Contributions To The Methodology Of Electrocardiographic Imaging (ECGI) And Application Of ECGI To Study Mechanisms Of Atrial Arrhythmia, Post Myocardial Infarction Electrophysiological Substrate, And Ventricular Tachycardia In Patients

ABSTRACT OF THE DISSERTATION Contributions to the Methodology of Electrocardiographic Imaging: ECGI) and Application of ECGI to Study Mechanisms of Atrial Arrhythmia, Post Myocardial Infarction Electrophysiological Substrate, and Ventricular Tachycardia in Patients by Yong Wang Doctor of Philosophy in Biomedical Engineering Washington University in St. Louis, 2009 Professor Yoram Rudy, Chair Electrocardiographic Imaging: ECGI) is a noninvasive imaging modality for cardiac electrophysiology and arrhythmia. ECGI reconstructs epicardial potentials, electrograms and isochrones from body-surface electrocardiograms combined with heart-torso geometry from computed tomography: CT). The application of a new meshless method, the Method of Fundamental Solutions: MFS) is introduced to ECGI with the following major advantages: 1. Elimination of meshing and manual mesh optimization processes, thereby enhancing automation and speeding the ECGI procedure. 2. Elimination of mesh-induced artifacts. 3. Simpler implementation. These properties of MFS enhance the practical application of ECGI as a clinical diagnostic tool. The current ECGI mode of operation is offline with generation of epicardial potential maps delayed to data acquisition. A real time ECGI procedure is proposed, by which the epicardial potentials can be reconstructed while the body surface potential data are acquired: \u3c 1msec/frame) during a clinical procedure. This development enables real-time monitoring, diagnosis, and interactive guidance of intervention for arrhythmia therapy. ECGI is applied to map noninvasively the electrophysiological substrate in eight post-MI patients during sinus rhythm: SR). Contrast-enhanced MRI: ceMRI) is conducted to determine anatomical scar. ECGI imaged regions of electrical scar corresponded closely in location, extent, and morphology to the anatomical scars. In three patients, late diastolic potentials are imaged in the scar epicardial border zone during SR. Scar-related ventricular tachycardia: VT) in two patients are imaged, showing the VT activation sequence in relation to the abnormal electrophysiological substrate. ECGI imaging the substrate in a beat-by-beat fashion could potentially help in noninvasive risk stratification for post-MI arrhythmias and facilitate substrate-based catheter ablation of these arrhythmias. ECGI is applied to eleven consecutive patients referred for VT catheter ablation procedure. ECGI is performed either before: 8 patients) or during: 3 patients) the ablation procedure. Blinded ECGI and invasive electrophysiology: EP) study results are compared. Over a wide range of VT types and locations, ECGI results are consistent with EP data regarding localization of the arrhythmia origin: including myocardial depth) and mechanism: focal, reentrant, fascicular). ECGI also provides mechanistic electrophysiological insights, relating arrhythmia patterns to the myocardial substrate. The study shows ECGI has unique potential clinical advantages, especially for hemodynamically intolerant VT or VT that is difficult to induce. Because it provides local cardiac information, ECGI may aid in better understanding of mechanisms of ventricular arrhythmia. Further prospective trials of ECGI with clinical endpoints are warranted. Many mechanisms for the initiation and perpetuation of atrial fibrillation: AF) have been demonstrated over the last several decades. The tools to study these mechanisms in humans have limitations, the most common being invasiveness of a mapping procedure. In this paper, we present simultaneous noninvasive biatrial epicardial activation sequences of AF in humans, obtained using the Electrocardiographic Imaging: ECGI) system, and analyzed in terms of mechanisms and complexity of activation patterns. We performed ECGI in 36 patients with a diagnosis of AF. To determine ECGI atrial accuracy, atrial pacing from different sites was performed in six patients: 37 pacing events), and ECGI was compared to registered CARTO images. Then, ECGI was performed on all 36 patients during AF and ECGI epicardial maps were analyzed for mechanisms and complexity. ECGI noninvasively imaged the low-amplitude signals of AF in a wide range of patients: 97% procedural success). The spatial accuracy in determining initiation sites as simulated by atrial pacing was ~ 6mm. ECGI imaged many activation patterns of AF, most commonly multiple wavelets: 92%), with pulmonary vein: 69%) and non-pulmonary vein: 62%) trigger sites. Rotor activity was seen rarely: 15%). AF complexity increased with longer clinical history of AF, though the degree of complexity of nonparoxysmal AF varied and overlapped. ECGI offers a way to identify unique epicardial activation patterns of AF in a patient-specific manner. The results are consistent with contemporary animal models of AF mechanisms and highlight the coexistence of a variety of mechanisms among patients

