Atrial fibrillation source area probability mapping using electrogram patterns of multipole catheters.

BACKGROUND: Catheter ablation therapy involving isolation of pulmonary veins (PVs) from the left atrium is performed to terminate atrial fibrillation (AF). Unfortunately, standalone PV isolation procedure has shown to be a suboptimal success with AF continuation or recurrence. One reason, especially in patients with persistent or high-burden paroxysmal AF, is known to be due to the formation of repeating-pattern AF sources with a meandering core inside the atria. However, there is a need for accurate mapping and localization of these sources during catheter ablation. METHODS: A novel AF source area probability (ASAP) mapping algorithm was developed and evaluated in 2D and 3D atrial simulated tissues with various arrhythmia scenarios and a retrospective study with three cases of clinical human AF. The ASAP mapping analyzes the electrograms collected from a multipole diagnostic catheter that is commonly used during catheter ablation procedure to intelligently sample the atria and delineate the trajectory path of a meandering repeating-pattern AF source. ASAP starts by placing the diagnostic catheter at an arbitrary location in the atria. It analyzes the recorded bipolar electrograms to build an ASAP map over the atrium anatomy and suggests an optimal location for the subsequent catheter location. ASAP then determines from the constructed ASAP map if an AF source has been delineated. If so, the catheter navigation is stopped and the algorithm provides the area of the AF source. Otherwise, the catheter is navigated to the suggested location, and the process is continued until an AF-source area is delineated. RESULTS: ASAP delineated the AF source in over 95% of the simulated human AF cases within less than eight catheter placements regardless of the initial catheter placement. The success of ASAP in the clinical AF was confirmed by the ablation outcomes and the electrogram patterns at the delineated area. CONCLUSION: Our analysis indicates the potential of the ASAP mapping to provide accurate information about the area of the meandering repeating-pattern AF sources as AF ablation targets for effective AF termination. Our algorithm could improve the success of AF catheter ablation therapy by locating and subsequently targeting patient-specific and repeating-pattern AF sources inside the atria.

Iterative navigation of multipole diagnostic catheters to locate repeating-pattern atrial fibrillation drivers.

INTRODUCTION: Targeting repeating-pattern atrial fibrillation (AF) sources (reentry or focal drivers) can help in patient-specific ablation therapy for AF; however, the development of reliable and accurate tools for locating such sources remains a major challenge. We describe iterative catheter navigation (ICAN) algorithm to locate AF drivers using a conventional circular Lasso catheter. METHODS AND RESULTS: At each step, the algorithm analyzes 10 bipolar electrograms recoded at a given catheter location and the history of previous catheter movements to determine if the source is inside the catheter loop. If not, it calculates new coordinates and selects a new position for the catheter. The process continues until a source is located. The algorithm was evaluated in a computer model of atrial tissue with various degrees of fibrosis under a broad range of arrhythmia scenarios. The latter included slow and fast reentry, macroreentry, figure-of-eight reentry, and fibrillatory conduction. Depending on the initial distance of the catheter from the source and scenario, it took about 3 to 16 steps to localize an AF source. In 94% of cases, the identified location was within 4 mm from the source, independently of the initial position of the catheter. The algorithm worked equally well in the presence of patchy fibrosis, low-voltage areas, fragmented electrograms, and dominant-frequency gradients. CONCLUSIONS: AF repeating-pattern sources can be localized using circular catheters without the need to map the entire tissue. The proposed algorithm has the potential to become a useful tool for patient-specific ablation of AF sources located outside the pulmonary veins.

Refraction of scroll-wave filaments at the boundary between two reaction-diffusion media.

We explore the shape and the dynamics of scroll-wave filaments in excitable media with an abruptly changing diffusion tensor, important for cardiac applications. We show that, similar to a beam of light, the filament refracts at the boundary separating domains with different diffusion. We derive the laws of filament refraction and test their validity in computational experiments. We discovered that at small angles to the interface, the filament can become unstable and develop oscillations. The nature of the observed instabilities, as well as overall theoretical and experimental significance of the findings, is discussed.

Optical Imaging of Cardiac Action Potential.

This chapter reviews the major milestones and scientific achievements facilitated by optical imaging of the action potential in the heart over more than four decades since its introduction. We discuss the limitations of this technique, which sometimes are not fully recognized; the unresolved issues, such as motion artifacts, and the newest developments and future directions.

