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 /

Prognostic value of Holter monitoring in congestive heart failure

Congestive heart failure (CHF) is an increasingly widespread, costly and deadly disease, frequently named as epidemics of the 21 century. Despite advancement in modern treatment, mortality rate in CHF patients remains high. Therefore, risk stratification in patients with CHF remains one of the major challenges of contemporary cardiology. Electrocardiographic parameters based on ambulatory Holter monitoring have been documented to be independent risk predictors of total mortality and progression of heart failure. Recent years brought an increased interest in evaluation of dynamic Holter-derived ECG markers reflecting changes in heart rate and ventricular repolarization behavior. It is widely accepted that structural changes reflecting myocardial substrate are better identified by means of imaging techniques, Holter monitoring on the other hand provides complementary information on myocardial vulnerability and autonomic nervous system. Therefore, combining the electrocardiographic stratification with assessment of myocardial substrate may provide the complex insight into interplay between factors contributing to death. The present article reviews the literature data on the prognostic role of various Holter-based ECG parameters, with special emphasis to dynamic ECG risk markers - heart rate variability, heart rate turbulence, repolarization dynamics and variability - in predicting mortality, as well as different modes of death in patients with CH

Applications of Vectorcardiography for Diagnosis and Risk Stratification in Subpopulations at Risk for Life-Threatening Arrhythmias

Introduction: Vectorcardiography, or 3-dimensional electrocardiography is a tool which can be used to identify subtle changes in the electrical forces of the heart, and which can be applied to atrial depolarization, ventricular depolarization and ventricular repolarization for prognostic and diagostic purposes. Methods: Kor’s regression-related and quasi orthogonal methods was used to derive vectorcardiographic parameters from the 12-lead electrocardiogram and applied to a cohort of cryptogenic stroke patients to assess atrial fibrillation, hypertrophic cardiomyopathy patients to assess for ventricular arrhythmias, applied with right-precordial directed quasi orthogonal method to arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC/D) patients for diagnosis, and applied to ventricular repolarization only to patients with genotype-positive/phenotype-negative Long QT2 syndrome (KNCH2 mutation) to assess for cardiac events. Parametric and non-parameteric parameters were presented as mean ± standard deviation and median (1st to 3rd interquartile ranges). Pearson and Spearman correlation coefficients were used for parametric and non-parametric data, respectively. Odds ratios with univariate and multivariate analyses as well as hazard ratios and Kaplan-Meier curves are presented. P-values under 0.05 were represented as significant. Results: In cryptogenic stroke patients, first atrial fibrillation event was predicted by baseline P-wave duration divided by P-wave vector magnitude (p<0.05). In hypertrophic cardiomyopathy patients, the spatial peaks QRS-T angle differentiated sustained ventricular arrhythmias (VA) from no VA (P < 0.001) and at 124.1 degrees gave positive and negative predictive values and an odds ratio of 36.7%, 96.1%, and 14.2 (95% confidence interval: 3.1-65.6), respectively. Combined right precordial-directed parameters were able to identify ARVD/C patients who otherwise met criteria but did not meet any ECG-specfiic 2010 Taskforce criteria from controls with a positive predictive value of 90.0% and negative predictive value of 83.3%. In patients with genotype positive KCNH2 mutations, without prolongation of the QTc, when dichotomized by the median of 0.30 mV, a low T-wave vector magnitude (TwVM) was associated with elevated cardiac event risk compared to those with high TwVM (HR=2.55, 95%CI 1.07-6.04, p=0.034) and the genotype-negative family members (HR=2.64, 95%CI 1.64-4.24, p<0.001). Conclusion: Vector magnitudes and spatial angles, involving atrial and ventricular depolarization as well as ventricular repolarization, can be helpful in identifying disease as well as first-onset arrhythmia in subpopulations at risk for sudden death or stroke

Arrhythmic risk prediction based on the analysis of ventricular repolarization markers from surface ECG

