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Normative Heart-Rate Corrected Values for Repolarisation Length From Holter Recordings in Children and Adults
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ORIGINAL ARTICLE
Heart, Lung and Circulation (2019) -, -–1443-9506/19/$36.00 https://doi.org/10.1016/j.hlc.2019.12.006
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Normative Heart-Rate Corrected Values for Repolarisation Length From Holter Recordings in Children and Adults Kathryn E. Waddell-Smith, MBBS, PhD, FRACP a,b,c, Alexandra A. Chaptynova b, Jian Li, BSc, MBChB a, Jackie R. Crawford, NZCS a, Halina Hinds, BAS c, Jonathan R. Skinner, MD, FHRS a,b,c,* a
Green Lane Paediatric and Congenital Cardiac Services, Starship Children’s Hospital Auckland New Zealand The University of Auckland, Department of Child Health, Auckland, New Zealand c Green Lane Cardiovascular Services, Auckland City Hospital, Auckland, New Zealand b
Received 5 September 2019; received in revised form 17 October 2019; accepted 5 December 2019; online published-ahead-of-print xxx
Background
Normative values for heart-rate corrected repolarisation length are not available in children and are scarce in adults. We wished to define repeatability and normative values of Holter recording measurements of repolarisation length in healthy individuals using a commercially available system, and compare measurements with those from 12-lead electrocardiograms (ECGs).
Methods
Twenty-four-hour (24)-hour Holter recordings were made on 99 Healthy volunteers: 52 children (7 months to 14 years) and 47 adults (15 yrs). Mean and peak values of QTc, and RTPc (R-wave to peak T-wave,) were assessed. Bazett heart rate correction was employed for each measurement and only heart rates between 40 and 120 bpm were analysed. The end of the T-wave was defined from the zero-crossing point. QTc was also determined from 12-lead ECGs from the same population by manual measurement recording the longest QTc of leads 2 and V5. The tangent technique was used to define the end of the T-wave.
Results
Interobserver repeatability: mean QTc 615 ms (CI 3.5%), peak QTc 625 ms (CI 4.5%), mean RTPc 63 ms (CI 1%), peak RTPc 644 ms (CI 11%). Mean values were very similar for ,15 years and all females and were therefore amalgamated: mean (62SD); mean QTc 424 ms (394–454), mean RTPc 291ms (263–319). Values were lower in males 15years; (mean QTc 408ms (370–446), p,0.01; mean RTPc 274ms (234–314), p,0.01. The highest mean QTc value was 467 ms in an adult female. QTc from 12-lead ECG: females ,15 years 409 ms (384–434) males ,15 years 408 ms (383–433), females 15 years 426 ms (401–451), males 15 years 385 ms (362–408).
Conclusions
Holter measurements of mean QTc and RTPc are highly repeatable. Males 15 years have shorter mean repolarisation length over 24 hours than males ,15 years and all females. Mean QTc Holter values were on average 15–17 ms longer than QTc from 12-lead ECGs except in females .15 years.
Keywords
QT interval Repolarisation Holter monitor Puberty Gonadal hormones Repeatability
Introduction Long QT syndrome (LQTS) predisposes to malignant ventricular arrhythmias causing cardiac arrest, predominantly in
the young [1]. Diagnosis can be challenging due to the variation in clinical expression [2]. with significant overlap in QT intervals between affected and unaffected individuals [3,4] and difficulties in measuring QT intervals [5]. Risk
*Corresponding author at: Green Lane Paediatric and Congenital Cardiac Services, Starship Children’s’ Hospital, Private Bag 92024, Auckland 1142, New Zealand. Tel.: 164 9 3074949; Fax: 164 9 6310785; Email: [email protected] Ó 2019 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Waddell-Smith KE, et al. Normative Heart-Rate Corrected Values for Repolarisation Length From Holter Recordings in Children and Adults. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.12.006
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stratification and allocation of appropriate therapy currently relies on either the manifestation of symptoms, which are often life threatening, or a corrected QT interval (QTc) exceeding 500 ms [1], which is frequently unrecognised by physicians [5]. Before these high risk features manifest, the young patient is exposed to a higher risk; unnecessary had they been identified at initial assessment. We wondered if Holter measurements might help identify genotype status or level of clinical risk but found that normative values are not available at all in children and are scarce in adults. The use of Holter recordings in the assessment of LQTS has previously been studied with variable results. Some have demonstrated a higher proportion of pathological ventricular arrhythmias [6], and others not [7], although a longer QTc in LQTS subjects is commonly seen [3,7,8]. Some of these techniques appear to be complex and repeatability has not been established [8,9], and they have not been adopted widely. We wished to trial a simplified Holter recording technique, using a commercially available system and software, to assess repolarisation length using the simple Bazett heartrate correction formula, hoping this might be more readily adopted into clinical practice. The Bazett heart rate correction formula has been shown to work well across all heart rates, including in children [10], and commercially available Holter systems provide this calculation within their software. This software also permits the restriction of beats measured by heart rate. We decided to restrict the heart rates examined to between 40 and 120. The Bazett formula is less well validated for extreme bradycardia [11], and at faster heart rates clinical experience shows that defining the end of the T-wave can be difficult partly due to associated physical exertion or excitement often leading to movement artifact, and the T-wave may blend in with the subsequent p-wave [12], Furthermore, differentiation of genotype carrier state is improved at rates below 120 beats per minute (BPM) after exercise [13]. We thus aimed firstly to find the most repeatable measurement between QTc, and RTPc (R-wave-to-peak-T-wave) for both peak and mean values, and then to establish normative upper and lower limits based on age and sex [14]. RTPc was selected as a potential alternative to QTc because the end of the T-wave can be challenging to determine precisely, and it is a measurement that is provided automatically by the company software. We also recorded 12-lead ECGs at the same visit to see how these QTc measurements compared with those from the Holter recordings.