Flexible microelectrode arrays to interface epicardial electrical signals with intracardial calcium transients in zebrafish hearts

The zebrafish (Danio rerio) is an emerging genetic model for regenerative medicine. In humans, myocardial infarction results in the irreversible loss of cardiomyocytes. However, zebrafish hearts fully regenerate after a 20% ventricular resection, without either scarring or arrhythmias. To study this cardiac regeneration, we developed implantable flexible multi-microelectrode membrane arrays that measure the epicardial electrocardiogram signals of zebrafish in real-time. The microelectrode electrical signals allowed for a high level of both temporal and spatial resolution (~20 μm), and the signal to noise ratio of the epicardial ECG was comparable to that of surface electrode ECG (7.1 dB vs. 7.4 dB, respectively). Processing and analysis of the signals from the microelectrode array demonstrated distinct ECG signals: namely, atrial conduction (P waves), ventricular contraction (QRS), and ventricular repolarization (QT interval). The electrical signals were in synchrony with optically measured Calcium concentration gradients in terms of d[Ca^(2+)]/dt at both whole heart and tissue levels. These microelectrodes therefore provide a real-time analytical tool for monitoring conduction phenotypes of small vertebral animals with a high temporal and spatial resolution

Validation and Opportunities of Electrocardiographic Imaging: From Technical chievements to Clinical Applications

[EN] Electrocardiographic imaging (ECGI) reconstructs the electrical activity of the heart from a dense array of body-surface electrocardiograms and a patient-specific heart-torso geometry. Depending on how it is formulated, ECGI allows the reconstruction of the activation and recovery sequence of the heart, the origin of premature beats or tachycardia, the anchors/hotspots of re-entrant arrhythmias and other electrophysiological quantities of interest. Importantly, these quantities are directly and non-invasively reconstructed in a digitized model of the patient's three-dimensional heart, which has led to clinical interest in ECGI's ability to personalize diagnosis and guide therapy. Despite considerable development over the last decades, validation of ECGI is challenging. Firstly, results depend considerably on implementation choices, which are necessary to deal with ECGI's ill-posed character. Secondly, it is challenging to obtain (invasive) ground truth data of high quality. In this review, we discuss the current status of ECGI validation as well as the major challenges remaining for complete adoption of ECGI in clinical practice. Specifically, showing clinical benefit is essential for the adoption of ECGI. Such benefit may lie in patient outcome improvement, workflow improvement, or cost reduction. Future studies should focus on these aspects to achieve broad adoption of ECGI, but only after the technical challenges have been solved for that specific application/pathology. We propose 'best' practices for technical validation and highlight collaborative efforts recently organized in this field. Continued interaction between engineers, basic scientists, and physicians remains essential to find a hybrid between technical achievements, pathological mechanisms insights, and clinical benefit, to evolve this powerful technique toward a useful role in clinical practice.This study received financial support from the Hein Wellens Fonds, the Cardiovascular Research and Training Institute (CVRTI), the Nora Eccles Treadwell Foundation, the National Institute of General Medical Sciences of the National Institutes of Health (P41GM103545), the National Institutes of Health (NIH HL080093), the French government as part of the Investments of the Future program managed by the National Research Agency (ANR-10-IAHU-04), from the VEGA Grant Agency in Slovakia (2/0071/16), from the Slovak Research and Development Agency (APVV-14-0875), the Fondo Europeo de Desarrollo Regional (FEDER), the Instituto de Salud Carlos III (PI17/01106) and from Conselleria d'Educacio, Investigacio, Cultura i Esport de la Generalitat Valenciana (AICO/2018/267) and NIH grant (HL125998) and National Science Foundation (ACI-1350374).Cluitmans, M.; Brooks, D.; Macleod, RS.; Dossel, O.; Guillem Sánchez, MS.; Van Dam, P.; Svehlikova, J.... 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Doctor of Philosophy

