Personalized ECG monitoring and adaptive machine learning.

This non-technical review introduces key concepts in personalized ECG monitoring (pECG), which aims to optimize the detection of clinical events and their warning signs as well as the selection of alarm thresholds. We review several pECG methods, including anomaly detection and adaptive machine learning (ML), in which learning is performed sequentially as new data are collected. We describe a distributed-network multiscale pECG system to show how the computational load and time associated with adaptive ML could be optimized. In this architecture, the limited analysis of ECG waveforms is performed locally (e.g., on a smart phone) to determine a small number of clinically important ECG elements, and an adaptive ML engine is located on a remote server (Internet cloud) to determine an individual's "fingerprint" basis patterns and to detect anomalies in those patterns.

High-energy external defibrillation and transcutaneous pacing during MRI: feasibility and safety.

BACKGROUND: Rapid application of external defibrillation, a crucial first-line therapy for ventricular fibrillation and cardiac arrest, is currently unavailable in the setting of magnetic resonance imaging (MRI), raising concerns about patient safety during MRI tests and MRI-guided procedures, particularly in patients with cardiovascular diseases. The objective of this study was to examine the feasibility and safety of defibrillation/pacing for the entire range of clinically useful shock energies inside the MRI bore and during scans, using defibrillation/pacing outside the magnet as a control. METHODS: Experiments were conducted using a commercial defibrillator (LIFEPAK 20, Physio-Control, Redmond, Washington, USA) with a custom high-voltage, twisted-pair cable with two mounted resonant floating radiofrequency traps to reduce emission from the defibrillator and the MRI scanner. A total of 18 high-energy (200-360 J) defibrillation experiments were conducted in six swine on a 1.5 T MRI scanner outside the magnet bore, inside the bore, and during scanning, using adult and pediatric defibrillation pads. Defibrillation was followed by cardiac pacing (with capture) in a subset of two animals. Monitored signals included: high-fidelity temperature (0.01 °C, 10 samples/sec) under the pads and 12-lead electrocardiogram (ECG) using an MRI-compatible ECG system. RESULTS: Defibrillation/pacing was successful in all experiments. Temperature was higher during defibrillation inside the bore and during scanning compared with outside the bore, but the differences were small (ΔT: 0.5 and 0.7 °C, p = 0.01 and 0.04, respectively). During scans, temperature after defibrillation tended to be higher for pediatric vs. adult pads (p = 0.08). MR-image quality (signal-to-noise ratio) decreased by ~ 10% when the defibrillator was turned on. CONCLUSIONS: Our study demonstrates the feasibility and safety of in-bore defibrillation for the full range of defibrillation energies used in clinical practice, as well as of transcutaneous cardiac pacing inside the MRI bore. Methods for Improving MR-image quality in the presence of a working defibrillator require further study.

Increased Nonalternans Repolarization Variability Precedes Ventricular Tachycardia Onset in Patients with Implantable Defibrillators.

BACKROUND: T-wave alternans (TWA) is associated with ventricular tachycardia (VT). Nonalternans repolarization variability (NARV) precedes VT in certain experimental models, but its link to clinical arrhythmia is unproven. This study was conducted to determine if NARV increases prior to VT in patients with implantable cardioverter defibrillators (ICDs). METHODS: TWA and NARV were calculated from shock-channel electrograms preceding onset of VT or non-VT events in patients with an ICD. In each patient, presence of both a VT and a non-VT event with the same QRS morphology before the event was required. Mixed linear model was used for data analysis, using heart rate (HR) and the number of analyzed beats as covariates. RESULTS: Five hundred and sixty-eight events from 64 patients (males/females 51/13, 67 ± 13 years) were analyzed. HR preceding non-VT events was higher than before VT events (RR interval 595 ± 159 vs 706 ± 111 ms; P < 0.0001). Both TWA and NARV increased with increasing HR (P < 0.001). TWA decreased with increasing number of analyzed beats. When controlled for number of analyzed beats and HR, both TWA and NARV were higher before VT than before non-VT events (P < 0.002 and P < 0.0005, respectively). CONCLUSIONS: NARV is elevated prior to spontaneous VT onset. Both NARV and TWA increase with HR. The decrease of TWA with increasing number of analyzed beats may indicate contamination with NARV or noise when only a small number of beats is available for analysis. NARV might be useful for VT prediction in the future.

