Left ventricular ejection fraction using a simplified wall motion score based on mid-parasternal short axis and apical four-chamber views for non-cardiologists.

BACKGROUND: There is a need for a convenient, yet reliable method to assess left ventricular ejection fraction (LVEF) with point-of-care ultrasound study (POCUS). We aim to validate a novel and simplified wall motion score LVEF based on the analysis of a simplified combination of echocardiographic views. METHODS: In this retrospective study, transthoracic echocardiograms of randomly selected patients were analysed by the standard 16-segments wall motion score index (WMSI) to derive the reference semi-quantitative LVEF. To develop our semi-quantitative simplified-views method, a limited combination of imaging views and only 4 segments per view were tested: (1) A combination of the three parasternal short-axis views (PSAX BASE, MID-, APEX); (2) A combination of the three apical views (apical 2-chamber, 3-chamber and 4-chamber) and (3) A more limited combination of PSAX-MID and apical 4-chamber is called the MID-4CH. Global LVEF is obtained by averaging segmental EF based on contractility (normal = 60%, hypokinesia = 40%, and akinesia = 10%). Accuracy of the novel semi-quantitative simplified-views WMS method compared to the reference WMSI was evaluated using Bland-Altman analysis and correlation was assessed in both emergency physicians and cardiologists. RESULTS: In the 46 patients using the 16 segments WMSI method, the mean LVEF was 34 ± 10%. Among the three combinations of the two or three imaging views analysed, the MID-4CH had the best correlation with the reference method (r2 = 0.90) with very good agreement (mean LVEF bias = - 0.2%) and precision (± 3.3%). CONCLUSIONS: Cardiac POCUS by emergency physicians and other non-cardiologists is a decisive therapeutic and prognostic tool. A simplified semi-quantitative WMS method to assess LVEF using the easiest technically achievable combination of mid-parasternal and apical four-chamber views provides a good approximative estimate for both non-cardiologist emergency physicians and cardiologists.

Right ventricular ejection fraction with cardiac magnetic resonance using a wall motion score.

BACKGROUND: The volumetric method in cardiac magnetic resonance (CMR), the reference standard for right ventricular ejection fraction (RVEF), requires expertise because of the complex right ventricular geometry and anatomical landmarks. AIM: The aim of our retrospective study was to describe a new method to evaluate RVEF based on wall motion score index (WMSI) in CMR. METHODS: Visual assessment of wall motion was performed using an eight-segment model (normokinesia=1, hypokinesia=2, akinesia=3). Correlation between WMSI (WMS/8) and the reference volumetric RVEF was analysed. A regression equation was derived to convert the WMSI into RVEF. The accuracy of CMR WMSI-derived RVEF compared with CMR volumetric RVEF was evaluated using Bland-Altman analysis. RESULTS: In the 112 patients using the volumetric method, the mean RVEF was 48±14%. Fifty-nine patients had normal RV kinetics (WMSI=1), which corresponded to a volumetric RVEF of 56% (standard deviation 7%; range 43-76%). CMR WMSI showed a strong correlation with CMR volumetric RVEF (Spearman's Rho=-0.69). A regression equation was created: RVEF=80-22×WMSI. Overall, the WMSI-derived RVEF resulted in good agreement with the CMR volumetric RVEF (mean bias-3%, standard deviation±7.5%). In addition, using a WMSI cut-off of≥1.5 was highly accurate (92%) to predict a reference RVEF of˂45%, an important prognostic indicator in CMR. CONCLUSIONS: Our results suggest that using the WMS in CMR (eight-segment) to estimate RVEF is accurate, and correlates well with the volumetric method. A WMSI≥1.5 is optimal to categorize patients in the higher-risk subset of CMR RVEF˂45%.

Novel criterion for the differential diagnosis of wide QRS complexes and wide complex tachycardia using the initial activation of QRS on leads V1 and V2: Differential diagnosis of wide QRS based on V1-V2.