Individualization of Atrial Tachycardia Models for Clinical Applications: Performance of Fiber-Independent Model.

One of the challenges in the development of patient-specific models of cardiac arrhythmias for clinical applications has been accounting for myocardial fiber organization. The fiber varies significantly from heart to heart, but cannot be directly measured in live tissue. The goal of this paper is to evaluate in-silico the accuracy of left atrium activation maps produced by a fiber-independent (isotropic) model with tuned diffusion coefficients, compares to a model incorporating myocardial fibers with the same geometry. For this study we utilize publicly available DT-MRI data from 7 ex-vivo hearts. The comparison is carried out in 51 cases of focal and rotor arrhythmias located in different regions of the atria. On average, the local activation time accuracy is 96% for focal and 93% for rotor arrhythmias. Given its reasonably good performance and the availability of readily accessible data for model tuning in cardiac ablation procedures, the fiber-independent model could be a promising tool for clinical applications.

Fiber Organization has Little Effect on Electrical Activation Patterns during Focal Arrhythmias in the Left Atrium.

Over the past two decades there has been a steady trend towards the development of realistic models of cardiac conduction with increasing levels of detail. However, making models more realistic complicates their personalization and use in clinical practice due to limited availability of tissue and cellular scale data. One such limitation is obtaining information about myocardial fiber organization in the clinical setting. In this study, we investigated a chimeric model of the left atrium utilizing clinically derived patient-specific atrial geometry and a realistic, yet foreign for a given patient fiber organization. We discovered that even significant variability of fiber organization had a relatively small effect on the spatio-temporal activation pattern during regular pacing. For a given pacing site, the activation maps were very similar across all fiber organizations tested.

Fiber Organization Has Little Effect on Electrical Activation Patterns During Focal Arrhythmias in the Left Atrium.

Over the past two decades there has been a steady trend towards the development of realistic models of cardiac conduction with increasing levels of detail. However, making models more realistic complicates their personalization and use in clinical practice due to limited availability of tissue and cellular scale data. One such limitation is obtaining information about myocardial fiber organization in the clinical setting. In this study, we investigated a chimeric model of the left atrium utilizing clinically derived patient-specific atrial geometry and a realistic, yet foreign for a given patient fiber organization. We discovered that even significant variability of fiber organization had a relatively small effect on the spatio-temporal activation pattern during regular pacing. For a given pacing site, the activation maps were very similar across all fiber organizations tested.

Extracting surface activation time from the optically recorded action potential in three-dimensional myocardium.

Optical mapping has become an indispensible tool for studying cardiac electrical activity. However, due to the three-dimensional nature of the optical signal, the optical upstroke is significantly longer than the electrical upstroke. This raises the issue of how to accurately determine the activation time on the epicardial surface. The purpose of this study was to establish a link between the optical upstroke and exact surface activation time using computer simulations, with subsequent validation by a combination of microelectrode recordings and optical mapping experiments. To simulate wave propagation and associated optical signals, we used a hybrid electro-optical model. We found that the time of the surface electrical activation (t(E)) within the accuracy of our simulations coincided with the maximal slope of the optical upstroke (t(F)*) for a broad range of optical attenuation lengths. This was not the case when the activation time was determined at 50% amplitude (t(F50)) of the optical upstroke. The validation experiments were conducted in isolated Langendorff-perfused rat hearts and coronary-perfused pig left ventricles stained with either di-4-ANEPPS or the near-infrared dye di-4-ANBDQBS. We found that t(F)* was a more accurate measure of t(E) than was t(F50) in all experimental settings tested (P = 0.0002). Using t(F)* instead of t(F50) produced the most significant improvement in measurements of the conduction anisotropy and the transmural conduction time in pig ventricles.

Anchoring of drifting spiral and scroll waves to impermeable inclusions in excitable media.

Anchoring of spiral and scroll waves in excitable media has attracted considerable interest in the context of cardiac arrhythmias. Here, by bombarding inclusions with drifting spiral and scroll waves, we explore the forces exerted by inclusions onto an approaching spiral and derive the equations of motion governing spiral dynamics in the vicinity of inclusion. We demonstrate that these forces nonmonotonically depend on distance and can lead to complex behavior: (a) anchoring to small but circumnavigating larger inclusions; (b) chirality-dependent anchoring.

