Abstract:

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.

Abstract:

During the contraction of the ventricles, the ventricles interact with the atria as well as with the pericardium and the surrounding tissue in which the heart is embedded. The atria are stretched, and the atrioventricular plane moves toward the apex. The atrioventricular plane displacement (AVPD) is considered to be a major contributor to the ventricular function, and a reduced AVPD is strongly related to heart failure. At the same time, the epicardium slides almost frictionlessly on the pericardium with permanent contact. Although the interaction between the ventricles, the atria and the pericardium plays an important role for the deformation of the heart, this aspect is usually not considered in computational models. In this work, we present an electromechanical model of the heart, which takes into account the interaction between ventricles, pericardium and atria and allows to reproduce the AVPD. To solve the contact problem of epicardium and pericardium, a contact handling algorithm based on penalty formulation was developed, which ensures frictionless and permanent contact. Two simulations of the ventricular contraction were conducted, one with contact handling of pericardium and heart and one without. In the simulation with contact handling, the atria were stretched during the contraction of the ventricles, while, due to the permanent contact with the pericardium, their volume increased. In contrast to that, in the simulations without pericardium, the atria were also stretched, but the change in the atrial volume was much smaller. Furthermore, the pericardium reduced the radial contraction of the ventricles and at the same time increased the AVPD.

Abstract:

Radiofrequency ablation (RFA) therapy is the gold standard in interventional treatment of many cardiac arrhythmias. A major obstacle are non transmural lesions, leading to recurrence of arrhythmias. Recent clinical studies have suggested intracardiac electrogram (EGM) criteria as a promising marker to evaluate lesion development. Seeking for a deeper understanding of underlying mechanisms, we established a simulation approach for acute RFA lesions. Ablation lesions were modeled by a passive necrotic core surrounded by a borderzone with properties of heated myocardium. Herein, conduction velocity and electrophysiological properties were altered. We simulated EGMs during RFA to study the relation between lesion formation and EGM changes using the bidomain model. Simulations were performed on a three dimensional setup including a geometrically detailed representation of the catheter with highly conductive electrodes. For validation, EGMs recorded during RFA procedures in five patients were analyzed and compared to simulation results. Clinical data showed major changes in the distal unipolar EGM. During RFA, the negative peak amplitude decreased up to 104% and maximum negative deflection was up to 88% smaller at the end of the ablation sequence. These changes mainly occurred in the first 10 s after ablation onset. Simulated unipolar EGM reproduced the clinical changes, reaching up to 83% negative peak amplitude reduction and 80% decrease in maximum negative deflection for transmural lesions. In future work, the established model may enable the development of further EGM criteria for transmural lesions even for complex geometries in order to support clinical therapy.

Abstract:

Chronic atrial fibrillation (AF) is a complex disease with underlying changes in electrophysiology, calcium signaling and the structure of atrial myocytes. How these individual remodeling targets and their emergent interactions contribute to cell physiology in chronic AF is not well understood. To approach this problem, we performed in silico experiments in a computational model of the human atrial myocyte. The remodeled function of cellular components was based on a broad literature review of in vitro findings in chronic AF, and these were integrated into the model to define a cohort of virtual cells. Simulation results indicate that while the altered function of calcium and potassium ion channels alone causes a pronounced decrease in action potential duration, remodeling of intracellular calcium handling also has a substantial impact on the chronic AF phenotype. We additionally found that the reduction in amplitude of the calcium transient in chronic AF as compared to normal sinus rhythm is primarily due to the remodeling of calcium channel function, calcium handling and cellular geometry. Finally, we found that decreased electrical resistance of the membrane together with remodeled calcium handling synergistically decreased cellular excitability and the subsequent inducibility of repolarization abnormalities in the human atrial myocyte in chronic AF. We conclude that the presented results highlight the complexity of both intrinsic cellular interactions and emergent properties of human atrial myocytes in chronic AF. Therefore, reversing remodeling for a single remodeled component does little to restore the normal sinus rhythm phenotype. These findings may have important implications for developing novel therapeutic approaches for chronic AF.

Abstract:

Left atrial fibrosis is thought to contribute to the manifestation of atrial fibrillation (AF). Late Gadolinium enhancement (LGE) MRI has the potential to image regions of low perfusion, which can be related to fibrosis. We show that a simulation with a patient-specific model including left atrial regional fibrosis derived from LGE-MRI reproduces local activation in the left atrium more precisely than the regular simulation without fibrosis. AF simulations showed a spontaneous termination of the arrhythmia in the absence of fibrosis and a stable rotor center in the presence of fibrosis. The methodology may provide a tool for a deeper understanding of the mechanisms maintaining AF and eventually also for the planning of substrate-guided ablation procedures in the future.

Abstract:

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.

Abstract:

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.