BACKGROUND: Many diagnostic criteria for the differential diagnosis of wide complex tachycardia (WCT) are complex and not completely accurate. Incorrect diagnosis is also related to error in applying criteria. OBJECTIVES: To propose a novel reliable criterion for wide QRS complexes' differential diagnosis. MATERIAL AND METHODS: One hundred Electrocardiograms (ECGs) with wide QRS complexes were analyzed using the ECG software. Five variables were measured during the first 20 ms of QRS in leads V1 and V2 and compared between premature ventricular contraction (PVC) and conducted supraventricular impulse with bundle branch block (BBB) groups. The best discriminant variable was identified. The validity of this variable was tested on a group of 20 patients who had WCT during an electrophysiology study. RESULTS: Almost all variables were statistically different between PVC and BBB groups. The sum of voltages in absolute value of vectors during the initial 20 ms of the QRS in leads V1 and V2 (ΣV1 + V2) was the most discriminant between the two groups (131 ±â€¯85 microvolt [µV] vs. 498 ±â€¯392 µV, p < 0.01). A ΣV1 + V2 < 258 µV (rounded to <0.25 millivolt [mV]) diagnosed PVCs with good sensitivity and specificity (90% and 85% respectively). The ΣV1 + V2 in WCT group had lower values in VT versus supra-ventricular tachycardia (SVT) group (0.53 ±â€¯0.35 mV vs. 1.79 ±â€¯1.04 mV, p = 0.004). CONCLUSIONS: The ΣV1 + V2 < 258 µV is a reliable criterion for PVC diagnosis. It could be measured accurately using ECG Software, which could be programmed to calculate it automatically, limiting the risk of human error. The ΣV1 + V2 also seems capable of discriminating between VT and SVT.

In silico study of multicellular automaticity of heterogeneous cardiac cell monolayers: Effects of automaticity strength and structural linear anisotropy.

The biological pacemaker approach is an alternative to cardiac electronic pacemakers. Its main objective is to create pacemaking activity from added or modified distribution of spontaneous cells in the myocardium. This paper aims to assess how automaticity strength of pacemaker cells (i.e. their ability to maintain robust spontaneous activity with fast rate and to drive neighboring quiescent cells) and structural linear anisotropy, combined with density and spatial distribution of pacemaker cells, may affect the macroscopic behavior of the biological pacemaker. A stochastic algorithm was used to randomly distribute pacemaker cells, with various densities and spatial distributions, in a semi-continuous mathematical model. Simulations of the model showed that stronger automaticity allows onset of spontaneous activity for lower densities and more homogeneous spatial distributions, displayed more central foci, less variability in cycle lengths and synchronization of electrical activation for similar spatial patterns, but more variability in those same variables for dissimilar spatial patterns. Compared to their isotropic counterparts, in silico anisotropic monolayers had less central foci and displayed more variability in cycle lengths and synchronization of electrical activation for both similar and dissimilar spatial patterns. The present study established a link between microscopic structure and macroscopic behavior of the biological pacemaker, and may provide crucial information for optimized biological pacemaker therapies.

Theoretical and experimental comparison of lag-based and time-based exponential moving average models of QT hysteresis.

OBJECTIVE: In the electrocardiogram, adaptation of the QT interval to variations in heart rate is not instantaneous. Quantification of this hysteresis phenomenon relies on mathematical models describing the relation between the RR and QT time series. These models reproduce hysteresis through an effective RR interval computed as a linear combination of the history of past RR intervals. This filter depends on a time constant parameter that may be used as a biomarker. APPROACH: The most common hysteresis model is based on an autoregressive filter with an impulse response that decreases exponentially with the beat number (lag-based model). Recognizing that the QT time series is unevenly spaced, we propose two exponential moving average filters (time-based models) to define the effective RR interval: one with an impulse response that decreases exponentially with time in seconds, and one with a step response that relaxes exponentially with time in seconds. These two filters are neither linear nor time-invariant. Recurrence formulas are derived to enable efficient implementation. MAIN RESULTS: Application to clinical signals recorded during tilt table test, exercise and 24 h Holter demonstrates that the three models perform similarly in terms of goodness-of-fit. When comparing the hysteresis time constant in two conditions with different heart rates, however, the time-based models are shown to reduce the bias on the hysteresis time constant caused by heart rate acceleration and deceleration. SIGNIFICANCE: Time-based models should be considered when intergroup differences in both heart rate and QT hysteresis are expected.

