Skip to main content
NCBI home page
Annals of Noninvasive Electrocardiology logoLink to Annals of Noninvasive Electrocardiology
. 2022 Aug 19;27(6):e12994. doi: 10.1111/anec.12994

Steep repolarization time gradients in pig hearts cause distinct changes in composite electrocardiographic T‐wave parameters

Jeanne van der Waal 1,✉, Laura Bear 2,3,4, Veronique Meijborg 1, Rémi Dubois 2,3,4, Matthijs Cluitmans 5, Ruben Coronel 1,3,4
PMCID: PMC9674780  PMID: 35986562

Abstract

Background

The T wave of the electrocardiogram (ECG) reflects ventricular repolarization. Repolarization heterogeneity is associated with reentrant arrhythmias. Several T‐wave markers (including QT interval) have been associated with ventricular arrhythmias, but studies linking such markers to underlying local repolarization time (RT) inhomogeneities are lacking. We aimed to investigate the relation of several T‐wave markers to controlled drug‐induced regional RT gradients in intact pig hearts.

Methods

Repolarization time gradients were created by regional infusion of dofetilide and pinacidil in four atrially paced porcine Langendorff‐perfused hearts placed inside a torso tank. From the 12‐lead ECG on the torso tank, the mean, maximum, and dispersion (max–min) of QTtime, JTtime, Tpeak–end, Twidth, TQratio, dV/dtmax, Tarea, Tamp, and T‐upslope duration were determined, as well as upslope end difference between leads V1 and V6.

Results

Temporal T‐wave parameters Tpeak–end, Twidth, and TQratio show a significant and high correlation with RT gradient, best reflected by mean value. Tarea (mean, max and dispersion) and dV/dtmax dispersion show only a moderate significant correlation. T‐upslope duration shows a significant correlation in particular for mean values. Mean, maximum, or dispersion of QTtime and V1–V6 upslope end difference were not significantly correlated with RT gradient.

Conclusion

Composite 12‐lead ECG T‐wave parameters Tpeak–end, Twidth, TQratio, upslope duration, and Tarea show a good correlation with underlying RT heterogeneity, whereas standard clinical metrics such as QTtime do not reflect local RT heterogeneity. The composite T‐wave metrics may thus provide better insights in arrhythmia susceptibility than traditional QTtime metrics.

Keywords: 12‐lead ECG, cardiac repolarization, electrophysiology, repolarization heterogeneity, torso tank, Tpeak–end/Tpe

In this article, we investigated the relation between (drug‐induced) repolarization time gradients (top) and T‐wave markers based on the 12‐lead ECG (bottom). We found that composite T‐wave markers, such as Tpeak–end, Twidth, and Tarea, show a good correlation with underlying RT heterogeneity, whereas standard clinical metrics such as QTtime do not reflect local RT heterogeneity.

graphic file with name ANEC-27-e12994-g006.jpg

1. INTRODUCTION

Cardiac ventricular arrhythmias are an important cause of death (Montagnana et al., 2008), and they are commonly caused by reentrant activation. Increased local repolarization gradients facilitate the initiation of reentry and life‐threatening arrhythmias (Han & Moe, 1964; Rivaud et al., 2021). Early risk stratification of patients with increased repolarization heterogeneities may help to reduce mortality caused by arrhythmias. The electrocardiogram (ECG) is a widely used clinical screening tool that may provide such information.

The QT interval as a traditional arrhythmia risk marker reflects repolarization duration rather than local repolarization time (RT) gradients. The few studies directly relating T‐wave parameters with underlying repolarization generally describe global rather than local repolarization inhomogeneities reflected as RT gradient (Srinivasan et al., 2019). Non‐invasive ECG markers that reflect actual underlying local RT inhomogeneities and not global repolarization duration may provide more relevant information about arrhythmic substrates and could be used to aid stratification of patients at risk for SCD. Although several T‐wave markers (e.g., the (heart rate corrected) QT interval [QT(c)], the JT interval, the Tpeak–Tend [TpTe] interval) have been associated with sudden cardiac death (SCD) or ventricular arrhythmias (Tse et al., 2018), the exact relation between the T‐wave morphology and underlying repolarization heterogeneity is not understood.

Here, we used selective intracoronary drug infusion to create several degrees of local RT inhomogeneities in intact pig hearts. We performed simultaneous measurement of body‐surface ECG and epicardial RT patterns. We studied the relation of several electrocardiographic T‐wave markers with the underlying local RT gradients.

2. METHODS

All experiments were approved by the institutional review committee for experiments on animals, and animal handling was in accordance with the European Directive for the Protection of Vertebrate Animals Used for Experimental and Other Scientific Purposes (European Union Directive 86/609/EEC).