Methods This study was approved by the Health and Disability Ethics Committee New Zealand and local area health board: number: 16/NTB/86.
Study Population Normative Holter recording data and 12-lead ECGs were obtained from healthy volunteers recruited through local
K.E. Waddell-Smith et al.
184 185 186 187 188 189 190 Data Collection 191 192 ECG analysis 193 The first three authors (KWS, AC, JL) performed the 12-lead 194 ECG analysis. None of the ECGs showed evidence of cardiac 195 pathology. The QT interval was measured from the begin196 ning of the QRS complex to the end of the T-wave as defined 197 by the “tangent technique” where the tangent of the steepest 198 slope of the second limb of the T-wave crosses the isoelectric 199 200 line [15,16]. 201 Holter recordings and analyses 202 All study subjects underwent a three-lead 24-hour Holter 203 204 recording, and all heart beats of adequate quality within the 205 restricted heart rate range were analysed from lead CM5 206 preferentially, or leads II or CM1 if the former was unavai207 lable. LifeCard CF monitors and Del Mar Impressario soft208 ware (Washington, USA) were used to calculate QT for heart Q2 209 rates between 40 and 120 beats per minute only. QT intervals 210 of faster and slower rates were not recorded. This commer211 212 cially available method uses semi-automated measurement, 213 detecting the end of the T-wave as the zero crossing point 214 using the Laguna algorithm [17] with caliper placement and 215 periodic adjustment by the technician if the caliper obviously 216 jumped from the appropriate position. This is uncommon, 217 but tends to occur a few times over each 24 hours with 218 baseline or movement artifact. Q-onset was defined as the 219 220 onset of the negative deflection associated with the QRS 221 complex, the R- and T-wave peaks were defined as the 222 highest points in each in lead CM5 and end T-wave defined 223 by zero crossing point at the baseline (Figure 1). 224 We anticipated that this method would tend to give a 225 longer QT than the “tangent’ technique but an algorithm for 226 automated measurement using the tangent method was not 227 228 available to us. Bazett correction was used to calculate QTc; 229 this is incorporated in the computer software and gives an 230 automated report. 231 R-wave to peak T-wave (RTP), was also recorded and 232 corrected in the same way for heart rate (RTPc). The effect of 233 puberty on ventricular repolarisation was examined by 234 comparing results before age 11 and after age 15. 235 236 Repeatability (reproducibility) was tested between and 237 within observers for mean and peak QTc and and RTPc. 238 Twenty (20) of the Holter recordings were analysed twice in 239 a blinded fashion to assess within-observer repeatability and 240 a second physiologist scanned the same 20 recordings to 241 assess between-observer repeatability. 242 243 244 Statistical Analyses 245 Assumptions of the t-test were tested and all data were 246 analysed by unpaired parametric and non-parametric t-tests 247 248 as appropriate. Chi-squared tests were used for binary
advertising within the hospital. Most were staff, or their relatives; all were unrelated to people with long QT syndrome. They were not taking QT prolonging medications; see Table 1 for Demographic Details.
Please cite this article in press as: Waddell-Smith KE, et al. Normative Heart-Rate Corrected Values for Repolarisation Length From Holter Recordings in Children and Adults. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.12.006
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Results 26 (6)
Study Population Normative ECG and Holter data were obtained from 99 healthy volunteers.
19
16-37 years; 0.12
0.006
0.007
variables. Statistical analyses were performed using GraphPad Prism version 6.0e for Mac, (GraphPad Software, La Jolla, CA, USA, www.graphpad.com.) Statistical analysis of observer repeatability tests was achieved through Bland Altman plots and 95% limits of repeatability. QTc, and RTPc intervals were compared using one-way Anova. These statistics were performed using SAS statistical package (version 8, SAS Institute, Cary, NC, USA). In all cases, two-tailed p,0.05 were considered statistically significant.
1-14 years;
9 (3)
1 – 37 years, 31
15.4 (9)
Repeatability of Holter Recording Assessment Ninety-five per cent (95%) confidence limits for interobserver repeatability are reported in Table 2. Repeatability values for averaged measurements were remarkably good, particularly in comparison to previous reports of 12-lead ECG interpretation of QTc [5]. Measurement to the peak of the T-wave (i.e. RTPc) was more repeatable than to the end of the T-wave (i.e. QTc) (Table 2), and repeatability of mean measurements was superior to peak measurements, (Table 2).
34 (11)
Abbreviations: yo, years old.
22.5 (16) 19 (13)
7.5 (4)
67 years;
– 14 years;
7 months – 21
67 years;
7 months
28
20-67 years;
50
Holter Findings of Healthy Volunteers
7 months – 49 99
Females ‡15yo vs males ‡15yo Females ,15yo vs males ,15yo Total Age range; mean (SD)
Total Females Total females age range females ,15 (years), ‡15yo (SD)
Females ‡15yo age range (years), (SD)
Total Age range, mean (SD)
Total Males males ,15yo age ,15 range (years), (SD)
Total Males males ‡15yo ‡15yo age range (years), (SD)
P-value Males Females
Age range; mean age (SD) Total
Table 1 Demographics of normative cohort. Healthy males ‡15 yo were younger than healthy females ‡15 yo.
