Repolarization Wavefronts Research Articles

Total cosine R-to-T for predicting ventricular arrhythmic and mortality outcomes: A systematic review and meta-analysis.

The total cosine R-to-T (TCRT), a vectorcardiographic marker reflecting the spatial difference between the depolarization and repolarization wavefronts, has been used to predict ventricular tachycardia/fibrillation (VT/VF) and sudden cardiac death (SCD) in different clinical settings. However, its prognostic value has been controversial. This systematic review and meta-analysis evaluated the significance of TRCT in predicting arrhythmic and/or mortality endpoints. PubMed and Embase databases were searched through December 31, 2016. Of the 890 studies identified initially, 13 observational studies were included in our meta-analysis. A total of 11,528 patients, mean age 47years old, 72% male, were followed for 43±6months. Data from five studies demonstrated lower TCRT values in myocardial infarction patients with adverse events (syncope, ventricular arrhythmias, or sudden cardiac death) compared to those without these events (mean difference=-0.36±0.05, p<.001; I2 =48%). By contrast, only two studies analyzed outcomes in heart failure, and pooled meta-analysis did not demonstrate significant difference in TCRT between event-positive and event-negative patients (mean difference=-0.01±0.10, p>.05; I2 =80%). TCRT is lower in MI patients at high risk of adverse events when compared to those free from such events. It can provide additional risk stratification beyond the use of clinical parameters and traditional electrocardiogram markers. Its value in other diseases such as heart failure requires further studies.

Effect of Loss of Heart Rate Variability on T-Wave Heterogeneity and QT Variability in Heart Failure Patients: Implications in Ventricular Arrhythmogenesis.

Heart rate variability (HRV) modulates dynamics of ventricular repolarization. A diminishing value of HRV is associated with increased vulnerability to life-threatening ventricular arrhythmias, however the causal relationship is not well-defined. We evaluated if fixed-rate atrial pacing that abolishes the effect of physiological HRV, will alter ventricular repolarization wavefronts and is relevant to ventricular arrhythmogenesis. The study was performed in 16 subjects: 8 heart failure patients with spontaneous ventricular tachycardia [HFVT], and 8 subjects with structurally normal hearts (H Norm). The T-wave heterogeneity descriptors [total cosine angle between QRS and T-wave loop vectors (TCRT, negative value corresponds to large difference in the 2 loops), T-wave morphology dispersion, T-wave loop dispersion] and QT intervals were analyzed in a beat-to-beat manner on 3-min records of 12-lead surface ECG at baseline and during atrial pacing at 80 and 100bpm. The global T-wave heterogeneity was expressed as mean values of each of the T-wave morphology descriptors and variability in QT intervals (QTV) as standard deviation of QT intervals. Baseline T-wave morphology dispersion and QTV were higher in HFVT compared to H Norm subjects (p≤0.02). While group differences in T-wave morphology dispersion and T-wave loop dispersion remained unaltered with atrial pacing, TCRT tended to fall more in HFVT patients compared to H Norm subjects (interaction p value=0.086). Atrial pacing failed to reduce QTV in both groups, however group differences were augmented (p<0.0001). Atrial pacing and consequent loss of HRV appears to introduce unfavorable changes in ventricular repolarization in HFVT subjects. It widens the spatial relationship between wavefronts of ventricular depolarization and repolarization. This may partly explain the concerning relation between poorer HRV and the risk of ventricular arrhythmias.

136-02: Effect of Loss of Heart Rate Variability on T-wave Heterogeneity and QT Variability in Heart Failure Patients: Implications in Ventricular Arrhythmogenesis

Background: A diminishing value of heart rate variability (HRV) robustly increases vulnerability to life-threatening ventricular arrhythmias, yet the electrophysiological mechanism of this dynamic relationship is still not well understood. We evaluated if fixed-rate atrial pacing, that abolishes the effect of physiological HRV, will modulate ventricular repolarization wavefronts and is relevant to ventricular arrhythmogenesis. Methods: The study was performed in 16 subjects: 8 heart failure patients with history of spontaneous ventricular tachycardia [HFVT], and 8 subjects with structurally normal hearts (HNorm). The T-wave heterogeneity descriptors [total cosine angle between QRS and T-wave loop vectors (TCRT, negative value corresponds to large difference in the 2 loops), T-wave morphology dispersion, T-wave loop dispersion] and QT intervals were analyzed in a beat-to-beat manner on 3-minutes records of 12-lead surface ECG at baseline and during atrial pacing at physically inert rates of 80 and 100 bpm. The global T-wave heterogeneity was expressed as mean values of each of the T-wave morphology descriptors and variability in QT intervals (QTV) as standard deviation of QT intervals. Results: Baseline T-wave morphology dispersion and QTV were higher in HFVT compared to HNorm subjects (p ≤ 0.02). While group differences in T-wave morphology dispersion and T-wave loop dispersion remained unaltered with atrial pacing, TCRT tended to fall more in HFVT patients compared to HNorm subjects (interaction p value = 0.086). Atrial pacing failed to reduce QTV in both groups, however group differences were augmented (p < 0.0001). Conclusions: Atrial pacing and consequent loss of HRV appears to introduce unfavorable changes in ventricular repolarization in HFVT subjects. It widens the spatial relationship between wavefronts of ventricular depolarization and repolarization (Figure). This may partly explain the concerning relation between poorer HRV and the risk of ventricular arrhythmias.

