Relationship between body surface potential maps and atrial electrograms in patients with atrial fibrillation

PhD ThesisAtrial fibrillation (AF) is the most common cardiac arrhythmia. It is distinguished by fibrillating or trembling of the atrial muscle instead of normal contraction. Patients in AF have a much higher risk of stroke. AF is often driven by the left atrium (LA) and the diagnosis of AF is normally made from lead V1 in a 12-lead electrocardiogram (ECG). However, lead V1 is dominated by right atrial activity due to its proximal location to the right atrium (RA). Consequently it is not well understood how electrical activity from the LA contributes to the ECG. Studies of the AF mechanisms from the LA are typically based on invasive recording techniques. From a clinical point of view it is highly desirable to have an alternative, non-invasive characterisation of AF. The aim of this study was to investigate how the LA electrical activity was expressed on the body surface, and if it could be observed preferentially in different sites on the body surface. For this purpose, electrical activity of the heart from 20 patients in AF were recorded simultaneously using 64-lead body surface potential mapping (BSPM) and bipolar 10-electrode catheters located in the LA and coronary sinus (CS). Established AF characteristics such as amplitude, dominant frequency (DF) and spectral concentration (SC) were estimated and analysed. Furthermore, two novel AF characteristics (intracardiac DF power distribution, and body surface spectral peak type) were proposed to investigate the relationship between the BSPM and electrogram (EGM) recordings. The results showed that although in individual patients there were body surface sites that preferentially represented the AF characteristics estimated from the LA, those sites were not consistent across all patients. It was found that the left atrial activity could be detected in all body surface sites such that all sites had a dominant or non-dominant spectral peak corresponding to EGM DF. However, overall the results suggested that body surface site 22 (close to lead V1) was more closely representative of the CS activity, and site 49 (close to the posterior lower central right) was more closely representative of the left atrial activity. There was evidence of more accurate estimation of AF characteristics using additional electrodes to lead V1

Characterization and processing of novel neck photoplethysmography signals for cardiorespiratory monitoring

Epilepsy is a neurological disorder causing serious brain seizures that severely affect the patients' quality of life. Sudden unexpected death in epilepsy (SUDEP), for which no evident decease reason is found after post-mortem examination, is a common cause of mortality. The mechanisms leading to SUDEP are uncertain, but, centrally mediated apneic respiratory dysfunction, inducing dangerous hypoxemia, plays a key role. Continuous physiological monitoring appears as the only reliable solution for SUDEP prevention. However, current seizure-detection systems do not show enough sensitivity and present a high number of intolerable false alarms. A wearable system capable of measuring several physiological signals from the same body location, could efficiently overcome these limitations. In this framework, a neck wearable apnea detection device (WADD), sensing airflow through tracheal sounds, was designed. Despite the promising performance, it is still necessary to integrate an oximeter sensor into the system, to measure oxygen saturation in blood (SpO2) from neck photoplethysmography (PPG) signals, and hence, support the apnea detection decision. The neck is a novel PPG measurement site that has not yet been thoroughly explored, due to numerous challenges. This research work aims to characterize neck PPG signals, in order to fully exploit this alternative pulse oximetry location, for precise cardiorespiratory biomarkers monitoring. In this thesis, neck PPG signals were recorded, for the first time in literature, in a series of experiments under different artifacts and respiratory conditions. Morphological and spectral characteristics were analyzed in order to identify potential singularities of the signals. The most common neck PPG artifacts critically corrupting the signal quality, and other breathing states of interest, were thoroughly characterized in terms of the most discriminative features. An algorithm was further developed to differentiate artifacts from clean PPG signals. Both, the proposed characterization and classification model can be useful tools for researchers to denoise neck PPG signals and exploit them in a variety of clinical contexts. In addition to that, it was demonstrated that the neck also offered the possibility, unlike other body parts, to extract the Jugular Venous Pulse (JVP) non-invasively. Overall, the thesis showed how the neck could be an optimum location for multi-modal monitoring in the context of diseases affecting respiration, since it not only allows the sensing of airflow related signals, but also, the breathing frequency component of the PPG appeared more prominent than in the standard finger location. In this context, this property enabled the extraction of relevant features to develop a promising algorithm for apnea detection in near-real time. These findings could be of great importance for SUDEP prevention, facilitating the investigation of the mechanisms and risk factors associated to it, and ultimately reduce epilepsy mortality.Open Acces

