While it is now well-understood that the extent of QT interval changes due to underlying heart rate differences (i.e., the QT/RR adaptation) needs to be distinguished from the speed with which the QT interval reacts to heart rate changes (i.e., the so-called QT/RR hysteresis), gaps still exist in the physiologic understanding of QT/RR hysteresis processes. This study was designed to address the questions of whether the speed of QT adaptation to heart rate changes is driven by time or by number of cardiac cycles; whether QT interval adaptation speed is the same when heart rate accelerates and decelerates; and whether the characteristics of QT/RR hysteresis are related to age and sex. The study evaluated 897,570 measurements of QT intervals together with their 5-min histories of preceding RR intervals, all recorded in 751 healthy volunteers (336 females) aged 34.3 ± 9.5 years. Three different QT/RR adaptation models were combined with exponential decay models that distinguished time-based and interval-based QT/RR hysteresis. In each subject and for each modelling combination, a best-fit combination of modelling parameters was obtained by seeking minimal regression residuals. The results showed that the response of QT/RR hysteresis appears to be driven by absolute time rather than by the number of cardiac cycles. The speed of QT/RR hysteresis was found decreasing with increasing age whilst the duration of individually rate corrected QTc interval was found increasing with increasing age. Contrary to the longer QTc intervals, QT/RR hysteresis speed was faster in females. QT/RR hysteresis differences between heart rate acceleration and deceleration were not found to be physiologically systematic (i.e., they differed among different healthy subjects), but on average, QT/RR hysteresis speed was found slower after heart rate acceleration than after rate deceleration.

Faculty of Medicine Department of Internal Medicine and Cardiology Masaryk University Brno Czechia

Faculty of Medicine Department of Internal Medicine and Cardiology University Hospital Brno Masaryk University Brno Czechia

Klinikum rechts der Isar Technische Universität München Munich Germany

National Heart and Lung Institute Imperial College London United Kingdom

Wilhelminenspital der Stadt Wien Vienna Austria

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Andršová I., Hnatkova K., Helánová K., Šišáková M., Novotný T., Kala P., et al. . (2019). Individually rate corrected QTc intervals in children and adolescents. Front. Physiol. 10:994. 10.3389/fphys.2019.00994 PubMed DOI PMC

Andršová I., Hnatkova K., Šišáková M., Toman O., Smetana P., Huster K. M., et al. . (2020). Heart rate dependency and inter-lead variability of the T peak – T end intervals. Front. Physiol. 11:595815. 10.3389/fphys.2020.595815 PubMed DOI PMC

Axelsson K. J., Gransberg L., Lundahl G., Vahedi F., Bergfeldt L. (2021). Adaptation of ventricular repolarization time following abrupt changes in heart rate: comparisons and reproducibility of repeated atrial and ventricular pacing. Am. J. Physiol. Heart Circ. Physiol. 320, H381–H392. 10.1152/ajpheart.00542.2020 PubMed DOI

Bauer A., Klemm M., Rizas K. D., Hamm W., von Stülpnagel L., Dommasch M., et al. . (2019). Prediction of mortality benefit based on periodic repolarisation dynamics in patients undergoing prophylactic implantation of a defibrillator: a prospective, controlled, multicentre cohort study. Lancet 394, 1344–1351. 10.1016/S0140-6736(19)31996-8 PubMed DOI

Baumert M., Lambert G. W., Dawood T., Lambert E. A., Esler M. D., McGrane M., et al. . (2008). QT interval variability and cardiac norepinephrine spillover in patients with depression and panic disorder. Am. J. Physiol. Heart Circ. Physiol. 295, H962–H968. 10.1152/ajpheart.00301.2008 PubMed DOI

Baumert M., Porta A., Vos M. A., Malik M., Couderc J. P., Laguna P., et al. . (2016). variability in body surface ECG: measurement, physiological basis, and clinical value: position statement and consensus guidance endorsed by the European Heart Rhythm Association jointly with the ESC Working Group on Cardiac Cellular Electrophysiology. Europace 18, 925–944. 10.1093/europace/euv405 PubMed DOI PMC

Bazett J. C.. (1920). An analysis of time relations of electrocardiograms. Heart 7, 353–367.

