Complexity analysis of electrical activity during endocardial and epicardial biventricular mapping of ventricular fibrillation.

BACKGROUND: Ventricular fibrillation (VF) is a lethal cardiac arrhythmia that is a significant cause of sudden cardiac death. Comprehensive studies of spatiotemporal characteristics of VF in situ are difficult to perform with current mapping systems and catheter technology. OBJECTIVE: The goal of this study was to develop a computational approach to characterize VF using a commercially available technology in a large animal model. Prior data suggests that characterization of spatiotemporal organization of electrical activity during VF can be used to provide better mechanistic understanding and potential ablation targets to modify VF and its substrate. We therefore evaluated intracardiac electrograms during biventricular mapping of the endocardium (ENDO) and epicardium (EPI) in acute canine studies. METHODS: To develop thresholds for organized and disorganized activity, a linear discriminant analysis (LDA)-based approach was performed to the known organized and disorganized activities recorded in ex vivo Langendorff-perfused rat and rabbit hearts using optical mapping experiments. Several frequency- and time-domain approaches were used as individual and paired features to identify the optimal thresholds for the LDA approach. Subsequently, VF was sequentially mapped in 4 canine hearts, using the CARTO mapping system with a multipolar mapping catheter in the ENDO left and right ventricles and EPI to capture the progression of VF at 3 discrete post-induction time intervals: VF period 1 (just after induction of VF to 15 min), VF period 2 (15 to 30 min), and VF period 3 (30 to 45 min). The developed LDA model, cycle lengths (CL), and regularity indices (RI) were applied to all recorded intracardiac electrograms to quantify the spatiotemporal organization of VF in canine hearts. RESULTS: We demonstrated the presence of organized activity in the EPI as VF progresses, in contrary to the ENDO, where the activity stays disorganized. The shortest CL always occurred in the ENDO, especially the RV, indicating a faster VF activity. The highest RI was found in the EPI in all hearts for all VF stages, indicating spatiotemporal consistency of RR intervals. CONCLUSION: We identified electrical organization and spatiotemporal differences throughout VF in canine hearts from induction to asystole. Notably, the RV ENDO is characterized by a high level of disorganization and faster VF frequency. In contrast, EPI has a high spatiotemporal organization of VF and consistently long RR intervals.

The impact of chronotropic incompetence on atrioventricular conduction times in heart failure patients.

BACKGROUND: Intrinsic atrioventricular (AV) conduction is used to optimize AV intervals with cardiac resynchronization therapy (CRT) in most device algorithms. Atrial pacing and heart rate affect conduction times, but little is known regarding differeces among chronotropic incompetent(CI) and competent(CC) patients to guide programming. METHODS: RAVE was a multicenter prospective trial of CRT patients. Heart rate was increased with incremental atrial pacing and with submaximal exercise. According to the maximal heart rate achieved during exercise, patients were classified as either CI or CC. For CI patients, an additional symptom-limited exercise with rate-adaptive pacing activated was performed. Intracardiac intervals were measured from the implantable lead electrograms in multiple postures. RESULTS: There were 12 subjects with CI and 24 with CC. With atrial pacing, AV interval immediately increased and gradually increased with incremental atrial pacing in all patients. However, the changes in the atrial to right ventricular (ARV) and atrial to left ventricular (ALV) intervals with increasing atrial pacing rates were about threefold greater in CI patients compared to CC patients (24.3 ± 28.9 vs. 7.2 ± 5.5 ms/10 bpm for ARV and 22.7 ± 25.6 vs. 7.1 ± 5.7 ms/10 bpm for ALV in the standing position, p < 0.05). In CI pacing with rate-adaptive pacing during exercise, AV interval changes with paced heart rate were variable. CONCLUSIONS: The AV response to overdrive atrial pacing at rest may provide a simple means of identifying chronotropic competence in CRT patients. For patients with CI, who often require rate-adaptive atrial pacing, rate-adaptive AV algorithms should be adjusted individually.

A Data-Driven Preprocessing Framework for Atrial Fibrillation Intracardiac Electrocardiogram Analysis.