dissertationInverse Electrocardiography (ECG) aims to noninvasively estimate the electrophysiological activity of the heart from the voltages measured at the body surface, with promising clinical applications in diagnosis and therapy. The main challenge of this emerging technique lies in its mathematical foundation: an inverse source problem governed by partial differential equations (PDEs) which is severely ill-conditioned. Essential to the success of inverse ECG are computational methods that reliably achieve accurate inverse solutions while harnessing the ever-growing complexity and realism of the bioelectric simulation. This dissertation focuses on the formulation, optimization, and solution of the inverse ECG problem based on finite element methods, consisting of two research thrusts. The first thrust explores the optimal finite element discretization specifically oriented towards the inverse ECG problem. In contrast, most existing discretization strategies are designed for forward problems and may become inappropriate for the corresponding inverse problems. Based on a Fourier analysis of how discretization relates to ill-conditioning, this work proposes refinement strategies that optimize approximation accuracy o f the inverse ECG problem while mitigating its ill-conditioning. To fulfill these strategies, two refinement techniques are developed: one uses hybrid-shaped finite elements whereas the other adapts high-order finite elements. The second research thrust involves a new methodology for inverse ECG solutions called PDE-constrained optimization, an optimization framework that flexibly allows convex objectives and various physically-based constraints. This work features three contributions: (1) fulfilling optimization in the continuous space, (2) formulating rigorous finite element solutions, and (3) fulfilling subsequent numerical optimization by a primal-dual interiorpoint method tailored to the given optimization problem's specific algebraic structure. The efficacy o f this new method is shown by its application to localization o f cardiac ischemic disease, in which the method, under realistic settings, achieves promising solutions to a previously intractable inverse ECG problem involving the bidomain heart model. In summary, this dissertation advances the computational research of inverse ECG, making it evolve toward an image-based, patient-specific modality for biomedical research

Model-based quantification of systolic and diastolic left ventricular mechanics

Het linker ventrikel (LV) is de meest gespierde kamer van het hart. Door het gecoördineerd samentrekken van de spiercellen in de LV-wand wordt zuurstofrijk bloed in de aorta gepompt (systolische fase). Daarna ontspannen de spiercellen zich snel waardoor het LV opnieuw met bloed wordt gevuld (diastolische fase). In de kliniek en de onderzoekswereld bestaat er een waaier van modelgebaseerde methoden en concepten om de performantie en de mechanische eigenschappen van het LV te kwantificeren. Invasief bekomen druk- en volumedata laten toe om de systolische en diastolische mechanica van het LV met grote nauwkeurigheid te kennen. In de klinische praktijk wordt echter vaker gebruik gemaakt van (Doppler-) echocardiografie, een snelle en veilige niet-invasieve beeldtechniek. In een eerste deel van dit doctoraatsonderzoek werd een originele methode voorgesteld om, op basis van echocardiografie en klassieke bloeddrukmetingen, de intrinsieke krachtontwikkeling (contractiliteit) van het LV te schatten. De methode werd toegepast bij 2524 mensen die deelnemen aan de Asklepios-studie. De onderzoeksresultaten verschaften ons nieuwe informatie over hoe de evolutie van de krachtontwikkeling verschilt tussen gezonde mannen en vrouwen. De mechanische en vloeistofdynamische fenomenen tijdens de diastole vormden het onderwerp van het tweede deel van het onderzoek. Met behulp van een hydraulisch model van het LV werd nagegaan welke factoren een belangrijke invloed uitoefenen op het gedrag van het LV tijdens de isovolumetrische ontspanningsfase. In dit deel werd eveneens een uitgebreid overzicht gegeven van de meest recente echocardiografische methoden om de diastolische LV-mechanica te begroten. Daarbij werden de bloedstroming, de wandbeweging en de interactie tussen beiden gedetailleerd behandeld