2.1. Experimental protocol

Langendorff isolated heart experiments have previously been described in Bear et al. (2019, 2021); drug infusion and RT gradient determination have previously been described in Cluitmans et al. (2021). A brief summary is given here, and a more thorough description is given in the Appendix. In short, hearts of male pigs (n = 4; weight 33–41 kg) were explanted and connected to a Langendorff perfusion setup (Bear et al., 2019, 2021). The heart was paced from the right atrium (cycle length 400 or 450 ms). The left anterior descending artery (LAD) was cannulated and infused separately. Epicardial potentials were recorded with a 108‐electrode sock wrapped around the ventricles (Figure 1a).

FIGURE 1.

FIGURE 1

Open in a new tab

(a) Placement of the 108‐electrode epicardial sock around the heart, (b) schematic representation of creation of repolarization time (RT) gradient by regional infusion of RT prolonging drugs (dofetilide) and regional infusion of RT shortening drugs (pinacidil), (c) the heart was placed inside a human torso‐shaped tank with body‐surface electrodes (in this figure only halfway filled for illustration purposes).

Hearts were placed inside a human‐shaped torso tank (Figure 1c) equipped with 256 body‐surface ECG electrodes. Nine electrodes were selected to most accurately represent the 12‐lead ECG as measured in humans. Epicardial and body‐surface potentials were recorded simultaneously. From the measured unipolar electrograms, activation and repolarization times (ATs and RTs) were determined as the maximum downward slope during activation and the maximum upward slope during repolarization, relative to the QRS‐onset on the ECG.

A drug infusion protocol was used to create RT differences as follows: baseline (no drugs), dofetilide at 125 nM (Dofhalf), and 250 nM (Doffull) in the aorta‐perfused region (i.e., everywhere except LAD), and additional infusion of pinacidil at 17.5 μM (Doffull + Pinhalf) and 35 μM (Doffull + Pinfull) in the LAD, followed by washout. This resulted in regions with pronounced RT prolongation (in the non‐LAD perfusion beds) and RT shortening (in the LAD perfusion bed) with steep gradients at their border (Figure 1b). Not all phases were implemented for all experiments. In heart 2, the dofetilide was not infused, and after full concentration of pinacidil, the heart went into VF. Defibrillation was not successful. Heart 4 went into refractory VF after infusion of dofetilide and half concentration pinacidil.

2.2. Repolarization gradient

An epicardial RT map was made from sock RTs (per electrode defined as the median RT of all electrodes within a radius of 20 mm) (Cluitmans et al., 2021). The local RT gradient (RTG, ms/cm) on each electrode position was defined as the largest local gradient steepness (RT difference divided by internode distance) within a 20‐mm distance. The 95th percentile value of all local RTGs was attributed to each condition. RT dispersion (RTD, in ms) was defined as the 95th percentile RT minus the 5th percentile RT.

2.3. T‐wave markers

ECG time indices were manually determined from the 12‐lead body‐surface ECG, filtered with linear offset removal, a bandpass 0.5–125 Hz filter and a 50 Hz notch filter. From the 12‐lead body‐surface ECG, several T‐wave parameters were manually determined (Table 1). QRSstart was determined as the time of the onset of QRS, Jpoint as time of end QRS, Tstart as start of T wave using the inflection point at the onset of the T wave, Tpeak as the time of maximum or minimum height of T wave, Tend as the end of the T wave (tangent method), see Figure 2. Leads with no distinguishable time indices (e.g., no Tpeak due to biphasic T wave or flat T wave) were excluded from analysis. With these time indices, several composite T‐wave parameters were determined (Table 1). For the temporal, area(‐derived), and morphology(‐derived) metrics, both the mean and the maximum of all leads were determined, as well as the dispersion (max–min value in all 12 leads). Since all hearts were paced at a constant cycle length, we did not apply heart rate correction.

TABLE 1.

Description of calculated T‐wave parameters

Temporal metrics
QTtime Time between QRSstart and Tend (ms)
JTtime Time between Jpoint and Tend (ms)
Tpeak–end Time between Tpeak and Tend (ms)
Twidth Time between Tstart and Tend (ms)
TQratio Tpeak–end divided by QTtime
dV/dtmax Time of maximum upward slope of T wave (ms)
Area‐derived metrics
Tarea Area under the T wave, from Jpoint to Tend (mV ms)
Ta25–75 Time difference between T‐wave area of 25% and 75% of maximum area (ms)
Morphology(‐derived) metrics
Tamp Maximum amplitude of T wave (mV)
Upslope Slope of the rising part of the T wave (mV/ms)
Upslope duration Duration of rising part of the T wave (ms)
Other parameters
V1–V6 upslope end difference Time difference between the end of the upslope of lead V1 and the end of the upslope of lead V6
Open in a new tab

FIGURE 2.

FIGURE 2

Open in a new tab

Illustration of the T‐wave parameters. The color of the mentioned parameter corresponds with the color of the arrow used.

2.4. Statistics and data analysis

Each heart served as its own control. For each parameter, Pearson's linear correlation coefficient R between the value of the parameter and the steepness of RTG is determined. A p‐value smaller than .05 was considered significant.