La dependencia de la duración del potencial de acción (APD, del inglés "Action Potential Duration") con el ritmo cardiaco (HR, del inglés "Heart Rate"), también conocida como cinética de restitución, es crítica a la hora de generar inestabilidades eléctricas en el corazón y proporciona información relevante en la estratificación del riesgo a sufrir arritmias ventriculares. La curva dinámica de restitución del APD (APDR, del inglés "APD restitution") cuantifica la relación entre el APD y el intervalo RR (inverso de HR) en condiciones estacionarias. Heterogeneidades en el ventrículo dan lugar a propiedades de la restitución no uniformes, haciendo que las curvas APDR presenten variaciones espaciales. La dispersión es una medida de dicha variación espacial. Recientemente se propuso en la literatura un índice derivado del electrocardiograma (ECG), Δα, que cuantifica la dispersión en las pendientes de las curvas dinámicas de APDR mediante la caracterización de la relación entre los intervalos del pico al final de la onda T (Tpe) y RR bajo condiciones estacionarias diferentes. En este Trabajo Fin de Máster (TFM) se ha desarrollado un método automático para obtener y evaluar, a partir de registros ambulatorios, Δα, como predictor independiente de muerte súbita cardiaca (SCD, del inglés "Sudden Cardiac Death") en pacientes con fallo cardiaco crónico (CHF, del inglés "Chronic Heart Failure"). Pacientes con CHF sintomático formaron parte del estudio "MUSIC" (MUerte Súbita en Insuficiencia Cardiaca). La base de datos contenía los registros Holter de 609 pacientes (48 víctimas de SCD, 64 de otras causas cardiacas, 25 de causas no cardiacas y 472 supervivientes) con ritmo sinusal. El preprocesado de las señales ECG realizado en este TFM consistió en un filtrado paso bajo a 40 Hz, interpolación de splines cúbicos y un detector de latidos ectópicos. Se aplicó una técnica de delineación "uniderivacional más reglas a posteriori" para seleccionar las muestras pertenecientes a la onda T y realizar un análisis de componentes principales. A continuación, se delineó la primera componente principal mediante una técnica uniderivacional y, a partir de las marcas de delineación, se obtuvieron las series de los intervalos RR y Tpe. Posteriormente, se interpolaron a una frecuencia de muestreo fs = 1 Hz. Como cada valor de la curva APDR está medido a un valor específico de RR, el índice de ECG Δα debería calcularse usando segmentos de ECG de ritmos cardiacos estables. Dichos segmentos son difíciles de conseguir en la práctica clínica y por lo tanto se modeló la dependencia del intervalo Tpe con una historia de intervalos previos de RR y se compensó por el retardo de memoria de Tpe. La relación entre Tpe y RR se caracterizó en los registros completos de ECG. Un umbral fijado en Δα>0.046 discriminó los pacientes en alto y bajo riesgo a sufrir SCD (p-valor = 0.003). El tiempo hasta el evento (SCD) fue aproximadamente el doble en los pacientes con Δα0.046 (p-valor = 0.001). Al combinar Δα con el índice de media de alternancias de onda T se mejoró la estratificación del riesgo a sufrir SCD (p-valor<0.001). Este estudio demuestra que la dispersión en APDR, cuantificada a partir de registros ECG Holter, es un predictor de SCD fuerte e independiente en pacientes con CHF. Estos resultados apoyan la hipótesis de que una dispersión de APDR elevada refleja un funcionamiento cardiaco anormal, con predisposición a sufrir SCD

QT interval variability in body surface ECG: measurement, physiological basis, and clinical value: position statement and consensus guidance endorsed by the European Heart Rhythm Association jointly with the ESCWorking Group on Cardiac Cellular Electrophysiology

This consensus guideline discusses the electrocardiographic phenomenon of beat-to-beat QT interval variability (QTV) on surface electrocardiograms. The text covers measurement principles, physiological basis, and clinical value of QTV. Technical considerations include QT interval measurement and the relation between QTV and heart rate variability. Research frontiers of QTV include understanding of QTV physiology, systematic evaluation of the link between QTV and direct measures of neural activity, modelling of the QTV dependence on the variability of other physiological variables, distinction between QTV and general T wave shape variability, and assessing of the QTV utility for guiding therapy. Increased QTV appears to be a risk marker of arrhythmic and cardiovascular death. It remains to be established whether it can guide therapy alone or in combination with other risk factors. QT interval variability has a possible role in non-invasive assessment of tonic sympathetic activity

Techniques for ventricular repolarization instability assessment from the ECG

Instabilities in ventricular repolarization have been documented to be tightly linked to arrhythmia vulnera- bility. Translation of the information contained in the repolar- ization phase of the electrocardiogram (ECG) into valuable clinical decision-making tools remains challenging. This work aims at providing an overview of the last advances in the pro- posal and quantification of ECG-derived indices that describe repolarization properties and whose alterations are related with threatening arrhythmogenic conditions. A review of the state of the art is provided, spanning from the electrophysio- logical basis of ventricular repolarization to its characteriza- tion on the surface ECG through a set of temporal and spatial risk markers