Electromechanical Wave Imaging

Cardiac conduction abnormalities and arrhythmias are associated with stroke, heart failure, and sudden cardiac death, and remain a major cause of death and disability. However, the imaging tools currently available to the physician to guide these treatments by mapping the activation sequence of the heart are invasive, ionizing, time-consuming, and costly. In this dissertation, Electromechanical Wave Imaging (EWI) is described with an aim to characterize normal and abnormal rhythms noninvasively, transmurally, at the point of care, and in real time. More specifically, the methods to map the electromechanical wave (EW), i.e., the transient deformations occurring in response to the electrical activation of the heart, are developed and optimized. The correlation between EW and the electrical activation sequence during both normal and abnormal rhythms is demonstrated in canines in vivo and in silico. Finally, EWI is shown to noninvasively detect and characterize arrhythmias and conduction disorders in humans. Novel ultrasound imaging methodologies were developed to track the EW. Radio-frequency (RF) frames acquired at high frame rates were used in conjunction with cross-correlation algorithms to map the onset of the small, localized, transient deformations resulting from the electrical activation and forming the EW. To validate the capability of the EW to characterize cardiac rhythm, it was compared against the electrical activation in vivo and in silico. A high correlation between the electrical and electromechanical activations was obtained in normal canines in vivo during various pacing schemes and sinus rhythm. An in vivo-in silico framework was also developed to demonstrate that this correlation is maintained transmurally and independently of the imaging angle. EWI was also validated in abnormal canine hearts in vivo during ischemia, left bundle branch block, or atrio-ventricular dissociation. In a clinical feasibility study, we demonstrated that EWI was capable of noninvasively mapping normal and abnormal activation patterns in all four cardiac chambers of human subjects using a readily available clinical ultrasound scanner. Specifically, EWI maps were generated for three heart failure patients with cardiac resynchronization therapy (CRT) devices and for three patients with atrial flutter who subsequently underwent catheter mapping and radiofrequency ablation. Preliminary validation of EWI maps against invasive transcutaneous electroanatomical cardiac mapping was also demonstrated. EWI has the potential of becoming a noninvasive and highly translational technology that can serve as a unique imaging tool for the early detection, diagnosis and treatment monitoring and follow-up of arrhythmias and conduction disorders through ultrasound-based mapping of the transmural electromechanical activation sequence reliably, at the point of care, and in real time

Critical appraisal of technologies to assess electrical activity during atrial fibrillation: a position paper from the European Heart Rhythm Association and European Society of Cardiology Working Group on eCardiology in collaboration with the Heart Rhythm Society, Asia Pacific Heart Rhythm Society, Latin American Heart Rhythm Society and Computing in Cardiology

We aim to provide a critical appraisal of basic concepts underlying signal recording and processing technologies applied for (i) atrial fibrillation (AF) mapping to unravel AF mechanisms and/or identifying target sites for AF therapy and (ii) AF detection, to optimize usage of technologies, stimulate research aimed at closing knowledge gaps, and developing ideal AF recording and processing technologies. Recording and processing techniques for assessment of electrical activity during AF essential for diagnosis and guiding ablative therapy including body surface electrocardiograms (ECG) and endo- or epicardial electrograms (EGM) are evaluated. Discussion of (i) differences in uni-, bi-, and multi-polar (omnipolar/Laplacian) recording modes, (ii) impact of recording technologies on EGM morphology, (iii) global or local mapping using various types of EGM involving signal processing techniques including isochronal-, voltage- fractionation-, dipole density-, and rotor mapping, enabling derivation of parameters like atrial rate, entropy, conduction velocity/direction, (iv) value of epicardial and optical mapping, (v) AF detection by cardiac implantable electronic devices containing various detection algorithms applicable to stored EGMs, (vi) contribution of machine learning (ML) to further improvement of signals processing technologies. Recording and processing of EGM (or ECG) are the cornerstones of (body surface) mapping of AF. Currently available AF recording and processing technologies are mainly restricted to specific applications or have technological limitations. Improvements in AF mapping by obtaining highest fidelity source signals (e.g. catheter–electrode combinations) for signal processing (e.g. filtering, digitization, and noise elimination) is of utmost importance. Novel acquisition instruments (multi-polar catheters combined with improved physical modelling and ML techniques) will enable enhanced and automated interpretation of EGM recordings in the near future