Probing field-induced tissue polarization using transillumination fluorescent imaging.

Despite major successes of biophysical theories in predicting the effects of electrical shocks within the heart, recent optical mapping studies have revealed two major discrepancies between theory and experiment: 1), the presence of negative bulk polarization recorded during strong shocks; and 2), the unexpectedly small surface polarization under shock electrodes. There is little consensus as to whether these differences result from deficiencies of experimental techniques, artifacts of tissue damage, or deficiencies of existing theories. Here, we take advantage of recently developed near-infrared voltage-sensitive dyes and transillumination optical imaging to perform, for the first time that we know of, noninvasive probing of field effects deep inside the intact ventricular wall. This technique removes some of the limitations encountered in previous experimental studies. We explicitly demonstrate that deep inside intact myocardial tissue preparations, strong electrical shocks do produce considerable negative bulk polarization previously inferred from surface recordings. We also demonstrate that near-threshold diastolic field stimulation produces activation of deep myocardial layers 2-6 mm away from the cathodal surface, contrary to theory. Using bidomain simulations we explore factors that may improve the agreement between theory and experiment. We show that the inclusion of negative asymmetric current can qualitatively explain negative bulk polarization in a discontinuous bidomain model.

Spontaneous onset of atrial fibrillation.

Most commonly, atrial fibrillation is triggered by rapid bursts of electrical impulses originating in the myocardial sleeves of pulmonary veins (PVs). However, the nature of such bursts remains poorly understood. Here, we propose a mechanism of bursting consistent with the extensive empirical information about the electrophysiology of the PVs. The mechanism is essentially non-local and involves the spontaneous initiation of non-sustained spiral waves in the distal end of the muscle sleeves of the PVs. It reproduces the experimentally observed dynamics of the bursts, including their frequency, their intermittent character, and the unusual shape of the electrical signals in the pulmonary veins that are reminiscent of so-called early afterdepolarizations (EADs).

Locating Atrial Fibrillation Rotor and Focal Sources Using Iterative Navigation of Multipole Diagnostic Catheters.

PURPOSE: Multi-polar diagnostic catheters are used to construct the 3D electro-anatomic mapping of the atrium during atrial fibrillation (AF) ablation procedures; however, it remains unclear how to use the electrograms recorded by these catheters to locate AF-driving sites known as focal and rotor source types. The purpose of this study is to present the first algorithm to iteratively navigate a circular multi-polar catheter to locate AF focal and rotor sources without the need to map the entire atria. METHODS: Starting from an initial location, the algorithm, which was blinded to the location and type of the AF source, iteratively advanced a Lasso catheter based on its electrogram characteristics. The algorithm stopped the catheter when it located of an AF source and identified the type. The efficiency of the algorithm is validated using a set of simulated focal and rotor-driven arrhythmias in fibrotic human 2D and 3D atrial tissue. RESULTS: Our study shows the feasibility of locating AF sources with a success rate of greater than 95.25% within average 7.56 ± 2.28 placements independently of the initial position of the catheter and the source type. CONCLUSIONS: The algorithm could play a critical role in clinical electrophysiology laboratories for mapping patient-specific ablation of AF sources located outside the pulmonary veins and improving the procedure success.

Extracting intramural wavefront orientation from optical upstroke shapes in whole hearts.

Information about intramural propagation of electrical excitation is crucial to understanding arrhythmia mechanisms in thick ventricular muscle. There is currently a controversy over whether it is possible to extract such information from the shape of the upstroke in optical mapping recordings. We show that even in the complex geometry of a whole guinea pig heart, optical upstroke morphology reveals the 3D wavefront orientation near the surface. To characterize the upstroke morphology, we use V(F)(*), the fractional level at which voltage-sensitive fluorescence, V(F), has maximal time derivative. Low values of V(F)(*)( approximately 0.2) indicate a wavefront moving away from the surface, high values of V(F)(*) ( approximately 0.6) a wavefront moving toward the surface, and intermediate values of V(F)(*) ( approximately 0.4) a wavefront moving parallel to the surface. We further performed computer simulations using Luo-Rudy II electrophysiology and a simplified 3D geometry. The simulated V(F)(*) maps for free wall and apical stimulations as well as for sinus rhythm are in good quantitative agreement with the averaged experimental results. Furthermore, computer simulations show that the effect of the curvature of the heart on wave propagation is negligible.

