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Abstract
Background : Congenital long QT syndrome (CLQTS) is a life-threatening ion channelopathy leading to syncope and sudden death. Early diagnosis during the prenatal period and timely intervention can prevent sudden cardiac death and catastrophic consequences of this genetic ion channelopathy. Fetal magnetocardiography and fetal electrocardiography (ECG) enable the measurement of fetal QT and JT intervals, but their inherently technically challenging and/or resource-intensiveness nature preclude their routine clinical application. On the other hand, the high-temporal resolution of M-mode echocardiography makes it a well-suited and widely available modality for the measurement of cardiac events.
Aims and Objectives : We aimed to investigate the mechanical counterparts of the electrical QT and JT intervals on M-mode echocardiographic images of the tricuspid, mitral and aortic valves, and aortic wall.
Methods : We performed a prospective study on consecutive children referred to the outpatient pediatric cardiology clinic at a tertiary children's hospital. We defined M-mode echocardiographic landmark points on tracings of tricuspid annular planar systolic excursion, mitral and aortic valves, and aortic wall with simultaneous electrocardiographic recording. We measured the mean±SD of the absolute time difference and RR-adjusted time difference in cases with non-coincident ECG events and echocardiographic landmarks.
Results : Fifty healthy children were enrolled in the study. In 47 (94%) out of the 50 children, Q was coincident with the starting point of the tricuspid annular plane systolic excursion. In all children, the Q was coincident with the mid-point of the A-C line of the mitral valve. In 38 (76%) cases, there was a bump on the anterior wall of the aortic root immediately before the change in the slope of the aortic wall. This was coincident with the Q wave in 100% of cases. In all cases, the J point coincided with the point of acceleration of velocity on TAPSE. In all children, the J point coincided with the initial maximal opening of the aortic cusps. The end of the T wave occurred coincident with the peak of the tricuspid annular planar systolic excursion in 47 children (94%). In 48 children (96%), the end of the T wave coincided with the aortic cusps' closure point.
Conclusions : Based on our findings, we propose to measure the averaged mechanical QT and JT intervals by using an angled M-mode tracing of the aortic and mitral valve in five consecutive beats in the parasternal long-axis view. This is the first study on mechanical QT and JT intervals in healthy children. The study opens the horizons into the in-utero diagnosis of congenital long QT syndrome by measuring fetal QT and JT intervals using the widely available M-mode echocardiography
Keywords: Congenital long QT syndrome, M-mode echocardiography, mechanical JT interval, mechanical QT interval
How to cite this article: Introduction 
Congenital long QT syndrome (CLQTS) is a life-threatening ion channelopathy leading to syncope and sudden death.[1],[2],[3],[4],[5] This channelopathy is frequently undiagnosed with an underestimated prevalence of 1/3000–10,000. Given the presence of cardiocerebral channelopathy, the timely diagnosis of this inherited abnormality becomes paramount.[6] Early diagnosis during the prenatal period and timely intervention can prevent sudden cardiac death and catastrophic consequences of this genetic ion channelopathy.[5] Although specific features such as bradycardia, complete heart block, tachydysrhythmia, including ventricular tachycardia, and evidence of heart failure have been reported with higher frequency in fetuses with long QT syndrome, robust tools are essential for reliable prenatal diagnosis of this potentially life-threatening inherited arrhythmia.[7],[8],[9],[10],[11],[12]
Mechanical PR interval, measured from the onset of the A-wave of the mitral valve to the onset of the flow of the aortic valve, has been introduced and validated as a surrogate for electrical PR interval in the fetal period.[13],[14],[15] Moreover, despite the emergence of advanced echocardiographic modalities, M-mode echocardiography is still a time-honored modality because of its superior temporal resolution, which enables recording of the cardiac events at a frame rate of 1000 per second.[16]
To the best of the authors' knowledge, there is no reported study on echocardiographic estimation of mechanical QT and JT to date. Therefore, inspired by the concept of mechanical PR and considering the advantage of the high temporal resolution of widely available M-mode echocardiography, we aimed to delineate the corresponding mechanical counterparts of the electrical QT and JT intervals on M-mode echocardiographic images of the tricuspid, mitral and aortic valves, and aortic wall by using the concurrent electrocardiographic (ECG) tracing on the monitor of the echocardiographic machine. Similarly, we defined the echocardiographic landmarks of the JT interval in our study because this interval is a more accurate measure of ventricular repolarization, particularly in patients with ventricular conduction abnormalities.[17],[18]
Methods Study design and study population
We performed a prospective study on consecutive children referred to the outpatient pediatric cardiology clinic of the Children's Medical Center for evaluation of cardiac murmur. After a complete cardiac examination and comprehensive color Doppler two-dimensional echocardiographic examination, children with normal hearts and informed consent of their parents or guardians were enrolled in the study. Patients with poor acoustic windows were excluded.