Development of a Novel Dataset and Tools for Non-Invasive Fetal Electrocardiography Research

This PhD thesis presents the development of a novel open multi-modal dataset for advanced studies on fetal cardiological assessment, along with a set of signal processing tools for its exploitation. The Non-Invasive Fetal Electrocardiography (ECG) Analysis (NInFEA) dataset features multi-channel electrophysiological recordings characterized by high sampling frequency and digital resolution, maternal respiration signal, synchronized fetal trans-abdominal pulsed-wave Doppler (PWD) recordings and clinical annotations provided by expert clinicians at the time of the signal collection. To the best of our knowledge, there are no similar dataset available. The signal processing tools targeted both the PWD and the non-invasive fetal ECG, exploiting the recorded dataset. About the former, the study focuses on the processing aimed at the preparation of the signal for the automatic measurement of relevant morphological features, already adopted in the clinical practice for cardiac assessment. To this aim, a relevant step is the automatic identification of the complete and measurable cardiac cycles in the PWD videos: a rigorous methodology was deployed for the analysis of the different processing steps involved in the automatic delineation of the PWD envelope, then implementing different approaches for the supervised classification of the cardiac cycles, discriminating between complete and measurable vs. malformed or incomplete ones. Finally, preliminary measurement algorithms were also developed in order to extract clinically relevant parameters from the PWD. About the fetal ECG, this thesis concentrated on the systematic analysis of the adaptive filters performance for non-invasive fetal ECG extraction processing, identified as the reference tool throughout the thesis. Then, two studies are reported: one on the wavelet-based denoising of the extracted fetal ECG and another one on the fetal ECG quality assessment from the analysis of the raw abdominal recordings. Overall, the thesis represents an important milestone in the field, by promoting the open-data approach and introducing automated analysis tools that could be easily integrated in future medical devices

Denoising Magnetic Resonance Spectroscopy (MRS) Data Using Stacked Autoencoder for Improving Signal-to-Noise Ratio and Speed of MRS

Background: Magnetic resonance spectroscopy (MRS) enables non-invasive detection and measurement of biochemicals and metabolites. However, MRS has low signal-to-noise ratio (SNR) when concentrations of metabolites are in the range of the million molars. Standard approach of using a high number of signal averaging (NSA) to achieve sufficient NSR comes at the cost of a long acquisition time. Purpose: We propose to use deep-learning approaches to denoise MRS data without increasing the NSA. Methods: The study was conducted using data collected from the brain spectroscopy phantom and human subjects. We utilized a stack auto-encoder (SAE) network to train deep learning models for denoising low NSA data (NSA = 1, 2, 4, 8, and 16) randomly truncated from high SNR data collected with high NSA (NSA=192) which were also used to obtain the ground truth. We applied both self-supervised and fully-supervised training approaches and compared their performance of denoising low NSA data based on improved SNRs. Results: With the SAE model, the SNR of low NSA data (NSA = 1) obtained from the phantom increased by 22.8% and the MSE decreased by 47.3%. For low NSA images of the human parietal and temporal lobes, the SNR increased by 43.8% and the MSE decreased by 68.8%. In all cases, the chemical shift of NAA in the denoised spectra closely matched with the high SNR spectra, suggesting no distortion to the spectra from denoising. Furthermore, the denoising performance of the SAE model was more effective in denoising spectra with higher noise levels. Conclusions: The reported SAE denoising method is a model-free approach to enhance the SNR of low NSA MRS data. With the denoising capability, it is possible to acquire MRS data with a few NSA, resulting in shorter scan times while maintaining adequate spectroscopic information for detecting and quantifying the metabolites of interest

