Abstract:

The interaction of spiral waves of excitation with atrial anatomy remains unclear. This simulation study isolates the role of atrial anatomical structures on spiral wave spontaneous drift in the human atrium. We implemented realistic and idealised 3D human atria models to investigate the functional impact of anatomical structures on the long-term ( approximately 40 s) behaviour of spiral waves. The drift of a spiral wave was quantified by tracing its tip trajectory, which was correlated to atrial anatomical features. The interaction of spiral waves with the following idealised geometries was investigated: (a) a wedge-like structure with a continuously varying atrial wall thickness; (b) a ridge-like structure with a sudden change in atrial wall thickness; (c) multiple bridge-like structures consisting of a bridge connected to the atrial wall. Spiral waves drifted from thicker to thinner regions and along ridge-like structures. Breakthrough patterns caused by pectinate muscles (PM) bridges were also observed, albeit infrequently. Apparent anchoring close to PM-atrial wall junctions was observed. These observations were similar in both the realistic and the idealised models. We conclude that spatially altering atrial wall thickness is a significant cause of drift of spiral waves. PM bridges cause breakthrough patterns and induce transient anchoring of spiral waves.

Abstract:

Models of cardiac mechanics are increasingly used to investigate cardiac physiology. These models are characterized by a high level of complexity, including the particular anisotropic material properties of biological tissue and the actively contracting material. A large number of independent simulation codes have been developed, but a consistent way of verifying the accuracy and replicability of simulations is lacking. To aid in the verification of current and future cardiac mechanics solvers, this study provides three benchmark problems for cardiac mechanics. These benchmark problems test the ability to accurately simulate pressure-type forces that depend on the deformed objects geometry, anisotropic and spatially varying material properties similar to those seen in the left ventricle and active contractile forces. The benchmark was solved by 11 different groups to generate consensus solutions, with typical differences in higher-resolution solutions at approximately 0.5%, and consistent results between linear, quadratic and cubic finite elements as well as different approaches to simulating incompressible materials. Online tools and solutions are made available to allow these tests to be effectively used in verification of future cardiac mechanics software.

Abstract:

Atrial fibrillation (AF) is the most common arrhythmia of the heart in industrialized countries. Its generation and the transitory behavior of paroxysmal AF are still not well understood. In this work we examine the interaction of two activation sources via an isthmus as possible cause for the initiation of fibrillation episodes. For this study, the electrophysiological model of Bueno-Orovio, Cherry and Fenton is adapted to atrial electrophysiology, both for physiological and electrophysiologically remodeled conditions due to AF. We show that the interaction of the pacemakers, combined with the geometrical constraints of the isthmus, can produce fibrillatory-type irregularities, which we quantify by the loss of spatial phase coherence in the transmembrane voltage. Transitions to irregular behavior occur when the frequencies of the pacemakers exceed certain thresholds, suggesting that AF episodes are initiated by frequency changes of the activating sources (sinus node, ectopic focus).

Abstract:

Over the last decades, the information content derived from cardiac electric and magnetic field measurements has been debated. Our co-workers Wilhelms et al. inves- tigated electrically silent acute ischemia in human ven- tricles caused by occlusion of a coronary artery. In the present work, we extend the previous study by calculating associated magnetic fields produced by early stage acute ischemia with varying transmural extent. Multiscale com- putational simulations were performed for calculations of body surface potential maps (BSPM) and magnetocardio- grams (MCG) on a magnetometer sensor matrix situated above the anterior chest wall. Depending on the ischemia size, the ST-segments of the simulated electrocardiograms (ECG) experienced depression for subendocardial cases and elevation for transmural ischemia. One intermedi- ate extent resulted in a zero ST-segment which makes it diagnostically indistinguishable from the healthy case. Magnetic field calculations for this electrically silent is- chemia also revealed no difference compared to the control case. Otherwise, both ECG and MCG signals during ST- segments showed either depression or elevation from zero line. In this simulation study, MCG did not deliver addi- tional information to uncover electrically silent ischemia. For a general conclusion, further in-silico investigations with different ischemia shapes, sizes and positions should be performed and clinical studies with recordings of both ECG and MCG signals have to be conducted.

