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.
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.
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. 418-422, 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.
Baseline wander removal is one important part of electrocardiogram (ECG) filtering. This can be achieved by many different approaches. This work investigates the influence of three different baseline wander removal techniques on ST changes. The chosen filters were phase-free Butterworth filtering, median filtering and baseline correction with cubic spline interpolation. 289 simulated ECGs containing ischemia were used to determine the influence of these filtering processes on the ST segment. Synthetic baseline wander and offsets were added to the simulated signals. All methods proved to be good approaches by removing most of the baseline wander in all signals. Correlation coefficients between the original signals and the filtered signals were greater than 0.93 for all ECGs. Cubic spline interpolation performed best regarding the preservation of the ST segment amplitude change when compared to the original signal. The approach modified the ST segment by 0.10mV±0.06mV at elevated K points. Median filtering introduced a variation of 0.33mV±0.29mV, Butterworth filtering reached 0.16mV±0.14mV at elevated K points. Thus, all methods manipulate the ST segment.
Diagnosis of atrial flutter caused by ablation of atrial fibrillation is complex due to ablation scars. This paper presents an approach to replicate the clinically measured flutter circuit in a dynamic computer model. In a first step, important anatomical features of the flutter circuit are extracted manually based on the clinical measurement. With the help of this information, the electrical excitation propagation is simulated on the atrial geometry using the fast marching method. The simulated flutter circuit is used to estimate the global and local conduction velocity by approximating it iteratively. The parameterized flutter simulation is supposed to support the physician during diagnosis and treatment of atrial flutter.
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.
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.