Using QRS loop descriptors to characterize the risk of sudden cardiac death in patients with structurally normal hearts.

The predictive value of non-invasive electrocardiographic examination findings for the risk of sudden cardiac death (SCD) in populations with structurally normal hearts remains unclear. This study aimed to investigate the characteristics of the QRS vectorcardiography of surface electrocardiography in patients with structurally normal hearts who experienced SCD. We consecutively enrolled patients who underwent vectorcardiography between March 2017 and December 2018 in a tertiary referral medical center. These patients didn't have structural heart diseases, histories of congestive heart failure, or reduced ejection fraction, and they were classified into SCD (with aborted SCD history and cerebral performance category score of 1) and control groups (with an intervention for atrioventricular node reentrant tachycardia and without SCD history). A total of 162 patients (mean age, 54.3±18.1 years; men, 75.9%), including 59 in the SCD group and 103 in the control group, underwent propensity analysis. The baseline demographic variables, underlying diseases, QRS loop descriptors (the percentage of the loop area, loop dispersion, and inter-lead QRS dispersion), and other electrocardiographic parameters were compared between the two groups. In the univariate and multivariate analyses, a smaller percentage of the loop area (odds ratio, 0.0003; 95% confidence interval, 0.00-0.02; p<0.001), more significant V4-5 dispersion (odds ratio, 1.04; 95% confidence interval, 1.02-1.07; p = 0.002), and longer QRS duration (odds ratio, 1.05; 95% confidence interval, 1.00-1.10; p = 0.04) were associated with SCD. In conclusion, the QRS loop descriptors of surface electrocardiography could be used as non-invasive markers to identify patients experiencing aborted SCD from a healthy population. A decreased percentage of loop area and elevated V4-5 QRS dispersion values assessed using vectorcardiography were associated with an increased risk of SCD in patients with structurally normal hearts.

Ventricular divergence correlates with epicardial wavebreaks and predicts ventricular arrhythmia in isolated rabbit hearts during therapeutic hypothermia.

INTRODUCTION: High beat-to-beat morphological variation (divergence) on the ventricular electrogram during programmed ventricular stimulation (PVS) is associated with increased risk of ventricular fibrillation (VF), with unclear mechanisms. We hypothesized that ventricular divergence is associated with epicardial wavebreaks during PVS, and that it predicts VF occurrence. METHOD AND RESULTS: Langendorff-perfused rabbit hearts (n = 10) underwent 30-min therapeutic hypothermia (TH, 30°C), followed by a 20-min treatment with rotigaptide (300 nM), a gap junction modifier. VF inducibility was tested using burst ventricular pacing at the shortest pacing cycle length achieving 1:1 ventricular capture. Pseudo-ECG (p-ECG) and epicardial activation maps were simultaneously recorded for divergence and wavebreaks analysis, respectively. A total of 112 optical and p-ECG recordings (62 at TH, 50 at TH treated with rotigaptide) were analyzed. Adding rotigaptide reduced ventricular divergence, from 0.13±0.10 at TH to 0.09±0.07 (p = 0.018). Similarly, rotigaptide reduced the number of epicardial wavebreaks, from 0.59±0.73 at TH to 0.30±0.49 (p = 0.036). VF inducibility decreased, from 48±31% at TH to 22±32% after rotigaptide infusion (p = 0.032). Linear regression models showed that ventricular divergence correlated with epicardial wavebreaks during TH (p<0.001). CONCLUSION: Ventricular divergence correlated with, and might be predictive of epicardial wavebreaks during PVS at TH. Rotigaptide decreased both the ventricular divergence and epicardial wavebreaks, and reduced the probability of pacing-induced VF during TH.

A novel noninvasive surface ECG analysis using interlead QRS dispersion in arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND: This study investigated the feasibility of using the precordial surface ECG lead interlead QRS dispersion (IQRSD) in the identification of abnormal ventricular substrate in arrhythmogenic right ventricular cardiomyopathy (ARVC). METHODS: Seventy-one consecutive patients were enrolled and reclassified into 4 groups: definite ARVC with epicardial ablation (Group 1), ARVC with ventricular tachycardia (VT, Group 2), idiopathic right ventricular outflow tract VT without ARVC (Group 3), and controls without VT (Group 4). IQRSD was quantified by the angular difference between the reconstruction vectors obtained from the QRS-loop decomposition, based on a principal component analysis (PCA). Electroanatomic mapping and simulated ECGs were used to investigate the relationship between QRS dispersion and abnormal substrate. RESULTS: The percentage of the QRS loop area in the Group 1-2 was smaller than the controls (P = 0.01). The IQRSD between V1-V2 could differentiate all VTs from control (P<0.01). Group 1-2 had a greater IQRSD than the Group 3-4 (V4-V5,P = 0.001), and Group 1 had a greater IQRSD than Group 3-4 (V6-Lead I, P<0.001). Both real and simulated data had a positive correlation between the maximal IQRSD (γ = 0.62) and the extent of corresponding abnormal substrate (γ = 0.71, both P<0.001). CONCLUSIONS: The IQRSD of the surface ECG precordial leads successfully differentiated ARVC from controls, and could be used as a noninvasive marker to identify the abnormal substrate and the status of ARVC patients who can benefit from epicardial ablation.