Nighttime instabilities of neurophysiological, cardiovascular, and respiratory activity: integrative modeling and preliminary results.

Unstable (cyclical alternating pattern, or CAP) sleep is associated with surges of sympathetic nervous system activity, increased blood pressure and vasoconstriction, heightened baroreflex sensitivity, and unstable heart rhythm and breathing. In susceptible persons, CAP sleep provokes clinically significant events, including hypertensive crises, sleep-disordered breathing, and cardiac arrhythmias. Here we explore the neurophysiology of CAP sleep and its impact on cardiovascular and respiratory functions. We show that: (i) an increase in neurophysiological recovery rate can explain the emergence of slow, self-sustained, hypersynchronized A1 CAP-sleep pattern and its transition to the faster A2-A3 CAP-sleep patterns; (ii) in a two-dimensional, continuous model of cardiac tissue with heterogeneous action potential duration (APD) distribution, heart rate accelerations during CAP sleep may encounter incompletely recovered electrical excitability in cell clusters with longer APD. If the interaction between short cycle length and incomplete, spatially heterogeneous repolarization persists over multiple cycles, irregularities and asymmetry of depolarization front may accumulate and ultimately lead to a conduction block, retrograde conduction, breakup of activation waves, reentrant activity, and arrhythmias; and (iii) these modeling results are consistent with the nighttime data obtained from patients with structural heart disease (N=13) that show clusters of atrial and ventricular premature beats occurring during the periods of unstable heart rhythm and respiration that accompany CAP sleep. In these patients, CAP sleep is also accompanied by delayed adaptation of QT intervals and T-wave alternans.

Novel technical solutions for wireless ECG transmission & analysis in the age of the internet cloud.

Current guidelines recommend early reperfusion therapy for ST-elevation myocardial infarction (STEMI) within 90 min of first medical encounter. Telecardiology entails the use of advanced communication technologies to transmit the prehospital 12-lead electrocardiogram (ECG) to offsite cardiologists for early triage to the cath lab; which has been shown to dramatically reduce door-to-balloon time and total mortality. However, hospitals often find adopting ECG transmission technologies very challenging. The current review identifies seven major technical challenges of prehospital ECG transmission, including: paramedics inconvenience and transport delay; signal noise and interpretation errors; equipment malfunction and transmission failure; reliability of mobile phone networks; lack of compliance with the standards of digital ECG formats; poor integration with electronic medical records; and costly hardware and software pre-requisite installation. Current and potential solutions to address each of these technical challenges are discussed in details and include: automated ECG transmission protocols; annotatable waveform-based ECGs; optimal routing solutions; and the use of cloud computing systems rather than vendor-specific processing stations. Nevertheless, strategies to monitor transmission effectiveness and patient outcomes are essential to sustain initial gains of implementing ECG transmission technologies.

Nocturnal peak in atrial tachyarrhythmia occurrence as a function of arrhythmia burden.

INTRODUCTION: We examined circadian periodicity of atrial tachyarrhythmias (AT/AF) in a large group of patients with implantable devices, which allow continuous collection of the event data over prolonged periods of time. METHODS AND RESULTS: A total of 16,130 AT/AF events were recorded in 236 patients (age: 63 ± 12 years, 27% female, 90% had a history of cardiovascular disease, 33% ischemic, LVEF: 49 ± 18%) over a period of 12 months. To exclude interactions with therapy, the patterns of arrhythmia occurrence were examined for all events and for those episodes that were preceded by at least 1, 6, and 24 hours of sinus rhythm. To prevent biasing toward patients with more frequent episodes, the patterns of AT/AF onset were analyzed both in absolute and patient-normalized (i.e., divided by the total number of events in each patient) units per hour per patient and then summarized for the entire group. In patients with <4 AT/AF events, the onset times were randomly distributed over 24-hour period. However, as the number of AT/AF events increased, a nocturnal pattern of occurrence (determined by the occurrence of a trough around noon) gradually emerged and became highly statistically significant (P < 10(-4) ). The magnitude of nocturnal peak of AT/AF events was well explained by a single-exponential function (R(2) = 0.97, P < 10(-2) ). CONCLUSION: Patients with more frequent atrial tachyarrhythmias are more likely to develop AT/AF at night. Knowledge of patient-specific circadian patterns of arrhythmia occurrence can be useful for personalized management of individuals with significant arrhythmia burden.