Cardiac contractility: Correction strategies applied to telemetry data from a HESI-sponsored consortium.

INTRODUCTION: QT has a long history of heart rate (HR) correction but limited investigations have been undertaken to assess the impact of cardiovascular parameters on left ventricular (LV) contractility in drug safety testing. Cardiac contractility is affected by preload (Cyon-Frank-Starling law), afterload (Anrep effect) and HR (Bowditch effect). We evaluated multi-parameter correction methods to help with dP/dtmax interpretation. METHODOLOGY: Modeling was undertaken using data from dogs in single or double 4×4 Latin square studies. Correction models (16 fitting formulas×2 modeling approaches (universal and individualized)×2 correction approaches (linear or proportional)) were evaluated. 3D/2D cloud analysis of the beat-to-beat data for the control, pimobendan, and either itraconazole or atenolol groups were used to evaluate correlations between parameters and derive an optimal correction method. RESULTS: Cardiac contractility (i.e., dP/dtmax) was best correlated to HR and systolic LV pressure with a correlation coefficient of 0.8. In decreasing order, dP/dtmin, mean arterial blood pressure (BP), systolic BP, diastolic BP, arterial pulse pressure and LV end diastolic pressure (LVEDP) showed a reduced correlation to dP/dtmax. Subject-specific models improved the correction by up to 14% when compared to universal correction models. The non-linear correction model was superior to the linear model. DISCUSSION: Results suggest that the optimal correction formula for dP/dtmax would be subject-specific, non-linear and would include HR and LV systolic pressure. Correcting contractility for HR and systolic LV pressure may enhance data interpretation in non-clinical drug safety assessments. Similar correction methods could be evaluated for other species used in safety pharmacology.

Estimation of the QT-RR relation: trade-off between goodness-of-fit and extrapolation accuracy.

Correction of the QT interval in the ECG for changes in heart rate (RR interval) is needed to compare groups of patients and assess the risk of sudden cardiac death. The QTc represents the QT interval at 60 bpm, although most patients typically have a faster heart rate, thus requiring extrapolation of the QT-RR relationship. OBJECTIVE: This paper investigates the ability of QT-RR models with increasing number of parameters to fit beat-to-beat variations in the QT interval and provide a reliable estimate of the QTc. APPROACH: One-, two- and three-parameter functions generalising the Bazett and Fridericia formulas were used in combination with hysteresis reduction (memory) obtained by time-averaging the history of RR intervals with exponentially-decaying weights. In normal men and women datasets of Holter recordings in normal subjects (24 h monitoring), two measures were computed for each model: the root mean square error (RMSE) of fitting and the difference between the estimated QTc and a reference QTc obtained by collecting data points around RR = 1000 ms. MAIN RESULTS: The two- and three-parameter functions all gave similar low RMSE with uncorrelated residues. An optimal memory parameter was found that still minimized the RMSE and could be used for all functions and subjects. This reduction in RMSE resulted from changes in the parameters linked to the increased steepness of the QT-RR relation after hysteresis reduction. At optimal memory, the two and three-parameter models provided poorer prediction of the QTc as compared to the Fridericia's model in subjects with fast heart rates, since accurate representation of the steeper QT-RR relation worsened the extrapolation that was then needed to determine the QTc. SIGNIFICANCE: As a result, among all models investigated, the Fridericia formulation offered the best trade-off for QTc prediction robust to memory and fast heart rates.

Vagal stimulation targets select populations of intrinsic cardiac neurons to control neurally induced atrial fibrillation.