Estimation of minimum sample size
The sample size was estimated using G*Power software (version 3.1.9.7, Germany).[19] At a power level of 95% and a significance level of 0.05%, a minimum sample size of 45 was estimated.
Echocardiographic examination
Echocardiography was performed using Philips Affiniti 50 C and probes S8-3 and S4-2 (Philips Healthcare, 3000 Minuteman Road, Andover, MA 01810, USA). Color tissue Doppler imaging of tricuspid annular planar systolic excursion (TAPSE), M-mode of the mitral and aortic valve, and aortic wall were obtained according to recommendations of the American Society of Echocardiography.[20] The simultaneous ECG recording was performed in all cases. All echocardiographic examinations were saved, and echocardiographic counterparts of Q, J, and end of T-wave were marked on recorded images of TAPSE, mitral and aortic valves, and the aortic wall on parasternal long-axis view. The sweep speed of the electrocardiography was adjusted according to the heart rate of the patient. We chose a channel that contained a recognizable Q- or q-wave or an initial r.
We chose four M-mode parameters: longitudinal M-mode parameter of TAPSE recorded by color tissue Doppler imaging, M-mode tracings of mitral and aortic valves, and the aortic wall on parasternal long-axis view.
Initially, a pilot study was performed to determine the most common landmarks on the M-mode tracings of the TAPSE, mitral and aortic valves, and the aortic wall. Consequently, echocardiographic landmark points were defined as described below on TAPSE and M-mode images of mitral and aortic valves and aortic walls [Figure 1].
Figure 1: Echocardiographic landmarks. Red, orange, and blue bullets represent Q, J, and end of the T-wave, respectively. (a) ECG landmarks, (b) Echocardiographic landmarks on M-mode of mitral valve obtained in parasternal long-axis view, (c) Echocardiographic landmarks on M-mode of the aortic valve and anterior aortic wall obtained in parasternal long-axis view, (d) Echocardiographic landmarks on the TAPSE obtained in apical four-chamber view, (e) Extrapolation of Q, J, and end of T-wave on the echocardiographic landmarks on the tracing of TAPSE: Q coincides with the start of excursion, J occurs at the time of velocity acceleration, and the end of T-wave is coincident with the peak of systolic excursion, TAPSE: Tricuspid annular planar systolic excursion, ECG: ElectrocardiographicTricuspid annular plane systolic excursion
The beginning point of the systolic excursionPoint of change in velocity (acceleration of velocity) in systolic excursion marked by a change in color of the recoding from red to bright red or orangePoint of peak systolic excursion.M-mode of the mitral valve (on parasternal long-axis view)
Mid-point of A-C linePoint of closure of the leaflets (C)Point of the beginning of the opening of the leaflets (D)M-mode of the aortic valve (on parasternal long-axis view)
Point of the beginning of the opening of the leafletsInitial complete separation of the leafletPoint of closing of the leaflets.M-mode of the anterior aortic wall (on parasternal long-axis view)
Early systolic bump on the anterior aortic wallThe nadir on the anterior aortic wallAortic wall peak anterior motion.Measurement of the time difference between the echocardiographic landmark and the electrocardiographic event
In patients in whom some beats or all were noncoincident with the predefined echocardiographic landmarks, the time differences between the echocardiographic landmark and the ECG event were measured and averaged [Figure 2].
Figure 2: The extrapolation of the J point on the anterior aortic wall. In the first, third, and fourth beats, J occurred 0.09, 0.02, and 0.05 s later than the nadir on the anterior aortic wall, respectively. The average of these time differences is 0.05 sAll measurements were carried out by a senior consultant (EMR). The echocardiographic studies of 17 children were repeated at an interval to assess the intra-observer variability of the measurements. Cohen's kappa and intra-class correlation coefficient (ICC) were calculated for categorical and continuous variables, respectively.