Accelerated junctional rhythm and nonalternans repolarization lability precede ventricular tachycardia in Casq2-/- mice.

BACKGROUND: Calsequestrin-2 (CASQ2) is a Ca(2+) buffering protein of myocardial sarcoplasmic reticulum. CASQ2 mutations underlie a form of catecholaminergic polymorphic ventricular tachycardia (CPVT). The CPVT phenotype is recapitulated in Casq2 -/- mice. Repolarization lability (RL)-beat-to-beat variability in the T wave morphology-has been reported in long-QT syndrome, but has not been evaluated in CPVT. METHODS AND RESULTS: ECG from Casq2 -/- mice was evaluated with respect to heart rate (HR) and RL changes prior to onset of ventricular tachycardia (VT) to gain insight into arrhythmogenesis in CPVT. Telemetry from unrestrained mice (3-month-old males, 5 animals of each genotype) and ECG before and after isoproterenol administration in anesthetized mice was analyzed. Average HR in sinus rhythm (SR), occurrence of nonsinus rhythm and RL were quantified. HR was slower in Casq2 -/- animals. Accelerated junctional rhythm (JR) occurred more frequently in Casq2 -/- mice and often preceded VT. In Casq2 -/- mice, HR increased prior to VT onset, prior to onset of JR and on transition from JR to VT. RL increased during progression from SR to VT and after isoproterenol administration in Casq2 -/-, but not in Casq2+/+ animals. Isoproterenol did not increase repolarization alternans in either genotype. CONCLUSIONS: Accelerated JR, likely caused by triggered activity in His/Purkinje system, occurs frequently in Casq2 -/- mice. The absence of CASQ2 results in increased RL. The increase in HR and in RL precede onset of arrhythmias in this CPVT model. Nonalternans RL precedes ventricular arrhythmia in wider range of conditions than previously appreciated.

Regional genomic regulation of cardiac sodium-calcium exchanger by oestrogen.

Female rabbit hearts are more susceptible to torsade de pointes (TdP) in acquired long QT type 2 than males, in-part due to higher L-type Ca2+ current (ICa,L) at the base of the heart. In principle, higher Ca2+ influx via ICa,L should be balanced by higher efflux, perhaps mediated by parallel sex differences of sodium-calcium exchange (NCX) current (INCX). We now show that NCX1, like Cav1.2α, is greater at the base of female than male left ventricular epicardium and greater at the base than at the apex in both sexes. In voltage-clamp studies, inward (0, +20 mV, P < 0.04) and outward (-80, -60, -40, -20 mV, P < 0.01) INCX densities were significantly higher (1.5-2 fold) in female base compared to apex and male (base and apex) myocytes. Myocytes were incubated ±17ß-oestradiol (E2 = 1 nm) and INCX was measured on days 0, 1, 2 and 3. Inward and outward INCX decreased over 2 days in female base myocytes becoming similar to INCX at the apex. E2 incubation (24 h) increased NCX1 (50%) and INCX (∼3-fold at 60 mV) in female base but not endocardium, apex or in male base myocytes. INCX upregulation by E2 was blunted by an oestrogen receptor (ER) antagonist (fulvestrant, 1 µm), and inhibition of transcription (actinomycin D, 5 µg ml-1) or translation (cycloheximide, 20 µg ml-1). Dofetilide (an IKr blocker) induced early afterdepolarizations (EADs) in female base myocytes cultured for 1 day if incubated with E2, but not without E2 or with E2+KB-R4973 (an INCX inhibitor), E2+fulvestrant or E2 with apex myocytes. Thus, E2 upregulates NCX1 by a genomic mechanism mediated by ERs, and de novo mRNA and protein biosynthesis, in a sex- and region-dependent manner which contributes to the enhanced propensity to EADs and TdP in female hearts.

Slow QT interval adaptation to heart rate changes in normal ambulatory subjects.