Mediastinal nerve stimulation (MNS) reproducibly evokes atrial fibrillation (AF) by excessive and heterogeneous activation of intrinsic cardiac (IC) neurons. This study evaluated whether preemptive vagus nerve stimulation (VNS) impacts MNS-induced evoked changes in IC neural network activity to thereby alter susceptibility to AF. IC neuronal activity in the right atrial ganglionated plexus was directly recorded in anesthetized canines (n = 8) using a linear microelectrode array concomitant with right atrial electrical activity in response to: 1) epicardial touch or great vessel occlusion vs. 2) stellate or vagal stimulation. From these stressors, post hoc analysis (based on the Skellam distribution) defined IC neurons so recorded as afferent, efferent, or convergent (afferent and efferent inputs) local circuit neurons (LCN). The capacity of right-sided MNS to modify IC activity in the induction of AF was determined before and after preemptive right (RCV)- vs. left (LCV)-sided VNS (15 Hz, 500 µs; 1.2× bradycardia threshold). Neuronal (n = 89) activity at baseline (0.11 ± 0.29 Hz) increased during MNS-induced AF (0.51 ± 1.30 Hz; P < 0.001). Convergent LCNs were preferentially activated by MNS. Preemptive RCV reduced MNS-induced changes in LCN activity (by 70%) while mitigating MNS-induced AF (by 75%). Preemptive LCV reduced LCN activity by 60% while mitigating AF potential by 40%. IC neuronal synchrony increased during neurally induced AF, a local neural network response mitigated by preemptive VNS. These antiarrhythmic effects persisted post-VNS for, on average, 26 min. In conclusion, VNS preferentially targets convergent LCNs and their interactive coherence to mitigate the potential for neurally induced AF. The antiarrhythmic properties imposed by VNS exhibit memory.

From Squid to Mammals with the HH Model through the Nav Channels' Half-Activation-Voltage Parameter.

The model family analyzed in this work stems from the classical Hodgkin-Huxley model (HHM). for a single-compartment (space-clamp) and continuous variation of the voltage-gated sodium channels (Nav) half-activation-voltage parameter ΔV1/2, which controls the window of sodium-influx currents. Unlike the baseline HHM, its parametric extension exhibits a richer multitude of dynamic regimes, such as multiple fixed points (FP's), bi- and multi-stability (coexistence of FP's and/or periodic orbits). Such diversity correlates with a number of functional properties of excitable neural tissue, such as the capacity or not to evoke an action potential (AP) from the resting state, by applying a minimal absolute rheobase current amplitude. The utility of the HHM rooted in the giant squid for the descriptions of the mammalian nervous system is of topical interest. We conclude that the model's fundamental principles are still valid (up to using appropriate parameter values) for warmer-blooded species, without a pressing need for a substantial revision of the mathematical formulation. We demonstrate clearly that the continuous variation of the ΔV1/2 parameter comes close to being equivalent with recent HHM 'optimizations'. The neural dynamics phenomena described here are nontrivial. The model family analyzed in this work contains the classical HHM as a special case. The validity and applicability of the HHM to mammalian neurons can be achieved by picking the appropriate ΔV1/2 parameter in a significantly broad range of values. For such large variations, in contrast to the classical HHM, the h and n gates' dynamics may be uncoupled--i.e. the n gates may no longer be considered in mere linear correspondence to the h gates. ΔV1/2 variation leads to a multitude of dynamic regimes--e.g. models with either 1 fixed point (FP) or with 3 FP's. These may also coexist with stable and/or unstable periodic orbits. Hence, depending on the initial conditions, the system may behave as either purely excitable or as an oscillator. ΔV1/2 variation leads to significant changes in the metabolic efficiency of an action potential (AP). Lower ΔV1/2 values yield a larger range of AP response frequencies, and hence provide for more flexible neural coding. Such lower values also contribute to faster AP conduction velocities along neural fibers of otherwise comparable-diameter. The 3 FP case brings about an absolute rheobase current. In comparison in the classical HHM the rheobase current is only relative--i.e. excitability is lost after a finite amount of elapsed stimulation time. Lower ΔV1/2 values translate in lower threshold currents from the resting state.

Dynamics of atrial arrhythmias modulated by time-dependent acetylcholine concentration: a simulation study.