Statistical analysis
Data were stated as number and frequency. We used IBM SPSS Statistics for Windows, version 25 (IBM Corp., Armonk, NY, USA) for statistical analysis. Shapiro–Wilk test was used to test the normality of the distribution of the variables. In cases where the ECG events were not coincident with the defined landmarks, we calculated the Pearson's correlation coefficient between the QT and JT intervals on ECG tracings on the echocardiographic screen and the corresponding intervals based on the echocardiographic landmarks. Furthermore, we presented the mean ± standard deviation (SD) of the absolute time difference and the RR-adjusted time difference (i.e., time difference divided by the RR interval) between ECG events and echocardiographic landmarks in these cases.
Ethical considerations
We obtained informed consent from the children's parents or guardians and the participants, if applicable. We followed the principles stated in the Helsinki Declaration on ethical principles for medical research involving human subjects.[21] The Institutional Committee approved this study for Ethics in Biomedical Research of the Medical School of Tehran University of Medical Sciences (ID: IR.TUMS.CHMC.REC.1399.190).
Results The basic characteristics of the study population are shown in [Table 1]. Fifty healthy children were enrolled in the study.
Extrapolation of Q of electrocardiographic on M-mode echocardiography of tricuspid annular plane systolic excursion, mitral and aortic valves, and anterior aortic wall
Tricuspid annular plane systolic excursion
In 47 (94%) out of the 50 children, Q was coincident with the starting point of the TAPSE. Only in three (6%) children, Q occurred slightly sooner than this point. The mean ± SD time difference between the Q on ECG and the starting point of TAPSE in noncoincident cases was 0.036 ± 0.011 s [Table 2].
Table 2: Mechanical counterparts of three points of Q, J, and end of T-wave on four M-mode tracings: Tricuspid annular planar systolic excursion, mitral valve, aortic valve, and aortic wall in 50 healthy childrenM-mode of mitral valve
In all children, the Q was coincident with the mid-point of the A-C line of the mitral valve [Figure 3], [Figure 4], [Figure 5].
Figure 3: (a and b) Schematic illustration showing extrapolation of Q, J, and end of T-wave on the echocardiographic landmarks on the M-mode tracing of the mitral valve obtained in the parasternal long-axis view. The red, orange, and blue bullets indicate Q, J, and the end of the T-wave, respectively. Q was coincident with the mid-point of the AC line in all cases. J and end of T-wave occurred on C and D points in 86% and 92% of the study population, respectively. The percentages in the box in the right lower corner show the coincidence of Q, J, and end of T-wave on ECG with these echocardiographic landmarks in this study. (c) M-mode tracing of the mitral valve obtained from the parasternal long-axis view shows the Q, J, and end of the T-wave. In this case, the J point occurs after the echocardiographic landmark (i.e., the C point), ECG: Electrocardiographic
Figure 4: (a) Extrapolation of Q, J, and the end of T-wave on the echocardiographic landmarks of the M-mode tracing of the anterior aortic wall recorded from the parasternal long-axis view, (b) Extrapolation of the J point on the M-mode of the anterior aortic wall, (c) Extrapolation of Q, J, and end of T-wave on the echocardiographic landmarks of the color tissue Doppler M-mode imaging of the anterior aortic wall recorded from the parasternal long-axis view, (d) A magnified view of the QJ bump is shown
Figure 5: The proposed echocardiographic landmarks for measurement of mechanical QT and JT intervals on M-mode echocardiographyM-mode of aortic valve
In 29 (58%) cases, Q occurred precisely coincident with the opening point of the aortic valve. However, in 31 children, it occurred slightly before the opening of the aortic valve, with a mean ± SD of time difference of 0.047 ± 0.011 [Figure 1].
M-mode of anterior aortic wall
In 38 (76%) cases, there was a bump on the anterior wall of the aortic root immediately before the change in the slope of the aortic wall. This bump was coincident with the Q-wave in 100% of cases [Figure 4]. However, this bump was absent in 12 (24%) children.
Extrapolation of J of electrocardiographic on M-mode echocardiography of tricuspid annular plane and mitral and aortic valves
Tricuspid annular plane systolic excursion
In all cases, the J point coincided with the point of acceleration of velocity [Figure 1]d and [Figure 1]e.
M-mode of mitral valve
J point was coincident with the C point in 43 (86%) of children. Notwithstanding, in seven cases (14%), the J point happened slightly after the C point at a mean ± SD time delay of 0.037 ± 0.004 s.
M-mode of aortic valve
In all children, the J point coincided with the initial maximal opening of the aortic cusps.