249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313
Females vs males
QTc from Holter recordings
Mean Holter QTc and RTPc values (mQTc and mRTPc) Given the better repeatability for mean values, we analysed these results to form normative values. We examined the results by age and gender, dividing the cohort into four groups: females ,15 years, males ,15 years, females 15 years and males 15 years. For both measurements, males 15 years had significantly shorter average values than the others females 15 years, females ,15 years and males ,15 years (Table 3 and Figure 2). To examine the potential effect of gonadal hormones on these results, we re-performed the analyses excluding adolescents aged 11–15 years on the assumption that most individuals 10 years old or younger have not yet reached puberty, and that the maximal changes would have occurred by the age of 16. Females aged 10 years had a similar mean QTc compared with adult females 15 years (p=0.85). Males aged 10 years had a shorter mean QTc compared with males 15 years (p=0.004). There was no significant difference between mRTPc values for the younger versus older females (p=0.84), but males 15 years had shorter mRTPc values than males ,10 years (p=0.005). Since excluding the peri-pubertal results made no material difference, all values were included in the generation of the mean and ranges for females and males. Formation of normative values Due to the similarities in results between females ,15 years, males ,15 years and females 15 years, these results could
Please cite this article in press as: Waddell-Smith KE, et al. Normative Heart-Rate Corrected Values for Repolarisation Length From Holter Recordings in Children and Adults. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.12.006
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Figure 1 The QRS-T complex in lead CM 5 is used to determine measurements of repolarisation on the Holter monitor. Line “1.” represents Q-onset, line “2.” R-wave, line “3.” peak of the T-wave and line “4.” the end of the T-wave (zero crossing point). In Figure 1A, the lines generated by the Holter system are shown. In Figure 1B, the dotted lines demonstrate how the tangent technique would produce a shorter QT interval on this trace; this method was used on the 12-lead ECGs because of its superior repeatability.
be amalgamated in the generation of normative values. These values were significantly longer than for males 15 years, p=0.0002 (QTc) and p=0.0001 (RTPc) respectively. Therefore, we formed two reference ranges by expressing two standard deviations from the mean (i.e. including 95.5% of the population): (1) all females and males ,15 years and (2) males 15 years (Table 4).
Discussion This study finds that Holter recordings of repolarisation length are highly reproducible between observers. Mean values were more repeatable than peak values, and the most repeatable was mean RTPc (confidence intervals of 1%), followed by mean values for QTc (CI 3.5%), so these show the greatest promise for application into clinical practice. It is important to note that the mean QTc measurements were generally longer than those obtained from the 12-lead ECG. This may partly or entirely be related to the difference in how the end of the T-wave is determined by each technique, Holter determination of the end of the T-wave being
Table 2 95% interobserver repeatability confidence limits for Holter recording measurements. 95% interobserver repeatability limits (ms)
95% interobserver repeatability limits (%)
mQTc
615ms
63.5%
mRTPc
63ms
61%
peakQTc peakRTPc
625ms 644ms
64.5% 611%
determined from the zero-crossing point, compared to the tangent technique in the 12-lead ECGs. A previous study of 21 healthy adults reported 95th centile values for mean QTc very similar to the upper limits we report here: they reported 439 ms in males versus 446 ms here, and 461 ms in females, versus 462 ms here [18]. Another study of 422 healthy adults observed differences in how QT interval changes against heart rate, producing nomograms of QT against heart rate by gender; with women generally having longer QT intervals [19]. The authors also found that healthy people aged over 50 years have longer QT intervals. Heart rate corrected values, and average values, were not reported. Repeatability of maximal values of repolarisation length was not as good, meaning that they are perhaps less likely to be of future clinical value. The confidence levels of repeatability are all very much less than those for manual QTc measurement from the 12-lead ECG found by other researchers [5]. This Holter technique may, therefore, prove to be especially attractive to non-LQT experts, for whom assessment of the 12-lead ECG is most challenging [5]. Furthermore, by including many hours of recordings we may be less likely by chance to miss a subject with long QT syndrome who has a normal QT interval for the few seconds the 12-lead ECG is obtained. Others have published that those with LQTS adapt poorly to changes in heart rate for example after exercise or standing [20,21], and we suspect that the Holter monitor takes advantage of this pathological process as a diagnostic tool. During a 24-hour Holter monitor period, there are many changes in heart rate, which can unmask the differences in repolarisation reserve between someone with LQTS and someone without. A striking result was the lower overall QTc and RTPc in males 15 years compared to younger males and all females. This suggests that testosterone may, in healthy individuals,
Please cite this article in press as: Waddell-Smith KE, et al. Normative Heart-Rate Corrected Values for Repolarisation Length From Holter Recordings in Children and Adults. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.12.006
444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508
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,0.0001 0.0007 0.41 0.55 274 (20) 293 (16) 291 (14) 290 (13)
Abbreviations: ECG, electrocardiogram.
ms=milliseconds.
291 (15) Mean Holter mRTPc (ms)
289 (11)
0.04 0.005 0.01 0.002 0.07 0.44 0.94 0.45 385 (23) 408 (19) 426 (25) 426 (18) 411 (25) 424 (15) 408 (24) 423 (14) 408 (25) 422 (13) 409 (25) 425 (16) First ECG QTc (ms) Mean Holter mQTc (ms)
Male ‡15 years vs All ,15 years Male ‡15 years vs Female ‡15 years Female ‡15 years vs All ,15 years Females ,15 years vs Males ,15 years
P-value
Male ‡15 years Female ‡15 years All ,15 years and Female ‡15 years All ,15 years Male ,15 years Female ,15 years
509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573
Table 3 Mean first ECG QTc, Holter mQTc and mRTPc values for healthy volunteers (21 females ,15years, 31 males ,15 years, 28 females .15 years and 19 males .15 years). Mean (SD).