AIM: The autonomic nervous system modulates atrial activity, notably through acetylcholine (ACh) release. This time-dependent action may alter the dynamics of atrial arrhythmia. Our aim is to investigate in a computer model the changes induced by ACh release and degradation on the dynamical regime of a reentry. METHODS AND RESULTS: A functional reentry was simulated in a 10 × 5 cm(2) two-dimensional tissue with canine atrial membrane kinetics including an ACh-dependent K(+) current. The local ACh concentration was altered over time in a circular region following a predefined spatiotemporal profile (ACh release and degradation) characterized by its maximum ACh level, time constant of release/degradation, and diameter of the region. Phase singularities were tracked to monitor the complexity of the dynamics. Four scenarios were identified: (i) the original reentry remained stable; (ii) repolarization gradients induced by ACh release caused wavebreaks, resulting in a transient complex dynamics that spontaneously converted to a single stable reentry; (iii) the reentry self-terminated through wavebreaks and wavefront interactions; (4) wavebreaks led to a complex dynamics that converted to two or three reentries that remained stable after ACh degradation. Higher ACh level, short ACh release time constant, larger heterogeneous region, and short distance between the heterogeneous region and the spiral tip were associated with higher occurrence of ACh-induced wavebreaks. CONCLUSION: Variation of ACh concentration over time may modulate the complexity of atrial arrhythmias.

Electrophysiological changes preceding the onset of atrial fibrillation after coronary bypass grafting surgery.

BACKGROUND: The incidence of Post-CABG atrial fibrillation (AF) lies between 25% and 40%. It worsens morbidity and raises post-operative costs. Detection of incoming AF soon enough for prophylactic intervention would be helpful. The study is to investigate the electrophysiological changes preceding the onset of AF and their relationship to the preoperative risk. METHODS AND RESULTS: Patients were recorded continuously for the first four days after coronary artery bypass grafting surgery (CABG) with three unipolar electrodes sutured to the atria (AEG). The patients experiencing an AF lasting more than 10 minutes were selected and the two hours before the onset were analyzed. Four variables were found to show significant changes in the two hours prior to the first prolonged AF: increasing rate of premature atrial activation, increasing incidence of short transient arrhythmias, acceleration of heart rate, and rise of low frequency content of heart rate. The main contrast was between the first and last hour before AF onset. Preoperative risk was not predictive of the onset time of AF and did not correlate with the amplitude of changes prior to AF. CONCLUSIONS: Post-CABG AF were preceded by electrophysiological changes occurring in the last hour before the onset of the arrhythmia, whereas none of these changes was found to occur in all AF patients. The risk was a weighted sum of factors related to the density of premature activations and the state of atrial substrate reflected by the sinus rhythm and its frequency content prior to AF. Preoperative risk score seems unhelpful in setting a detection threshold for the AF onset.

Energy-optimal electrical-stimulation pulses shaped by the Least-Action Principle.

Electrical stimulation (ES) devices interact with excitable neural tissue toward eliciting action potentials (AP's) by specific current patterns. Low-energy ES prevents tissue damage and loss of specificity. Hence to identify optimal stimulation-current waveforms is a relevant problem, whose solution may have significant impact on the related medical (e.g. minimized side-effects) and engineering (e.g. maximized battery-life) efficiency. This has typically been addressed by simulation (of a given excitable-tissue model) and iterative numerical optimization with hard discontinuous constraints--e.g. AP's are all-or-none phenomena. Such approach is computationally expensive, while the solution is uncertain--e.g. may converge to local-only energy-minima and be model-specific. We exploit the Least-Action Principle (LAP). First, we derive in closed form the general template of the membrane-potential's temporal trajectory, which minimizes the ES energy integral over time and over any space-clamp ionic current model. From the given model we then obtain the specific energy-efficient current waveform, which is demonstrated to be globally optimal. The solution is model-independent by construction. We illustrate the approach by a broad set of example situations with some of the most popular ionic current models from the literature. The proposed approach may result in the significant improvement of solution efficiency: cumbersome and uncertain iteration is replaced by a single quadrature of a system of ordinary differential equations. The approach is further validated by enabling a general comparison to the conventional simulation and optimization results from the literature, including one of our own, based on finite-horizon optimal control. Applying the LAP also resulted in a number of general ES optimality principles. One such succinct observation is that ES with long pulse durations is much more sensitive to the pulse's shape whereas a rectangular pulse is most frequently optimal for short pulse durations.