M-mode of the anterior aortic wall
In 40 (80%) children, J point occurred at the nadir on the anterior aortic wall on M-mode echocardiography in the parasternal long-axis view. In the remainder, it happened after the nadir on the aortic wall. In the presence of the bump, this nadir point was also coincident with the end of the bump on the anterior aortic wall. The beginning of this bump reflected Q and the end of the J point [Figure 4].
Extrapolation of end of T (T end) of electrocardiographic on M-mode echocardiography of tricuspid annular plane and mitral and aortic valves
Tricuspid annular plane systolic excursion
The end of the T-wave occurred coincident with the peak of the TAPSE in 47 children (94%). In three cases, the end of the T-wave happened earlier at a mean ± SD of time difference of 0.050 ± 0.010 [Figure 1]e.
M-mode of mitral valve
In 46 (92%) children, the end of the T-wave was coincident with the D point, and in only four cases (8%), it occurred 0.047 ± 0.018 s earlier [Figure 1]b and [Figure 1]c.
M-mode of aortic valve
In 48 (96%) children, the end of the T-wave coincided with the aortic cusps' closure point. In only two cases (4%), the end of the T-wave occurred later at a delay of 0.03 and 0.04 s, respectively.
M-mode of the anterior aortic wall
In 30 (60%) children, the end of the T-wave was simultaneous with the peak anterior motion of the anterior wall of the aortic wall on M-mode imaging in parasternal long-axis view [Figure 4]d.
Time difference with echocardiographic landmark points in noncoincident cases
The comparison of the values of electrocardiographic-based and predefined echocardiographic landmark-based QT and JT intervals on tricuspid annular plane systolic excursion, M-mode of mitral and aortic valves, and anterior aortic wall is depicted in [Table 3].
Table 3. Comparison of the values of ECG-based and pre-defined Echocardiographic Landmark-based QT and JT intervals on TAPSE, M-mode of mitral and aortic valves and anterior aortic wallThere was excellent intra-observer reproducibility between the pairs of the repeated measures and observations on categorical and continuous variables (ICC and Cohen's kappa coefficient ≥0.99, respectively).
Discussion This study is the first investigation to define mechanical QT and JT intervals using the M-mode echocardiography [Table 4].
Table 4: Summary of M-mode echocardiographic corresponding points of Q, J, and T with their respective coincidence percentages (M-mode and electrocardiographic landmarks) and permutation combinations for calculation of mechanical QT and JT intervalsCorresponding points of Q, J, and end of T-wave on M-mode echocardiography
Q-wave
In all cases, the Q-wave coincided with the onset of the bump on the anterior aortic wall. Since the beginning of this bump was coincident with Q and the end of that with J, we called this QJ bump. Similarly, the Q-wave and mid-point of the A-C line of the mitral valve co-occurred in all cases. Of note, given the relationship between the A-C duration and PR interval, this finding applies to children with normal PR intervals.
The origin of the QJ bump is not elucidated. Tan and Tsang noted the exquisite motion and function of the aortic wall.[26] The anterior wall of the aorta is in continuity with the interventricular septum. We speculate this right-ventricular inclined bump may correspond with the initial vector of depolarization that depolarizes the ventricular septum from left to right and from apex to base and produces an initial q in lead V6 and an r in lead V1.[27] This speculation needs to be confirmed.
J point
The J point coincided with the point of change in velocity or velocity acceleration point on TAPSE and the initial separation of the aortic valve leaflets in all cases.
End of the T-wave
Closure point of the aortic valve corresponded to the end of the T-wave in 96% of cases.
Q, J, and end of T-wave noncoincident with the echocardiographic landmarks
The occurrence of Q and J earlier than the echocardiographic landmark led to the underestimation of the QT and JT intervals by echocardiography and vice versa. In contrast, the occurrence of the end of the T-wave sooner than the echocardiographic landmark led to an overestimation of QT and JT. This should be considered when we measure the mechanical QT and JT intervals [Table 2].
Despite significant advances in cardiac resynchronization therapy in the pediatric population, the normal range of electromechanical dyssynchrony, defined as the time difference between the electrical event on the ECG and its mechanical counterpart on echocardiography, is not reported.[28],[29] However, this study shows the existence of dyssynchrony between the timing of ECG events and their M-mode echocardiographic counterparts in normal children.
A practical proposal for measuring mechanical QT and JT intervals
Based on our findings, we propose to measure QT and JT intervals by using an angled M-mode tracing of the aortic and mitral valve. The intervals are measured in five consecutive beats and are averaged [Figure 5]. This would yield a crude and reliable estimate of these intervals. However, a validation study is essential before this method can be applied to the fetus.