QTc from Holter recordings
be a more powerful influence on QTc than the female sex hormones, confirming the conclusion of others from 27 years ago based on 12-lead ECG assessments [22]. In the practical sense, it means that the normative range is lower in males 15 years than all other groups. Larger numbers of males 15 years now need to be studied which will likely bring the normative upper limit down; for example the highest mean RTPc recorded in males 15 years was 303 ms, but the upper limit of normal derived from two standard deviations is 314 ms, due to the relatively small sample size. Another practical point to note is that almost 2.5% of the normal population will have values above the 2SD “normative” limits- and so a single value does not imply long QT syndrome is present— which has a prevalence of 0.05%. Such a measurement may raise suspicion along with other clinical features. Values from the long QT population need to be compared in future reports. Mean RTPc had an even tighter repeatability than mean QTc (1% vs 3.5%). We consider this is most likely to be due to the automated detection algorithm for the end of the T-wave sometimes failing; the Laguna algorithm defines the zero crossing point. The cardiac technical staff often observed a jump of the caliper away from the T-wave, particularly when the end of the T-wave had a shallow slope or there was movement artifact or baseline wander. This was corrected when seen, but the algorithm detecting the peak of the T-wave was much more reliable. Whether this will be of clinical importance in the assessment of other types of long QT syndrome remains to be seen, given the variety of T-wave morphologies encountered. The study has a number of weaknesses and limitations. The software did not allow us to use different heart rate correction formulae. We took a pragmatic approach to heart rate limitation at the outset (40–120 bpm), we cannot undo that and reanalyse all heart rates, which would be interesting for future studies, though recent work has suggested that the Bazett formula is in fact the best even for young children and infants with fast heart rates [10]. We have also not yet studied diurnal variation [9]. We also were not able to analyse changes in T-wave morphology, a science which has considerable promise. Nevertheless, to our knowledge it is the first to report repeatability of a Holter technique to assess repolarisation and to produce age and sex based normative values for heart-rate corrected QT and RTP intervals, and may form the basis for research into factors influencing repolarisation length, such as genetic and pharmacological influences.
Conclusion This study finds that a commercially available Holter recording system can provide highly repeatable assessment of repolarisation length and produces age and sex based normative mean values. A mean QTc of over 470 msec was not seen in healthy children or women, and a mean QTc over 450 msec was not seen in healthy males over 15 years of age.
Please cite this article in press as: Waddell-Smith KE, et al. Normative Heart-Rate Corrected Values for Repolarisation Length From Holter Recordings in Children and Adults. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.12.006
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704 705 706 707 708 709 710 711 712 713 714 715 716 717 718 719 720 721 722 723 724 725 726 727 728 729 730 731 732 733 734 Figure 2 The mean QTc values from Holter recordings in 99 healthy volunteers with heart rates between 40 and 120 beats 735 per minute analysed. Results are displayed in four age/gender subgroups. The height of the column shows the average 736 mean QTc, and the bars show 2 standard deviations from the mean. The absolute values are shown in Table 2. 737 Q5 738 739 740 the dominant role in determining cardiac repolarisation The study finds that males 15 years have shorter mean 741 length in healthy individuals. repolarisation length than women and children suggesting 742 that testosterone rather than oestrogen or progesterone plays 743 744 Table 4 Mean Holter mQTc and mRTPc findings for 745 each age/sex based normative group. The newly formed 746 The authors gratefully acknowledge the statistical advice reference range is shown in bold in the third column. 747 from Dr Joanna Stewart from the Department of Biostatis748 tics, the University of Auckland, the cardiac physiologists Mean Lower and Highest 749 value (SD) upper limits mean who interpreted the Holter investigations and Charlene Nell 750 (mean - 2SD value for assistance with manuscript preparation from the 751 and mean + recorded 752 Department of Cardiovascular Services, Green Lane Car2SD) 753 diovascular Services, Auckland City Hospital, Auckland, a mQTc all females 424 (15) 394-454 467 754 New Zealand. and males 755 <15years (ms) 756 757 mQTc males 408 (19) 370-446 436 758 ‡15years (ms) 759 a mRTPc all females 291 (14) 263-319 325 There authors have no conflicts of interest to declare. 760 and males 761 <15years (ms) 762 mRTPc males 274 (20) 234-314 303 763 ‡15years (ms) 764 This study was part funded by Cure Kids and the TM 765 Hoskins Trust. Dr Waddell-Smith was supported by the 766 ms=milliseconds. Q3 767 a Green Lane Research and Education Fund and the Heart This value was recorded in an adult female. 768 Foundation (New Zealand).
Acknowledgements
Conflicts of Interest
Funding
Please cite this article in press as: Waddell-Smith KE, et al. Normative Heart-Rate Corrected Values for Repolarisation Length From Holter Recordings in Children and Adults. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.12.006
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769 770 771 772 773 774 775 776 777 778 779 780 781 782 783 784 785 786 787 788 789 790 791 792 793 794 795 796 797 798 799 800 801 802 803 804 805 806 807 808 809 810 811 812 813 814 815 816
Ethics Approval This study was approved by the Health and Disability Ethics Committee New Zealand and local area health board: number: 16/NTB/86.
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[10] Phan DQ, Silka MJ, Lan YT, Chang RK. Comparison of formulas for calculation of the corrected QT interval in infants and young children. J Pediatr 2015;166:960–4.e1–2. [11] Milne JR, Ward DE, Spurrell RA, Camm AJ. The ventricular paced QT interval–the effects of rate and exercise. Pacing & Clinical Electrophysiology 1982;5:352–8. [12] Berger WR, Gow RM, Kamberi S, Cheung M, Smith KR, Davis AM. The QT and corrected QT interval in recovery after exercise in children. Circ Arrhythm Electrophysiol 2011;4:448–55. [13] Swan H, Toivonen L, Viitasalo M. Rate adaptation of QT intervals during and after exercise in children with congenital long QT syndrome. Eur Heart J 1998;19:508–13. [14] Goldenberg I, Moss AJ. Long QT syndrome. J Am Coll Cardiol 2008;51:2291–300. [15] Postema PG, De Jong JS, Van der Bilt IA, Wilde AA. Accurate electrocardiographic assessment of the QT interval: teach the tangent. Heart Rhythm 2008;5:1015–8. [16] Waddell-Smith K, Gow RM, Skinner JR. How to measure a QT interval. Med J Aust 2017;207:107–10. [17] Laguna P, Thakor NV, Caminal P, Jane R, Yoon HR, Bayes de Luna A, et al. New algorithm for QT interval analysis in 24-hour Holter ECG: performance and applications. Med Biol Eng Comput 1990;28:67–73. [18] Molnar J, Zhang F, Weiss J, Ehlert FA, Rosenthal JE. Diurnal pattern of QTc interval: how long is prolonged? Possible relation to circadian triggers of cardiovascular events. J Am Coll Cardiol 1996;27:76–83. [19] Sugao M, Fujiki A, Sakabe M, Nishida K, Tsuneda T, Iwamoto J, et al. New quantitative methods for evaluation of dynamic changes in QT interval on 24 hour Holter ECG recordings: QT interval in idiopathic ventricular fibrillation and long QT syndrome. Heart 2006;92:201–7. [20] Sy RW, van der Werf C, Chattha IS, Chockalingam P, Adler A, Healey JS, et al. Derivation and validation of a simple exercise-based algorithm for prediction of genetic testing in relatives of LQTS probands. Circulation 2011;124:2187–94. [21] Viskin S, Postema PG, Bhuiyan ZA, Rosso R, Kalman JM, Vohra JK, et al. The response of the QT interval to the brief tachycardia provoked by standing: a bedside test for diagnosing long QT syndrome. J Am Coll Cardiol 2010;55:1955–61. [22] Rautaharju P, Zhou SH, Wong S, Calhoun HP, Berenson GS, Prineas R, et al. Sex differences in the evolution of the electrocardiographic QT interval with age. Can J Cardiol 1992;8:690–5.