3. RESULTS

3.1. Creation of repolarization gradient

Figure 3 shows an example of the RTs and corresponding RTGs during six different phases of one experiment, displayed on the unfolded epicardial electrode sock. The local RTs and total RT dispersion increase with the infusion of the drugs. Infusion of dofetilide in the aorta causes prolonged repolarization in the non‐LAD area (b & c). Simultaneous LAD‐infusion of pinacidil shortens repolarization in LAD area (d), in a concentration‐dependent fashion (e). The corresponding RTG maps highlight the presence of steep gradients at the border of the LAD region. After washout of the drugs, the repolarization times approximately return to baseline values (f). In all experiments, the RTG steepness follows this pattern (Figure 4). RT dispersion (range of minimum RT to maximum RT) and RT gradients (local steepness of heterogeneity) correlate (Figure S1).

FIGURE 3.

FIGURE 3

Open in a new tab

Measured repolarization times (RTs, top) on the 108‐electrode epicardial sock and corresponding RT gradients (RTGs, bottom) for heart 1 in all six different phases of drug infusion. Values below indicate the maximum RTG for each RT map.

FIGURE 4.

FIGURE 4

Open in a new tab

Maximum repolarization time gradient per phase for all different hearts

Figure 5 shows an example of the ECG from the same experiment as Figure 3. Upon drug infusion, significant T‐wave changes can be observed in all ECG leads. With dofetilide, a prolongation of the QT interval and a widening of the T wave is seen. Additional infusion of pinacidil advanced the upslope of the T wave, while the end of the T wave returned to baseline values. Note that the normalization of the end of the T wave implies that a normal QT occurred when RT gradients were steepest. In this experiment, lead V3 was excluded due to low voltage T waves. The same T‐wave changes can be observed in the RMS signal (obtained from 12‐lead ECG, lower panel).

FIGURE 5.

FIGURE 5

Open in a new tab

Example of ECGs in heart 1 in different stages of drug infusion. In this experiment, the ECGs of lead V3 are excluded due to low voltage T waves.

3.2. T‐wave metrics versus repolarization gradient

The value of the RTG is plotted against T‐wave parameters in Figure 6. The correlations with T‐wave parameters (and their mean, maximum, and dispersion) and their significance are given in Table 2. There is a poor correlation between mean, maximum, or dispersion of QTtime and RT gradient. The temporal T‐wave parameters Tpeak–end, Twidth, and TQratio show a significant and high correlation with RT gradient. The mean value of these parameters had a higher correlation than its maximum or dispersion values. The dV/dtmax only shows a high correlation for dispersion, albeit lower than aforementioned temporal T‐wave parameters. Tarea shows a similar significant correlation for mean, max, and dispersion. Upslope duration shows a significant correlation in particular for mean values. V1–V6 upslope end difference was not significantly correlated with steepness of RT gradient in this study, although the correlation plot in Figure 6 shows that this is mainly due to an absence of correlation with RT gradient in heart 2. All parameters have also been investigated for correlation with RT dispersion, and results are similar to those calculated with RT gradients (Table S1).

FIGURE 6.

FIGURE 6

Open in a new tab

Correlation plots of repolarization gradient versus selected ECG T‐wave parameters. Correlation coefficient R is mentioned in the figure, with * indicating a p‐value of <.05.

TABLE 2.

Correlation value (Pearson's R) between the maximum epicardial RT gradient and the mean, max, and dispersion of selected T‐wave parameters of the body‐surface ECG leads

Mean Max Dispersion
R R R
Temporal metrics
QTtime .31 .23 −.18
JTtime .28 .22 −.11
Tpeak–end .95* .93* .33
Twidth .91* .74* .69*
TQratio .92* .91* .30
dV/dtmax .01 .26 .63*
Area (‐derived) metrics
Tarea .77* .69* .68*
Ta25–75 −.05 −.23 −.43
Morphology (‐derived) metrics
Tamp .13 .27 .30
Upslope duration .80* .47* .02
Upslope .20 .21 .10
Other parameters R
V1–V6 upslope end diff .42
Open in a new tab
*

p < .05.

4. DISCUSSION

We have investigated various electrocardiographic parameters that are thought to give information about underlying repolarization patterns and RT gradients. The use of a torso tank with a submerged explanted heart with separate infusion beds enabled us to artificially create different levels of repolarization heterogeneity, allowing comparison of the change in T‐wave parameters within and between subjects. Our results show that both the interval between Tpeak and Tend (Tpeak–end) and the duration of the T wave (Twidth) have a very high correlation with underlying drug‐induced repolarization gradients. Contrastingly, the clinically widely used parameters for repolarization QTtime and QTdispersion did not correlate with the underlying RT gradient.