The isolated ventricular wedge preparation: A valid proof of relevance

b ( o a l P t A What exactly are the electrophysiologic bases accountable for the various ECG waves? In the search for an answer to this fundamental question (in particular with regard to the ST segment and the T wave), 16 years ago Yan and Antzelevitch reported the creation of an innovative experimental model—the isolated, coronary-perfused canine ventricular wedge preparation. The thought was to use it as a tool for studying the temporal correlation between action potentials recorded across the ventricular wall and the corresponding “transmural” (pseudo) ECG. In that the ECG electrodes are placed facing the epicardial (Epi [ ]) and endocardial (Endo [ ]) surfaces of these preparations, stimulation applied to Endo results in a depolarization wavefront in the Endo-to-Epi direction, which, in turn, accounts for the electrocardiographic R wave. Conversely, since the repolarization wavefront follows the same direction, the T wave is upright. At the start, a well-defined parameter (of potential clinical relevance) readily derived from the ECG of these isolated tissues. I am referring to the “terminal portion of the T wave,” which is (certainly in the wedge) an expression of transmural dispersion of repolarization and, therefore, an index of vulnerability to arrhythmogenesis. The critical observation is that its peak appreciably coincides with full repolarization of the Epi and its end with full repolarization of the sub-Endo (M-cell) action potentials. This time interval was understandably called Tpeak-Tend. The article by Liu et al in this issue of HeartRhythm eports the results of an encouraging, truly blinded validaion study that further highlights the capability of the wedge reparation—in this case isolated from the left ventricle of he rabbit heart. In their study, not only the proarrhythmic isk of several cardiac and noncardiac drugs could be quanified, but their underlying mechanisms of action could also e “blindly” recognized. In essence, their experimental proocols were designed to differentiate the effect of 14 comounds (at various concentrations and pacing rates) on the asis of their effects on the QRS, QT, Tpeak-Tend, and

Postexercise recovery of the spatial QRS/T angle as a predictor of sudden cardiac death

Postexercise measurement of heart rate (HR) recovery and QT interval dynamics provides prognostic information in various patient populations. The purpose of this study was to assess whether the measurement of the spatial relationship between the depolarization and repolarization wavefronts (total cosine R-to-T [TCRT]) during the postexercise recovery phase would yield prognostic information. The population consisted of 1297 patients (56 ± 13 years; 67% men) who performed a clinically indicated bicycle stress test. The exercise-recovery hysteresis of TCRT was quantified from the 12-lead exercise electrocardiogram by measuring the TCRT/HR loop area bounded by the exercise and first 3-minute postexercise recovery curves. The HR-corrected TCRT/HR hysteresis was calculated by dividing the area with the HR decrement during the first 3 minutes of recovery. HR recovery was measured at 1 minute postexercise recovery. End points were cardiac death and sudden cardiac death. During an average follow-up of 45 ± 12 months, 74 patients died (5.7%); 35 (2.6%) were cardiac deaths and 24 (1.9%) were sudden cardiac deaths. Reduced TCRT/HR loop area and TCRT/HR hysteresis were associated with cardiac mortality (P <.001). After adjustments for clinical variables, including ejection fraction, TCRT/HR loop area remained an independent predictor of cardiac death (hazard ratio 5.6; 95% confidence interval 1.6-19.1; P = .007) and sudden cardiac death (10.7; 95% confidence interval 1.4-83.7; P = .024). HR recovery did not remain a significant predictor in the multivariate analysis. Attenuated hysteresis of the depolarization and repolarization wavefronts during postexercise recovery is associated with an increased risk of cardiac and sudden cardiac death. Analysis of repolarization dynamics from exercise electrocardiogram represents a promising tool for risk stratification.