Estrazione non invasiva del segnale elettrocardiografico fetale da registrazioni con elettrodi posti sull’addome della gestante (Non-invasive extraction of the fetal electrocardiogram from abdominal recordings by positioning electrodes on the pregnant woman’s abdomen)

openIl cuore è il primo organo che si sviluppa nel feto, particolarmente nelle primissime settimane di gestazione. Rispetto al cuore adulto, quello fetale ha una fisiologia ed un’anatomia significativamente differenti, a causa della differente circolazione cardiovascolare. Il benessere fetale si valuta monitorando l’attività cardiaca mediante elettrocardiografia fetale (ECGf). L’ECGf invasivo (acquisito posizionando elettrodi allo scalpo fetale) è considerato il gold standard, ma l’invasività che lo caratterizza ne limita la sua applicabilità. Al contrario, l’uso clinico dell’ECGf non invasivo (acquisito posizionando elettrodi sull’addome della gestante) è limitato dalla scarsa qualità del segnale risultante. L’ECGf non invasivo si estrae da registrazioni addominali, che sono corrotte da differenti tipi di rumore, fra i quali l’interferenza primaria è rappresentata dall’ECG materno. Il Segmented-Beat Modulation Method (SBMM) è stato da me recentemente proposto come una nuova procedura di filtraggio basata sul calcolo del template del battito cardiaco. SBMM fornisce una stima ripulita dell’ECG estratto da registrazioni rumorose, preservando la fisiologica variabilità ECG del segnale originale. Questa caratteristica è ottenuta grazie alla segmentazione di ogni battito cardiaco per indentificare i segmenti QRS e TUP, seguito dal processo di modulazione/demodulazione (che include strecciamento e compressione) del segmento TUP, per aggiustarlo in modo adattativo alla morfologia e alla durata di ogni battito originario. Dapprima applicato all’ECG adulto al fine di dimostrare la sua robustezza al rumore, l’SBMM è stato poi applicato al caso fetale. Particolarmente significativi sono i risultati relativi alle applicazioni su ECGf non invasivo, dove l’SBMM fornisce segnali caratterizzati da un rapporto segnale-rumore comparabile a quello caratterizzante l’ECGf invasivo. Tuttavia, l’SBMM può contribuire alla diffusione dell’ECGf non invasiva nella pratica clinica.The heart is the first organ that develops in the fetus, particularly in the very early stages of pregnancy. Compared to the adult heart, the physiology and anatomy of the fetal heart exhibit some significant differences. These differences originate from the fact that the fetal cardiovascular circulation is different from the adult circulation. Fetal well-being evaluation may be accomplished by monitoring cardiac activity through fetal electrocardiography (fECG). Invasive fECG (acquired through scalp electrodes) is the gold standard but its invasiveness limits its clinical applicability. Instead, clinical use of non-invasive fECG (acquired through abdominal electrodes) has so far been limited by its poor signal quality. Non-invasive fECG is extracted from the abdominal recording and is corrupted by different kind of noise, among which maternal ECG is the main interference. The Segmented-Beat Modulation Method (SBMM) was recently proposed by myself as a new template-based filtering procedure able to provide a clean ECG estimation from a noisy recording by preserving physiological ECG variability of the original signal. The former feature is achieved thanks to a segmentation procedure applied to each cardiac beat in order to identify the QRS and TUP segments, followed by a modulation/demodulation process (involving stretching and compression) of the TUP segments to adaptively adjust each estimated cardiac beat to the original beat morphology and duration. SBMM was first applied to adult ECG applications, in order to demonstrate its robustness to noise, and then to fECG applications. Particularly significant are the results relative to the non-invasive applications, where SBMM provided fECG signals characterized by a signal-to-noise ratio comparable to that characterizing invasive fECG. Thus, SBMM may contribute to the spread of this noninvasive fECG technique in the clinical practice.INGEGNERIA DELL'INFORMAZIONEAgostinelli, AngelaAgostinelli, Angel