Abstract:

The fiber orientation in the atria has a significant contribution to the electrophysiologic behavior of the heart and to the genesis of arrhythmia. Atrial fiber orientation has a direct effect on excitation propagation, activation patterns and the P-wave. We present a rule-based algorithm that works robustly on different volumetric meshes composed of either isotropic hexahedra or arbitrary tetrahedra as well as on 3-dimensional triangular surface meshes in patient-specific geometric models. This method fosters the understanding of general pro-arrhythmic mechanisms and enhances patient-specific modeling approaches.

Abstract:

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.

Abstract:

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.

Abstract:

This work aimed at the detection of rotor centers within the atrial cavity during atrial fibrillation on the basis of phase singularities. A voxel based method was established which employs the Hilbert transform and the phase of unipolar electrograms. The method provides a 3D overview of phase singularities at the endocardial surface and within the blood volume. Mapping those phase singularities from the inside of the atria at the endocardium yielded rotor center trajectories.We discuss the results for an unstable and a more stable rotor. The side length of the areas covered by the trajectories varied from 1.5mm to 10 mm. These results are important for cardiologists who target rotors with RF ablation in order to cure atrial fibrillation.

Abstract:

Using OpenCL, we developed a cross-platform software to compute electrical excitation conduction in cardiac tissue. OpenCL allowed the software to run parallelized and on different computing devices (e.g., CPUs and GPUs).We used the macroscopic mono-domain model for excitation conduction and an atrial myocyte model by Courtemanche et al. for ionic currents. On a CPU with 12 HyperThreading-enabled Intel Xeon 2.7 GHz cores, we achieved a speed-up of simulations by a factor of 1.6 against existing software that uses OpenMPI. On two high-end AMD FirePro D700 GPUs the OpenCL software ran 2.4 times faster than the OpenMPI implementation. The more nodes the discretized simulation domain contained, the higher speed-ups were achieved.

Abstract:

ECG markers derived from the P-wave are used frequently to assess atrial function and anatomy, e.g. left atrial enlargement. While having the advantage of being routinely acquired, the processes under- lying the genesis of the P-wave are not understood in their entirety. Particularly the distinct contributions of the two atria have not been analyzed mechanistically. We used an in silico approach to simulate P-waves originating from the left atrium (LA) and the right atrium (RA) separately in two realistic models. LA contribution to the P-wave integral was limited to 30% or less. Around 20 % could be attributed to the first third of the P-wave which reflected almost only RA depolarization. Both atria contributed to the second and last third with RA contribution being about twice as large as LA contribution. Our results foster the comprehension of the difficulties related to ECG-based LA assessment.

Abstract:

Atrial fibrillation is a common irregular heart rhythm. Until today there is still a need for research to quantify typical signal characteristics of rotors, which can induce atrial fibrillation. In this work, signal characteristics of a stable and a more unstable rotor in a realistic heart model including fiber orientation were analyzed with the following methods: peak-to-peak amplitude, Hilbert phase, approximate entropy and RS-difference. In this simulation model the stable rotor rotated with a cycle length of 145 ms and stayed in an area of 1.5 mm x 3 mm. Another more unstable rotor with a cycle length of 190 ms moved in an area of 10 mm × 4 mm. In a distance of 2 mm to the rotor tip, the peak-to-peak amplitude decreased significantly, whereas the RS-difference and the approximate entropy were maximal. The rotor center trajectories were detected by phase singularity points determined by the Hilbert transform. We showed that more unstable rotors resulted in more amplitude changes over time and also the cycle length differed more. Furthermore, we presented typical activation time patterns of the Lasso catheter centered at the rotor tip and in different distances to the rotor tip. We suggest that cardiologists use a combination of the described methods to determine a rotor tip position in a more robust manner.