BACKGROUND: Clinical formulas for QT correction utilize instantaneous HR. We showed previously that longer-term HR affects QT duration. We extend these findings, identifying more accurate models of QT behavior. METHOD: Multiple models of QT dependence on HR were tested in 2 independent populations. Holter recordings were analyzed in population A (healthy volunteers, n = 14, 6 males, age 26.9 ± 12.3 yr). The hypotheses generated in population A were tested in an independent group population B, healthy volunteers, n = 15, 9 males, age 52.9 ± 15.6 yr). Linear models of QT interval dependence on a weighted average of RR intervals in the preceding 3 minutes were compared to models based on the immediately preceding RR interval (instantaneous HR). RESULTS: In population A, linear models based on RR intervals over the preceding minute performed better than the best nonlinear model based on the single RR interval immediately preceding the QT interval. Linear models including HR values preceding the QT interval by more than 60 s further improved model fit. This model hierarchy was confirmed in population B. Linear formula for QT correction based on exponential decay of HR effect with 60 s time constant outperformed Bazett and Fridericia formulas in both populations. CONCLUSIONS: QT duration in normal ambulatory subjects is affected by noninstantaneous HR, including HR history dating back more than 60 s. Exponential decay of this "memory effect" with time constant of 1 minute provides an accurate description of QT adaptation. This may be of clinical importance when HR is not steady.

Cardiac repolarization instability during psychological stress in patients with ventricular arrhythmias.

INTRODUCTION: Changes in the autonomic nervous system activity are a major trigger of life-threatening ventricular tachyarrhythmias (VTAs). Mental arithmetic, a condition administered in a laboratory setting, can provide insight into the autonomic nervous system activity effects on cardiac physiology. We examined the responses of cardiac repolarization to laboratory-induced psychological stressors in patients with implantable cardioverter-defibrillators (ICDs) with the objective of identifying the indices that differentiate patients with and without subsequent VTA in follow-up. METHODS: Continuous electrocardiographic signals were recorded using 3 standard bipolar (Holter) leads in 56 patients (age, 63.6 ± 11.9; female, 12%; left ventricular ejection fraction, 32.3 ± 11) with ICDs during mental arithmetic. The patients were separated into those with subsequent VTA during 3 to 4 years of follow-up (group 1: n = 9) and those without VTA (group 2: n = 47). Changes in repolarization (QT interval, mean T wave amplitude [Tamp], and T wave area) were analyzed during 5 minutes at baseline, stress, and recovery. The temporal instability of Tamp and T wave area was examined using the range (Δ) and variance (σ(2)) of beat-to-beat variations of the corresponding parameters. RESULTS: There were no significant differences in heart rate between the 2 groups at baseline (61 vs 63 beats per minute, P = .97), stress (64 vs 65 beats per minute, P = .40), and recovery (62 vs 61 beats per minute, P = .88). However, during mental stress and poststress recovery, ΔTamp was almost 2-fold greater in group 1 compared with group 2 (111 [57-203] vs 68 [44-94] µV, P = .04, respectively). Changes in QT intervals were also greater in group 1 compared with group 2 (P = .02). CONCLUSION: Among patients with ICDs, changes of Tamp after psychological stress were greater in those with subsequent arrhythmic events. This might signal proarrhythmic repolarization response and help identify patients who would benefit the most from ICD implantation and proactive management.

Circadian Pattern of Ion Channel Gene Expression in Failing Human Hearts.

BACKGROUND: Ventricular tachyarrhythmias and sudden cardiac death show a circadian pattern of occurrence in patients with heart failure. In the rodent ventricle, a significant portion of genes, including some ion channels, shows a circadian pattern of expression. However, genes that define electrophysiological properties in failing human heart ventricles have not been examined for a circadian expression pattern. METHODS: Ventricular tissue samples were collected from patients at the time of cardiac transplantation. Two sets of samples (n=37 and 46, one set with a greater arrhythmic history) were selected to generate pseudo-time series according to their collection time. A third set (n=27) of samples was acquired from the nonfailing ventricles of brain-dead donors. The expression of 5 known circadian clock genes and 19 additional ion channel genes plausibly important to electrophysiological properties were analyzed by real-time polymerase chain reaction and then analyzed for the percentage of expression variation attributed to a 24-hour circadian pattern. RESULTS: The 5 known circadian clock gene transcripts showed a strong circadian expression pattern. Compared with rodent hearts, the human circadian clock gene transcripts showed a similar temporal order of acrophases but with a ≈7.6 hours phase shift. Five of the ion channel genes also showed strong circadian expression. Comparable studies of circadian clock gene expression in samples recovered from nonheart failure brain-dead donors showed acrophase shifts, or weak or complete loss of circadian rhythmicity, suggesting alterations in circadian gene expression. CONCLUSIONS: Ventricular tissue from failing human hearts display a circadian pattern of circadian clock gene expression but phase-shifted relative to rodent hearts. At least 5 ion channels show a circadian expression pattern in the ventricles of failing human hearts, which may underlie a circadian pattern of ventricular tachyarrhythmia/sudden cardiac death. Nonfailing hearts from brain-dead donors show marked differences in circadian clock gene expression patterns, suggesting fundamental deviations from circadian expression.

