Abstract:

Cardiologists measure electric signals inside the human heart aiming at a better diagnosis and optimized therapy of atrial arrhythmias like atrial flutter and atrial fibrillation. The catheters that are used for this purpose are improving: now they are able to pick up the electric signals at up to 64 positions inside the heart simultaneously. The patterns of electric depolarization are sometimes very simple, comparable to plane waves. But in case of patients with severe atrial arrhythmias they can be quite complex: U-turns around a line of block, ectopic centres, break throughs, reentry circuits, rotors, fractionated signals and chaotic patterns are often observed. Methods of biosignal analysis can support the cardiologists in classifying the signals and extract information of high diagnostic relevance. Computer models of the electrophysiology of the human heart can serve to design better algorithms for data analysis and to test algorithms, because the ground truth is known.

Abstract:

AIMS: P-wave morphology correlates with the risk for atrial fibrillation (AF). Left atrial (LA) enlargement could explain both the higher risk for AF and higher P-wave terminal force (PTF) in lead V1. However, PTF-V1 has been shown to correlate poorly with LA size. We hypothesize that PTF-V1 is also affected by the earliest activated site (EAS) in the right atrium and its proximity to inter-atrial connections (IAC), which both show tremendous variability. METHODS AND RESULTS: Atrial excitation was triggered from seven different EAS in a cohort of eight anatomically personalized computational models. The posterior IACs were non-conductive in a second set of simulations. Body surface ECGs were computed and separated by left and right atrial contributions. Mid-septal EAS yielded the highest PTF-V1. More anterior/superior and more inferior EAS yielded lower absolute PTF-V1 values deviating by a factor of up to 2.0 for adjacent EAS. Earliest right-to-left activation was conducted via Bachmann's Bundle (BB) for anterior/superior EAS and shifted towards posterior IACs for more inferior EAS. Non-conducting posterior IACs increased PTF-V1 by up to 150% compared to intact posterior IACs for inferior EAS. LA contribution to the P-wave integral was 24% on average. CONCLUSION: The electrical contributor's site of earliest activation and intactness of posterior IACs affect PTF-V1 significantly by changing LA breakthrough sites independent from LA size. This should be considered for interpretation of electrocardiographical signs of LA abnormality and LA enlargement.

Abstract:

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.

Abstract:

Whole-chamber mapping using a 64-pole basket catheter (BC) has become a featured approach for the analysis of excitation patterns during atrial fibrillation. A flexible catheter design avoids perforation but may lead to spline bunching and influence coverage. We aim to quantify the catheter deformation and endocardial coverage in clinical situations and study the effect of catheter size and electrode arrangement using an in silico basket model. Atrial coverage and spline separation were evaluated quantitatively in an ensemble of clinical measurements. A computational model of the BC was implemented including an algorithm to adapt its shape to the atrial anatomy. Two clinically relevant mapping positions in each atrium were assessed in both clinical and simulated data. The simulation environment allowed varying both BC size and electrode arrangement. Results showed that interspline distances of more than 20 mm are common, leading to a coverage of less than 50% of the left atrial (LA) surface. In an ideal in silico scenario with variable catheter designs, a maximum coverage of 65% could be reached. As spline bunching and insufficient coverage can hardly be avoided, this has to be taken into account for interpretation of excitation patterns and development of new panoramic mapping techniques.

Abstract:

One promising application of electrocardiographic (ECG) imaging is noninvasive reconstruction of atrial activities. However, despite numerous clinical studies, which are mostly concerned with complex irregular excitation patterns, there are relatively few in silico investigations on the imaging of ectopic activation. In the present work, we explore the localization accuracy of ECG imaging regarding atrial focal sites. For the forward calculations, we used four realistic geometrical models with complex anatomical structure and a rule-based fiber orientation embedded into the atrial model. Excitation propagation was simulated with the monodomain model. For each geometrical model, 20 activation sequences originating from the posterior wall of the left atrium were simulated. Based on the bidomain theory, the body surface potential maps resulting from these focal events were computed. For the inverse reconstructions, we employed a full-search procedure based on the fastest route algorithm assuming uniform excitation propagation. Localization errors were revealed to be dependent on the model-specific atrial geometry. We also performed similarity analysis for the first halves of the P wave duration, which improved the results in three models.