Atrial Fibrillation (AF) is the most common cardiac arrhythmia. Signal-processing approaches are widely used for the analysis of intracardiac electrograms (iEGMs), which are collected during catheter ablation from patients with AF. In order to identify possible targets for ablation therapy, dominant frequency (DF) is widely used and incorporated in electroanatomical mapping systems. Recently, a more robust measure, multiscale frequency (MSF), for iEGM data analysis was adopted and validated. However, before completing any iEGM analysis, a suitable bandpass (BP) filter must be applied to remove noise. Currently, no clear guidelines for BP filter characteristics exist. The lower bound of the BP filter is usually set to 3-5 Hz, while the upper bound (BP¯th) of the BP filter varies from 15 Hz to 50 Hz according to many researchers. This large range of BP¯th subsequently affects the efficiency of further analysis. In this paper, we aimed to develop a data-driven preprocessing framework for iEGM analysis, and validate it based on DF and MSF techniques. To achieve this goal, we optimized the BP¯th using a data-driven approach (DBSCAN clustering) and demonstrated the effects of different BP¯th on subsequent DF and MSF analysis of clinically recorded iEGMs from patients with AF. Our results demonstrated that our preprocessing framework with BP¯th = 15 Hz has the best performance in terms of the highest Dunn index. We further demonstrated that the removal of noisy and contact-loss leads is necessary for performing correct data iEGMs data analysis.

A Bionic Testbed for Cardiac Ablation Tools.

Bionic-engineered tissues have been proposed for testing the performance of cardiovascular medical devices and predicting clinical outcomes ex vivo. Progress has been made in the development of compliant electronics that are capable of monitoring treatment parameters and being coupled to engineered tissues; however, the scale of most engineered tissues is too small to accommodate the size of clinical-grade medical devices. Here, we show substantial progress toward bionic tissues for evaluating cardiac ablation tools by generating a centimeter-scale human cardiac disk and coupling it to a hydrogel-based soft-pressure sensor. The cardiac tissue with contiguous electromechanical function was made possible by our recently established method to 3D bioprint human pluripotent stem cells in an extracellular matrix-based bioink that allows for in situ cell expansion prior to cardiac differentiation. The pressure sensor described here utilized electrical impedance tomography to enable the real-time spatiotemporal mapping of pressure distribution. A cryoablation tip catheter was applied to the composite bionic tissues with varied pressure. We found a close correlation between the cell response to ablation and the applied pressure. Under some conditions, cardiomyocytes could survive in the ablated region with more rounded morphology compared to the unablated controls, and connectivity was disrupted. This is the first known functional characterization of living human cardiomyocytes following an ablation procedure that suggests several mechanisms by which arrhythmia might redevelop following an ablation. Thus, bionic-engineered testbeds of this type can be indicators of tissue health and function and provide unique insight into human cell responses to ablative interventions.

Vitrification and Rewarming of Magnetic Nanoparticle-Loaded Rat Hearts.

To extend the preservation of donor hearts beyond the current 4-6 h, this paper explores heart cryopreservation by vitrification-cryogenic storage in a glass-like state. While organ vitrification is made possible by using cryoprotective agents (CPA) that inhibit ice during cooling, failure occurs during convective rewarming due to slow and non-uniform rewarming which causes ice crystallization and/or cracking. Here an alternative, "nanowarming", which uses silica-coated iron oxide nanoparticles (sIONPs) perfusion loaded through the vasculature is explored, that allows a radiofrequency coil to rewarm the organ quickly and uniformly to avoid convective failures. Nanowarming has been applied to cells and tissues, and a proof of principle study suggests it is possible in the heart, but proper physical and biological characterization especially in organs is still lacking. Here, using a rat heart model, controlled machine perfusion loading and unloading of CPA and sIONPs, cooling to a vitrified state, and fast and uniform nanowarming without crystallization or cracking is demonstrated. Further, nanowarmed hearts maintain histologic appearance and endothelial integrity superior to convective rewarming and indistinguishable from CPA load/unload control hearts while showing some promising organ-level (electrical) functional activity. This work demonstrates physically successful heart vitrification and nanowarming and that biological outcomes can be expected to improve by reducing or eliminating CPA toxicity during loading and unloading.

Novel mapping techniques for rotor core detection using simulated intracardiac electrograms.