Adrenergic stimulation promotes T-wave alternans and arrhythmia inducibility in a TNF-alpha genetic mouse model of congestive heart failure.

T-wave alternans (TWA) is a proarrhythmic repolarization instability that is common in congestive heart failure (CHF). Although transgenic mice are commonly used to study the mechanisms of arrhythmogenesis in CHF, little is known about the dynamics of TWA in these species. We hypothesized that TWA is present in a TNF-alpha model of CHF and can be further promoted by adrenergic stimulation. We studied 16 TNF-alpha mice and 12 FVB controls using 1) in vivo intracardiac electrophysiological testing and 2) ambulatory telemetry during 30 min before and after an intraperitoneal injection of isoproterenol. TWA was examined using both linear and nonlinear filtering applied in the time domain. In addition, changes in the mean amplitude of the T wave and area under the T wave were computed. During intracardiac electrophysiological testing, none of the animals had TWA or inducible arrhythmias before the injection of isoproterenol. After the injection, sustained TWA and inducible ventricular tachyarrhythmias were observed in TNF-alpha mice but not in FVB mice. In ambulatory telemetry, before the isoproterenol injection, the cardiac cycle length (CL) was longer in TNF-alpha mice than in FVB mice (98 +/- 9 and 88 +/- 3 ms, P = 0.04). After the injection of isoproterenol, the CL became 8% and 6% shorter in TNF-alpha and FVB mice (P < 10(-4)); however, the 2% difference between the groups in the magnitude of CL changes was not significant. In TNF-alpha mice, the magnitude of TWA was 1.5-2 times greater than in FVB mice both before and after the isoproterenol injection. The magnitude of TWA increased significantly after the isoproterenol injection compared with the baseline in TNF-alpha mice (P = 0.003) but not in FVB mice. The mean amplitude of the T wave and area under the T wave increased 60% and 80% in FVB mice (P = 0.006 and 0.009) but not in TNF-alpha mice. In conclusion, TWA is present in a TNF-alpha model of CHF and can be further promoted by adrenergic stimulation, along with the enhanced susceptibility for ventricular arrhythmias.

QT interval variability and adaptation to heart rate changes in patients with long QT syndrome.

BACKGROUND: Increased QT variability (QTV) has been reported in conditions associated with ventricular arrhythmias. Data on QTV in patients with congenital long QT syndrome (LQTS) are limited. METHODS: Ambulatory electrocardiogram recordings were analyzed in 23 genotyped LQTS patients and in 16 healthy subjects (C). Short-term QTV was compared between C and LQTS. The dependence of QT duration on heart rate was evaluated with three different linear models, based either on the RR interval preceding the QT interval (RR(0)), the RR interval preceding RR(0) (RR(-1)), or the average RR interval in the 60-second period before QT interval (mRR). RESULTS: Short-term QTV was significantly higher in LQTS than in C subjects (14.94 +/- 9.33 vs 7.31 +/- 1.29 ms; P < 0.001). It was also higher in the non-LQT1 than in LQT1 patients (23.00 +/- 9.05 vs 8.74 +/- 1.56 ms; P < 0.001) and correlated positively with QTc in LQTS (r = 0.623, P < 0.002). In the C subjects, the linear model based on mRR predicted QT duration significantly better than models based on RR(0) and RR(-1). It also provided better fit than any nonlinear model based on RR(0). This was also true for LQT1 patients. For non-LQT1 patients, all models provided poor prediction of QT interval. CONCLUSIONS: QTV is elevated in LQTS patients and is correlated with QTc in LQTS. Significant differences with respect to QTV exist among different genotypes. QT interval duration is strongly affected by noninstantaneous heart rate in both C and LQT1 subjects. These findings could improve formulas for QT interval correction and provide insight on cellular mechanisms of QT adaptation.

