Quantification of Ventricular Repolarization Dispersion Using Digital Processing of the Surface ECG

Digital processing of electrocardiographic records was one of the first applications of signal processing on medicine. There are many ways to analyze and study electrical cardiac activity using the surface electrocardiogram (ECG) and nowadays a good clinical diagnostic and prevention of cardiac risk are the principal goal to be achieved. One aim of digital processing of ECG signals has been quantification of ventricular repolarization dispersion (VRD), phenomenon which mainly is determined by heterogeneity of action potential durations (APD) in different myocardial regions. The APD differs not only between myocytes of apex and the base of both ventricles, but those of endocardial and epicardial surfaces (transmural dispersion) and between both ventricles. Also, it was demonstrated that several electrophysiologically and functionally different myocardial cells, like epicardial, endocardial and mid-myocardial M cells. The APD inequalities develop global and/or local voltage gradients that play an important role in the inscription of ECG T-wave morphology. In this way, we can assume that T-wave is a direct expression of ventricular repolarization inhomogeneities on surface ECG. Experimental and clinical studies have demonstrated a relationship between VRD and severe ventricular arrhythmias. In addition, patients having increased VRD values have a higher risk of developing reentrant arrhythmias. Frequently the heart answer to several pathological states produced an increase of VRD; this phenomenon may develop into malignant ventricular arrhythmia (MVA) and/or sudden cardiac death (SCD). Moreover, it has been showed that the underlying mechanisms in MVA and/or SCD are cardiac re-entry, increased automation, influence of autonomic nervous system and arrhythmogenic substrates linked with cardiac pathologies. These cardiac alterations could presented ischemia, hypothermia, electrolyte imbalance, long QT syndrome, autonomic system effects and others. Digital processing of ECG has been proved to be useful for cardiac risk assessment, with additional advantages like of being non invasive treatments and applicable to the general population. With the aim to identify high cardiac risk patients, the researchers have been tried to quantify the VRD with different parameters obtained by mathematic-computational processing of the surface ECG. These parameters are based in detecting changes of T-wave intervals and T-wave morphology during cardiac pathologies, linking these changes with VRD. In this chapter, we have presented a review of VRD indexes based on digital processing of ECG signals to quantify cardiac risk. The chapter is organized as follows: Section 2 explains ECG preprocessing and delineation of fiducial points. In Section 3, indexes of VRD quantification, such as: QT interval dispersion, QT interval variability and T-wave duration, are described. In Section 4, different repolarization indexes describing T-wave morphology and energy are examined, including complexity of repolarization, T-wave residuum, angle between the depolarization and repolarization dominant vectors, micro T-wave alternans, T-wave area and amplitude and T-wave spectral variability. Finally, in Section 5 conclusions are presented.Fil: Vinzio Maggio, Ana Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Saavedra 15. Instituto Argentino de Matemática Alberto Calderón; ArgentinaFil: Bonomini, Maria Paula. Universidad de Buenos Aires. Facultad de Ingeniería. Instituto de Ingeniería Biomédica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Laciar Leber, Eric. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de San Juan. Facultad de Ingeniería; ArgentinaFil: Arini, Pedro David. Universidad de Buenos Aires. Facultad de Ingeniería. Instituto de Ingeniería Biomédica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Saavedra 15. Instituto Argentino de Matemática Alberto Calderón; Argentin

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 /

Spatiotemporal Control Of Action Potential Duration Alternans In Ventricular Tissue

Cardiac electrical alternans, sometimes referred to as action potential duration (APD) alternans, is a beat-to-beat alternation in action potential waveform, which naturally occurs at sufficiently fast pacing rates. Its presence has been putatively linked to the onset of cardiac reentry, which is a precursor to ventricular fibrillation (VF). Because of the established link between APD alternans and the onset of VF, it may be beneficial to develop means to terminate and/or prevent alternans in cardiac tissue. Closed-loop feedback mechanisms aimed at controlling a dynamically stable period-2 rhythm (alternans) to an unstable period-1 rhythm (no alternans) using singlesite intervention from an external source may be one such option. Previous studies that have utilized this alternans control approach have shown that closed-loop alternans control techniques that apply a succession of externally-administered cycle perturbations at a single site provide limited spatially-extended alternans elimination in sufficiently large cardiac substrates. However, detailed investigations into the spatial dynamics of alternans control have been largely restricted to Purkinje fiber studies. A complete understanding of alternans control in the more clinically relevant ventricular tissue is needed if more advanced electrode-based intervention techniques are to be developed for cardiac alternans therapy. In this work, both mathematical modeling of simulated cardiac tissue and fluorescence imaging of right ventricular cardiac preparations were used to better understand the characteristics of alternans and alternans control in ventricular tissue. In the first part of this work, alternans and alternans control was simulated in one-dimensional cables using the Shiferaw-Sato-Karma (SSK) computational model. The model parameters were varied in order to simulate alternans and alternans control under several different mechanistic manifestations of alternans. Furthermore, the spatial extent of alternans control was systematically probed under varying cable lengths and basic cycle lengths (BCLs) in an attempt to quantify spatial alternans dynamics. In the second part of the study, alternans and alternans control experiments were performed using a custom-designed optical mapping system capable of highresolution imaging. In this way, the spatial efficacy of alternans control was quantified in an experimental setting, and furthermore, the observation and analysis of APD and repolarization dynamics were made possible. In the third part of the study, the effects of noise on alternans control were investigated using SSK implemented simulations of single cell and 1-D arrangements of ventricular tissue. The results of this study will aid in future alternans control experiments, which can occur in the presence of varying amounts of noise. This work represents the first attempts to directly investigate alternans and alternans control in ventricular tissue. Clinical realization of advanced electrodebased therapies for alternans and other related cardiac electrical abnormalities will benefit from the insights gained from this and future related studies

