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 /

Estudio de repetibilidad y variación circadiana del índice de alternancias de la onda T del electrocardiograma en registros ambulatorios

Las alternancias en la Onda T en el electrocardiograma (ECG) miden la inestabilidad del corazón y son un indicador de posible riesgo a arritmias malignas. Se propone un estudio de la repetibilidad en las alternancias en registros Holters de 24 horas teniendo en cuenta el ritmo circadiano. Se comprobará la repetibilidad de la medida en distintos registros de los mismos pacientes, y se estudiará la variación intradía de este índice, y si pueden ser más predictivas o no del riesgo en función de la hora en que se midan.<br /

Caracterización de las alternancias de onda T en la señal electrocardiográfica durante isquemia prolongada de miocardio en modelo animal

Una de las principales causas de mortalidad, sobre todo en paises industrializados, la costituyen las afecciones cardiovasculares. Buena parte de estas muertes se deben a paros cardiacos inducidos por arritmias ventriculares malignas que aparecen de manera repentina, dando lugar a la comúnmente conocida como Muerte Súbita Cardiaca. En este proyecto se han aplicado técnicas de procesado de la señal electrocardiográfica para el análisis y estimación de las alternancias de la onda T (AOT), asociadas a la isquemia aguda de miocardio. Estas alternancias se definen como una fluctuación consistente latido a latido de la amplitud, duración o morfología de la repolarización con un período de repetición de dos latidos y, a día de hoy, son consideradas como uno de los índices clínicos no invasivos más prometedores en la predicción de Muerte Súbita Cardiaca. Este tipo de alternancia ha sido ya caracterizada en estudios con pacientes durante la oclusión de una de las arterias coronarias principales mediante PTCA, modelando así los primeros minutos de isquemia aguda en la zona ocluída. Nuestro objetivo en este proyecto ha sido estudiar y caracterizar las alternancias de la onda T durante oclusiones de mayor duración en un modelo animal, contando para ello con dos bases de datos diferentes. En la primera de ellas, se ha practicado a 29 cerdos durante 40 minutos una PTCA, ocluyendo la aretia descendente anterior izquierda (LAD). Disponemos de los registros en reposo, oclusión y reperfusión. La segunda de ellas cuenta con los registros de base y oclusión de 10 cerdos, monitorizando en este caso derivaciones de electrogramas intracavitarios tomados directamente en el seno coronario, los ventrículos izquierdo y derecho y el epicardio. En ambos casos, tanto los registros de control como los de oclusión han sido procesados utilizando un detector multiderivacional de alternancias, basado en el Análisis de las Componentes Periódicas (pi-CA) junto con el Método de Verosimilitud Laplaciano. Así pues, hemos estudiado en ambas bases de datos la presencia, evolución temporal así como la distribución espacial de la AOT. Ambos resultados han resulado muy cohetentes, así como con estudios anteriores. Además hemos podido caracterizar este fenómeno desde el interior del músculo cardiaco. Adicionalmente, se ha estudiado la relación de esta AOT con la presencia de arritmias durante la oclusión

Estimación del tiempo de adaptación del intervalo QT a los cambios en el intervalo RR en registros Holter de 24 horas en pacientes con insuficiencia cardíaca mediante la técnica Phase-Rectified Signal Averaging.

