Comparative Evaluation of Methodologies for T-wave Alternans Mapping in Electrograms.

Electrograms (EGM) recorded from the surface of the myocardium are becoming more and more accessible. T-wave alternans (TWA) is associated with increased vulnerability to ventricular tachycardia/fibrillation and it occurs before the onset of ventricular arrhythmias. Thus, accurate methodologies for time-varying alternans estimation/detection in EGM are needed. In this paper, we perform a simulation study based on epicardial EGM recorded in vivo in humans to compare the accuracy of four methodologies: the spectral method (SM), modified moving average method (MMA), laplacian likelihood ratio method (LLR) and a novel method based on time-frequency distributions (TFD). A variety of effects are considered, which include the presence of wide band noise, respiration and impulse artifacts. We found that (a) EGM-TWA can be detected accurately when the standard deviation of wide band noise is equal or smaller than 10 times the magnitude of EGM-TWA. (b) Respiration can be critical for EGM-TWA analysis, even at typical respiratory rates. (c) Impulse noise strongly reduces the accuracy of all methods, except LLR. (d) If depolarization time is used as a fiducial point, the localization of the T-wave is not critical for the accuracy of EGMTWA detection. (e) According to this study, all methodologies provided accurate EGM-TWA detection/quantification in ideal conditions, while LLR was the most robust, providing better detection-rates in noisy conditions. Application on epicardial mapping of the in-vivo human heart shows that EGM-TWA has heterogeneous spatio-temporal distribution

Evaluation of T-wave alternans activity under stress conditions after 5 d and 21 d of sedentary head-down bed rest

It is well known that prolonged microgravity leads to cardiovascular deconditioning, inducing significant changes in autonomic control of the cardiovascular system. This may adversely influence cardiac repolarization, and provoke cardiac rhythm disturbances. T-wave alternans (TWA), reflecting temporal and spatial repolarization heterogeneity, could be affected. The aim of this work was to test the hypothesis that 5 d and 21 d head-down (-6°) bed rest (HDBR) increases TWA, thus suggesting a higher underlying electrical instability and related arrhythmogenic risk.Forty-four healthy male volunteers were enrolled in the experiments as part of the European Space Agency's HDBR studies. High-fidelity ECG was recorded during orthostatic tolerance (OT) and aerobic power (AP) tests, before (PRE) and after HDBR (POST). A multilead scheme for TWA amplitude estimation was used, where non-normalized and T-wave amplitude normalized TWA indices were computed. In addition, spectral analysis of heart rate variability during OT was assessed.Both 5 d and 21 d HDBR induced a reduction in orthostatic tolerance time (OTT), as well as a decrease in maximal oxygen uptake and reserve capacity, thus suggesting cardiovascular deconditioning. However, TWA indices were found not to increase. Interestingly, subjects with lower OTT after 5 d HDBR also showed higher TWA during recovery after OT testing, associated with unbalanced sympathovagal response, even before the HDBR. In contrast with previous observations, augmented ventricular heterogeneity related to 5 d and 21 d HDBR was not sufficient to increase TWA under stress conditions

In-vivo human sock-mapping validation of a simple model that explains unipolar electrogram morphology in relation to conduction-repolarization dynamics

INTRODUCTION: The unipolar electrogram (UEG) provides local measures of cardiac activation and repolarization and is an important translational link between patient and laboratory. A simple theoretical model of the UEG was previously proposed and tested in-silico. METHOD AND RESULTS: The aim of this study was to use epicardial sock-mapping data to validate the simple model's predictions of unipolar electrogram morphology in the in-vivo human heart. The simple model conceptualizes the UEG as the difference between a local cardiac action potential and a position-independent component representing remote activity, which is defined as the average of all action potentials. UEGs were recorded in 18 patients using a multi-electrode sock containing 240 electrodes and activation (AT) and repolarization time (RT) were measured using standard definitions. For each cardiac site, a simulated local action potential was generated by adjusting a stylized action potential to fit AT and RT measured in-vivo. The correlation coefficient (cc) measuring the morphological similarity between 13,637 recorded and simulated UEGs was cc = 0.89 (0.72-0.95), median (Q1 -Q3 ), for the entire UEG, cc = 0.90 (0.76-0.95) for QRS complexes, and cc = 0.83 (0.58-0.92) for T-waves. QRS and T-wave areas from recorded and simulated UEGs showed cc > 0.89 and cc > 0.84, respectively, indicating good agreement between voltage isochrones maps. Simulated UEGs accurately reproduced the interaction between AT and QRS morphology and between RT and T-wave morphology observed in-vivo. CONCLUSIONS: Human in-vivo whole heart data support the validity of the simple model, which provides a framework for improving the understanding of the UEG and its clinical utility. This article is protected by copyright. All rights reserved