Simultaneous epicardial and noncontact endocardial mapping of the canine right atrium: simulation and experiment.

Epicardial high-density electrical mapping is a well-established experimental instrument to monitor in vivo the activity of the atria in response to modulations of the autonomic nervous system in sinus rhythm. In regions that are not accessible by epicardial mapping, noncontact endocardial mapping performed through a balloon catheter may provide a more comprehensive description of atrial activity. We developed a computer model of the canine right atrium to compare epicardial and noncontact endocardial mapping. The model was derived from an experiment in which electroanatomical reconstruction, epicardial mapping (103 electrodes), noncontact endocardial mapping (2048 virtual electrodes computed from a 64-channel balloon catheter), and direct-contact endocardial catheter recordings were simultaneously performed in a dog. The recording system was simulated in the computer model. For simulations and experiments (after atrio-ventricular node suppression), activation maps were computed during sinus rhythm. Repolarization was assessed by measuring the area under the atrial T wave (ATa), a marker of repolarization gradients. Results showed an epicardial-endocardial correlation coefficients of 0.80 and 0.63 (two dog experiments) and 0.96 (simulation) between activation times, and a correlation coefficients of 0.57 and 0.46 (two dog experiments) and 0.92 (simulation) between ATa values. Despite distance (balloon-atrial wall) and dimension reduction (64 electrodes), some information about atrial repolarization remained present in noncontact signals.

Bifurcations, sustained oscillations and torus bursting involving ionic concentrations dynamics in a canine atrial cell model.

Atrial fibrillation is a disorganization of the electrical propagation in the atria often initiated by ectopic beats. This spontaneous activity might be associated with the appearance of sustained oscillations in some portion of the tissue. Adrenergic stress and specific gene polymorphisms known to promote atrial fibrillation are notably related to calcium and potassium channel conductances. We performed codimension-one and two bifurcation analysis along these conductances in an ionic canine atrial myocyte model. Two Hopf bifurcations were found, related to two distinct mechanisms: (1) a fast calcium gating-driven oscillator, and (2) a slow concentration-driven oscillator. These two mechanisms interact through a double Hopf bifurcation (HH) in a neighborhood of which a torus (Neimark-Sacker) bifurcation leads to bursting. A complex codimension-two theoretical scenario was identified around HH, through systematic comparison with the attractors found numerically. The concentration oscillator was further decomposed to reveal the minimal oscillating subnetwork, in which the Na(+)/Ca(2+) exchanger plays a prominent role.

Network interactions within the canine intrinsic cardiac nervous system: implications for reflex control of regional cardiac function.

The aims of the study were to determine how aggregates of intrinsic cardiac (IC) neurons transduce the cardiovascular milieu versus responding to changes in central neuronal drive and to determine IC network interactions subsequent to induced neural imbalances in the genesis of atrial fibrillation (AF). Activity from multiple IC neurons in the right atrial ganglionated plexus was recorded in eight anaesthetized canines using a 16-channel linear microelectrode array. Induced changes in IC neuronal activity were evaluated in response to: (1) focal cardiac mechanical distortion; (2) electrical activation of cervical vagi or stellate ganglia; (3) occlusion of the inferior vena cava or thoracic aorta; (4) transient ventricular ischaemia, and (5) neurally induced AF. Low level activity (ranging from 0 to 2.7 Hz) generated by 92 neurons was identified in basal states, activities that displayed functional interconnectivity. The majority (56%) of IC neurons so identified received indirect central inputs (vagus alone: 25%; stellate ganglion alone: 27%; both: 48%). Fifty per cent transduced the cardiac milieu responding to multimodal stressors applied to the great vessels or heart. Fifty per cent of IC neurons exhibited cardiac cycle periodicity, with activity occurring primarily in late diastole into isovolumetric contraction. Cardiac-related activity in IC neurons was primarily related to direct cardiac mechano-sensory inputs and indirect autonomic efferent inputs. In response to mediastinal nerve stimulation, most IC neurons became excessively activated; such network behaviour preceded and persisted throughout AF. It was concluded that stochastic interactions occur among IC local circuit neuronal populations in the control of regional cardiac function. Modulation of IC local circuit neuronal recruitment may represent a novel approach for the treatment of cardiac disease, including atrial arrhythmias.