Abstract:

BACKGROUND: Investigations on adverse biological effects of nanoparticles (NPs) in the lung by in vitro studies are usually performed under submerged conditions where NPs are suspended in cell culture media. However, the behaviour of nanoparticles such as agglomeration and sedimentation in such complex suspensions is difficult to control and hence the deposited cellular dose often remains unknown. Moreover, the cellular responses to NPs under submerged culture conditions might differ from those observed at physiological settings at the air-liquid interface. RESULTS: In order to avoid problems because of an altered behaviour of the nanoparticles in cell culture medium and to mimic a more realistic situation relevant for inhalation, human A549 lung epithelial cells were exposed to aerosols at the air-liquid interphase (ALI) by using the ALI deposition apparatus (ALIDA). The application of an electrostatic field allowed for particle deposition efficiencies that were higher by a factor of more than 20 compared to the unmodified VITROCELL deposition system. We studied two different amorphous silica nanoparticles (particles produced by flame synthesis and particles produced in suspension by the Stober method). Aerosols with well-defined particle sizes and concentrations were generated by using a commercial electrospray generator or an atomizer. Only the electrospray method allowed for the generation of an aerosol containing monodisperse NPs. However, the deposited mass and surface dose of the particles was too low to induce cellular responses. Therefore, we generated the aerosol with an atomizer which supplied agglomerates and thus allowed a particle deposition with a three orders of magnitude higher mass and of surface doses on lung cells that induced significant biological effects. The deposited dose was estimated and independently validated by measurements using either transmission electron microscopy or, in case of labelled NPs, by fluorescence analyses. Surprisingly, cells exposed at the ALI were less sensitive to silica NPs as evidenced by reduced cytotoxicity and inflammatory responses. CONCLUSION: Amorphous silica NPs induced qualitatively similar cellular responses under submerged conditions and at the ALI. However, submerged exposure to NPs triggers stronger effects at much lower cellular doses. Hence, more studies are warranted to decipher whether cells at the ALI are in general less vulnerable to NPs or specific NPs show different activities dependent on the exposure method.

Abstract:

Orientations of myocytes impact electric excitation propagation and mechanical contraction in the human heart. Measured fiber angles in experiments are obtained from different species (e. g. rat, canine, dog, human heart) and vary by various reasons. It is unclear to what ex- tent non-exact fiber angles impact the quality of computa- tional simulations. In this paper, mechanical simulations with different ventricular angles were performed and com- pared. The simulations covered the complete heart with both ventricles, both atria and the pericardium and were performed using finite element method. Helix angles were varied between 20\0 and 70\0 on endocardium and \070\0 and \020\0 on epicardium. Results showed that fiber ori- entations had only a minor contribution to the difference between endsystolic and enddiastolic pressure of < 8.3 %. The influence on stroke volume as well as AVPD is sig- nificant (changes by 34 % for SV and 241 % for APVD) , but it could not be observed that a higher AVPD yields a higher stroke volume. Concludingly, fiber orientations are important for reliable computational simulations of human hearts and should be incorporated with great care.

Abstract:

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 (&#63743;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.

Abstract:

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.

Abstract:

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).

Abstract:

Fibrosis is strongly linked with the mechanisms of atrial fibrillation (AF), the most common arrhythmia. Direct electrotonic coupling between atrial myocytes and fibroblast has been suggested to contribute to these mechanisms. We use a 3D biophysical model of the atria to study the effects of fibrosis on atrial electrophysiology. Realistic tissue geometry, regional heterogeneity and myofiber anisotropy are integrated in the model. The model also accounts for the effects AF induced ionic remodeling, which has been shown to promote AF. The model simulations demonstrated that fibrosis significantly reduced both the atrial conduction velocity and action potential duration. Both these factors contributed to a large (45%) reduction of the atrial activation wavelength. This is comparable with the wavelength reduction (65%) due to ionic remodeling. As a result, the sustenance of re- entrant waves in the 3D atria was substantially increased with both fibrosis and remodeling. Hence, the elecrotonic changes induced by fibrosis can be comparable to those due to ionic remodeling, and both factors can provide substrate for re-entry in the 3D atria model.

Abstract:

There is still a need for research to understand the co- herences of the origin of arrhythmias such like rotors and possible ablation strategies. The aim of this work was the analysis of typical signal characteristics near a rotor cen- ter. Rotors were simulated on 2D patch geometry (100 mm x 100 mm) with spatial resolution of 0.1mm. Based on extracellular potentials, different features were evalu- ated: Local activation time, peak to peak amplitude, steep- est negative slope and approximate entropy were com- pared regarding their ability to indicate the rotor tip lo- cation. Furthermore, typical signal patterns of different mapping catheters centered at the rotor tip position were analyzed. The determined maximum distances between the focal point of phase singularities and determined centers by the peak to peak amplitudes were maximal 1.7 mm.