En la actualidad, una de las causas principales de mortalidad en países industrializados son las enfermedades cardiovasculares, siendo la insuficiencia cardíaca una de ellas. La insuficiencia cardíaca es una afección en la cual el corazón no es capaz de bombear la sangre rica en oxígeno de forma eficiente al resto del cuerpo. El electrocardiograma es una prueba simple y no invasiva que mide la actividad eléctrica del corazón, proporcionando información relevante sobre el estado del órgano. En el electrocardiograma es posible ver una serie de ondas representando las distintas partes del ciclo cardiaco. Mediante la detección de los complejos QRS, que representan la depolarización de los ventrículos, es posible calcular la duración de cada ciclo cardiaco, conocido como intervalo RR (distancia entre dos ondas R consecutivas). Además, se ha demostrado que el intervalo QT, que mide el tiempo desde el inicio de la depolarización hasta el fin de la repolarización del ventrículo en cada latido, depende de la duración de una serie ciclos (intervalos RR) anteriores a él y no solamente por el inmediatamente anterior. Se ha demostrado que un tiempo de adaptación del intervalo QT a cambios abruptos en el RR está asociado a un mayor riesgo arrítmico. En este trabajo se propone cuantificar esta dependencia entre el intervalo QT y la duración del ciclo cardiaco mediante la implementación de la técnica Phase-Rectified Signal Averaging (PRSA) y una variante de ella, Bivariate Phase-Rectified Signal Averaging (BPRSA). Mediante el uso de estas dos técnicas, se intentará caracterizar con distintos índices esta relación QT/RR, tanto en fibrilación auricular como en ritmo sinusal, y se evaluará su valor predictivo para el riesgo de muerte cardiovascular. Para ello, se han utilizado registros ECG Holter (24 horas) de un total de 171 pacientes diferentes en fibrilación auricular y 651 pacientes en ritmo sinusal pertenecientes al estudio multicéntrico MUSIC (Muerte súbita en insuficiencia cardiaca). Se han extraído las series de intervalos RR y QT y se han aplicado las técnicas PRSA y BPRSA con el fin de estudiar esta dependencia. En primer lugar, se ha llevado a cabo un estudio de simulación con el fin de evaluar cómo variaciones en el tiempo de adaptación QT/RR se reflejan en la señal BPRSA. Tras ello, con el estudio clínico en MUSIC, los resultados muestran que algunos índices de riesgo extraídos sobre las señales BPRSA están significativamente asociados al riesgo de padecer muerte cardiaca por fallo de bomba, tanto en fibrilación auricular como en ritmo sinusal.<br /

Transient and rapid QRS widening associated with J-wave pattern predicts impending ventricular fibrillation in experimental myocardial infarction.

Certain types of the early repolarization (ER) phenomenon, previously considered to be benign, have been reported to be associated with ventricular fibrillation (VF), both in population-based studies and in the myocardial infarction (MI) settings

ECG-based monitoring of blood potassium concentration: Periodic versus principal component as lead transformation for biomarker robustness

Objective: The aim of this study is to compare the performance of two electrocardiogram (ECG) lead-space reduction (LSR) techniques in generating a transformed ECG lead from which T-wave morphology markers can be reliably derived to non-invasively monitor blood potassium concentration ([K+]) in end-stage renal disease (ESRD) patients undergoing hemodialysis (HD). These LSR techniques are: (1) principal component analysis (PCA), learned on the T wave, and (2) periodic component analysis (πCA), either learned on the whole QRST complex (πCB) or on the T wave (πCT). We hypothesized πCA is less sensitive to non-periodic disturbances, like noise and body position changes (BPC), than PCA, thus leading to more reliable T wave morphology markers. Methods: We compared the ability of T wave morphology markers obtained from PCA, πCB and πCT in tracking [K+] in an ESRD-HD dataset, including 29 patients, during and after HD (evaluated by correlation and residual fitting error analysis). We also studied their robustness to BPC using an annotated database, including 20 healthy individuals, as well as to different levels of noise using a simulation set-up (assessed by means of Mann–Whitney U test and relative error, respectively). Results: The performance of both πCB and πCT-based markers in following [K+]-variations during HD was comparable, and superior to that from PCA-based markers. Moreover, πCT-based markers showed superior robustness against BPC and noise. Conclusion: Both πCB and πCT outperform PCA in terms of monitoring [K+] in ESRD-HD patients, as well as of robustness against BPC and low SNR, with πCT showing the highest stability for continuous post-HD monitoring. Significance: The usage of πCA (i) increases the accuracy in monitoring dynamic [K+] variations in ESRD-HD patients and (ii) reduces the sensitivity to BPC and noise in deriving T wave morphology markers. © 2021 The Author(s