Assessment of the sensitivity of detecting drug-induced QTc changes using subject-specific rate correction.

AIMS: To quantify the sensitivity of QT heart-rate correction methods for detecting drug-induced QTc changes in thorough QT studies. METHODS: Twenty-four-hour Holter ECGs were analyzed in 66 normal subjects during placebo and moxifloxacin delivery (single oral dose). QT and RR time series were extracted. Three QTc computation methods were used: (1) Fridericia's formula, (2) Fridericia's formula with hysteresis reduction, and (3) a subject-specific approach with transfer function-based hysteresis reduction and three-parameter non-linear fitting of the QT-RR relation. QTc distributions after placebo and moxifloxacin delivery were compared in sliding time windows using receiver operating characteristic (ROC) curves. The area under the ROC curve (AUC) served as a measure to quantify the ability of each method to detect moxifloxacin-induced QTc prolongation. RESULTS: Moxifloxacin prolonged the QTc by 10.6 ± 6.6 ms at peak effect. The AUC was significantly larger after hysteresis reduction (0.87 ± 0.13 vs. 0.82 ± 0.12, p<0.01) at peak effect, indicating a better discriminating capability. Subject-specific correction further increased the AUC to 0.91 ± 0.11 (p<0.01 vs. Fridericia with hysteresis reduction). The performance of the subject-specific approach was the consequence of a substantially lower intra-subject QTc standard deviation (5.7 ± 1.1 ms vs. 8.8 ± 1.2 ms for Fridericia). CONCLUSION: The ROC curve provides a tool for quantitative comparison of QT heart rate correction methods in the context of detecting drug-induced QTc prolongation. Results support a broader use of subject-specific QT correction.

Evaluation of a subject-specific transfer-function-based nonlinear QT interval rate-correction method.

The QT interval in the electrocardiogram (ECG) is a measure of total duration of depolarization and repolarization. Correction for heart rate is necessary to provide a single intrinsic physiological value that can be compared between subjects and within the same subject under different conditions. Standard formulas for the corrected QT (QTc) do not fully reproduce the complexity of the dependence in the preceding interbeat intervals (RR) and inter-subject variability. In this paper, a subject-specific, nonlinear, transfer function-based correction method is formulated to compute the QTc from Holter ECG recordings. The model includes five parameters: three describing the static QT-RR relationship and two representing memory/hysteresis effects that intervene in the calculation of effective RR values. The parameter identification procedure is designed to minimize QTc fluctuations and enforce zero correlation between QTc and effective RR. Weighted regression is used to better handle unbalanced or skewed RR distributions. The proposed optimization approach provides a general mathematical framework for further extensions of the model. Validation, robustness evaluation and comparison with existing QT correction formulas is performed on ECG signals recorded during sinus rhythm, atrial pacing, tilt-table tests, stress tests and atrial flutter (29 subjects in total). The resulting average modeling error on the QTc is 4.9 ± 1.1 ms with a sampling interval of 2 ms, which outperforms correction formulas currently used. The results demonstrate the benefits of subject-specific rate correction and hysteresis reduction.

Automaticity in acute ischemia: bifurcation analysis of a human ventricular model.