Characterizing the Quantum Confined Stark Effect in Semiconductor Quantum Dots and Nanorods for Single-Molecule Electrophysiology

We optimized the performance of quantum confined Stark effect QCSE based voltage nanosensors. A high throughput approach for single particle QCSE characterization was developed and utilized to screen a library of such nanosensors. Type II ZnSe CdS seeded nanorods were found to have the best performance among the different nanosensors evaluated in this work. The degree of correlation between intensity changes and spectral changes of the excitons emission under applied field was characterized. An upper limit for the temporal response of individual ZnSe CdS nanorods to voltage modulation was characterized by high throughput, high temporal resolution intensity measurements using a novel photon counting camera. The measured 3.5 us response time is limited by the voltage modulation electronics and represents about 30 times higher bandwidth than needed for recording an action potential in a neuron.Comment: 36 pages, 6 figure

Ischemia detection from morphological QRS angles changes

In this paper, an ischemia detector is presented based on the analysis of QRS-derived angles. The detector has been developed by modeling ischemic effects on the QRS angles as a gradual change with a certain transition time and assuming a Laplacian additive modeling error contaminating the angle series. Both standard and non-standard leads were used for analysis. Non- standard leads were obtained by applying the PCA technique over specific lead subsets to represent different potential locations of the ischemic zone. The performance of the proposed detector was tested over a population of 79 patients undergoing percutaneous coronary intervention in one of the major coronary arteries (LAD (n = 25), RCA (n = 16) and LCX (n = 38)). The best detection performance, obtained for standard ECG leads, was achieved in the LAD group with values of sensitivity and specificity of Se = 90.9%, Sp = 95.4%, followed by the RCA group with Se = 88.9%, Sp = 94.4 and the LCX group with Se = 86.1%, Sp = 94.4%, notably outperforming detection based on the ST series in all cases, with the same detector structure. The timing of the detected ischemic events ranged from 30 s up to 150 s (mean = 66.8 s) following the start of occlusion. We conclude that changes in the QRS angles can be used to detect acute myocardial ischemi

The relationship between repolarisation alternans and the production of ventricular arrhythmia in heart failure

Microvolt T-wave alternans is thought to predict the risk of ventricular arrhythmias in patients with heart disease, although recent clinical studies have conflicting results. Understanding the cellular basis for alternans may not only inform more effective utilisation of the clinical test, but also provide new insights into the causes of lethal arrhythmias in man. Cellular repolarisation alternans is thought to underlie T-wave alternans and in recent years, the concept of discordant repolarisation alternans has emerged as a new paradigm for the induction of re-entrant ventricular arrhythmia. This experimental observation has not been examined in clinically relevant models of pathology and so the aim of this study was to investigate whether increased transmural heterogeneity of repolarisation as a result of heart failure following myocardial infarction in the rabbit would predispose to the development of arrhythmogenic discordant alternans. A rabbit ventricular wedge preparation was developed and the transmural electrophysiology of intact rabbit ventricle was characterised using optical imaging techniques. This revealed transmural gradients of repolarisation in intact rabbit myocardium, which appeared to be influenced by electrotonic load, rather than purely being a reflection of intrinsic cellular differences. Interestingly, repolarisation alternans also appeared in transmural patterns, which were also modified by activation sequence, underlining the role of conduction and electrotonic influences in dictating the spatial patterns of alternans, which may be crucial in determining spatially discordant alternans. In this study, similar baseline electrophysiological characteristics were apparent in the remodelled myocardium of failing hearts compared with normal hearts, underlining the possible importance of dynamic factors in producing the increased vulnerability to re-entrant arrhythmias observed in failing hearts. Repolarisation alternans, elicited by low temperature and rapid pacing, occurred at lower heart rates in failing hearts. At physiological temperature, repolarisation alternans was also more common in failing hearts. Spatially discordant alternans was not consistently observed on the transmural surface and did not appear to be directly related to the development of arrhythmia. Failing hearts displayed an increased vulnerability to ventricular arrhythmia. Although heart failure was associated with both alternans and ventricular arrhythmia, there was no demonstrable mechanistic link between alternans and ventricular arrhythmias in failing hearts. These data establish the occurrence of repolarisation alternans in a clinically relevant pathology, and so constitute an important step forward in our understanding of the experimental paradigm. However, a definitive mechanistic link between alternans and arrhythmia in heart failure is yet to be shown