The many faces of repolarization instability: which one is prognostic?

Instabilities of the STT segment's magnitude, and particularly the 0.5 beat/cycle oscillations (T-wave alternans, or TWA), have been linked to the heightened risk of ventricular tachyarrhythmias (VTA) and sudden cardiac death (SCD). During the last decade theoretical, experimental and clinical research efforts have focused primarily on TWA, examining its mechanisms and predictive value using time-invariant cutoff values. However, recent evidence suggests that such a single-snapshot test of a single-frequency (TWA) oscillation using a constant cutoff value might be suboptimal for risk stratification because of several reasons. First, it is well known that the risk of VTA/SCD evolves over time with changes in electrophysiologic substrate, environmental and physiologic triggers, and the impact of other physiologic (eg, circadian) rhythmicity. Hence, the outcome of TWA testing might depend on the time of day, as Holter-based TWA studies have demonstrated. Furthermore, currently used single-snapshot testing with a binary cutoff value may not coincide with the periods of heightened risk for VTA/SCD and may not yield prognostic information, as a recent TWA substudy of the sudden cardiac death in heart failure trial has showed. Second, the analysis focused on TWA alone ignores the existence of multiple (alternating and nonalternating) forms of repolarization instability that have been shown to arise or increase before the onset of VTA/SCD. Summarizing, recent studies have identified multiple forms of repolarization instabilities modulated by distinct mechanisms, which might have different prognostic values. Therefore, the assessment of TWA needs to be dynamic and personalized to take into account the time evolution of risk and individual history.

Magnetic Resonance Imaging of Contracting Ultrathin Cardiac Tissue.

OBJECTIVE: Integrating cardiac-tissue patches into the beating heart and evaluating the long-term effects of such integration on cardiac contractility are two challenges in an emerging field of regenerative medicine. This pilot study presents tools for the imaging of contracting multicellular cardiac tissue constructs (MTCs) in vitro and demonstrates the feasibility of tracking the early development of strand geometry and contractions in ultrathin strands and layers of cardiac tissue using CINE MRI. APPROACH: Cultured, ultrathin (~50-100-micron) MTCs of rat neonatal cardiomyocytes were plated in rectangular cell chambers (4.5 × 2.0 cm) with and without ultrathin, carbon EP electrodes embedded in the floor of the cell chamber. Two-dimensional, steady-state free precession (SSFP) CINE MRI, cell microscopy, and tissue photography were performed on Days 5-9 of cell development. Potential confounders and MRI artifacts were evaluated using non-contracting cardiac tissues and cell-free chambers filled with the cell-culture medium. MAIN RESULTS: Synchronized contractions formed by Day 7; individual contracting tissue strands became identifiable by Day 9. The global patterns and details of the strand geometry and movement patterns in the SSFP images were in excellent agreement with microscopic and photographic images. No synchronized movement was identifiable by either microscopy or CINE MRI in the non-contracting MTCs or the cell-free medium. The EP recordings revealed well-defined depolarization and repolarization waveforms; the imaging artifacts generated by the carbon electrodes were small. SIGNIFICANCE: This pilot study demonstrates the feasibility of imaging cardiac-strand patterns and contractile activity in ultrathin, two-dimensional cardiac tissue in commonly used clinical scanners.

From baseline to epileptiform activity: a path to synchronized rhythmicity in large-scale neural networks.