4.1. Parameter interpretation and previous studies

4.1.1. QTtime

The QT interval relates the latest moment of repolarization to the earliest moment of activation (at potentially different locations). Therefore, an increased QTtime may be due to APD changes, but may also reflect (regional) differences in activation time or conduction. Additionally, QT prolongation may occur without increasing RT gradients, for example, when all RTs are prolonged homogeneously. This theoretically limits the use of QTtime for assessing repolarization heterogeneity and may explain disparate results in predicting arrhythmia vulnerability (Anderson, 2006; Hondeghem, 2011). This is confirmed in our study. Although dispersion of QT has been suggested to reflect abnormal ventricular repolarization (Statters et al., 1994), it may be caused by the different projection of the T‐wave vector in different ECG leads (Lee et al., 1998). Our findings support the lack of relation between mean, max, or dispersion in QTtime and RT gradients. We therefore also investigated composite T‐wave parameters.

4.1.2. Tpeak–end and Twidth

Tpeak–end has been a topic for discussion in relation to repolarization heterogeneity in recent literature (Malik et al., 2019). Studies report a relation between Tpeak–end and arrhythmia risk in patients with heart failure (Rosenthal et al., 2015), ischemic heart disease (Shenthar et al., 2015) and BrS (Castro Hevia et al., 2006), although other studies contradict that prolonged Tpeak–end interval is proarrhythmic (Michalek et al., 2020; O'Neal et al., 2017). We have previously shown that the onset of the electrocardiographic T wave occurs before first measured RT and that 75% of recording sites repolarized after Tpeak (Meijborg et al., 2014). Combined, this suggests that Tpeak–end reflects the majority of the repolarization phase and that Tpeak–end is a measure of global repolarization heterogeneity (Opthof et al., 2007). Indeed, we found a significant correlation of both Tpeak–end and Twidth with RTG. Because the determination of T‐wave onset is often difficult, Twidth is likely to be less accurate as a parameter for repolarization heterogeneity than Tpeak–end.

Srinivasan et al. did not observe a correlation between Tpeak–end and dispersion of repolarization along any major anatomical axis (Srinivasan et al., 2019). However, dispersion of repolarization was assessed by contact catheter recordings during an invasive study, and only global left–right and apex‐base repolarization dispersion was studied, not pathologically increased RTGs. In our recent study in which an RT gradient was pharmacologically induced, the RTGs correlated well with increased arrhythmia vulnerability (Cluitmans et al., 2021).

4.1.3. Amplitude/area

The amplitude and area of the T wave also have been considered as a marker for dispersion of repolarization or even as a prognostic risk marker for cardiovascular death (Arteyeva & Azarov, 2017). We did not find a significant correlation between Tamp and RTG. Mean Tamp is even constant within each heart during all phases of drug infusion, although it varies between hearts (Figure S2). This complies with the observation that ECG amplitude is sensitive to individual patient characteristics (Rautaharju et al., 1994).

Measuring the T‐wave area does not rely on precise determination of the start and end of the T wave and is not hampered by flat or biphasic T wave. T‐wave area, which combines morphology and time parameters, is expected to correlate to (local) dispersion of repolarization. Indeed, Punke et al. show a significant correlation between T‐wave area and dispersion of repolarization in isolated canine hearts (Punske et al., 1999). Additionally, if Tamp is independent of RTG, and Twidth and Tpeak–end are directly related to RTG as is apparent from our data, then Tarea should relate to RTG as well. This is supported by Kentta et al., who showed that dispersion in T‐wave area is a predictor for SCD in the adult population (Kentta et al., 2018).

4.1.4. TQratio

TQratio is a predictor for SCD in patients with gene‐associated hypertrophic cardiomyopathy (Shimizu et al., 2002) and was associated with arrhythmia inducibility in patients with Brugada syndrome (BrS) (Letsas et al., 2010). However, a large retrospective study in patients with BrS did not show a difference in Tpeak–end or TQratio between asymptomatic patients and those with syncope and malignant arrhythmias (Mugnai et al., 2017). While the literature is equivocal, we show that both Tpeak–end and TQratio show a similarly high correlation with repolarization gradient. TQratio is supposed to be independent of heart rate. Since in our experiments, the heart rate was kept constant, we could not investigate this substantial benefit in clinical situations to determine cut‐off values for risk stratifications that are independent of patient's heart rate.

4.1.5. dV/dt max dispersion

If the ECG reflects a local unipolar electrogram, the dV/dtmax of the T wave likely provides information about regional repolarization (Orini et al., 2018). Indeed, it has been shown that RV repolarization occurred on the upslope of leads V1, V2, and V3, while LV repolarization occurred on the upslope of leads V6 and I (Srinivasan et al., 2019). We indeed found a correlation between dV/dt max dispersion and repolarization gradient (albeit not as strong as for Tpeak–end). In addition, this parameter may be more sensitive to the orientation of RT gradients than time‐dependent metrics.