Steady-state anatomical and quantitative magnetic resonance imaging of the heart using RF-frequencymodulated techniques

Cardiovascular disease (CVD) is the leading cause of death in the United States and Europe and generates healthcare costs of hundreds of billions of dollars annually. Conventional methods of diagnosing CVD are often invasive and carry risks for the patient. For example, the gold standard for diagnosing coronary artery disease, a major class of CVD, is x-ray coronary angiography, which has the disadvantages of being invasive, being expensive, using ionizing radiation, and having a ris k of complications. Conversely, coronary MR angiography (MRA) does not use ionizing radiation, can effectively visualize tissues without the need for exogenous contrast agents, and benefits from an adaptable temporal resolution. However, the acquisition time of cardiac MRI is far longer than the temporal scales of cardiac and respiratory motion, necessitating some method of compensating for this motion. The free-running framework is a novel development in our lab, benefitting from advances over the past three decades, that attempts to address disadvantages of previous cardiac MRI approaches: it provides fully self-gated 5D cardiac MRI with a simplified workflow, improved ease-of-use, reduced operator dependence, and automatic patient-specific motion detection. Free-running imaging increases the amount of information available to the clinician and is flexible enough to be translated to different app lications within cardiac MRI. Moreover, the self-gating of the free-running framework decoupled the acquisition from the motion compensation and thereby opened up cardiac MRI to the wider class of steady-state-based techniques utilizing balanced steady-state free precession (bSSFP) sequences, which have the benefits of practical simplicity and high signal-to-noise ratio. The focus of this thesis was therefore on the application of steady- state techniques to cardiac MRI. The first part addressed the long acquisition time of the current free-running framework and focused on anatomical coronary imaging. The published protocol of the free- running framework used an interrupted bSSFP acquisition where CHESS fat saturation modules were inserted to provide blood-fat contrast, as they suppress the signal of fat tissue surrounding the coronary arteries, and were followed by ramp-up pulses to reduce artefacts arising from the return to steady-state. This interrupted acquisition, however, suffered from an interrupted steady-state, reduced time efficiency, and higher specific absorption rate (SAR). Using novel lipid-insensitive binomial off-resonant RF excitation (LIBRE) pulses developed in our lab, the first project showed that LIBRE pulses incorporated into an uninterrupted free-running bSSFP sequence could be successfully used for 5D cardiac MRI at 1.5T. The free-running LIBRE approach reduced the acquisition time and SAR relative to the previous interrupted approach while maintaining image quality and vessel conspicuity. Furthermore, this had been the first successful use of a fat-suppressing RF excitation pulse in an uninterrupted bSSFP sequence for cardiac imaging, demonstrating that uninterrupted bSSFP can be used for cardiac MRI and addressing the problem of clinical sequence availability. Inspired by the feasibility of uninterrupted bSSFP for cardiac MRI, the second part investigated the potential of PLANET, a novel 3D multiparametric mapping technique, for free-running 5D myocardial mapping. PLANET utilizes a phase-cycled bSSFP acquisition and a direct ellipse-fitting algorithm to calculate T1 and T2 relaxation times, which suggested that it could be readily