In large-scale neural networks in the brain the emergence of global behavioral patterns, manifested by electroencephalographic activity, is driven by the self-organization of local neuronal groups into synchronously functioning ensembles. However, the laws governing such macrobehavior and its disturbances, in particular epileptic seizures, are poorly understood. Here we use a mean-field population network model to describe a state of baseline physiological activity and the transition from the baseline state to rhythmic epileptiform activity. We describe principles which explain how this rhythmic activity arises in the form of spatially uniform self-sustained synchronous oscillations. In addition, we show how the rate of migration of the leading edge of the synchronous oscillations can be theoretically predicted, and compare the accuracy of this prediction with that measured experimentally using multichannel electrocorticographic recordings obtained from a human subject experiencing epileptic seizures. The comparison shows that the experimentally measured rate of migration of the leading edge of synchronous oscillations is within the theoretically predicted range of values. Computer simulations have been performed to investigate the interactions between different regions of the brain and to show how organization in one spatial region can promote or inhibit organization in another. Our theoretical predictions are also consistent with the results of functional magnetic resonance imaging (fMRI), in particular with observations that lower-frequency electroencephalographic (EEG) rhythms entrain larger areas of the brain than higher-frequency rhythms. These findings advance the understanding of functional behavior of interconnected populations and might have implications for the analysis of diverse classes of networks.

Upsurge in T-wave alternans and nonalternating repolarization instability precedes spontaneous initiation of ventricular tachyarrhythmias in humans.

BACKGROUND: Analysis of repolarization instability, manifested by T-wave alternans (TWA), has proved useful for arrhythmia risk assessment. However, temporal relations between TWA and the spontaneous initiation of ventricular tachyarrhythmias (VTA) in humans are unknown. We examined continuous dynamics of repolarization in Holter electrocardiograms with spontaneous sustained (>30 seconds) VTA. METHODS AND RESULTS: Ambulatory electrocardiograms from 42 patients (79% with ischemic heart disease; left ventricular ejection fraction, 37+/-15%) were digitized, and the lead with the highest magnitude of the T wave was selected for analysis. TWA was examined by the modified moving average and intrabeat average analyses. To examine non-TWA (longer-period) oscillations in the repolarization segment, spectral energy of oscillations of consecutive T-wave amplitudes was calculated with the use of the short-time Fourier transform. Heart rate variability was assessed with the Fourier transform as well. TWA increased before the onset of VTA and reached a peak value of 23.6+/-11.7 microV 10 minutes before the event (P=0.0007). Spectral power of the oscillations of consecutive T-wave amplitudes increased nonuniformly, with the greatest increase in the respiratory range (2.6 microV2; P=0.005). In the TWA range, the change was smaller but highly pronounced relative to the 60- to 120-minute level (65%; P=0.003). The low-frequency and high-frequency heart rate variability power declined before the arrhythmia (P=0.04 and P=0.06, respectively). CONCLUSIONS: The magnitude of repolarization instability, manifested by TWA and beat-to-beat oscillations of T-wave amplitudes at other frequencies, increased before the onset of VTA. Tracking of these dynamics can facilitate timely detection of high-risk periods and may be useful for initiation of preventive treatments.

Implantable cardioverter-defibrillator shocks increase T-wave alternans.

INTRODUCTION: While implantable defibrillator shocks save lives, shock can lead to ventricular arrhythmias. However, the mechanism of shock-related proarrhythmia remains unclear. We evaluated the impact of ICD shock on repolarization instability, a factor associated with ventricular arrhythmogenesis. METHODS AND RESULTS: Sixty-five patients with ICDs underwent ambulatory ECG monitoring during defibrillation testing 3 months postimplant. TWA was analyzed continuously in the time domain during baseline, sedated, and post-shock states. RR, QRS, and QT intervals and catecholamines were also measured continuously. Adequate pre- and post-shock Holter data were recorded in 55 patients, 48 male, mean 64 +/- 12 years, 50 with coronary disease, 48 with prior spontaneous or induced arrhythmia. TWA significantly increased after shock, from 9.6 +/- 0.5 to 11.9 +/- 0.6 microV, as did QRS duration, epinephrine, and norepinephrine levels, compared with sedated and baseline states. RR intervals decreased minimally. TWA changes with shock were not associated with RR or QRS duration changes, but were associated with changes in epinephrine. CONCLUSIONS: ICD shock, even in the sedated state, increases repolarization instability as measured by TWA, an effect mediated in part by sympathetic stimulation. This association between shock and TWA may have important mechanistic and clinical implications for optimization of defibrillation therapy.

A sodium channel pore mutation causing Brugada syndrome.