4.1.6. Upslope metrics

The design of the upslope metric is based on the observation that the polarity of the T wave on the precordial leads reflects the polarity of the unipolar signal recorded on the nearby myocardium (Srinivasan et al., 2019). Per definition, the upslope duration equals Tstart–Tpeak for positive T waves and Tpeak–Tend for negative T waves. In the unipolar electrogram, the time of repolarization is determined by time of dV/dtmax of the T wave, irrespective of its polarity (Coronel et al., 2006). In our study, the upslope duration was calculated over all leads and correlated significantly with RTG. Including precordial leads only cause a small decrease in the correlation parameters (data not shown). Given that the upslope duration and Tpeak–end are the same for negative T waves, the lower correlation of upslope duration suggests that this metric likely depends on its correlation with Tpeak–end, and thus on the presence of negative T waves. If we excluded negative T waves (n = 89 in the total selection), the correlation values decreased, while if we excluded positive T waves (n = 109 in the total selection) from analyses the correlation values increased. This indeed suggests that Tpeak–end is a more predictive parameter for RTG than upslope duration.

The difference between V1 and V6 upslope end, introduced by Srinivasan et al. (2019), showed a correlation with right‐to‐left dispersion in their dataset, but did not show a significant correlation with repolarization gradient in our data. This metric depends on the polarity of the T waves (Figure 6: heart 2 has positive T waves in V1 and V6; thus, V1–V6 upslope end difference equals a difference between Tpeak in both leads, whereas this equals a difference between a Tpeak and a Tend in other hearts that have a positive T wave in lead V1 and a negative T wave in lead V6). This indicates that this metric is sensitive to orientation or location of the RT gradient and suggests that combined temporal metrics such as Tpeak–end would be a more reliable measure of repolarization dispersion.

4.2. Limitations

The torso tank is an accepted technique to study the relation between local changes in cardiac electrophysiology to the surface ECG (Lux, 2002), with exclusion of confounding factors (the autonomic nervous system and hemodynamics). However, even in a tank shaped like a human torso, the use of a pig heart prevents the exact replication of a human 12‐lead ECG. In pig hearts, the QRS complex and T wave are typically discordant, while in human, they are generally concordant. Nevertheless, the changes in T wave due to increased RT gradients should be comparable between pigs and humans. Studies that employed repolarization vectorcardiography in humans support extension of our mechanistic findings to human application, and may help in assessing repolarization gradients in more detail under clinical conditions (Perez‐Alday et al., 2019; van Dam et al., 2021).

The local infusion of pharmacologic agents allowed us to reliably create RTGs of varying steepness and to investigate its influence on the body‐surface ECG within the same individual in the absence of confounding factors that influence repolarization. As a result of this approach, the RTGs investigated in this study are steep and are present in a large region of the heart. RT gradients in patients at risk for cardiac arrest may be more subtle, although studies describing detailed repolarization patterns in both healthy and diseased hearts are scarce. It has been shown that increased RTGs lead to increased arrhythmia vulnerability for a single extra‐stimulus (Cluitmans et al., 2021). In addition, the steepness of RT gradients as observed with non‐invasive mapping is related to arrhythmia occurrence in humans (Cluitmans et al., 2021; Zhang et al., 2017).

The selected 12‐lead T‐wave markers were compared with regional measures of epicardial RT gradients as a gold standard. We have no information about endocardial RTs, and therefore also not about transmural RT gradients. However, we previously demonstrated that transmural dispersion of repolarization in the human and pig heart is negligible (Meijborg et al., 2014; Opthof et al., 2016). In addition, a study with a similar dataset showed that local drug infusion through the major arteries did not lead to changes in dispersion of transmural RTs (Meo et al., 2020).

5. CONCLUSION

Twelve‐lead ECG T‐wave parameters Tpeak–end, Twidth, and TQratio show a good quantitative correlation with underlying repolarization heterogeneity that is lacking for standard clinical metrics such as QTtime. In our drug‐induced RTG model, repolarization heterogeneity is better characterized by composite parameters highlighting multiple moments of local repolarization (Twidth, Tpeak–end, and Tarea) than by parameters reflecting the single time point of latest global repolarization (QTtime and QTdispersion). Our data suggest that Tpeak–end or Twidth contains information about both repolarization duration and heterogeneity, contrary to clinically used parameters QTtime and QTdispersion. In addition, TQratio is a potentially valuable parameter for repolarization heterogeneity as it is independent on a patient's heart rate. When studying the role of repolarization in human arrhythmogenesis, the composite temporal T‐wave metrics may thus provide better insights in arrhythmia susceptibility than traditional metrics.

AUTHOR CONTRIBUTION

JW drafted the manuscript, LB and MC performed the animal experiments, JW, LB, VM and MC performed data analysis, MC and RC supervised this work. All authors contributed to study design, and all authors critically revised the article and accepted its final version.

FUNDING INFORMATION

This work was supported by the Leducq Foundation [RHYTHM transatlantic network, grant number 16CVD02], and the French National Research Agency (ANR‐10‐IAHU04‐LIRYC). Matthijs Cluitmans is supported by a Veni grant from The Netherlands Organization for Scientific Research (TTW 16772).