Quality estimation of the electrocardiogram using cross-correlation among leads

Background Fast and accurate quality estimation of the electrocardiogram (ECG) signal is a relevant research topic that has attracted considerable interest in the scientific community, particularly due to its impact on tele-medicine monitoring systems, where the ECG is collected by untrained technicians. In recent years, a number of studies have addressed this topic, showing poor performance in discriminating between clinically acceptable and unacceptable ECG records. Methods This paper presents a novel, simple and accurate algorithm to estimate the quality of the 12-lead ECG by exploiting the structure of the cross-covariance matrix among different leads. Ideally, ECG signals from different leads should be highly correlated since they capture the same electrical activation process of the heart. However, in the presence of noise or artifacts the covariance among these signals will be affected. Eigenvalues of the ECG signals covariance matrix are fed into three different supervised binary classifiers. Results and conclusion The performance of these classifiers were evaluated using PhysioNet/CinC Challenge 2011 data. Our best quality classifier achieved an accuracy of 0.898 in the test set, while having a complexity well below the results of contestants who participated in the Challenge, thus making it suitable for implementation in current cellular devices.National Institute of General Medical Sciences (U.S.) (Grant R01GM104987)Spain (Research Grant TEC2013-46067-R)Spain (Research Grant TEC2013-48439-C4-1-R)Spain (Research Grant TEC2010-19263

Calcium Remodeling through Different Signaling Pathways in Heart Failure: Arrhythmogenesis Studies of Pyk2, Dystrophin, and β-adrenergic Receptor Signaling

Heart failure is a common clinical syndrome that ensues when the heart is no longer able to generate sufficient cardiac output to meet the demands of the body. It is one of the leading causes of death worldwide but with limited and non-ideal therapies at the moment. One reason behind this may be the complexity of significant alterations in multiple signaling pathways and concomitant structural and functional remodeling, especially Ca handling. Ca is critical in both the electrical and mechanical properties of cardiac myoctyes, and much is known about ionic currents and the normal excitation-contraction coupling process. In heart failure, distinct impaired signaling pathways induce significant alterations in how cardiac Ca handling is regulated. These alterations either directly cause certain arrhythmias or facilitate arrhythmias by association with electrical remodeling. The goal of this dissertation was to investigate the mechanisms of calcium remodeling through different signaling pathways in heart failure, and mechanisms on how the intricate and dynamic interactions between Ca handling and signaling pathways impairment facilitate arrhythmias in heart failure. To achieve this goal, a dual optical mapping system was designed to investigate electrical activity and Ca transient simultaneously. High spatio-temporal resolution mapping allows for quantifying conduction, repolarization and Ca cycling, especially on the interactions between action potential and Ca handling. In this dissertation, I investigated Ca remodeling in three different signaling pathways: stress activated signaling, cytoskeletal signaling and β adrenergic receptor signaling pathway. Proline-rich tyrosine kinase 2: Pyk2) is a non-receptor protein kinase regulated by intracellular Ca. It mediates a typical stress activated signaling pathways along with c-Src, P38 MAPK and regulates a broad range of key biological responses. By optically mapping the genetically engineered mouse model: Pyk2 knockout, I detected a protective role of Pyk2 with respect to ventricular tachyarrhythmia during parasympathetic stimulation by regulation of gene expression related to calcium handling. The mdx mouse model was introduced in the investigation of cytoskeletal signaling pathway. mdx mice is a common model for Duchenne muscular dystrophy, which is a clinical syndrome resulted from recessive of dystrophin and eventually develops into heart failure. The project suggested the association of mechanical stimulation and deficiency of dystrophin account for the cardiac mechanical defects and resulting Ca mishandling, but not either of the two above-mentioned entities alone. Ca mishandling leads to Ca cycling dispersion, which facilitates generation of arrhythmias. β Adrenergic receptor signaling pathway was investigated on explanted donor and failing human hearts. Distinct β adrenergic receptor subtypes were found to regulate remodeling differently. The association between remodeling of action potential and Ca transient provides crucial arrhythmic drivers and substrate in heart failure