Acute ischemia (restriction in blood supply to part of the heart as a result of myocardial infarction) induces major changes in the electrophysiological properties of the ventricular tissue. Extracellular potassium concentration ([K(o)(+)]) increases in the ischemic zone, leading to an elevation of the resting membrane potential that creates an "injury current" (I(S)) between the infarcted and the healthy zone. In addition, the lack of oxygen impairs the metabolic activity of the myocytes and decreases ATP production, thereby affecting ATP-sensitive potassium channels (I(Katp)). Frequent complications of myocardial infarction are tachycardia, fibrillation, and sudden cardiac death, but the mechanisms underlying their initiation are still debated. One hypothesis is that these arrhythmias may be triggered by abnormal automaticity. We investigated the effect of ischemia on myocyte automaticity by performing a comprehensive bifurcation analysis (fixed points, cycles, and their stability) of a human ventricular myocyte model [K. H. W. J. ten Tusscher and A. V. Panfilov, Am. J. Physiol. Heart Circ. Physiol. 291, H1088 (2006)] as a function of three ischemia-relevant parameters [K(o)(+)], I(S), and I(Katp). In this single-cell model, we found that automatic activity was possible only in the presence of an injury current. Changes in [K(o)(+)] and I(Katp) significantly altered the bifurcation structure of I(S), including the occurrence of early-after depolarization. The results provide a sound basis for studying higher-dimensional tissue structures representing an ischemic heart.

Extraction and analysis of T waves in electrocardiograms during atrial flutter.

Analysis of T waves in the ECG is an essential clinical tool for diagnosis, monitoring, and follow-up of patients with heart dysfunction. During atrial flutter, this analysis has been so far limited by the perturbation of flutter waves superimposed over the T wave. This paper presents a method based on missing data interpolation for eliminating flutter waves from the ECG during atrial flutter. To cope with the correlation between atrial and ventricular electrical activations, the CLEAN deconvolution algorithm was applied to reconstruct the spectrum of the atrial component of the ECG from signal segments corresponding to TQ intervals. The locations of these TQ intervals, where the atrial contribution is presumably dominant, were identified iteratively. The algorithm yields the extracted atrial and ventricular contributions to the ECG. Standard T-wave morphology parameters (T-wave amplitude, T peak-T end duration, QT interval) were measured. This technique was validated using synthetic signals, compared to average beat subtraction in a patient with a pacemaker, and tested on pseudo-orthogonal ECGs from patients in atrial flutter. Results demonstrated improvements in accuracy and robustness of T-wave analysis as compared to current clinical practice.

ST segment elevation by current-to-load mismatch: an experimental and computational study.

BACKGROUND: Recently, we demonstrated that ajmaline caused ST segment elevation in the heart of an SCN5A mutation carrier by excitation failure in structurally discontinuous myocardium. In patients with Brugada syndrome, ST segment elevation is modulated by cardiac sodium (I(Na)), transient outward (I(to)), and L-type calcium currents (I(CaL)). OBJECTIVE: To establish experimentally whether excitation failure by current-to-load mismatch causes ST segment elevation and is modulated by I(to) and I(CaL). METHODS: In porcine epicardial shavings, isthmuses of 0.9, 1.1, or 1.3 mm in width were created parallel to the fiber orientation. Local activation was recorded electrically or optically (di-4-ANEPPS) simultaneously with a pseudo-electrocardiogram (ECG) before and after ajmaline application. Intra- and extracellular potentials and ECGs were simulated in a computer model of the heart and thorax before and after introduction of right ventricular structural discontinuities and during varying levels of I(Na), I(to), and I(CaL). RESULTS: In epicardial shavings, conduction blocked after ajmaline in a frequency-dependent manner in all preparations with isthmuses ≤ 1.1 mm width. Total conduction block occurred in three of four preparations with isthmuses of 0.9 mm versus one of seven with isthmuses ≥ 1.1 mm (P<.05). Excitation failure resulted in ST segment elevation on the pseudo-ECG. In computer simulations, subepicardial structural discontinuities caused local activation delay and made the success of conduction sensitive to I(Na), I(to), and I(CaL). Reduction of I(to) and increase of I(CaL) resulted in a higher excitatory current, overcame subepicardial excitation failure, and reduced the ST segment elevation. CONCLUSIONS: Excitation failure by current-to-load mismatch causes ST segment elevation and, like ST segment elevation in Brugada patients, is modulated by I(to) and I(CaL).