CONFLICT OF INTEREST

MC is part‐timely employed by Philips Research, Eindhoven, The Netherlands.

ETHICAL STATEMENT

All experiments were approved by the local ethical committee of Bordeaux CEEA50, and animal handling was in accordance with the European Directive for the Protection of Vertebrate Animals Used for Experimental and Other Scientific Purposes (European Union Directive 86/609/EEC).

Supporting information

Appendix S1

Click here for additional data file. (171.2KB, docx)

van der Waal, J. , Bear, L. , Meijborg, V. , Dubois, R. , Cluitmans, M. , & Coronel, R. (2022). Steep repolarization time gradients in pig hearts cause distinct changes in composite electrocardiographic T‐wave parameters. Annals of Noninvasive Electrocardiology, 27, e12994. 10.1111/anec.12994

Matthijs Cluitmans and Ruben Coronel contributed equally.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.

REFERENCES

  1. Anderson, M. E. (2006). QT interval prolongation and arrhythmia: An unbreakable connection? Journal of Internal Medicine, 259(1), 81–90. [DOI] [PubMed] [Google Scholar]
  2. Arteyeva, N. V. , & Azarov, J. E. (2017). Effect of action potential duration on Tpeak–Tend interval, T‐wave area and T‐wave amplitude as indices of dispersion of repolarization: Theoretical and simulation study in the rabbit heart. Journal of Electrocardiology, 50(6), 919–924. [DOI] [PubMed] [Google Scholar]
  3. Bear, L. R. , Cluitmans, M. , Abell, E. , Rogier, J. , Labrousse, L. , Cheng, L. K. , LeGrice, I. , Lever, N. , Sands, G. B. , Smaill, B. , Haïssaguerre, M. , Bernus, O. , Coronel, R. , & Dubois, R. (2021). Electrocardiographic imaging of repolarization abnormalities. Journal of the American Heart Association, 10(9), e020153. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bear, L. R. , Walton, R. D. , Abell, E. , Coudiere, Y. , Haissaguerre, M. , Bernus, O. , & Rémi, D. (2019). Optical imaging of ventricular action potentials in a torso tank: A new platform for non‐invasive electrocardiographic imaging validation. Frontiers in Physiology, 10, 146. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Castro Hevia, J. , Antzelevitch, C. , Tornés Bárzaga, F. , Dorantes Sánchez, M. , Dorticós Balea, F. , Zayas Molina, R. , Quiñones Pérez, M. A. , & Fayad Rodríguez, Y. (2006). Tpeak‐tend and Tpeak‐tend dispersion as risk factors for ventricular tachycardia/ventricular fibrillation in patients with the Brugada syndrome. Journal of the American College of Cardiology, 47(9), 1828–1834. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cluitmans, M. J. M. , Bear, L. R. , Nguyên, U. C. , van Rees, B. , Stoks, J. , Ter Bekke, R. M. A. , Mihl, C. , Heijman, J. , Lau, K. D. , Vigmond, E. , Bayer, J. , Belterman, C. N. W. , Abell, E. , Labrousse, L. , Rogier, J. , Bernus, O. , Haïssaguerre, M. , Hassink, R. J. , Dubois, R. , … Volders, P. G. A. (2021). Noninvasive detection of spatiotemporal activation‐repolarization interactions that prime idiopathic ventricular fibrillation. Science Translational Medicine, 13(620), eabi9317. [DOI] [PubMed] [Google Scholar]
  7. Coronel, R. , de Bakker, J. M. , Wilms‐Schopman, F. J. , Opthof, T. , Linnenbank, A. C. , Belterman, C. N. , & Janse, M. J. (2006). Monophasic action potentials and activation recovery intervals as measures of ventricular action potential duration: Experimental evidence to resolve some controversies. Heart Rhythm, 3(9), 1043–1050. [DOI] [PubMed] [Google Scholar]
  8. Han, J. , & Moe, G. (1964). Nonuniform recovery of excitability in ventricular muscle. Circulation Research, 14, 44–60. [DOI] [PubMed] [Google Scholar]
  9. Hondeghem, L. M. (2011). QTc prolongation as a surrogate for drug‐induced arrhythmias: Fact or fallacy? Acta Cardiologica, 66(6), 685–689. [DOI] [PubMed] [Google Scholar]
  10. Kenttä, T. V. , Sinner, M. F. , Nearing, B. D. , Freudling, R. , Porthan, K. , Tikkanen, J. T. , Müller‐Nurasyid, M. , Schramm, K. , Viitasalo, M. , Jula, A. , Nieminen, M. S. , Peters, A. , Salomaa, V. , Oikarinen, L. , Verrier, R. L. , Kääb, S. , Junttila, M. J. , & Huikuri, H. V. (2018). Repolarization heterogeneity measured with T‐wave area dispersion in standard 12‐Lead ECG predicts sudden cardiac death in general population. Circulation. Arrhythmia and Electrophysiology, 11(2), e005762. [DOI] [PubMed] [Google Scholar]