Probing the Fractal Pattern of Heartbeats in Drosophila Pupae by Visible Optical Recording System.

Judiciously tuning heart rates is critical for regular cardiovascular function. The fractal pattern of heartbeats - a multiscale regulation in instantaneous fluctuations - is well known for vertebrates. The most primitive heart system of the Drosophila provides a useful model to understand the evolutional origin of such a fractal pattern as well as the alterations of fractal pattern during diseased statuses. We developed a non-invasive visible optical heart rate recording system especially suitable for long-term recording by using principal component analysis (PCA) instead of fluorescence recording system to avoid the confounding effect from intense light irradiation. To deplete intracellular Ca(2+) levels, the expression of sarco-endoplasmic reticulum Ca(2+)-ATPase (SERCA) was tissue-specifically knocked down. The SERCA group shows longer heart beat intervals (Mean ± SD: 1009.7 ± 151.6 ms) as compared to the control group (545.5 ± 45.4 ms, p < 0.001). The multiscale correlation of SERCA group (scaling exponent: 0.77 ± 0.07), on the other hand, is weaker than that of the control Drosophila (scaling exponent: 0.85 ± 0.03) (p = 0.016).

Interactive Effects of Dorsomedial Hypothalamic Nucleus and Time-Restricted Feeding on Fractal Motor Activity Regulation.

One evolutionary adaptation in motor activity control of animals is the anticipation of food that drives foraging under natural conditions and is mimicked in laboratory with daily scheduled food availability. Food anticipation is characterized by increased activity a few hours before the feeding period. Here we report that 2-h food availability during the normal inactive phase of rats not only increases activity levels before the feeding period but also alters the temporal organization of motor activity fluctuations over a wide range of time scales from minutes up to 24 h. We demonstrate this multiscale alteration by assessing fractal patterns in motor activity fluctuations-similar fluctuation structure at different time scales-that are robust in intact animals with ad libitum food access but are disrupted under food restriction. In addition, we show that fractal activity patterns in rats with ad libitum food access are also perturbed by lesion of the dorsomedial hypothalamic (DMH)-a neural node that is involved in food anticipatory behavior. Instead of further disrupting fractal regulation, food restriction restores the disrupted fractal patterns in these animals after the DMH lesion despite the persistence of the 24-h rhythms. This compensatory effect of food restriction is more clearly pronounced in the same animals after the additional lesion of the suprachiasmatic nucleus (SCN)-the central master clock in the circadian system that generates and orchestrates circadian rhythms in behavior and physiological functions in synchrony with day-night cycles. Moreover, all observed influences of food restriction persist even when data during the food anticipatory and feeding period are excluded. These results indicate that food restriction impacts dynamics of motor activity at different time scales across the entire circadian/daily cycle, which is likely caused by the competition between the food-induced time cue and the light-entrained circadian rhythm of the SCN. The differential impacts of food restriction on fractal activity control in intact and DMH-lesioned animals suggest that the DMH plays a crucial role in integrating these different time cues to the circadian network for multiscale regulation of motor activity.

Tai Chi training reduced coupling between respiration and postural control.