Please cite this article in press as: Waddell-Smith KE, et al. Normative Heart-Rate Corrected Values for Repolarisation Length From Holter Recordings in Children and Adults. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.12.006
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ORIGINAL ARTICLE
Heart, Lung and Circulation (2019) -, -–1443-9506/19/$36.00 https://doi.org/10.1016/j.hlc.2019.12.006
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Normative Heart-Rate Corrected Values for Repolarisation Length From Holter Recordings in Children and Adults Kathryn E. Waddell-Smith, MBBS, PhD, FRACP a,b,c, Alexandra A. Chaptynova b, Jian Li, BSc, MBChB a, Jackie R. Crawford, NZCS a, Halina Hinds, BAS c, Jonathan R. Skinner, MD, FHRS a,b,c,* a
Green Lane Paediatric and Congenital Cardiac Services, Starship Children’s Hospital Auckland New Zealand The University of Auckland, Department of Child Health, Auckland, New Zealand c Green Lane Cardiovascular Services, Auckland City Hospital, Auckland, New Zealand b
Received 5 September 2019; received in revised form 17 October 2019; accepted 5 December 2019; online published-ahead-of-print xxx
Background
Normative values for heart-rate corrected repolarisation length are not available in children and are scarce in adults. We wished to define repeatability and normative values of Holter recording measurements of repolarisation length in healthy individuals using a commercially available system, and compare measurements with those from 12-lead electrocardiograms (ECGs).
Methods
Twenty-four-hour (24)-hour Holter recordings were made on 99 Healthy volunteers: 52 children (7 months to 14 years) and 47 adults (15 yrs). Mean and peak values of QTc, and RTPc (R-wave to peak T-wave,) were assessed. Bazett heart rate correction was employed for each measurement and only heart rates between 40 and 120 bpm were analysed. The end of the T-wave was defined from the zero-crossing point. QTc was also determined from 12-lead ECGs from the same population by manual measurement recording the longest QTc of leads 2 and V5. The tangent technique was used to define the end of the T-wave.
Results
Interobserver repeatability: mean QTc 615 ms (CI 3.5%), peak QTc 625 ms (CI 4.5%), mean RTPc 63 ms (CI 1%), peak RTPc 644 ms (CI 11%). Mean values were very similar for ,15 years and all females and were therefore amalgamated: mean (62SD); mean QTc 424 ms (394–454), mean RTPc 291ms (263–319). Values were lower in males 15years; (mean QTc 408ms (370–446), p,0.01; mean RTPc 274ms (234–314), p,0.01. The highest mean QTc value was 467 ms in an adult female. QTc from 12-lead ECG: females ,15 years 409 ms (384–434) males ,15 years 408 ms (383–433), females 15 years 426 ms (401–451), males 15 years 385 ms (362–408).
Conclusions
Holter measurements of mean QTc and RTPc are highly repeatable. Males 15 years have shorter mean repolarisation length over 24 hours than males ,15 years and all females. Mean QTc Holter values were on average 15–17 ms longer than QTc from 12-lead ECGs except in females .15 years.