integrated into the free-running framework without interrupting the steady-state. After initially calibrating the acquisition, the possibility of accelerating the static PLANET acquisition was explored prior to applying it to the moving heart. It was shown that PLANET accuracy and precision could be maintained with two-fold acceleration with a 3D Cartesian spiral trajectory, suggesting that PLANET for myocardial mapping with the free-running 5D radial acquisition is feasible. Further work should investigate optimizing the reconstruction scheme, improving the coil sensitivity estimate, and examining the use of the radial trajectory with a view to implementing free-running 5D myocardial T1 and T2 mapping. This thesis presents two approaches utilizing RF-frequency-modulated steady-state techniques for cardiac MRI. The first approach involved the novel application of an uninterrupted bSSFP acquisition with off-resonant RF excitation for anatomical coronary imaging. The second approach investigated the use of phase-cycled bSSFP for free-running 5D myocardial T1 and T2 mapping. Both methods addressed the challenge of clinical availability of sequences in cardiac MRI, by showing that a common and simple sequence like bSSFP can be used for acquisition while the steps of motion compensation and reconstruction can be handled offline, and thus have the potential to improve adoption of cardiac MRI. -- Les maladies cardiovasculaires (MCV) représentent la principale cause de décès aux États-Unis et en Europe et génèrent des coûts de santé de plusieurs centaines de milliards de dollars par an. Les méthodes conventionnelles de diagnostic des MCV sont souvent invasives et comportent des risques pour le patient. Par exemple, la méthode de référence pour le diagnostic de la maladie coronarienne, une catégorie majeure de MCV, est la coronarographie par rayons X qui a comme inconvénients son caractère invasif, son coût, l’utilisation de rayonnements ionisants et le risque de complications. A l’inverse, l'angiographie coronarienne par résonance magnétique (ARM) n'utilise pas de rayonnements ionisants, permet de visualiser efficacement les tissus sans avoir recours à des agents de contraste exogènes et bénéficie d'une résolution temporelle ajustable. Cependant, le temps d'acquisition en IRM cardiaque est bien plus long que les échelles temporelles des mouvements cardiaques et respiratoires en jeu, ce qui rend la compensation de ces mouvements indispensable. Le cadre dit de « free -running » est un nouveau développement de notre laboratoire qui bénéficie des progrès réalisés au cours des trois dernières décennies et tente de remédier aux inconvénients des approches précédentes pour l'IRM cardiaque : il fournit une IRM cardiaque en cinq dimensions (5D) complètement « self-gated » , c’est-à-dire capable de détecter les mouvements cardiaques et respiratoires, forte d’une implémentation simplifiée, d’une plus grande facilité d'utilisation, d’une dépendance réduite vis-à-vis de l'opérateur et d’une détection automatique des mouvements spécifiques du patient. L'imagerie « free- running » augmente la quantité d'informations à disposition du clinicien et est suffisamment flexible pour être appliquée à différents domaines de l'IRM cardiaque. De plus, le « self-gating » du cadre « free-running » a découplé l'acquisition de la compensation de mouvement et a ainsi ouvert l'IRM cardiaque à la classe plus large des techniques basées sur l'état stationnaire utilisant des séquences de précession libre équilibrée en état stationnaire (bSSFP), qui se distinguent par leur simplicité d’utilisation et leur rapport signal sur bruit élevé. Le thème de cette thèse est donc l'application des techniques