In order to maintain stable upright stance, the postural control system must account for the continuous perturbations to the body's center-of-mass including those caused by spontaneous respiration. Both aging and disease increase "posturo-respiratory synchronization;" which reflects the degree to which respiration affects postural sway fluctuations over time. Tai Chi training emphasizes the coordination of respiration and bodily movements and may therefore optimize the functional interaction between these two systems. The purpose of the project was to examine the effect of Tai Chi training on the interaction between respiration and postural control in older adults. We hypothesized that Tai Chi training would improve the ability of the postural control system to compensate for respiratory perturbations and thus, reduce posturo-respiratory synchronization. Participants were recruited from supportive housing facilities and randomized to a 12-week Tai Chi intervention (n=28; 86 ± 5 yrs) or educational-control program (n=34, 85 ± 6 yrs). Standing postural sway and respiration were simultaneously recorded with a force plate and respiratory belt under eyes-open and eyes-closed conditions. Posturo-respiratory synchronization was determined by quantifying the variation of the phase relationship between the dominant oscillatory mode of respiration and corresponding oscillations within postural sway. Groups were similar in age, gender distribution, height, body mass, and intervention compliance. Neither intervention altered average sway speed, sway magnitude or respiratory rate. As compared to the education-control group, however, Tai Chi training reduced posturo-respiratory synchronization when standing with eyes open or closed (p<0.001). Tai Chi training did not affect traditional parameters of standing postural control or respiration, yet reduced the coupling between respiration and postural control. The beneficial effects of Tai Chi training may therefore stem in part from optimization of this multi-system interaction.

Suprachiasmatic neuron numbers and rest-activity circadian rhythms in older humans.

The suprachiasmatic nucleus (SCN) of the hypothalamus, the master mammalian circadian pacemaker, synchronizes endogenous rhythms with the external day-night cycle. Older humans, particularly those with Alzheimer disease (AD), often have difficulty maintaining normal circadian rhythms compared to younger adults, but the basis of this change is unknown. We report that the circadian rhythm amplitude of motor activity in both AD subjects and age-matched controls is correlated with the number of vasoactive intestinal peptide-expressing SCN neurons. AD was additionally associated with delayed circadian phase compared to cognitively healthy subjects, suggesting distinct pathologies and strategies for treating aging- and AD-related circadian disturbances.

Simulated shift work in rats perturbs multiscale regulation of locomotor activity.

Motor activity possesses a multiscale regulation that is characterized by fractal activity fluctuations with similar structure across a wide range of timescales spanning minutes to hours. Fractal activity patterns are disturbed in animals after ablating the master circadian pacemaker (suprachiasmatic nucleus, SCN) and in humans with SCN dysfunction as occurs with aging and in dementia, suggesting the crucial role of the circadian system in the multiscale activity regulation. We hypothesized that the normal synchronization between behavioural cycles and the SCN-generated circadian rhythms is required for multiscale activity regulation. To test the hypothesis, we studied activity fluctuations of rats in a simulated shift work protocol that was designed to force animals to be active during the habitual resting phase of the circadian/daily cycle. We found that these animals had gradually decreased mean activity level and reduced 24-h activity rhythm amplitude, indicating disturbed circadian and behavioural cycles. Moreover, these animals had disrupted fractal activity patterns as characterized by more random activity fluctuations at multiple timescales from 4 to 12 h. Intriguingly, these activity disturbances exacerbated when the shift work schedule lasted longer and persisted even in the normal days (without forced activity) following the shift work. The disrupted circadian and fractal patterns resemble those of SCN-lesioned animals and of human patients with dementia, suggesting a detrimental impact of shift work on multiscale activity regulation.

Detecting phase-amplitude coupling with high frequency resolution using adaptive decompositions.

BACKGROUND: Phase-amplitude coupling (PAC)--the dependence of the amplitude of one rhythm on the phase of another, lower-frequency rhythm - has recently been used to illuminate cross-frequency coordination in neurophysiological activity. An essential step in measuring PAC is decomposing data to obtain rhythmic components of interest. Current methods of PAC assessment employ narrowband Fourier-based filters, which assume that biological rhythms are stationary, harmonic oscillations. However, biological signals frequently contain irregular and nonstationary features, which may contaminate rhythms of interest and complicate comodulogram interpretation, especially when frequency resolution is limited by short data segments. NEW METHOD: To better account for nonstationarities while maintaining sharp frequency resolution in PAC measurement, even for short data segments, we introduce a new method of PAC assessment which utilizes adaptive and more generally broadband decomposition techniques - such as the empirical mode decomposition (EMD). To obtain high frequency resolution PAC measurements, our method distributes the PAC associated with pairs of broadband oscillations over frequency space according to the time-local frequencies of these oscillations. COMPARISON WITH EXISTING METHODS: We compare our novel adaptive approach to a narrowband comodulogram approach on a variety of simulated signals of short duration, studying systematically how different types of nonstationarities affect these methods, as well as on EEG data. CONCLUSIONS: Our results show: (1) narrowband filtering can lead to poor PAC frequency resolution, and inaccuracy and false negatives in PAC assessment; (2) our adaptive approach attains better PAC frequency resolution and is more resistant to nonstationarities and artifacts than traditional comodulograms.