Future studies: Validation of mechanical QT and JT intervals
Since there is no study on mechanical QT and JT intervals, we have to compare our study with the available literature on mechanical PR intervals. Accordingly, two methods of validation have been described for mechanical PR interval.
Pasquini et al. compared electrical and mechanical PR intervals in 50 healthy fetuses and reported a mean difference of −16.47 ms with a 95% confidence interval of −43.43–10.44.[30] Similarly, Friedman et al. defined the agreement of prenatal echocardiographic and postnatal ECG measurements to validate the fetal mechanical PR interval.[31] Whereas, Glickstein et al. compared measurements of mechanical PR interval by 15 perinatologists or pediatric cardiologists and stated, a difference of equal or less than 30 msonds with the measurement of the principal reader is regarded as acceptable.[13] In other words, Pasquini and Friedman used agreement between prenatal mechanical measurements and postnatal electrical ECG as the validation method, while Glickstein et al. considered reproducibility as a surrogate of validation. Both of these methods are essential for the newly reported mechanical QT and JT intervals. Accordingly, serial measurement of fetal mechanical QT and JT intervals in a fetal cohort study and comparison with postnatal measurements are necessary as the initial step.
Future applications
This study sets the stage for future application of this technique to fetal echocardiography for timely diagnosis of the hereditary long QT syndromes in the prenatal period using anatomic M-mode echocardiography. Anatomic M-mode can overcome the technical challenges in the prenatal echocardiographic examination for obtaining appropriate images. The fetal ECG recording is time-consuming, and the equipment is not widely available in resource-limited countries.[22],[23],[24],[25] In contrast, the excellent temporal and axial resolution of M-mode echocardiography and display of the entire cardiac cycle in a single frame as a unidimensional imaging modality make it well suited for this purpose. Nevertheless, applying the findings of this study to fetal echocardiography is contentious and needs further investigation.
The main practical implication of this study is to provide the correlated echocardiographic points for the measurement of QT and JT intervals that have the potential to be used in fetal echocardiography. Furthermore, given the increasing popularity of the application of artificial intelligence and machine learning in echocardiography, another clinical application of this scientific observation may be the feasibility of automatic reporting QT and JT intervals and their corrected values during echocardiographic examination in the near future.[32]
Conclusions This is the first study on mechanical QT and JT intervals in healthy children. The study opens the horizons into the in utero diagnosis of CLQTS by measuring fetal QT and JT intervals using the widely available M-mode echocardiographic methods.
Limitations
In this study, we compared the mechanical QT and JT with concurrent ECG tracing on the monitor of the echocardiography machine. Therefore, the major limitation of this study was that we did not investigate the consistency between the mechanical QT and JT intervals with the surface ECG intervals. Thus, in the future, a comparative study for investigation of the reliability among these three sets of data on QT and JT intervals, including M-mode echocardiographic measurements, concurrently obtained ECG tracings on the monitor of the echocardiography machine and surface ECG (obtained immediately before or after the echocardiographic examination) is warranted. Furthermore, evaluating normal values of electromechanical window, as studied by Sugrue et al., is essential in healthy children.[33]
We did not use Color Doppler tissue M-mode for all of the measurements. The addition of Color Doppler tissue imaging might increase the precision of echocardiographic landmarks.
Ethics approval and consent to participate
We obtained informed consent from the children's parents or guardians and the participants, if applicable. We followed the principles stated in the Helsinki Declaration on ethical principles for medical research involving human subjects. The Institutional Committee approved this study for Ethics in Biomedical Research of the Medical School of Tehran University of Medical Sciences (ID: IR.TUMS.CHMC.REC.1399.190).[21]
Availability of data and materials
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Acknowledgment
The authors fully appreciate the kind permission of the distinguished colleagues Dr. Keyhan Sayadpour Zanjani, Dr. Ehsan Aghaei-Moghadam, Dr. Reza Shabanian, and Dr. Mojtaba Gorji to enroll their patients (referred to their outpatient clinic of the Children's Medical Center) in this study. The authors are grateful to the children and their parents for participation in this study.
Our special gratitude goes to the distinguished reviewers who helped us improve this manuscript's quality by their insightful and constructive comments.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References 
Correspondence Address:
Prof. Elaheh Malakan Rad
Children's Medical Center (Pediatric Center of Excellence), Tehran University of Medical Sciences, No. 62, Dr. Gharib's Street, End of Keshavarz Boulevard, Tehran 1419733151
Iran
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/apc.apc_169_21
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