A Time-Varying Non-Parametric Methodology for Assessing Changes in QT Variability Unrelated to Heart Rate Variability

OBJECTIVE: To propose and test a novel methodology to measure changes in QT interval variability (QTV) unrelated to RR interval variability (RRV) in non-stationary conditions. METHODS: Time-frequency coherent and residual spectra representing QTV related (QTVrRRV) and unrelated (QTVuRRV) to RRV, respectively, are estimated using time-frequency Cohen's class distributions. The proposed approach decomposes the non-stationary output spectrum of any two-input one-output model with uncorrelated inputs into two spectra representing the information related and unrelated to one of the two inputs, respectively. An algorithm to correct for the bias of the time-frequency coherence function between QTV and RRV is proposed to provide accurate estimates of both QTVuRRV and QTVrRRV. Two simulation studies were conducted to assess the methodology in challenging non-stationary conditions and data recorded during head-up tilt in 16 healthy volunteers were analyzed. RESULTS: In the simulation studies, QTVuRRV changes were tracked with only a minor delay due to the filtering necessary to estimate the non-stationary spectra. The correlation coefficient between theoretical and estimated patterns was >0.92 even for extremely noisy recordings (SNR in QTV =-10dB). During head-up tilt, QTVrRRV explained the largest proportion of QTV, whereas QTVuRRV showed higher relative increase than QTV or QTVrRRV in all spectral bands (P<0.05 for most pairwise comparisons). CONCLUSION: The proposed approach accurately tracks changes in QTVuRRV. Head-up tilt induced a slightly greater increase in QTVuRRV than in QTVrRRV. SIGNIFICANCE: The proposed index QTVuRRV may represent an indirect measure of intrinsic ventricular repolarization variability, a marker of cardiac instability associated with sympathetic ventricular modulation and sudden cardiac death

Pulse Arrival Time and Pulse Interval as Accurate Markers to Detect Mechanical Alternans

Mechanical alternans (MA) is a powerful predictor of adverse prognosis in patients with heart failure and cardiomyopathy, but its use remains limited due to the need of invasive continuous arterial pressure recordings. This study aims to assess novel cardiovascular correlates of MA in the intact human heart to facilitate affordable and non-invasive detection of MA and advance our understanding of the underlying pathophysiology. Arterial pressure, respiration, and ECG were recorded in 12 subjects with healthy ventricles during voluntarily controlled breathing at different respiratory rate, before and after administration of beta-blockers. MA was induced by ventricular pacing. A total of 67 recordings lasting approximately 90 s each were analyzed. Mechanical alternans (MA) was measured in the systolic blood pressure. We studied cardiovascular correlates of MA, including maximum pressure rise during systole (dPdtmax), pulse arrival time (PAT), pulse wave interval (PI), RR interval (RRI), ECG QRS complexes and T-waves. MA was detected in 30% of the analyzed recordings. Beta-blockade significantly reduced MA prevalence (from 50 to 11%, p < 0.05). Binary classification showed that MA was detected by alternans in dPdtmax (100% sens, 96% spec), PAT (100% sens, 81% spec) and PI (80% sens, 81% spec). Alternans in PAT and in PI also showed high degree of temporal synchronization with MA (80 ± 33 and 73 ± 40%, respectively). These data suggest that cardiac contractility is a primary factor in the establishment of MA. Our findings show that MA was highly correlated with invasive measurements of PAT and PI. Since PAT and PI can be estimated using non-invasive technologies, these markers could potentially enable affordable MA detection for risk-prediction

Non-Invasive Detection of Mechanical Alternans Utilizing Photoplethysmography

Background and Significance: Mechanical alternans (MA) is a biomarker associated with mortality and life-threatening arrhythmias in heart failure patients. Despite showing prognostic value, its use is limited by the requirement of measuring continuous blood pressure (BP), which is costly and impractical. Objective: To develop and test, for the first time, non-invasive MA surrogates based on photoplethysmography (PPG). Methods: Continuous BP and PPG were recorded during clinical procedures and tests in 35 patients. MA was induced either by ventricular pacing (Group A, N=19) or exercise (Group B, N=16). MA was categorized as sustained or intermittent if MA episodes were observed in at least 20 or between 12 to 20 consecutive beats, respectively. Eight features characterizing pulse morphology were derived from the PPG and MA surrogates were evaluated. Results: Sustained alternans was observed in 9 patients (47%) from Group A, whereas intermittent alternans was observed in 13 patients (68%) from Group A and in 10 patients (63%) from Group B. The PPG-based MA surrogate showing the highest accuracy, V'M, was based on the maximum of the first derivative of the PPG pulse. It detected both sustained and intermittent MA with 100% sensitivity and 100% specificity in Group A and intermittent MA with 100% sensitivity and 83% specificity in Group B. Furthermore, the magnitudes of MA and its PPG-based surrogate were linearly correlated (R 2 =0.83, p<0.001). Conclusion: MA can be accurately identified non-invasively through PPG analysis. This may have important clinical implications for risk stratification and remote monitoring