Abstract:

P-wave assessment is frequently used in clinical practice to recognize atrial abnormalities. However, the use of P-wave criteria to diagnose specific atrial abnormalities such as left atrial enlargement has shown to be of limited use since these abnormalities can be difficult to distinguish using P-wave criteria to date. Hence, a mechanistic understanding how specific atrial abnormalities affect the P-wave is desirable. In this study, we investigated the effect of left atrial hypertrophy on P-wave morphology using an in silico approach. In a cohort of four realistic patient models, we homogeneously increased left atrial wall thickness in up to seven degrees of left atrial hypertrophy. Excitation conduction was simulated using a monodomain finite element approach. Then, the resulting transmembrane voltage distribution was used to calculate the corresponding extracellular potential distribution on the torso by solving the forward problem of electrocardiography. In our simulation setup, left atrial wall thickening strongly correlated with an increased absolute value of the P-wave terminal force (PTF) in Wilson lead V1 due to an increased negative amplitude while P-wave duration was unaffected. Remarkably, an increased PTF-V1 has often been associated with left atrial enlargement which is defined as a rather increased left atrial volume than a solely thickened left atrium. Hence, the observed contribution of left atrial wall thickness changes to PTF-V1 might explain the poor empirical correlation of left atrial enlargement with PTF-V1.

Abstract:

P-wave morphology correlates with the risk for atrial fibrillation (AF). Left atrial (LA) enlargement could ex- plain both the higher risk for AF and higher P-wave ter- minal force (PTF) in ECG lead V1. However, PTF-V1 has been shown to correlate poorly with LA size. We hypoth- esize that LA hypertrophy, i.e. a thickening of the myocar- dial wall, also contributes to increased PTF-V1 and is part of the reason for the rather low specificity of increased PTF-V1 regarding LA enlargement. To show this, atrial excitation propagation was simulated in a cohort of four anatomically individualized models in- cluding rule-based myocyte orientation and spatial elec- trophysiological heterogeneity using the monodomain ap- proach. The LA wall was thickened symmetrically in steps of 0.66 mm by up to 3.96 mm. Interatrial conduction was possible via discrete connections at the coronary sinus, Bachmann’s bundle and posteriorly. Body surface ECGs were computed using realistic, heterogeneous torso mod- els. During the early P-wave stemming from sources in the RA, no changes were observed. Once the LA got activated, the voltage in V1 tended to lower values for higher degrees of hypertrophy. Thus, the amplitude of the late positive P- wave decreased while the amplitude of the subsequent neg- ative terminal phase increased. PTF-V1 and LA wall thick- ening showed a correlation of 0.95. The P-wave duration was almost unaffected by LA wall thickening (∆ ≤2 ms). Our results show that PTF-V1 is a sensitive marker for LA wall thickening and elucidate why it is superior to P-wave area. The interplay of LA hypertrophy and dilation might cause the poor empirical correlation of LA size and PTF- V1.

Abstract:

P-wave morphology correlates with the risk for AF. Left atrial (LA) enlargement could explain both the higher risk for AF and higher P-wave terminal force (PTF) in lead V1. However, PTF-V1 has been shown to correlate poorly with LA size. We hypothesize that PTF-V1 is also affected by the earliest activated site (EAS) in the right atrium and its proximity to inter-atrial connections (IAC), which both show tremendous variability. Atrial excitation was triggered from seven different EAS on the epicardial surface around the sinus node region in eight anatomically personalized computational models including rule-based myocyte orientation and spatial electrophysiological heterogeneity. EAS1 was located midway between the tip of the right atrial appendage (RAA) and its junction with the superior vena cava (SVC), EAS2 at the superior part of the anterior wall, and EAS3 at the junction of the RAA and the SVC. EAS4 to EAS7 were uniformly distributed along the crista terminalis between EAS3 and orifice of the inferior vena cava (EAS7). IACs connected the atria at Bachmann’s bundle, coronary sinus and posteriorly. The posterior IACs were non-conductive in a second set of simulations. Body surface ECGs were computed using realistic, heterogeneous torso models. Mid-septal EAS yielded the highest PTF-V1 measured as the product of the duration and the maximal amplitude of the negative phase of the P-wave in V1. More anterior/superior and more inferior EAS yielded lower absolute values deviating by a factor of up to 2.0 for adjacent EAS. Earliest right-to-left activation was conducted via BB for EAS1-3 and shifted towards posterior IACs for EAS 4-7. Non-conducting posterior IACs increased PTF-V1 by up to 150%. The electrical contributors EAS and intactness of posterior IACs affect PTF-V1 significantly by changing LA breakthrough sites. This should be considered when assessing LA anatomy based on the ECG.

Abstract:

Aim: P-wave morphology correlates with the risk for AF. Left atrial enlargement could explain both the higher risk for AF and higher P-wave terminal force in lead V1 (PTF-V1). However, PTF-V1 has been shown to correlate poorly with left atrial size. We hypothesize that PTF-V1 is also affected by the earliest activated site (EAS) in the right atrium and its proximity to inter-atrial connections (IACs), which both show tremendous variability. Methods: Atrial excitation was triggered from seven different EASs (Fig 1A,B) in eight anatomically personalized computational models including rule-based fiber orientation and spatial electrophysiological heterogeneity. IACs connected the atria at Bachmann’s bundle, coronary sinus, and posteriorly. The posterior IACs were non-conductive in a second set of simulations. Body surface ECGs were computed using realistic, heterogeneous torso models of the same subjects. Results: Mid-septal EASs yielded the highest PTF-V1 measured as the product of the duration and the maximal amplitude of the negative phase of the P-wave in V1. More anterior/superior and more inferior EASs yielded lower absolute values deviating by a factor of up to 2.0 for adjacent EAS (Fig 1C). Earliest right-to-left activation was conducted via BB for EAS1-EAS3 and shifted towards posterior IACs for EAS4-EAS7. Non- conducting posterior IACs increased PTF-V1 by up to 150% (Fig 1D). Conclusions: Location of EAS in the right atrium and its proximity to functioning IACs affect PTF-V1 independently of the left atrial size and further support the caution that needs to be exercised when interpreting electrocardiographically signs of left atrial abnormality, which include PTF-V1.

Abstract:

Atrial arrhythmia is the most common cardiac arrhythmia. Parameters such as conduction velocity (CV), CV restitution etc. are under analysis in order to understand the cardiac arrhythmias. A number of methods have been proposed for CV calculation in simulation as well as clinical environments. Regional CV gives the information about the magnitude and direction of the propagating depolarization wavefronts on the atrium with homogeneous and heterogeneous tissue. The CV in different regions can provide important quantitative electrophysiological information about the underlying tissue. In this work the regional CV has been calculated using simulated local activation times (LAT) on clinical atrial geometries. Regions with homogeneous and heterogeneous propagation were manually selected for LAT simulation and later the regional CV has been calculated. The calculated CV for both the homogeneous and heterogeneous cases for all the clinical cases have been visualized on the atrial geometries. The visualization of the CV on the atrium represents insight into the regional behavior of the atrial substrate. The benefit of the region-specific study in clinical context is that it could enable the localization of critical sites in the patient specific atrial anatomies. Thus, this could aid physicians in cardiac therapies.

Abstract:

Half of the patients suffering from atrial fibrillation (AF) cannot be treated adequately, today. This thesis presents multi-scale computational methods to advance our understanding of patho-mechanisms, to improve the diagnosis of patients harboring an arrhythmogenic substrate, and to tailor therapy. The modeling pipeline ranges from ion channels on the subcellular level up to the ECG on the body surface. The tailored therapeutic approaches carry the potential to reduce the burden of AF.