Cassani González R., Engels E. B., Dubé B., Nadeau R., Vinet A., LeBlanc A. R., et al. . (2012). Assessment of the sensitivity of detecting drug-induced QTc changes using subject-specific rate correction. J. Electrocardiol. 45, 541–545. 10.1016/j.jelectrocard.2012.07.004 PubMed DOI

Davey P. P., Barlow C., Hart G. (2000). Prolongation of the QT interval in heart failure occurs at low but not at high heart rates. Clin. Sci. 98, 603–610. 10.1042/CS19990261 PubMed DOI

Einthoven W.. (1903). Die galvanometrischeRegistrierung des menschlichenElektrokardiogramms, zugleicheineBeurteilung der Anwendung des Kapillar-Elektrometers in der Physiologie. Pflügers Arch. 99, 472–480. 10.1007/BF01811855 DOI

El-Hamad F., Javorka M., Czippelova B., Krohova J., Turianikova Z., Porta A., et al. . (2019). Repolarization variability independent of heart rate during sympathetic activation elicited by head-up tilt. Med. Biol. Eng. Comput. 57, 1753–1762. 10.1007/s11517-019-01998-9 PubMed DOI

El-Hamad F., Lambert E., Abbott D., Baumert M. (2015). Relation between QT interval variability and muscle sympathetic nerve activity in normal subjects. Am. J. Physiol. Heart Circ. Physiol. 309, H1218–H1224. 10.1152/ajpheart.00230.2015 PubMed DOI

Fossa A. A.. (2017). Beat-to-beat ECG restitution: a review and proposal for a new biomarker to assess cardiac stress and ventricular tachyarrhythmia vulnerability. Ann. Noninvasive Electrocardiol. 22:e12460. 10.1111/anec.12460 PubMed DOI PMC

Franz M. R., Swerdlow C. D., Liem L. B., Schaefer J. (1988). Cycle length dependence of human action potential duration in vivo. Effects of single extrastimuli, sudden sustained rate acceleration and deceleration, and different steady-state frequencies. J. Clin. Invest. 82, 972–979. 10.1172/JCI113706 PubMed DOI PMC

Fridericia L. S.. (1920). Die SystolendauerimElekrokardiogrammbeinormalen Menschen und beiHerzkranken. Acta Med. Scand. 53, 469–486. 10.1111/j.0954-6820.1920.tb18266.x DOI

Garrod A. H.. (1870). On the relative duration of the component parts of the radial sphygmograph trace in health. J. Anat. Physiol. 18, 351–354. 10.1098/rspl.1869.0079 DOI

Garrod A. H.. (1875). On some points connected with circulation of the blood, arrived at from astudy of the sphygmograph-trace. J. Anat. Physiol. 23, 140–151. 10.1098/rspl.1874.0019 DOI

Gravel H., Curnier D., Dahdah N., Jacquemet V. (2017). Categorization and theoretical comparison of quantitative methods for assessing QT/RR hysteresis. Ann. Noninvasive Electrocardiol. 22:e12463. 10.1111/anec.12463 PubMed DOI PMC

Gravel H., Jacquemet V., Dahdah N., Curnier D. (2018). Clinical applications of QT/RR hysteresis assessment: a systematic review. Ann. Noninvasive Electrocardiol. 23:e12514. 10.1111/anec.12514 PubMed DOI PMC

Guideline ICH.. (2001). Safety pharmacology studies for human pharmaceuticals S7A. Fed. Regist. 66, 36791–36792. PubMed

Halámek J., Jurák P., Villa M., Soucek M., Frána P., Nykodým J., et al. . (2007). Dynamic coupling between heart rate and ventricular repolarisation. Biomed. Tech. 52, 255–263. 10.1515/BMT.2007.044 PubMed DOI

Hnatkova K., Andršová I., Toman O., Smetana P., Huster K. M., Šišáková M., et al. . (2021). Spatial distribution of physiologic 12-lead QRS complex. Sci. Rep. 11:4289. 10.1038/s41598-021-83378-8 PubMed DOI PMC

Hnatkova K., Kowalski D., Keirns J. J., van Gelderen E. M., Malik M. (2014). QTc changes after meal intake: sex differences and correlates. J. Electrocardiol. 47, 856–862. 10.1016/j.jelectrocard.2014.07.026 PubMed DOI

Hnatkova K., Malik M. (2020). Sources of QTc variability: implications for effective ECG monitoring in clinical practice. Ann Noninvasive Electrocardiol. 25:e12730. 10.1111/anec.12730 PubMed DOI PMC