Developing a novel comprehensive framework for the investigation of cellular and whole heart electrophysiology in the in situ human heart: Historical perspectives, current progress and future prospects

Understanding the mechanisms of fatal ventricular arrhythmias is of great importance. In view of the many electrophysiological differences that exist between animal species and humans, the acquisition of basic electrophysiological data in the intact human heart is essential to drive and complement experimental work in animal and in-silico models. Over the years techniques have been developed to obtain basic electrophysiological signals directly from the patients by incorporating these measurements into routine clinical procedures which access the heart such as cardiac catheterisation and cardiac surgery. Early recordings with monophasic action potentials provided valuable information including normal values for the in vivo human heart, cycle length dependent properties, the effect of ischaemia, autonomic nervous system activity, and mechano-electric interaction. Transmural recordings addressed the controversial issue of the mid myocardial “M” cell. More recently, the technique of multielectrode mapping (256 electrodes) developed in animal models has been extended to humans, enabling mapping of activation and repolarisation on the entire left and right ventricular epicardium in patients during cardiac surgery. Studies have examined the issue of whether ventricular fibrillation was driven by a “mother” rotor with inhomogeneous and fragmented conduction as in some animal models, or by multiple wavelets as in other animal studies; results showed that both mechanisms are operative in humans. The simpler spatial organisation of human VF has important implications for treatment and prevention. To link in-vivo human electrophysiological mapping with cellular biophysics, multielectrode mapping is now being combined with myocardial biopsies. This technique enables region-specific electrophysiology changes to be related to underlying cellular biology, for example: APD alternans, which is a precursor of VF and sudden death. The mechanism is incompletely understood but related to calcium cycling and APD restitution. Multielectrode sock mapping during incremental pacing enables epicardial sites to be identified which exhibit marked APD alternans and sites where APD alternans is absent. Whole heart electrophysiology is assessed by activation repolarisation mapping and analysis is performed immediately on-site in order to guide biopsies to specific myocardial sites. Samples are analysed for ion channel expression, Ca2+-handling proteins, gap junctions and extracellular matrix. This new comprehensive approach to bridge cellular and whole heart electrophysiology allowed to identify 20 significant changes in mRNA for ion channels Ca2+-handling proteins, a gap junction channel, a Na+–K+ pump subunit and receptors (particularly Kir 2.1) between the positive and negative alternans sites

Quantification of Beat-To-Beat Variability of Action Potential Durations in Langendorff-Perfused Mouse Hearts

Background: Beat-to-beat variability in action potential duration (APD) is an intrinsic property of cardiac tissue and is altered in pro-arrhythmic states. However, it has never been examined in mice.Methods: Left atrial or ventricular monophasic action potentials (MAPs) were recorded from Langendorff-perfused mouse hearts during regular 8 Hz pacing. Time-domain, frequency-domain and non-linear analyses were used to quantify APD variability.Results: Mean atrial APD (90% repolarization) was 23.5 ± 6.3 ms and standard deviation (SD) was 0.9 ± 0.5 ms (n = 6 hearts). Coefficient of variation (CoV) was 4.0 ± 1.9% and root mean square (RMS) of successive differences in APDs was 0.3 ± 0.2 ms. The peaks for low- and high-frequency were 0.7 ± 0.5 and 2.7 ± 0.9 Hz, respectively, with percentage powers of 39.0 ± 20.5 and 59.3 ± 22.9%. Poincaré plots of APDn+1 against APDn revealed ellipsoid shapes. The ratio of the SD along the line-of-identity (SD2) to the SD perpendicular to the line-of-identity (SD1) was 8.28 ± 4.78. Approximate and sample entropy were 0.57 ± 0.12 and 0.57 ± 0.15, respectively. Detrended fluctuation analysis revealed short- and long-term fluctuation slopes of 1.80 ± 0.15 and 0.85 ± 0.29, respectively. When compared to atrial APDs, ventricular APDs were longer (ANOVA, P &lt; 0.05), showed lower mean SD and CoV but similar RMS of successive differences in APDs and showed lower SD2 (P &lt; 0.05). No difference in the remaining parameters was observed.Conclusion: Beat-to-beat variability in APD is observed in mouse hearts during regular pacing. Atrial MAPs showed greater degree of variability than ventricular MAPs. Non-linear techniques offer further insights on short-term and long-term variability and signal complexity

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