Keywords
QT interval Repolarisation Holter monitor Puberty Gonadal hormones Repeatability
Introduction Long QT syndrome (LQTS) predisposes to malignant ventricular arrhythmias causing cardiac arrest, predominantly in
the young [1]. Diagnosis can be challenging due to the variation in clinical expression [2]. with significant overlap in QT intervals between affected and unaffected individuals [3,4] and difficulties in measuring QT intervals [5]. Risk
*Corresponding author at: Green Lane Paediatric and Congenital Cardiac Services, Starship Children’s’ Hospital, Private Bag 92024, Auckland 1142, New Zealand. Tel.: 164 9 3074949; Fax: 164 9 6310785; Email: [email protected] Ó 2019 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Waddell-Smith KE, et al. Normative Heart-Rate Corrected Values for Repolarisation Length From Holter Recordings in Children and Adults. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.12.006
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stratification and allocation of appropriate therapy currently relies on either the manifestation of symptoms, which are often life threatening, or a corrected QT interval (QTc) exceeding 500 ms [1], which is frequently unrecognised by physicians [5]. Before these high risk features manifest, the young patient is exposed to a higher risk; unnecessary had they been identified at initial assessment. We wondered if Holter measurements might help identify genotype status or level of clinical risk but found that normative values are not available at all in children and are scarce in adults. The use of Holter recordings in the assessment of LQTS has previously been studied with variable results. Some have demonstrated a higher proportion of pathological ventricular arrhythmias [6], and others not [7], although a longer QTc in LQTS subjects is commonly seen [3,7,8]. Some of these techniques appear to be complex and repeatability has not been established [8,9], and they have not been adopted widely. We wished to trial a simplified Holter recording technique, using a commercially available system and software, to assess repolarisation length using the simple Bazett heartrate correction formula, hoping this might be more readily adopted into clinical practice. The Bazett heart rate correction formula has been shown to work well across all heart rates, including in children [10], and commercially available Holter systems provide this calculation within their software. This software also permits the restriction of beats measured by heart rate. We decided to restrict the heart rates examined to between 40 and 120. The Bazett formula is less well validated for extreme bradycardia [11], and at faster heart rates clinical experience shows that defining the end of the T-wave can be difficult partly due to associated physical exertion or excitement often leading to movement artifact, and the T-wave may blend in with the subsequent p-wave [12], Furthermore, differentiation of genotype carrier state is improved at rates below 120 beats per minute (BPM) after exercise [13]. We thus aimed firstly to find the most repeatable measurement between QTc, and RTPc (R-wave-to-peak-T-wave) for both peak and mean values, and then to establish normative upper and lower limits based on age and sex [14]. RTPc was selected as a potential alternative to QTc because the end of the T-wave can be challenging to determine precisely, and it is a measurement that is provided automatically by the company software. We also recorded 12-lead ECGs at the same visit to see how these QTc measurements compared with those from the Holter recordings.
Methods This study was approved by the Health and Disability Ethics Committee New Zealand and local area health board: number: 16/NTB/86.
Study Population Normative Holter recording data and 12-lead ECGs were obtained from healthy volunteers recruited through local
K.E. Waddell-Smith et al.
184 185 186 187 188 189 190 Data Collection 191 192 ECG analysis 193 The first three authors (KWS, AC, JL) performed the 12-lead 194 ECG analysis. None of the ECGs showed evidence of cardiac 195 pathology. The QT interval was measured from the begin196 ning of the QRS complex to the end of the T-wave as defined 197 by the “tangent technique” where the tangent of the steepest 198 slope of the second limb of the T-wave crosses the isoelectric 199 200 line [15,16]. 201 Holter recordings and analyses 202 All study subjects underwent a three-lead 24-hour Holter 203 204 recording, and all heart beats of adequate quality within the 205 restricted heart rate range were analysed from lead CM5 206 preferentially, or leads II or CM1 if the former was unavai207 lable. LifeCard CF monitors and Del Mar Impressario soft208 ware (Washington, USA) were used to calculate QT for heart Q2 209 rates between 40 and 120 beats per minute only. QT intervals 210 of faster and slower rates were not recorded. This commer211 212 cially available method uses semi-automated measurement, 213 detecting the end of the T-wave as the zero crossing point 214 using the Laguna algorithm [17] with caliper placement and 215 periodic adjustment by the technician if the caliper obviously 216 jumped from the appropriate position. This is uncommon, 217 but tends to occur a few times over each 24 hours with 218 baseline or movement artifact. Q-onset was defined as the 219 220 onset of the negative deflection associated with the QRS 221 complex, the R- and T-wave peaks were defined as the 222 highest points in each in lead CM5 and end T-wave defined 223 by zero crossing point at the baseline (Figure 1). 224 We anticipated that this method would tend to give a 225 longer QT than the “tangent’ technique but an algorithm for 226 automated measurement using the tangent method was not 227 228 available to us. Bazett correction was used to calculate QTc; 229 this is incorporated in the computer software and gives an 230 automated report. 231 R-wave to peak T-wave (RTP), was also recorded and 232 corrected in the same way for heart rate (RTPc). The effect of 233 puberty on ventricular repolarisation was examined by 234 comparing results before age 11 and after age 15. 235 236 Repeatability (reproducibility) was tested between and 237 within observers for mean and peak QTc and and RTPc. 238 Twenty (20) of the Holter recordings were analysed twice in 239 a blinded fashion to assess within-observer repeatability and 240 a second physiologist scanned the same 20 recordings to 241 assess between-observer repeatability. 242 243 244 Statistical Analyses 245 Assumptions of the t-test were tested and all data were 246 analysed by unpaired parametric and non-parametric t-tests 247 248 as appropriate. Chi-squared tests were used for binary
advertising within the hospital. Most were staff, or their relatives; all were unrelated to people with long QT syndrome. They were not taking QT prolonging medications; see Table 1 for Demographic Details.
Please cite this article in press as: Waddell-Smith KE, et al. Normative Heart-Rate Corrected Values for Repolarisation Length From Holter Recordings in Children and Adults. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.12.006
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Results 26 (6)
Study Population Normative ECG and Holter data were obtained from 99 healthy volunteers.
19
16-37 years; 0.12
0.006
0.007
variables. Statistical analyses were performed using GraphPad Prism version 6.0e for Mac, (GraphPad Software, La Jolla, CA, USA, www.graphpad.com.) Statistical analysis of observer repeatability tests was achieved through Bland Altman plots and 95% limits of repeatability. QTc, and RTPc intervals were compared using one-way Anova. These statistics were performed using SAS statistical package (version 8, SAS Institute, Cary, NC, USA). In all cases, two-tailed p,0.05 were considered statistically significant.
1-14 years;
9 (3)
1 – 37 years, 31
15.4 (9)
Repeatability of Holter Recording Assessment Ninety-five per cent (95%) confidence limits for interobserver repeatability are reported in Table 2. Repeatability values for averaged measurements were remarkably good, particularly in comparison to previous reports of 12-lead ECG interpretation of QTc [5]. Measurement to the peak of the T-wave (i.e. RTPc) was more repeatable than to the end of the T-wave (i.e. QTc) (Table 2), and repeatability of mean measurements was superior to peak measurements, (Table 2).
34 (11)
Abbreviations: yo, years old.