basées sur l'état stationnaire à l'IRM cardiaque. La première partie porte sur le long temps d'acquisition de l'actuel cadre « free-running» et se concentre sur l'imagerie anatomique coronaire. Le protocole publié utilise une acquisition bSSFP interrompue où des modules de saturation de graisse (CHESS) sont insérés de façon à fournir un contraste sang-graisse puisqu’ils suppriment le signal du tissu graisseux entourant les artères coronaires, et sont suivis par des impulsions en rampe pour réduire les artefacts résultant du retour à l'état stable. Cette acquisition interrompue souffre cependant d'un état d'équilibre interrompu, d'une efficacité temporelle réduite et d'un débit d'absorption spécifique (DAS) plus élevé. En utilisant les nouvelles impulsions d'excitation radiofréquence (RF) binomiales hors -résonance insensibles aux lipides (LIBRE) développées dans notre laboratoi re, ce premier projet montre que les impulsions LIBRE incorporées dans une séquence bSSFP ininterrompue et « free-running » peuvent être utilisées avec succès pour l'IRM cardiaque 5D à 1,5 T. L'approche « free-running LIBRE » permet de réduire le temps d'acquisition et le DAS par rapport à l'approche interrompue précédente, tout en maintenant la perceptibilité des artères coronariennes. En outre, il s'agit de la première utilisation réussie d'une impulsion d'excitation RF supprimant la graisse dans une séquence bSSFP ininterrompue pour l'imagerie cardiaque, ce qui démontre le potentiel d’utilisation de la séquence bSSFP ininterrompue pour l'IRM cardiaque et résout le problème de la disponibilité de la séquence en clinique. Inspirée par la faisabilité d’utilisation de la séquence bSSFP ininterrompue pour l'IRM cardiaque, la deuxième partie étudie le potentiel de PLANET, une nouvelle technique de cartographie 3D multiparamétrique, pour la cartographie 5D du myocarde via l’imagerie « free-running ». PLANET utilise une acquisition bSSFP à cycle de phase et un algorithme d'ajustement d'ellipse direct pour calculer les temps de relaxation T1 et T2, ce qui suggère que cette méthode pourrait être facilement intégrée au cadre « free - running » sans interruption de l’état d'équilibre. Après calibration de l'acquisition, nous explorons la possibilité d'accélérer l'acquisition statique de PLANET pour l'appliquer au cœur. Nous démontrons que l'exactitude et la précision de PLANET peuvent être maintenues pour une accélération double avec une trajectoire 3D cartésienne en spirale, ce qui suggère que PLANET est réalisable pour la cartographie du myocarde avec une acquisition radiale 5D « free-running ». D'autres travaux devraient porter sur l'optimisation du schéma de reconstruction, l'amélioration de l'estimation de la sensibilité de l’antenne et l'examen de l'utilisation de la trajectoire radiale en vue de la mise en œuvre de la cartographie 5D « free-running » T1 et T2 du myocarde. Cette thèse présente deux approches utilisant des techniques de modulation de fréquence radio en état stationnaire pour l'IRM cardiaque. La première approche implique l'application nouvelle d'une acquisition bSSFP ininterrompue avec une excitation RF hors résonance pour l'imagerie anatomique coronaire. La seconde approche porte sur l'utilisation d’une séquence bSSFP à cycle de phase pour la cartographie 5D T1 et T2 du myocarde. Ces deux méthodes permettent de répondre au défi posé par la disponibilité des séquences en IRM cardiaque en montrant qu'une séquence commune et simple comme la bSSFP peut être utilisée pour l'acquisition, tandis que les étapes de compensation du mouvement et de reconstruction peuvent être traitées hors ligne. Ainsi, ces méthodes ont le potentiel de favoriser l'adoption de l'IRM cardiaque