The use of signal analyses of ventricular tachycardia electrograms to predict the response of antitachycardia pacing in patients with implantable cardioverter-defibrillators.

INTRODUCTION: Antitachycardia pacing (ATP), a quick, painless, and effective therapy available in implantable cardioverter-defibrillators (ICDs), can terminate most, but not all, sustained ventricular tachycardias (VTs). This study investigated the possible ventricular electrogram (EGM) factors for predicting the effectiveness of ATP therapy from ICD recordings. METHODS AND RESULTS: In this study, we analyzed 113 EGMs of VT episodes acquired from 20 patients who received ATP or shock to terminate tachyarrhythmias during follow-up after ICD implantations. The relationship between the outcome of ATP and VT EGM features (such as voltage, width, cycle length, and beat-to-beat morphologic variation) was investigated. The divergence (beat-to-beat morphologic variation) of the VT EGMs was determined by calculating the total deviation of all EGMs away from the average template after all VT EMGs were aligned. In total, 72 (63.7%) successful (Group I) and 41 (36.3%) unsuccessful (Group II) ATP therapy episodes were analyzed. The mean amplitude, cycle length, and EGM width were similar between these 2 groups (P > 0.05). A multivariate analysis demonstrated that the only predictor of successful ATP was the divergence among the VT EGMs (0.56 ± 0.32 vs 1.07 ± 0.64, P < 0.001, for Groups 1 and 2, respectively). The optimal cutoff value for determining a successful ATP therapy was 0.73 (with an area under the curve of 0.769, sensitivity of 81.9% [95% CI = 71.1-90.0], and specificity of 65.9% [95% CI = 49.4-79.9], P < 0.0001). CONCLUSION: Signal analyses from stored EGMs of VT can predict the response of ATP therapy in patients with ICD implantations. A lesser ventricular beat-to-beat morphologic variation in the intracardiac recordings from ICDs correlated with a higher probability of a successful ATP.

Prevalence, characteristics, mapping, and catheter ablation of potential rotors in nonparoxysmal atrial fibrillation.

BACKGROUND: Identification of critical atrial substrates in patients with nonparoxysmal atrial fibrillation (AF) failing to respond to pulmonary vein isolation is important. This study investigated the signal characteristics, substrate nature, and ablation results of rotors during AF. METHODS AND RESULTS: In total, 53 patients (age=55±8), 31 with persistent AF and 22 with long-lasting AF, underwent pulmonary vein isolation and substrate modification of complex fractionated atrial electrograms. Small-radius-reentrant rotors were identified from signal analyses of the dominant frequency and fractionation interval and nonlinear analyses (newly developed, beat-to-beat nonlinear measurement of the repetitiveness of the electrogram morphology>6 seconds). In 15% of the patients, activation maps demonstrated occurrences of rotor-like small-radius reentrant circuits (n=9; 1.1 per patient; cycle length=110±21 ms; diameter=11±6 mm) with fibrillation occurring outside these areas. Rotors were identified by conventional point-by-point mapping and signal analyses and were subsequently eradicated by catheter ablation in these patients. Persistent AF for <1 year, a smaller left atrial size, substrates with higher mean voltages and shorter total activation durations predicted a higher incidence of rotors (all P<0.05). In the multivariable model, areas of reentrant circuits exhibited a higher dominant frequency, kurtosis, and higher degree of a beat-to-beat electrogram similarity than areas without or outside the rotors (all P<0.05). CONCLUSIONS: Rotor-like re-entry with fibrillatory conduction was found in a limited number of patients with nonparoxysmal AF after pulmonary vein isolation. Those areas were characterized by rapid repetitive activity with a high degree of electrogram similarity.

A new method to estimate the amplitude spectrum analysis of ventricular fibrillation during cardiopulmonary resuscitation.