Reconstructing subsurface electrical wave orientation from cardiac epi-fluorescence recordings: Monte Carlo versus diffusion approximation.

The development of voltage-sensitive dyes has revolutionized cardiac electrophysiology and made optical imaging of cardiac electrical activity possible. Photon diffusion models coupled to electrical excitation models have been successful in qualitatively predicting the shape of the optical action potential and its dependence on subsurface electrical wave orientation. However, the accuracy of the diffusion equation in the visible range, especially for thin tissue preparations, remains unclear. Here, we compare diffusion and Monte Carlo (MC) based models and we investigate the role of tissue thickness. All computational results are compared to experimental data obtained from intact guinea pig hearts. We show that the subsurface volume contributing to the epi-fluorescence signal extends deeper in the tissue when using MC models, resulting in longer optical upstroke durations which are in better agreement with experiments. The optical upstroke morphology, however, strongly correlates to the subsurface propagation direction independent of the model and is consistent with our experimental observations.

Nondestructive optical determination of fiber organization in intact myocardial wall.

Mapping the myocardial fiber organization is important for assessing the electrical and mechanical properties of normal and diseased hearts. Current methods to determine the fiber organization have several limitations: histological sectioning mechanically distorts the tissue and is labor-intensive, while diffusion tensor imaging has low spatial resolution and requires expensive MRI scanners. Here, we utilized optical clearing, a fluorescent dye, and confocal microscopy to create three-dimensional reconstructions of the myocardial fiber organization of guinea pig and mouse hearts. We have optimized the staining and clearing procedure to allow for the nondestructive imaging of whole hearts with a thickness up to 3.5 mm. Myocardial fibers could clearly be identified at all depths in all preparations. We determined the change of fiber orientation across strips of guinea pig left ventricular wall. Our study confirms the qualitative result that there is a steady counterclockwise fiber rotation across the ventricular wall. Quantitatively, we found a total fiber rotation of 105.7+/-14.9 degrees (mean+/-standard error of the mean); this value lies within the range reported by previous studies. These results show that optical clearing, in combination with a fluorescent dye and confocal microscopy, is a practical and accurate method for determining myocardial fiber organization.

Developing an Iterative Tracking Algorithm to Guide a Catheter Towards Atrial Fibrillation Rotor Sources in Simulated Fibrotic Tissue.

Locating atrial fibrillation (AF) rotor sources can help target ablation therapy for AF. Our aim was to develop a catheter-tracking algorithm to locate AF rotor sources using a conventional 20-electrode circular catheter. We simulated rotor-driven arrhythmias in homogeneous and fibrotic human atrial tissue and evaluated the algorithm for different initial catheter positions. The algorithm guided and detected a rotor with a success rate of greater than 97.9% independently of the initial position of the catheter with an accuracy of greater than 2.3±1.4 mm.

Development of a Rotor-Mapping Algorithm to Locate Ablation Targets During Atrial Fibrillation.

Catheter ablation therapy involving isolation of pulmonary veins (PVs) remains the cornerstone procedure to treat AF. However, due to the sub-optimal success rates of PV isolation, there is a need for new ablation techniques to locate AF ablation targets known as rotors, outside of the PVs. In this paper, we developed a novel rotor-mapping algorithm that uses a conventional diagnostic catheter, Lasso, to locate a rotor source. The algorithm, called the Region of Rotor (ROR) Mapping, utilizes the characteristics of local bipolar electrograms to navigate the catheter's iterative placements while generating a map, overlaid on the atrial anatomy, that displays the potential rotor region. We evaluated the developed ROR mapping algorithm using a 2D simulation of AF on a tissue with heterogeneous conduction properties. The results demonstrated a significant success rate of 93% in accurately locating the region of the rotor with a mean distance of 1.4mm from the ground truth trajectory. The algorithm could play a critical role in mapping non-PV AF ablation targets and improving the outcome of AF ablation.

Bioinformatic identification of novel putative photoreceptor specific cis-elements.