Assessment of ventricular repolarization instability and cardiac risk stratification in different pathological and abnormal conditions

Cardiovascular diseases (CVDs) represents the leading cause of mortality worldwide [1,2]. These pathological conditions are mainly characterized by a structurally abnormal heart, that is, a vulnerable substrate, prone to the abnormal generation and/or propagation of the electrical impulse, determining the onset of ventricular arrhythmias, which can result in sudden cardiac death (SCD) [3]. In this context, the assessment of ventricular repolarization from the electrocardiogram (ECG) signal has been shown to provide with valuable information for risk stratification and several electrocardiographic indices have been proposed in the literature [4]. The main objective of this thesis is to propose methodological advances for the assessment of ventricular repolarization instability in pathological and abnormal conditions. These contributions are aimed at improving the prediction of ventricular arrhythmias and, consequently, better identifying SCD risk. In particular, we have addressed this objective by developing robust methodologies for the assessment of T-wave alternans (TWA) and ventricular repolarization instability, in invasive and non-invasive cardiac signals, that have been evaluated in both experimental and clinical conditions. In the first part of the thesis, TWA was simultaneously characterized (prevalence, magnitude, time-course, and alternans waveform) in body-surface ECG and intracardiac electrograms (EGMs) signals during coronary artery occlusion. Signals from both body surface ECG and intracardiac EGMs recorded from 4 different anatomical heart locations (coronary sinus, epicardial space and left and right ventricles) were analyzed following a multilead strategy. Leads were linearly combined using the periodic component analysis (πCA) [5], which maximizes the 2-beat periodicity (TWA periodicity) content present on the available leads. Then the Laplacian Likelihood Ratio method (LLRM) [6] was applied for TWA detection and estimation. A sensitivity study for TWA detection from the 5 different locations of leads was performed, revealing that it is the combination of the ECG leads that better performs. In addition, this multilead approach allowed us to find the optimal combination of intracardiac leads usable for in-vivo monitorization of TWA directly from an implantable device, with a sensitivity comparable to the ECG analysis. These results encourage further research to determine the feasibility of predicting imminent VT/VF episodes by TWA analysis implemented in implantable cardioverter defibrillator’s (ICD) technology.Then, we have studied the potential changes induced by a prolonged exposure to simulated microgravity on ventricular repolarization in structurally normal hearts. It is well known that this environmental condition affects the control of autonomic and cardiovascular systems [7], with a potential increase on cardiac electrical instability. The effects of short- (5 days), mid- (21 days) and long- (60 days) exposure to simulated microgravity on TWA using the head-down bed-rest (HDBR) model [8] were assessed. TWA was evaluated before (PRE), during and after (POST) the immobilization period, by the long-term averaging technique in ambulatory ECG Holter recordings [9]. Additionally, we proposed an adapted short-term averaging approach for shorter, non-stationary ECG signals obtained during two stress manoeuvres (head-up tilt-table and bicycle exercise tests). Both approaches are based on the multilead analysis used in the previous study. The absence of significant changes between PRE and POST-HDBR on TWA indices suggests that a long-term exposure to simulated microgravity is not enough to induce alterations in healthy myocardial substrate up to the point of reflecting electrical instability in terms of TWA on the ECG. Finally, methodological advances were proposed for the assessment of ventricular repolarization instability from the ECG signal in the presence of sporadic (ventricular premature contractions, VPCs) and sustained (atrial fibrillation) rhythm disturbances.On the one hand, a methodological improvement for the estimation of TWA amplitude in ambulatory ECG recordings was proposed, which deals with the possible phase reversal on the alternans sequence induced by the presence of VPCs [10]. The performance of the algorithm was first evaluated using synthetic signals. Then, the effect of the proposed method in the prognostic value of TWA amplitude was assessed in real ambulatory ECG recordings from patients with chronic heart failure (CHF). Finally, circadian TWA changes were evaluated as well as the prognostic value of TWA at different times of the day. A clinical study demonstrated the enhancement in the predictive value of the index of average alternans (IAA) [9] for SCD stratification. In addition, results suggested that alternans activity is modulated by the circadian pattern, preserving its prognostic information when computed just during the morning, which is also the day interval with the highest reported SCD incidence. Thus, suggesting that time of the day should be considered for SCD risk prediction. On the other hand, the high irregularity of the ventricular response in atrial fibrillation (AF) limits the use of the most common ECG-derived markers of repolarization heterogeneity, including TWA, under this clinical condition [11]. A new method for assessing ventricular repolarization changes based on a selective averaging technique was developed and new non-invasive indices of repolarization variation were proposed. The positive impact in the prognostic value of the computed indices was demonstrated in a clinical study, by analyzing ECG Holter recordings from CHF patients with AF. To the best of our knowledge, this is the first study that attempts a non-invasive SCD stratification of patients under AF rhythm by assessing ventricular repolarization instability from the ECG signal. To conclude, the research presented in this thesis sheds some light in the identification of pro-arrhythmic factors, which plays an important role in adopting efficient therapeutic strategies. In particular, the optimal configuration for real-time monitoring of repolarization alternans from intracardiac EGMs, together with the prognostic value of the proposed non-invasive indices of alternans activity and ventricular instability variations in case of AF rhythms demonstrated in two clinical studies, would increase the effectiveness of (ICD) therapy. Finally, the analysis of ECG signals recorded during HDBR experiments in structurally healthy hearts, also provides interesting information on cardiovascular alterations produced in immobilized or bedridden patients.<br /