22.5 (16) 19 (13)
7.5 (4)
67 years;
– 14 years;
7 months – 21
67 years;
7 months
28
20-67 years;
50
Holter Findings of Healthy Volunteers
7 months – 49 99
Females ‡15yo vs males ‡15yo Females ,15yo vs males ,15yo Total Age range; mean (SD)
Total Females Total females age range females ,15 (years), ‡15yo (SD)
Females ‡15yo age range (years), (SD)
Total Age range, mean (SD)
Total Males males ,15yo age ,15 range (years), (SD)
Total Males males ‡15yo ‡15yo age range (years), (SD)
P-value Males Females
Age range; mean age (SD) Total
Table 1 Demographics of normative cohort. Healthy males ‡15 yo were younger than healthy females ‡15 yo.
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Females vs males
QTc from Holter recordings
Mean Holter QTc and RTPc values (mQTc and mRTPc) Given the better repeatability for mean values, we analysed these results to form normative values. We examined the results by age and gender, dividing the cohort into four groups: females ,15 years, males ,15 years, females 15 years and males 15 years. For both measurements, males 15 years had significantly shorter average values than the others females 15 years, females ,15 years and males ,15 years (Table 3 and Figure 2). To examine the potential effect of gonadal hormones on these results, we re-performed the analyses excluding adolescents aged 11–15 years on the assumption that most individuals 10 years old or younger have not yet reached puberty, and that the maximal changes would have occurred by the age of 16. Females aged 10 years had a similar mean QTc compared with adult females 15 years (p=0.85). Males aged 10 years had a shorter mean QTc compared with males 15 years (p=0.004). There was no significant difference between mRTPc values for the younger versus older females (p=0.84), but males 15 years had shorter mRTPc values than males ,10 years (p=0.005). Since excluding the peri-pubertal results made no material difference, all values were included in the generation of the mean and ranges for females and males. Formation of normative values Due to the similarities in results between females ,15 years, males ,15 years and females 15 years, these results could
Please cite this article in press as: Waddell-Smith KE, et al. Normative Heart-Rate Corrected Values for Repolarisation Length From Holter Recordings in Children and Adults. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.12.006
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K.E. Waddell-Smith et al.
Figure 1 The QRS-T complex in lead CM 5 is used to determine measurements of repolarisation on the Holter monitor. Line “1.” represents Q-onset, line “2.” R-wave, line “3.” peak of the T-wave and line “4.” the end of the T-wave (zero crossing point). In Figure 1A, the lines generated by the Holter system are shown. In Figure 1B, the dotted lines demonstrate how the tangent technique would produce a shorter QT interval on this trace; this method was used on the 12-lead ECGs because of its superior repeatability.
be amalgamated in the generation of normative values. These values were significantly longer than for males 15 years, p=0.0002 (QTc) and p=0.0001 (RTPc) respectively. Therefore, we formed two reference ranges by expressing two standard deviations from the mean (i.e. including 95.5% of the population): (1) all females and males ,15 years and (2) males 15 years (Table 4).
Discussion This study finds that Holter recordings of repolarisation length are highly reproducible between observers. Mean values were more repeatable than peak values, and the most repeatable was mean RTPc (confidence intervals of 1%), followed by mean values for QTc (CI 3.5%), so these show the greatest promise for application into clinical practice. It is important to note that the mean QTc measurements were generally longer than those obtained from the 12-lead ECG. This may partly or entirely be related to the difference in how the end of the T-wave is determined by each technique, Holter determination of the end of the T-wave being
Table 2 95% interobserver repeatability confidence limits for Holter recording measurements. 95% interobserver repeatability limits (ms)
95% interobserver repeatability limits (%)
mQTc
615ms
63.5%
mRTPc
63ms
61%
peakQTc peakRTPc
625ms 644ms
64.5% 611%
determined from the zero-crossing point, compared to the tangent technique in the 12-lead ECGs. A previous study of 21 healthy adults reported 95th centile values for mean QTc very similar to the upper limits we report here: they reported 439 ms in males versus 446 ms here, and 461 ms in females, versus 462 ms here [18]. Another study of 422 healthy adults observed differences in how QT interval changes against heart rate, producing nomograms of QT against heart rate by gender; with women generally having longer QT intervals [19]. The authors also found that healthy people aged over 50 years have longer QT intervals. Heart rate corrected values, and average values, were not reported. Repeatability of maximal values of repolarisation length was not as good, meaning that they are perhaps less likely to be of future clinical value. The confidence levels of repeatability are all very much less than those for manual QTc measurement from the 12-lead ECG found by other researchers [5]. This Holter technique may, therefore, prove to be especially attractive to non-LQT experts, for whom assessment of the 12-lead ECG is most challenging [5]. Furthermore, by including many hours of recordings we may be less likely by chance to miss a subject with long QT syndrome who has a normal QT interval for the few seconds the 12-lead ECG is obtained. Others have published that those with LQTS adapt poorly to changes in heart rate for example after exercise or standing [20,21], and we suspect that the Holter monitor takes advantage of this pathological process as a diagnostic tool. During a 24-hour Holter monitor period, there are many changes in heart rate, which can unmask the differences in repolarisation reserve between someone with LQTS and someone without. A striking result was the lower overall QTc and RTPc in males 15 years compared to younger males and all females. This suggests that testosterone may, in healthy individuals,
Please cite this article in press as: Waddell-Smith KE, et al. Normative Heart-Rate Corrected Values for Repolarisation Length From Holter Recordings in Children and Adults. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.12.006
444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508
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,0.0001 0.0007 0.41 0.55 274 (20) 293 (16) 291 (14) 290 (13)
Abbreviations: ECG, electrocardiogram.
ms=milliseconds.