ECG modeling for simulation of arrhythmias in time-varying conditions

The present paper proposes an ECG simulator that advances modeling of arrhythmias and noise by introducing time-varying signal characteristics. The simulator is built around a discrete-time Markov chain model for simulating atrial and ventricular arrhythmias of particular relevance when analyzing atrial fibrillation (AF). Each state is associated with statistical information on episode duration and heartbeat characteristics. Statistical, time-varying modeling of muscle noise, motion artifacts, and the influence of respiration is introduced to increase the complexity of simulated ECGs, making the simulator well suited for data augmentation in machine learning. Modeling of how the PQ and QT intervals depend on heart rate is also introduced. The realism of simulated ECGs is assessed by three experienced doctors, showing that simulated ECGs are difficult to distinguish from real ECGs. Simulator usefulness is illustrated in terms of AF detection performance when either simulated or real ECGs are used to train a neural network for signal quality control. The results show that both types of training lead to similar performance

Los cambios en la morfología del intervalo Tpico-Tfin medidos mediante time-warping se asocian con la fibrilación ventricular inducida por la isquemia en un modelo porcino

La dispersión de la repolarización ventricular reflejada en el intervalo Tpe ha mostrado potencial en la predicción del riesgo arrítmico, y no está expuesta a errores de anotación en la determinación del inicio de la onda T como consecuencia de la elevación del ST. Utilizamos el índice de variación morfológica basado en time-warping propuesto por Ramírez, dw, restringido al intervalo entre el pico y el final de la onda T, y evaluamos su asociación con la aparición de episodios de fibrilación ventricular (FV) en condiciones isquémicas. El índice dw permite monitorizar los cambios de repolarización inducidos por la isquemia. Los aumentos dinámicos del índice dw durante la progresión de la isquemia en cerdos se asocian con la aparición de FV y sugiere una evaluación adicional en humanos

Análisis de los cambios en la Onda P para la predicción de los episodios de la Fibrilación Auricular

Atrial fibrillation (AF) is the most frequent arrhythmia in clinical practice. It usually initiates as a paroxysmal activity (PxAF), with the subject having sinus rhythm, with interleaved AF episodes. The objective of the study is to evaluate the observations made by Pyotr Platonov, who hypothesized that slower conduction in the atria and the presence of fibrosis in the atrial myocardium, both associated to AF, lead to P waves widened, more complex and with increased rugosity. The study shows that P wave morphology significantly changes prior to the onset of AF episodes in PxAF, increasing the variability, making more complex P-wave loop, and enlarging the duration, which can be attributed to the de-structuring of the atrial wavefront.La fibrilación auricular (FA) es las arritmia m´ás frecuente en la práctica clínica. Se inicia generalmente como una actividad paroxística donde el sujeto presenta ritmo sinusal con episodios de FA intermitentes. El objetivo del estudio es evaluar y confirmar las observaciones realizadas por Pyotr Platonov, quien planteó la hipótesis de que una conducción más lenta en las aurículas y la presencia de fibrosis en el miocardio auricular, ambas asociadas a la FA, producen ondas P ensanchadas, más complejas y con mayor rugosidad. El estudio muestra que la morfología de la onda P cambia significativamente antes del inicio de los episodios de FA, incrementándose la variabilidad, produciendo un bucle de la onda P más complejo y aumentando la duración, lo que puede atribuirse a la desestructuración del frente de onda auricular

Atrial fibrillation episode patterns as predictor of clinical outcome of catheter ablation

Methods for characterization of atrial fibrillation (AF) episode patterns have been introduced without establishing clinical significance. This study investigates, for the first time, whether post-ablation recurrence of AF can be predicted by evaluating episode patterns. The dataset comprises of 54 patients (age 56 ± 11 years; 67% men), with an implantable cardiac monitor, before undergoing the first AF catheter ablation. Two parameters of the alternating bivariate Hawkes model were used to characterize the pattern: AF dominance during the monitoring period (log(mu)) and temporal aggregation of episodes (beta1). Moreover, AF burden and AF density, a parameter characterizing aggregation of AF burden, were studied. The four parameters were computed from an average of 29 AF episodes before ablation. The risk of AF recurrence after catheter ablation using the Hawkes parameters log(mu) and beta1, AF burden, and AF density was evaluated. While the combination of AF burden and AF density is related to a non-significant hazard ratio, the combination of log(mu) and beta1 is related to a hazard ratio of 1.95 (1.03–3.70; p < 0.05). The Hawkes parameters showed increased risk of AF recurrence within 1 year after the procedure for patients with high AF dominance and high episode aggregation and may be used for pre-ablation risk assessment