AIMS: Accurate ventricular fibrillation (VF) waveform analysis usually requires rescuers to discontinue cardiopulmonary resuscitation (CPR). However, prolonged "hands-off" time has a deleterious impact on the outcome. We developed a new filter technique that could clean the CPR artifacts and help preserve the shockability index of VF METHODS: We analyzed corrupted ECGs, which were constructed by randomly adding different scaled CPR artifacts to the VF waveforms. A newly developed algorithm was used to identify the CPR fluctuations. The algorithm contained two steps. First, decomposing the raw data by empirical mode decomposition (EMD) into several intrinsic mode fluctuations (IMFs) and combining the dominant IMFs to reconstruct a new signal. Second, calculating each CPR cycle frequency from the new signal and fitting the new signal to the original corrupted ECG by least square mean (LSM) method to derive the CPR artifacts. The estimated VF waveform was derived by subtraction of the CPR artifacts from the corrupted ECG. We then performed amplitude spectrum analysis (AMSA) for original VF, corrupted ECG and estimated VF. RESULTS: A total of 150 OHCA subjects with initial VF rhythm were included for analysis. Ten CPR artifacts signals were used to construct corrupted ECG. Even though the correlations of AMSA between the corrupted ECG vs. the original VF and the estimated VF vs. the original VF are all high (all p<0.001), the values of AMSA were obviously biased in corrupted ECG with wide limits of agreement in Bland-Altman mean-difference plot. ROC analysis of the AMSA in the prediction of defibrillation success showed that the new algorithm could preserve the cut-off AMSA value for CPR artifacts with power ratio to VF from 0 to 6 dB. CONCLUSION: The new algorithm could efficiently filter the CPR-related artifacts of the VF ECG and preserve the shockability index of the original VF waveform.

Nonlinear analysis of fibrillatory electrogram similarity to optimize the detection of complex fractionated electrograms during persistent atrial fibrillation.

INTRODUCTION: Currently, the identification of complex fractionated atrial electrograms (CFEs) in the substrate modification is mostly based on cycle length-derived algorithms. The characteristics of the fibrillation electrogram morphology and their consistency over time are not clear. The aim of this study was to optimize the detection algorithm of crucial CFEs by using nonlinear measure electrogram similarity. METHODS AND RESULTS: One hundred persistent atrial fibrillation patients that underwent catheter ablation were included. In patients who required CFE ablation (79%), the time-domain fibrillation signals (6 seconds) were acquired for a linear analysis (mean fractionation interval and dominant frequency [DF]) and nonlinear-based waveform similarity analysis of the local electrograms, termed the similarity index (SI). Continuous CFEs were targeted with an endpoint of termination. Predictors of the various signal characteristics on the termination and clinical outcome were investigated. Procedural termination was observed in 39% and long-term sinus rhythm maintenance in 67% of the patients. The targeted CFEs didn't differ based on the linear analysis modalities between the patients who responded and did not respond to CFE ablation. In contrast, the average SI of the targeted CFEs was higher in termination patients, and they had a better outcome. Multivariate regression analysis showed that a higher SI independently predicted sites of termination (≥ 0.57; OR = 4.9; 95% CI = 1.33-18.0; P = 0.017). CONCLUSIONS: In persistent AF patients, a cycle length-based linear analysis could not differentiate culprit CFEs from bystanders. This study suggested that sites with a high level of fibrillation electrogram similarity at the CFE sites were important for AF maintenance.

Novel assessment of temporal variation in fractionated electrograms using histogram analysis of local fractionation interval in patients with persistent atrial fibrillation.

BACKGROUND: The characteristics of atrial electrograms associated with atrial fibrillation (AF) termination are controversial. We investigated the electrogram characteristics that indicate procedural AF termination during continuous complex fractionated electrogram ablation. METHODS AND RESULTS: Fifty-two consecutive patients with persistent AF (47 men; aged 54 ± 9 years), who underwent electrogram-based catheter ablation in the left atrium and coronary sinus after pulmonary vein isolation, were enrolled. The intracardiac bipolar atrial electrogram recordings were characterized by (1) fractionation interval (FI) analysis (>6 seconds), (2) kurtosis (shape of the FI histogram), and (3) skewness (asymmetry of the FI histogram). Sites showing complex, fractionated electrograms (mean FI ≤ 60 ms) were targeted, and AF was terminated in 20 patients (38%) after the pulmonary vein isolation. The conventional complex fractionated electrogram sites (mean ≤ 120 ms) in patients with AF termination exhibited higher median kurtosis (2.69 [interquartile range, 2.03-3.46] versus 2.35 [interquartile range, 1.79-2.48]; P=0.024) and higher complex fractionated electrogram-mean interval (102.7 ± 19.8 versus 87.7 ± 15.0; P=0.008) than patients without AF termination. Furthermore, AF termination sites had higher median kurtosis than targeted sites without AF termination (5.13 [interquartile range, 3.51-6.47] versus 4.18 [interquartile range, 2.91-5.34]; P<0.01) in patients with procedural termination. In addition, patients with AF termination had a higher sinus rhythm maintenance rate after a single procedure than patients without AF termination (log-rank test, P=0.007). CONCLUSIONS: A kurtosis analysis using the FI histogram may be a useful tool in identifying the critical substrate for persistent AF and potential responders to catheter ablation.