291 (15) Mean Holter mRTPc (ms)
289 (11)
0.04 0.005 0.01 0.002 0.07 0.44 0.94 0.45 385 (23) 408 (19) 426 (25) 426 (18) 411 (25) 424 (15) 408 (24) 423 (14) 408 (25) 422 (13) 409 (25) 425 (16) First ECG QTc (ms) Mean Holter mQTc (ms)
Male ‡15 years vs All ,15 years Male ‡15 years vs Female ‡15 years Female ‡15 years vs All ,15 years Females ,15 years vs Males ,15 years
P-value
Male ‡15 years Female ‡15 years All ,15 years and Female ‡15 years All ,15 years Male ,15 years Female ,15 years
509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573
Table 3 Mean first ECG QTc, Holter mQTc and mRTPc values for healthy volunteers (21 females ,15years, 31 males ,15 years, 28 females .15 years and 19 males .15 years). Mean (SD).
QTc from Holter recordings
be a more powerful influence on QTc than the female sex hormones, confirming the conclusion of others from 27 years ago based on 12-lead ECG assessments [22]. In the practical sense, it means that the normative range is lower in males 15 years than all other groups. Larger numbers of males 15 years now need to be studied which will likely bring the normative upper limit down; for example the highest mean RTPc recorded in males 15 years was 303 ms, but the upper limit of normal derived from two standard deviations is 314 ms, due to the relatively small sample size. Another practical point to note is that almost 2.5% of the normal population will have values above the 2SD “normative” limits- and so a single value does not imply long QT syndrome is present— which has a prevalence of 0.05%. Such a measurement may raise suspicion along with other clinical features. Values from the long QT population need to be compared in future reports. Mean RTPc had an even tighter repeatability than mean QTc (1% vs 3.5%). We consider this is most likely to be due to the automated detection algorithm for the end of the T-wave sometimes failing; the Laguna algorithm defines the zero crossing point. The cardiac technical staff often observed a jump of the caliper away from the T-wave, particularly when the end of the T-wave had a shallow slope or there was movement artifact or baseline wander. This was corrected when seen, but the algorithm detecting the peak of the T-wave was much more reliable. Whether this will be of clinical importance in the assessment of other types of long QT syndrome remains to be seen, given the variety of T-wave morphologies encountered. The study has a number of weaknesses and limitations. The software did not allow us to use different heart rate correction formulae. We took a pragmatic approach to heart rate limitation at the outset (40–120 bpm), we cannot undo that and reanalyse all heart rates, which would be interesting for future studies, though recent work has suggested that the Bazett formula is in fact the best even for young children and infants with fast heart rates [10]. We have also not yet studied diurnal variation [9]. We also were not able to analyse changes in T-wave morphology, a science which has considerable promise. Nevertheless, to our knowledge it is the first to report repeatability of a Holter technique to assess repolarisation and to produce age and sex based normative values for heart-rate corrected QT and RTP intervals, and may form the basis for research into factors influencing repolarisation length, such as genetic and pharmacological influences.
Conclusion This study finds that a commercially available Holter recording system can provide highly repeatable assessment of repolarisation length and produces age and sex based normative mean values. A mean QTc of over 470 msec was not seen in healthy children or women, and a mean QTc over 450 msec was not seen in healthy males over 15 years of age.
Please cite this article in press as: Waddell-Smith KE, et al. Normative Heart-Rate Corrected Values for Repolarisation Length From Holter Recordings in Children and Adults. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.12.006
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704 705 706 707 708 709 710 711 712 713 714 715 716 717 718 719 720 721 722 723 724 725 726 727 728 729 730 731 732 733 734 Figure 2 The mean QTc values from Holter recordings in 99 healthy volunteers with heart rates between 40 and 120 beats 735 per minute analysed. Results are displayed in four age/gender subgroups. The height of the column shows the average 736 mean QTc, and the bars show 2 standard deviations from the mean. The absolute values are shown in Table 2. 737 Q5 738 739 740 the dominant role in determining cardiac repolarisation The study finds that males 15 years have shorter mean 741 length in healthy individuals. repolarisation length than women and children suggesting 742 that testosterone rather than oestrogen or progesterone plays 743 744 Table 4 Mean Holter mQTc and mRTPc findings for 745 each age/sex based normative group. The newly formed 746 The authors gratefully acknowledge the statistical advice reference range is shown in bold in the third column. 747 from Dr Joanna Stewart from the Department of Biostatis748 tics, the University of Auckland, the cardiac physiologists Mean Lower and Highest 749 value (SD) upper limits mean who interpreted the Holter investigations and Charlene Nell 750 (mean - 2SD value for assistance with manuscript preparation from the 751 and mean + recorded 752 Department of Cardiovascular Services, Green Lane Car2SD) 753 diovascular Services, Auckland City Hospital, Auckland, a mQTc all females 424 (15) 394-454 467 754 New Zealand. and males 755 <15years (ms) 756 757 mQTc males 408 (19) 370-446 436 758 ‡15years (ms) 759 a mRTPc all females 291 (14) 263-319 325 There authors have no conflicts of interest to declare. 760 and males 761 <15years (ms) 762 mRTPc males 274 (20) 234-314 303 763 ‡15years (ms) 764 This study was part funded by Cure Kids and the TM 765 Hoskins Trust. Dr Waddell-Smith was supported by the 766 ms=milliseconds. Q3 767 a Green Lane Research and Education Fund and the Heart This value was recorded in an adult female. 768 Foundation (New Zealand).
Acknowledgements
Conflicts of Interest
Funding
Please cite this article in press as: Waddell-Smith KE, et al. Normative Heart-Rate Corrected Values for Repolarisation Length From Holter Recordings in Children and Adults. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.12.006
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Ethics Approval This study was approved by the Health and Disability Ethics Committee New Zealand and local area health board: number: 16/NTB/86.
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Please cite this article in press as: Waddell-Smith KE, et al. Normative Heart-Rate Corrected Values for Repolarisation Length From Holter Recordings in Children and Adults. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.12.006
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