local minima, conventional optimization strategies like Powells algorithm and conjugate gradient do not ensure to find the global minimum. To overcome this, a PSO was implemented that inserts several dependent particles randomly into the search space. It is based on the social behavior of swarms. As the particles are independent during each iteration the procedure can be calculated in parallel. The measurement data used for this work were current traces of a voltage-clamp protocol of reggae mutant hERG channels. The same protocol as for the measurement was assigned to the model of Lu et al. describing hERG function with a Markovian model. The value to be minimized was the sum of mean square errors between measured and simulated currents at certain time instances. Both Powell and PSO were started several times with random starting values. In 94% of the cases PSO found the minimum compared to 16% for Powell. On the other hand PSO needed approximately 100 times more function evaluations. The parallelization decreased the overall time needed by the PSO to about the same amount Powell needed. Therefore, the parallel PSO is a fast and reliable approach for adapting ion channel models to measured data.
The sinus node (SN) is the primary pacemaker of the heart. It is a heterogeneous structure in the right atrium composed of two types of cells with different electrophysiological properties. One type is distributed more densely in the periphery the other in the center. Different gap junction types and densities exist leading to a heterogeneity in conduction. It is supposed that this complex interplay of heterogeneities is the basic mechanism that the small SN is able to electrically drive the surrounding atrial muscle. If this interplay is disturbed, the function of the SN can be effected massively. In this simulation study we want to demonstrate the effects of the L532P mutation in hERG called reggae on SN electrophysiology.Mutant hERG channels were expressed in xenopus oocytes and the channel properties were measured with voltage-clamp technique. The data showed mainly a shift of the steady-state inactivation to more positive potentials. This leads to an increase of the ionic current during the depolarized phase. The data was integrated in the heterogeneous rabbit SN model of Zhang et al. by adapting the parameters of the IKr channel with aid of optimization methods using the same stimulation protocol as in the measurements.The most sensitive parameter was the shift voltage of the steady-state inactivation from -19.2 mV in the physiological case to 10.1 mV in the mutant model. When inserting this mutant IKr in the central SN model the ability of the central cells to depolarize spontaneously was eliminated. Peripheral cell still beat but are affected by the mutation. The slope of the pre-potential and the upstroke velocity were not changed. The maximum diastolic potential was increased by 2 mV and the maximum systolic potential decreased by 1.5 mV. The diastolic interval was shortened slightly by 3 ms. The main effect was a reduction of the action potential duration from 108 ms to 84 ms leading to a frequency increase from 6.37 Hz to 7.62 Hz.These effects lead to a changing SN function. The increase of the shift voltage is in good agreement with the measured changes. Especially the loss of auto-rhythmicity in the central zone is expected to change the overall SN activity. Although peripheral SN cells beat faster we expect a bradycardial function of the complete SN because of electrotonic interactions with the silent central SN cells and the low resting membrane voltage of surrounding atrial muscle cells. In a further study this suggestion has to be investigated in an anisotropic and heterogeneous 3D model.
Generally, models of cardiac electrophysiology describe physiologic conditions in detail. However, other conditions, such as drug interactions or mutations of ion channels are of interest for research. Therefore, the simulated ion currents have to be fitted to measured voltage or patch clamp data. In this work, three different methods for the model parametrization were compared: one based on Powells algorithm implemented in a modular C++ framework and two optimization techniques realized in Matlab. The latter two approaches differed in solving the ordinary differential equations describing the channel gating. They can either be approximated numerically or solved analytically, since the transmembrane voltage is a piecewise constant function during the applied clamp protocol. All three methods were compared regarding computing time and quality of the fit using least squares. The modular C++ framework was slower than the numerical Matlab method, which took longer than the analytical one. The quality of the fit was similar for almost all analyzed methods. Therefore, the analytical method grants a fast and reliable solution for the calibration of ion current models for applications with constant membrane voltage, as e.g. in case of voltage or patch clamp data.