QRS-T morphology measured from exercise electrocardiogram as a predictor of cardiac mortality

Total cosine R-to-T (TCRT) measured from the standard 12-lead electrocardiogram (ECG) reflects the spatial relationship between depolarization and repolarization wavefronts and a low TCRT value is a marker of poor prognosis. We tested the hypothesis that measurement of TCRT or QRS/T angle from exercise ECG would provide even more powerful prognostic information. The prognostic significances of TCRT and QRS/T angle were assessed from exercise ECG recordings in 1297 patients [age 56 ± 13 years (mean ± SD), 67% males] undergoing a clinically indicated bicycle stress-test and the subsequent follow-up. During an average follow-up of 45 ± 12 months, 74 patients died (5.7%); 34 (2.6%) were cardiac deaths, and 24 (1.9%) were sudden cardiac deaths. Total cosine R-to-T and QRS/T angle exhibited a correlation with the RR intervals in the total cohort, but the individual responses were variable, e.g. median correlation of TCRT-RR was 0.89 with an inter-quartile range from 0.55 to 0.98. A reduced correlation of TCRT-RR during the recovery phase of exercise ECG predicted cardiac death [adjusted heart rate (HR) 3.5, 95% confidence interval (CI): 1.8-6.8, P= 0.001] similarly as the baseline TCRT measured from ECG at rest (adjusted HR 3.4, 95% CI: 1.4-8.1, P= 0.01). The poor correlation between the TCRT-RR both during the exercise and recovery was specifically related to a risk of sudden cardiac death (adjusted HR 6.2, 95% CI: 2.1-17.8, P< 0.001). Loss of rate-adaptation of the spatial relationship between depolarization and repolarization wavefronts is a strong predictor of cardiac death, especially of sudden cardiac death.

Dynamics and Rate-Dependence of the Spatial Angle between Ventricular Depolarization and Repolarization Wave Fronts during Exercise ECG

QRS/T angle and the cosine of the angle between QRS and T-wave vectors (TCRT), measured from standard 12-lead electrocardiogram (ECG), have been used in risk stratification of patients. This study assessed the possible rate dependence of these variables during exercise ECG in healthy subjects. Forty healthy volunteers, 20 men and 20 women, aged 34.6 +/- 3.4, underwent an exercise ECG testing. Twelve-lead ECG was recorded from each test subject and the spatial QRS/T angle and TCRT were automatically analyzed in a beat-to-beat manner with custom-made software. The individual TCRT/RR and QRST/RR patterns were fitted with seven different regression models, including a linear model and six nonlinear models. TCRT and QRS/T angle showed a significant rate dependence, with decreased values at higher heart rates (HR). In individual subjects, the second-degree polynomic model was the best regression model for TCRT/RR and QRST/RR slopes. It provided the best fit for both exercise and recovery. The overall TCRT/RR and QRST/RR slopes were similar between men and women during exercise and recovery. However, women had predominantly higher TCRT and QRS/T values. With respect to time, the dynamics of TCRT differed significantly between men and women; with a steeper exercise slope in women (women, -0.04/min vs -0.02/min in men, P < 0.0001). In addition, evident hysteresis was observed in the TCRT/RR slopes; with higher TCRT values during exercise. The individual patterns of TCRT and QRS/T angle are affected by HR and gender. Delayed rate adaptation creates hysteresis in the TCRT/RR slopes.

Effects of transmural electrical heterogeneities and electrotonic interactions on the dispersion of cardiac repolarization and action potential duration: A simulation study

It has been shown in the literature that myocytes isolated from the ventricular walls at various intramural depths have different action potential durations (APDs). When these myocytes are embedded in the ventricular wall, their inhomogeneous properties affect the sequence of repolarization and the actual distribution of the APDs in the entire wall. In this article, we implement a mathematical model to simulate the combined effect of (a) the non-homogeneous intrinsic membrane properties (in particular the non-homogeneous APDs) and (b) the electrotonic currents that modulate the APDs when the myocytes are embedded in the ventricular myocardium. In particular, we study the effect of (a) and (b) on the excitation and repolarization sequences and on the distribution of APDs in the ventricles. We implement a Monodomain tissue representation that includes orthotropic anisotropy, transmural fiber rotation and homogeneous or heterogeneous transmural intrinsic membrane properties, modeled according to the phase I Luo–Rudy membrane ionic model. Three-dimensional simulations are performed in a cartesian slab with a parallel finite element solver employing structured isoparametric trilinear finite elements in space and a semi-implicit adaptive method in time. Simulations of excitation and repolarization sequences elicited by epicardial or endocardial pacing show that in a homogeneous slab the repolarization pathways approximately follow the activation sequence. Conversely, in the heterogeneous cases considered in this study, we observed two repolarization wavefronts that started from the epi and the endocardial faces respectively and collided in the thickness of the wall and in one case an additional repolarization wave starting from an intramural site. Introducing the heterogeneities along the transmural epi-endocardial direction affected both the repolarization sequence and the APD dispersion, but these effects were clearly discernible only in transmural planes. By contrast, in planes parallel to epi- and endocardium the APD distribution remained remarkably similar to that observed in the homogeneous model. Therefore, the patterns of the repolarization sequence and APD dispersion on the epicardial surface (or any other intramural surface parallel to it) do not reveal the uniform transmural heterogeneity.