BACKGROUND: Catheter ablation is associated with limited success rates in patients with persistent atrial fibrillation (AF). Currently, existing mapping systems fail to identify critical target sites for ablation. Recently, we proposed and validated several techniques (multiscale frequency [MSF], Shannon entropy [SE], kurtosis [Kt], and multiscale entropy [MSE]) to identify pivot point of rotors using ex-vivo optical mapping animal experiments. However, the performance of these techniques is unclear for the clinically recorded intracardiac electrograms (EGMs), due to the different nature of the signals. OBJECTIVE: This study aims to evaluate the performance of MSF, MSE, SE, and Kt techniques to identify the pivot point of the rotor using unipolar and bipolar EGMs obtained from numerical simulations. METHODS: Stationary and meandering rotors were simulated in a 2D human atria. The performances of new approaches were quantified by comparing the "true" core of the rotor with the core identified by the techniques. Also, the performances of all techniques were evaluated in the presence of noise, scar, and for the case of the multielectrode multispline and grid catheters. RESULTS: Our results demonstrate that all the approaches are able to accurately identify the pivot point of both stationary and meandering rotors from both unipolar and bipolar EGMs. The presence of noise and scar tissue did not significantly affect the performance of the techniques. Finally, the core of the rotors was correctly identified for the case of multielectrode multispline and grid catheter simulations. CONCLUSION: The core of rotors can be successfully identified from EGMs using novel techniques; thus, providing motivation for future clinical implementations.

Similarity Score for the Identification of Active Sites in Patients With Atrial Fibrillation.

BACKGROUND: Atrial fibrillation (AF) is the most common cardiac arrhythmia and precursor to other cardiac diseases. Catheter ablation is associated with limited success rates in patients with persistent AF. Currently, existing mapping systems fail to identify critical target sites for ablation. Recently, we proposed and validated several individual techniques, such as dominant frequency (DF), multiscale frequency (MSF), kurtosis (Kt), and multiscale entropy (MSE), to identify active sites of arrhythmias using simulated intracardiac electrograms (iEGMs). However, the individual performances of these techniques to identify arrhythmogenic substrates are not reliable. OBJECTIVE: This study aimed to develop a similarity score using various iEGM analysis techniques to more accurately identify the spatial location of active sites of arrhythmia in patients with AF. METHODS: Clinical bipolar iEGMs were obtained from patients with AF who underwent either successful (m = 4) or unsuccessful (m = 4) catheter ablation. A similarity score (0-3) was developed via the earth mover's distance (EMD) approach based on a combination of DF, MSF, MSE, and Kt techniques. RESULTS: Individual techniques successfully discriminated between successful and unsuccessful AF ablation patients but were not reliable in identifying active spatial sites of AF. However, the proposed similarity score was able to pinpoint the spatial sites with high values (active AF sites) that were observed only in patients with unsuccessful AF termination, suggesting that these active sites were missed during the ablation procedure. CONCLUSION: Arrhythmogenic substrates with abnormal electrical activity are identified in patients with unsuccessful AF termination after catheter ablation, suggesting clinical efficacy of similarity score.

Towards the Development of Nonlinear Approaches to Discriminate AF from NSR Using a Single-Lead ECG.

Paroxysmal atrial fibrillation (Paro. AF) is challenging to identify at the right moment. This disease is often undiagnosed using currently existing methods. Nonlinear analysis is gaining importance due to its capability to provide more insight into complex heart dynamics. The aim of this study is to use several recently developed nonlinear techniques to discriminate persistent AF (Pers. AF) from normal sinus rhythm (NSR), and more importantly, Paro. AF from NSR, using short-term single-lead electrocardiogram (ECG) signals. Specifically, we adapted and modified the time-delayed embedding method to minimize incorrect embedding parameter selection and further support to reconstruct proper phase plots of NSR and AF heart dynamics, from MIT-BIH databases. We also examine information-based methods, such as multiscale entropy (MSE) and kurtosis (Kt) for the same purposes. Our results demonstrate that embedding parameter time delay ( τ ), as well as MSE and Kt values can be successfully used to discriminate between Pers. AF and NSR. Moreover, we demonstrate that τ and Kt can successfully discriminate Paro. AF from NSR. Our results suggest that nonlinear time-delayed embedding method and information-based methods provide robust discriminating features to distinguish both Pers. AF and Paro. AF from NSR, thus offering effective treatment before suffering chaotic Pers. AF.

Optimizing Multiscale Entropy Approach for Rotor Core Identification using Simulated Intracardiac Electrograms.