BACKGROUND: Brugada and long QT type 3 syndromes are linked to sodium channel mutations and clinically cause arrhythmias that lead to sudden death. We have identified a novel threonine-to-isoleucine missense mutation at position 353 (T353I) adjacent to the pore-lining region of domain I of the cardiac sodium channel (SCN5A) in a family with Brugada syndrome. Both male and female carriers are symptomatic at young ages, have typical Brugada-type electrocardiogram changes, and have relatively normal corrected QT intervals. OBJECTIVES: To characterize the properties of the newly identified cardiac sodium channel (SCN5A) mutation at the cellular level. RESULTS: Using whole-cell voltage clamp, we found that heterologous expression of SCN5A containing the T353I mutation resulted in 74% +/- 6% less peak macroscopic sodium current when compared with wild-type channels. A construct of the T353I mutant channel fused with green fluorescent protein failed to traffic properly to the sarcolemma, with a large proportion of channels sequestered intracellularly. Overnight exposure to 0.1 mM mexiletine, a Na(+) channel blocking agent, increased T353I channel trafficking to the membrane to near normal levels, but the mutant channels showed a significant late current that was 1.6% +/- 0.2% of peak sodium current at 200 ms, a finding seen with long QT mutations. CONCLUSIONS: The clinical presentation of patients carrying the T353I mutation is that of Brugada syndrome and could be explained by a cardiac Na(+) channel trafficking defect. However, when the defect was ameliorated, the mutated channels had biophysical properties consistent with long QT syndrome. The lack of phenotypic changes associated with the long QT syndrome could be explained by a T353I-induced trafficking defect reducing the number of mutant channels with persistent currents present at the sarcolemma.

Karhunen-Loève representation distinguishes ST-T wave morphology differences in emergency department chest pain patients with non-ST-elevation myocardial infarction versus nonacute coronary syndrome.

UNLABELLED: Patients presenting to the emergency department with chest pain are triaged to early reperfusion therapies based on their initial 12-lead electrocardiogram (ECG). The standard 12-lead ECG lacks sensitivity to detect acute myocardial infarction (AMI). Electrocardiographic diagnosis of non-ST-elevation myocardial infarction (non-STEMI) is especially difficult and is delayed until cardiac biomarkers turn positive, indicating onset of myocardial necrosis. STUDY AIMS: The purpose of this analysis was to extract global ST-T waveform features from patients with chest pain, compare these features in patients with and without AMI, and then identify features that distinguish diagnostic categories. METHODS: This is a secondary analysis of data from the Ischemia Monitoring and Mapping in the Emergency Department in Appropriate Triage and Evaluation of Acute Ischemic Myocardium study, a prospective clinical trial in which patients were attached to Holter monitor devices to obtain 24 hours of continuous ECG data. Digital recordings from 176 patients were analyzed: 88 with AMI (STEMI and non-STEMI) and 88 without AMI or unstable angina. The non-acute coronary syndrome (ACS) group was further subdivided into those with non-ACS cardiac conditions such as heart failure and those without cardiac disease who had noncardiac chest pain. For each patient, 10 consecutive waveforms were obtained within the first 120 minutes of emergency department presentation. The waveforms were time-aligned to the QRS, signal-averaged, baseline-adjusted. ST-T waveforms were complied according to diagnostic category and pooled for further analysis. Eigenvector-lead feature coefficients (Karhunen-Loève [K-L] coefficients) were obtained for each patient by taking the dot product of the ST-T wave (ST segment or entire waveform) and the first 3 common eigenvectors, producing 24 K-L coefficients. Cumulative probability distribution function curves were plotted for each diagnostic category. Statistical significance of category coefficient distribution differences was determined. Multinomial regression was used to assess accuracy of feature coefficients to predict diagnostic category. RESULTS: Non-STEMI and non-ACS cardiac category K-L coefficient curves were statistically different in 11 of 24 feature curves (P < .001-.047). ST-segment (50 samples) coefficients predicted non-ACS cardiac patients 11.5% more often (P = .02) than those derived from the entire ST-T wave. CONCLUSION: Patients diagnosed with non-STEMI have distinct distribution of K-L coefficients compared with non-ACS cardiac patients. Coefficients from the first 50 samples of the ST-T wave (ST segment) better predict diagnostic category than do coefficients derived from the entire ST-T wave. Karhunen-Loève coefficient feature analysis may provide early diagnostic information to distinguish patients with non-STEMI vs non-ACS cardiac patients.