  11. Lee, K. W. , Kligfield, P. , Okin, P. M. , & Dower, G. E. (1998). Determinants of precordial QT dispersion in normal subjects. Journal of Electrocardiology, 31(Suppl), 128–133. [DOI] [PubMed] [Google Scholar]
  12. Letsas, K. P. , Weber, R. , Astheimer, K. , Kalusche, D. , & Arentz, T. (2010). Tpeak‐tend interval and Tpeak‐tend/QT ratio as markers of ventricular tachycardia inducibility in subjects with Brugada ECG phenotype. Europace, 12(2), 271–274. [DOI] [PubMed] [Google Scholar]
  13. Lux, R. L. (2002). Electrocardiographic potential correlations: Rationale and basis for lead selection and ECG estimation. Journal of Electrocardiology, 35(Suppl), 1–5. [DOI] [PubMed] [Google Scholar]
  14. Malik, M. , Huikuri, H. V. , Lombardi, F. , Schmidt, G. , Verrier, R. L. , Zabel, M. , & e‐Rhythm Group of EHRA . (2019). Is the Tpeak‐Tend interval as a measure of repolarization heterogeneity dead or just seriously wounded? Heart Rhythm, 16(6), 952–953. [DOI] [PubMed] [Google Scholar]
  15. Meijborg, V. M. , Conrath, C. E. , Opthof, T. , Belterman, C. N. , de Bakker, J. M. , & Coronel, R. (2014). Electrocardiographic T wave and its relation with ventricular repolarization along major anatomical axes. Circulation. Arrhythmia and Electrophysiology, 7(3), 524–531. [DOI] [PubMed] [Google Scholar]
  16. Meo, M. , Bonizzi, P. , Bear, L. R. , Cluitmans, M. , Abell, E. , Haïssaguerre, M. , Bernus, O. , & Dubois, R. (2020). Body surface mapping of ventricular repolarization heterogeneity: An ex‐vivo multiparameter study. Frontiers in Physiology, 11, 933. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Michalek, P. , Hatahet, S. B. , Svetlosak, M. , Margitfalvi, P. , Waczulikova, I. , Trnovec, S. , et al. (2020). No association between T‐peak to T‐end interval on the resting ECG and long‐term incidence of ventricular arrhythmias triggering ICD interventions. Frontiers in Physiology, 11, 1115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Montagnana, M. , Lippi, G. , Franchini, M. , Targher, G. , & Cesare Guidi, G. (2008). Sudden cardiac death: Prevalence, pathogenesis, and prevention. Annals of Medicine, 40(5), 360–375. [DOI] [PubMed] [Google Scholar]
  19. Mugnai, G. , Hunuk, B. , Hernandez‐Ojeda, J. , Stroker, E. , Velagic, V. , Ciconte, G. , de Regibus, V. , Coutino‐Moreno, H. E. , Takarada, K. , Choudhury, R. , Abugattas de Torres, J. P. , Pappaert, G. , Chierchia, G. B. , Brugada, P. , & de Asmundis, C. (2017). Role of electrocardiographic Tpeak‐Tend for the prediction of ventricular arrhythmic events in the Brugada syndrome. The American Journal of Cardiology, 120(8), 1332–1337. [DOI] [PubMed] [Google Scholar]
  20. O'Neal, W. T. , Singleton, M. J. , Roberts, J. D. , Tereshchenko, L. G. , Sotoodehnia, N. , Chen, L. Y. , Marcus, G. M. , & Soliman, E. Z. (2017). Association between QT‐interval components and sudden cardiac death: The ARIC study (atherosclerosis risk in communities). Circulation. Arrhythmia and Electrophysiology, 10(10), e005485. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Opthof, T. , Coronel, R. , Wilms‐Schopman, F. J. , Plotnikov, A. N. , Shlapakova, I. N. , Danilo, Jr P. , Rosen, M. R. , & Janse, M. J. (2007). Dispersion of repolarization in canine ventricle and the electrocardiographic T wave: Tp‐e interval does not reflect transmural dispersion. Heart Rhythm, 4(3), 341–348. [DOI] [PubMed] [Google Scholar]
  22. Opthof, T. , Janse, M. J. , Meijborg, V. M. , Cinca, J. , Rosen, M. R. , & Coronel, R. (2016). Dispersion in ventricular repolarization in the human, canine and porcine heart. Progress in Biophysics and Molecular Biology, 120(1–3), 222–235. [DOI] [PubMed] [Google Scholar]
  23. Orini, M. , Srinivasan, N. T. , Taggart, P. , & Lambiase, P. D. (2018). Evaluation of multi‐Lead ECG markers to track changes in dispersion of ventricular repolarization in the intact human heart. Computing in Cardiology Conference: IEEE, 45, 1–4. [Google Scholar]