Atrial Fibrillation (AF) is most common sustained cardiac arrhythmia and a precursor to many fatal cardiac conditions. Catheter ablation, which is a minimally invasive treatment, is associated with limited success rates in patients with persistent AF. Rotors are believed to maintain AF and core of rotors are considered to be robust targets for ablation. Recently, multiscale entropy (MSE) was proposed to identify the core of rotors in ex-vivo rabbit hearts. However, MSE technique is sensitive to intrinsic parameters, such as scale factor and template dimension, that may lead to an imprecise estimation of entropy measures. The purpose of this research is optimize MSE approach to improve its accuracy and sensitivity in rotor core identification using simulated EGMs from human atrial model. Specifically, we have identified the optimal time scale factor (τopt) and optimal template dimension (Τopt) that are needed for efficient rotor core identification. The τopt was identified to be 10, using a convergence graph, and the Τopt (~20 ms) remained the same at different sampling rates, indicating that optimized MSE will be efficient in identifying core of the rotor irrespective of the signal acquisition system.

In Situ Expansion, Differentiation, and Electromechanical Coupling of Human Cardiac Muscle in a 3D Bioprinted, Chambered Organoid.

RATIONALE: One goal of cardiac tissue engineering is the generation of a living, human pump in vitro that could replace animal models and eventually serve as an in vivo therapeutic. Models that replicate the geometrically complex structure of the heart, harboring chambers and large vessels with soft biomaterials, can be achieved using 3-dimensional bioprinting. Yet, inclusion of contiguous, living muscle to support pump function has not been achieved. This is largely due to the challenge of attaining high densities of cardiomyocytes-a notoriously nonproliferative cell type. An alternative strategy is to print with human induced pluripotent stem cells, which can proliferate to high densities and fill tissue spaces, and subsequently differentiate them into cardiomyocytes in situ. OBJECTIVE: To develop a bioink capable of promoting human induced pluripotent stem cell proliferation and cardiomyocyte differentiation to 3-dimensionally print electromechanically functional, chambered organoids composed of contiguous cardiac muscle. METHODS AND RESULTS: We optimized a photo-crosslinkable formulation of native ECM (extracellular matrix) proteins and used this bioink to 3-dimensionally print human induced pluripotent stem cell-laden structures with 2 chambers and a vessel inlet and outlet. After human induced pluripotent stem cells proliferated to a sufficient density, we differentiated the cells within the structure and demonstrated function of the resultant human chambered muscle pump. Human chambered muscle pumps demonstrated macroscale beating and continuous action potential propagation with responsiveness to drugs and pacing. The connected chambers allowed for perfusion and enabled replication of pressure/volume relationships fundamental to the study of heart function and remodeling with health and disease. CONCLUSIONS: This advance represents a critical step toward generating macroscale tissues, akin to aggregate-based organoids, but with the critical advantage of harboring geometric structures essential to the pump function of cardiac muscle. Looking forward, human chambered organoids of this type might also serve as a test bed for cardiac medical devices and eventually lead to therapeutic tissue grafting.

Evaluation of Multiscale Frequency Approach for Visualizing Rotors in Patients with Atrial Fibrillation.

Atrial Fibrillation (AF) is most common cardiac arrhythmia. It is associated with increased risk of stroke, heart failure and sudden cardiac death. Catheter ablation is a treatment used to control AF and has had suboptimal success for patients with persistent AF, which is primarily maintained by rotors outside of the pulmonary veins (PV) region. The pivot point (core) of the rotor is considered an efficient target for ablation. Currently available electro-anatomical mapping systems cannot accurately predict the exact location of the pivot point of rotors outside of the PV region, so there is a need for novel approaches to accurately identify and distinguish sites for ablation. Recently, a multiscale frequency (MSF) technique was developed for accurate identification of the pivot point of rotors and validated using optical mapping experiments in exvivo rabbit hearts, where electrical activity can be directly visualized. However, the nature of optical signals and its spatial resolution are very different from clinical intracardiac electrograms (iEGM). Here we extend the MSF approach to 3D iEGM and compare its prediction with the traditional dominant frequency (DF) approach, using Pearson's correlation and earth mover's distance methods. Our results demonstrate that the similarity between MSF and DF are high in some regions, but very low in other spatial regions of the human atria. This indicates the inconsistency in the traditional DF approach in identifying pivot points and identifying such low similarity regions can be used to find sites for successful ablation.