BACKGROUND: Cell specific gene expression is largely regulated by different combinations of transcription factors that bind cis-elements in the upstream promoter sequence. However, experimental detection of cis-elements is difficult, expensive, and time-consuming. This provides a motivation for developing bioinformatic methods to identify cis-elements that could prioritize future experimental studies. Here, we use motif discovery algorithms to predict transcription factor binding sites involved in regulating the differences between murine rod and cone photoreceptor populations. RESULTS: To identify highly conserved motifs enriched in promoters that drive expression in either rod or cone photoreceptors, we assembled a set of murine rod-specific, cone-specific, and non-photoreceptor background promoter sequences. These sets were used as input to a newly devised motif discovery algorithm called Iterative Alignment/Modular Motif Selection (IAMMS). Using IAMMS, we predicted 34 motifs that may contribute to rod-specific (19 motifs) or cone-specific (15 motifs) expression patterns. Of these, 16 rod- and 12 cone-specific motifs were found in clusters near the transcription start site. New findings include the observation that cone promoters tend to contain TATA boxes, while rod promoters tend to be TATA-less (exempting Rho and Cnga1). Additionally, we identify putative sites for IL-6 effectors (in rods) and RXR family members (in cones) that can explain experimental data showing changes to cell-fate by activating these signaling pathways during rod/cone development. Two of the predicted motifs (NRE and ROP2) have been confirmed experimentally to be involved in cell-specific expression patterns. We provide a full database of predictions as additional data that may contain further valuable information. IAMMS predictions are compared with existing motif discovery algorithms, DME and BioProspector. We find that over 60% of IAMMS predictions are confirmed by at least one other motif discovery algorithm. CONCLUSION: We predict novel, putative cis-elements enriched in the promoter of rod-specific or cone-specific genes. These are candidate binding sites for transcription factors involved in maintaining functional differences between rod and cone photoreceptor populations.

Depth-resolved optical imaging of transmural electrical propagation in perfused heart.

We present a study of the 3-dimensional (3D) propagation of electrical waves in the heart wall using Laminar Optical Tomography (LOT). Optical imaging contrast is provided by a voltage sensitive dye whose fluorescence reports changes in membrane potential. We examined the transmural propagation dynamics of electrical waves in the right ventricle of Langendorf perfused rat hearts, initiated either by endo-cardial or epi-cardial pacing. 3D images were acquired at an effective frame rate of 667Hz. We compare our experimental results to a mathematical model of electrical transmural propagation. We demonstrate that LOT can clearly resolve the direction of propagation of electrical waves within the cardiac wall, and that the dynamics observed agree well with the model of electrical propagation in rat ventricular tissue.

Near-infrared voltage-sensitive fluorescent dyes optimized for optical mapping in blood-perfused myocardium.

BACKGROUND: Styryl voltage-sensitive dyes (e.g., di-4-ANEPPS) have been used successfully for optical mapping in cardiac cells and tissues. However, their utility for probing electrical activity deep inside the myocardial wall and in blood-perfused myocardium has been limited because of light scattering and high absorption by endogenous chromophores and hemoglobin at blue-green excitation wavelengths. OBJECTIVE: The purpose of this study was to characterize two new styryl dyes--di-4-ANBDQPQ (JPW-6003) and di-4-ANBDQBS (JPW-6033)--optimized for blood-perfused tissue and intramural optical mapping. METHODS: Voltage-dependent spectra were recorded in a model lipid bilayer. Optical mapping experiments were conducted in four species (mouse, rat, guinea pig, and pig). Hearts were Langendorff perfused using Tyrode's solution and blood (pig). Dyes were loaded via bolus injection into perfusate. Transillumination experiments were conducted in isolated coronary-perfused pig right ventricular wall preparations. RESULTS: The optimal excitation wavelength in cardiac tissues (650 nm) was >70 nm beyond the absorption maximum of hemoglobin. Voltage sensitivity of both dyes was approximately 10% to 20%. Signal decay half-life due to dye internalization was 80 to 210 minutes, which is 5 to 7 times slower than for di-4-ANEPPS. In transillumination mode, DeltaF/F was as high as 20%. In blood-perfused tissues, DeltaF/F reached 5.5% (1.8 times higher than for di-4-ANEPPS). CONCLUSION: We have synthesized and characterized two new near-infrared dyes with excitation/emission wavelengths shifted >100 nm to the red. They provide both high voltage sensitivity and 5 to 7 times slower internalization rate compared to conventional dyes. The dyes are optimized for deeper tissue probing and optical mapping of blood-perfused tissue, but they also can be used for conventional applications.