Effects of the gap junction uncoupler palmitoleic acid on the activation and repolarization wavefronts in isolated rabbit hearts.

1. The heart normally acts as an electrical syncytium coupled via gap junctional channels. Since closure of these channels has been considered arrhythmogenic, we wanted to elucidate, how activation and repolarization wavefronts are altered during progressive pharmacological gap junctional uncoupling. 2. We used the well known gap junction uncoupler palmitoleic acid (PA). The specificity of PA was tested in rabbit papillary muscles, which exhibited slowed conduction without affecting action potential morphology. We submitted isolated rabbit hearts (Langendorff-technique) to increasing concentrations of palmitoleic acid (0.2, 1, 2, 5, 10, 20 microM), while 256 channel epicardial potential mapping was carried out. 3. In presence of PA activation recovery intervals (ARI) at the 256 electrodes became highly inhomogeneous with a dramatic increase in the dispersion of activation recovery intervals (from 6 to 35 ms, P>0.01; EC50=7 microM), while the mean ARI-duration at 256 sites remained stable. PA led to marked alterations of the activation pattern, expressed as percentage of unchanged activation vectors (reduction from 32 to 10%, P<0.01, EC50=3.3 microM), to prolongation of atrioventricular conduction time (from 58 to 107 ms, P<0.01; EC50=8 microM) of total activation time (from 7 to 14 ms, P<0.05, EC50=11 microM) and of QRS-complex-duration. 4. In additional experiments the ventricle was paced via a bipolar electrode during the mapping procedure. From the isochrones longitudinal and transversal velocities were assessed showing that PA reduced transversal conduction velocity more distinctly than longitudinal. 5. With regard to maximum effects and EC50 values we conclude that gap junction uncoupling by PA mainly affects atrioventricular conduction, ARI-dispersion and ventricular activation pattern. As important arrhythmogenic effects of uncoupling enhancement of dispersion with concomitant disturbation of the normal activation pattern and slowing of conduction might be considered.

Waveform changes due to conduction block and their underlying mechanism in spinal somatosensory evoked potential: a computer simulation. Technical note.

Based on a square-wave solid-angle analysis, a simplified mathematical model was produced for computing a sequence of potential change in a volume conductor generated by an impulse traveling along a nerve fiber. A conduction block was simulated as a phenomenon in which a depolarization wavefront stops traveling when it reaches a certain point, although the following repolarization wavefront continues to travel until it reaches the same point. The spinal somatosensory evoked potential (SSEP) was produced as an algebraic sum of simulated nerve fiber action potentials (NFAPs). With a conduction block, an NFAP that was normally triphasic showed a positive-negative diphasic wave with reduced negativity at the point of the block, diphasic waves with enhanced negativity at points immediately preceding the block, and initial-positive waves alone or abolition of any wave at points beyond the block. The absence of their terminal-positive phases paradoxically enhanced the negative peak of the spinal SSEPs in a partial block that involved only the constituent fastest fibers, because phase cancellation of the phases between the terminal-positive phases of the fastest fibers and the negative phases of the slower fibers, which normally happens, failed to occur. At the points immediately preceding the block, the identical mechanism sustained the spinal SSEP enhancement even when every fiber was included in the block. The computer model predicted that localization of the precise site of conduction block can be achieved by demonstrating an abrupt reduction in the amplitude of the spinal SSEP, which is accompanied by an increased negative wave caudally and an enhanced monophasic positive wave rostrally.

Evolution of QRS-T relationship from birth to adolescence in Frank-lead orthogonal electrocardiograms of 1492 normal children.

Patterns of evolution of QRS-T relationship were investigated by determining statistical distributions of QRS and STT integral vectors and the ventricular gradient vector in 1492 normal children divided into 12 age groups from birth to the age of 16 years. From birth to the age of 4 days, the ventricular gradient vector shifts posteriorly and to the left due to posterior shift of the STT integral vector and an increase in the spatial angle between QRS and STT integral vectors to a mean value of 103 degrees. These early neonatal changes in QRS-T relationship probably reflect the sudden reduction of hemodynamic load and the subsequent postnatal atrophy of the right ventricle while the left ventricular load slowly increases. The magnitude of the ventricular gradient vector increases from age 3 weeks until about 7 years. The increase appears to be related to a gradual increase in the magnitude of the QRS and STT integral vectors and a drastic decrease in the spatial angle between them. The spatial angle between QRS and STT integral vectors reaches it minimum (22 degrees) in the age group 1.5--4.5 years, suggesting that at that age the average direction of ventricular excitation and repolarization wavefronts are nearly opposite to each other. In addition to the shifting balance between the left and right ventricular hemodynamic load, other factors, such as the maturation of the sympathetic nervous system, may be important in determining spatial gradients in the duration of action potentials, thus influencing the relationship between ventricular excitation and repolarization.