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.
In case of chest pain, immediate diagnosis of myocardial ischemia is required to respond with an appropriate treatment. The diagnostic capability of the electrocardiogram (ECG), however, is strongly limited for ischemic events that do not lead to ST elevation. This computational study investigates the potential of different electrode setups in detecting early ischemia at 10 minutes after onset: standard 3-channel and 12-lead ECG as well as body surface potential maps (BSPMs). Further, it was assessed if an additional ECG electrode with optimized position or the right-sided Wilson leads can improve sensitivity of the standard 12-lead ECG. To this end, a simulation study was performed for 765 different locations and sizes of ischemia in the left ventricle. Improvements by adding a single, subject specifically optimized electrode were similar to those of the BSPM: 211% increased detection rate depending on the desired specificity. Adding right-sided Wilson leads had negligible effect. Absence of ST deviation could not be related to specific locations of the ischemic region or its transmurality. As alternative to the ST time integral as a feature of ST deviation, the K point deviation was introduced: the baseline deviation at the minimum of the ST-segment envelope signal, which increased 12-lead detection rate by 7% for a reasonable threshold.
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.
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.
A. Loewe, M. Wilhelms, O. Dössel, and G. Seemann. Influence of chronic atrial fibrillation induced remodeling in a computational electrophysiological model. In Biomedizinische Technik / Biomedical Engineering, vol. 59(S1) , pp. S929-S932, 2014
Atrial fibrillation (AF) is a common arrhythmia with progressive nature. This progression is partly caused by AF itself by modifying amongst others the electrophysiological properties of the myocytes. These changes are referred to as electrical remodeling and were integrated in a computational model of human atrial myocytes in this work.In particular, the maximum conductivities of Ito, IK1, IKs, IKur, ICa,L, INa,Ca, and the Ca2+ leak current from the sarcoplasmic reticulum, as well as the cell capacitance were altered. In an additional setup, the influence of potential gap junction remodeling was investigated.Wavelength was reduced from 225 mm to 110 mm, respectively 92 mm when considering gap junction remodeling at a basic cycle length of 400 ms. Action potential morphology was changed from spike-and-dome to a more triangular repolarization phase. However, our results show that including IKur remodeling prevents the plateau phase from disappearing completely.
Y. Lutz, A. Loewe, O. Dössel, and G. Seemann. Specific antiarrhythmic therapy for familial atrial fibrillation in a numerical model of human atrial electrophysiology. In Biomedizinische Technik / Biomedical Engineering, vol. 59(s1) , pp. s933-s936, 2014
Atrial fibrillation (AF) is still a major health problem in the western society. Especially for familial AF, the pharmacological therapy is still not sufficiently successful. In this work, channel blocker properties were in-silico adapted to optimize drug therapy for patients suffering from familial AF. The Courtemanche-Ramirez-Nattel (CRN) cell model was the basis for the simulations. Adaptations in the model due to familial AF were implemented using an existing description of the L532P mutation. A fitting algorithm was designed which adapted all conductivities of the ion channels described in the CRN model to restore the healthy action potential (AP). To find the minimal deviation of the healthy AP and the AP of the L532P mutation, the trust-region-reflective algorithm was used. The best matched APs were achieved by a significant blockade of the IKr and the IKur current. 1D tissue strand simulations were performed using different basic cycle lengths (BCL) to evaluate the results of the optimization. It was shown that for the found adaptation of the conductivities, the AP duration, and the progressions of the conduction velocity, effective refractory period, and wavelength (WL) could be restored. The WL was increased by 53.37% compared to the mutation and had a value of 233.48 mm (BCL = 1 s).
A computer-implemented method for calculating a multi-dimensional wavelet transform in an image processing system comprising a plurality of computation units includes receiving multi-dimensional image data. An overlap value corresponding to a number of non-zero filter coefficients associated with the multi-dimensional wavelet transform is identified. Then the multi-dimensional image data is divided into a plurality of multi-dimensional arrays, wherein the multi-dimensional arrays overlap in each dimension by a number of pixels equal to the overlap value. A multi-dimensional wavelet transform is calculated for each multi-dimensional array, in parallel, across the plurality of computation units
A computer-implemented method for reconstruction of a magnetic resonance image includes acquiring a first incomplete k-space data set comprising a plurality of first k-space lines spaced according to an acceleration factor and one or more calibration lines. A parallel imaging reconstruction technique is applied to the first incomplete k-space data to determine a plurality of second k-space lines not included in the first incomplete k-space data set, thereby yielding a second incomplete k-space data set. Then, the parallel imaging reconstruction technique is applied to the second incomplete k-space data to determine a plurality of third k-space lines not included in the second incomplete k-space data, thereby yielding a complete k-space data set.