  24. Perez‐Alday, E. A. , Li‐Pershing, Y. , Bender, A. , Hamilton, C. , Thomas, J. A. , Johnson, K. , Lee, T. L. , Gonzales, R. , Li, A. , Newton, K. , & Tereshchenko, L. G. (2019). Importance of the heart vector origin point definition for an ECG analysis: The atherosclerosis risk in communities (ARIC) study. Computers in Biology and Medicine, 104, 127–138. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Punske, B. B. , Lux, R. L. , MacLeod, R. S. , Fuller, M. S. , Ershler, P. R. , Dustman, T. J. , Vyhmeister, Y. , & Taccardi, B. (1999). Mechanisms of the spatial distribution of QT intervals on the epicardial and body surfaces. Journal of Cardiovascular Electrophysiology, 10(12), 1605–1618. [DOI] [PubMed] [Google Scholar]
  26. Rautaharju, P. M. , Zhou, S. H. , & Calhoun, H. P. (1994). Ethnic differences in ECG amplitudes in north American white, black, and Hispanic men and women. Effect of obesity and age. Journal of Electrocardiology, 27(Suppl), 20–31. [DOI] [PubMed] [Google Scholar]
  27. Rivaud, M. R. , Bayer, J. D. , Cluitmans, M. , van der Waal, J. , Bear, L. R. , Boukens, B. J. , Belterman, C. , Gottlieb, L. , Vaillant, F. , Abell, E. , Dubois, R. , VMF, M. , & Coronel, R. (2021). Critical repolarization gradients determine the induction of reentry‐based torsades de pointes arrhythmia in models of long QT syndrome. Heart Rhythm, 18(2), 278–287. [DOI] [PubMed] [Google Scholar]
  28. Rosenthal, T. M. , Stahls, P. F. 3rd , Abi Samra, F. M. , Bernard, M. L. , Khatib, S. , Polin, G. M. , Xue, J. Q. , & Morin, D. P. (2015). T‐peak to T‐end interval for prediction of ventricular tachyarrhythmia and mortality in a primary prevention population with systolic cardiomyopathy. Heart Rhythm, 12(8), 1789–1797. [DOI] [PubMed] [Google Scholar]
  29. Shenthar, J. , Deora, S. , Rai, M. , & Nanjappa Manjunath, C. (2015). Prolonged Tpeak‐end and Tpeak‐end/QT ratio as predictors of malignant ventricular arrhythmias in the acute phase of ST‐segment elevation myocardial infarction: A prospective case–control study. Heart Rhythm, 12(3), 484–489. [DOI] [PubMed] [Google Scholar]
  30. Shimizu, M. , Ino, H. , Okeie, K. , Yamaguchi, M. , Nagata, M. , Hayashi, K. , Itoh, H. , Iwaki, T. , Oe, K. , Konno, T. , & Mabuchi, H. (2002). T‐peak to T‐end interval may be a better predictor of high‐risk patients with hypertrophic cardiomyopathy associated with a cardiac troponin I mutation than QT dispersion. Clinical Cardiology, 25(7), 335–339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Srinivasan, N. T. , Orini, M. , Providencia, R. , Simon, R. , Lowe, M. , Segal, O. R. , Chow, A. W. , Schilling, R. J. , Hunter, R. J. , Taggart, P. , & Lambiase, P. D. (2019). Differences in the upslope of the precordial body surface ECG T wave reflect right to left dispersion of repolarization in the intact human heart. Heart Rhythm, 16(6), 943–951. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Statters, D. J. , Malik, M. , Ward, D. E. , & Camm, A. J. (1994). QT dispersion: Problems of methodology and clinical significance. Journal of Cardiovascular Electrophysiology, 5(8), 672–685. [DOI] [PubMed] [Google Scholar]
  33. Tse, G. , Gong, M. , Meng, L. , Wong, C. W. , Bazoukis, G. , MTV, C. , MCS, W. , Letsas, K. P. , Baranchuk, A. , Yan, G. X. , Liu, T. , & WKK, W. (2018). Predictive value of Tpeak – Tend indices for adverse outcomes in acquired QT prolongation: A meta‐analysis. Frontiers in Physiology, 9, 1226. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. van Dam, P. M. , Boonstra, M. , Locati, E. T. , & Loh, P. (2021). The relation of 12 lead ECG to the cardiac anatomy: The normal CineECG. Journal of Electrocardiology, 69S, 67–74. [DOI] [PubMed] [Google Scholar]
  35. Zhang, J. , Hocini, M. , Strom, M. , Cuculich, P. S. , Cooper, D. H. , Sacher, F. , Haïssaguerre, M. , & Rudy, Y. (2017). The electrophysiological substrate of early repolarization syndrome: Noninvasive mapping in patients. JACC Clinical Electrophysiology, 3(8), 894–904. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Appendix S1

Click here for additional data file. (171.2KB, docx)

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Articles from Annals of Noninvasive Electrocardiology are provided here courtesy of International Society for Holter and Noninvasive Electrocardiology, Inc. and Wiley Periodicals, Inc.

RESOURCES