Hnatkova K., Šišáková M., Smetana P., Toman O., Huster K. M., Novotný T., et al. . (2019b). Sex differences in heart rate responses to postural provocations. Int. J. Cardiol. 297, 126–134. 10.1016/j.ijcard.2019.09.044 PubMed DOI PMC

Hnatkova K., Smetana P., Toman O., Bauer A., Schmidt G., Malik M. (2009). Systematic comparisons of electrocardiographic morphology increase the precision of QT interval measurement. Pacing Clin. Electrophysiol. 32, 119–130. 10.1111/j.1540-8159.2009.02185.x PubMed DOI

Hnatkova K., Vicente J., Johannesen L., Garnett C., Stockbridge N., Malik M. (2019a). Errors of fixed QT heart rate corrections used in the assessment of drug-induced QTc changes. Front. Physiol. 10:635. 10.3389/fphys.2019.00635 PubMed DOI PMC

Huikuri H. V., Pikkujämsä S. M., Airaksinen K. E., Ikäheimo M. J., Rantala A. O., Kauma H., et al. . (1996). Sex-related differences in autonomic modulation of heart rate in middle-aged subjects. Circulation 94, 122–125. 10.1161/01.CIR.94.2.122 PubMed DOI

Jacquemet V., Cassani González R., Sturmer M., Dubé B., Sharestan J., Vinet A., et al. . (2014). interval measurement and correction in patients with atrial flutter: a pilot study. J. Electrocardiol. 47, 228–235. 10.1016/j.jelectrocard.2013.11.002 PubMed DOI

Jacquemet V., Dubé B., Knight R., Nadeau R., LeBlanc A. R., Sturmer M., et al. . (2011). Evaluation of a subject-specific transfer-function-based nonlinear QT interval rate-correction method. Physiol. Meas. 32, 619–635. 10.1088/0967-3334/32/6/001 PubMed DOI

Kenttä T., Karsikas M., Junttila M. J., Perkiömäki J. S., Seppänen T., Kiviniemi A., et al. . (2011). morphology measured from exercise electrocardiogram as a predictor of cardiac mortality. Europace 13, 701–707. 10.1093/europace/euq461 PubMed DOI

Kuch B., Hense H. W., Sinnreich R., Kark J. D., von Eckardstein A., Sapoznikov D., et al. . (2001). Determinants of short-period heart rate variability in the general population. Cardiology 95, 131–138. 10.1159/000047359 PubMed DOI

Lau C. P., Freeman A. R., Fleming S. J., Malik M., Camm A. J., Ward D. E. (1988). Hysteresis of the ventricular paced QT interval in response to abrupt changes in pacing rate. Cardiovasc. Res. 22, 67–72. 10.1093/cvr/22.1.67 PubMed DOI

Linde C., Bongiorni M. G., Birgersdotter-Green U., Curtis A. B., Deisenhofer I., Furokawa T., et al. . (2018). Sex differences in cardiac arrhythmia: a consensus document of the European Heart Rhythm Association, endorsed by the Heart Rhythm Society and Asia Pacific Heart Rhythm Society. Europace 20, 1565–1565. 10.1093/europace/euy067 PubMed DOI

Malik M.. (2008). Beat-to-beat QT variability and cardiac autonomic regulation. Am. J. Physiol. Heart Circ. Physiol. 295, H923–H925. 10.1152/ajpheart.00709.2008 PubMed DOI

Malik M.. (2014). QT/RR hysteresis. J. Electrocardiol. 47, 236–239. 10.1016/j.jelectrocard.2014.01.002 PubMed DOI

Malik M.. (2018). Methods of subject-specific heart rate corrections. J. Clin. Pharmacol. 58, 1020–1024. 10.1002/jcph.1269 PubMed DOI

Malik M., Hnatkova K., Batchvarov V., Gang Y., Smetana P., Camm A. J. (2004). Sample size, power calculations, and their implications for the cost of thorough studies of drug induced QT interval prolongation. Pacing Clin. Electrophysiol. 27, 1659–1669. 10.1111/j.1540-8159.2004.00701.x PubMed DOI

Malik M., Hnatkova K., Kowalski D., Keirns J. J., van Gelderen E. M. (2013). QT/RR curvatures in healthy subjects: sex differences and covariates. Am. J. Physiol. Heart Circ. Physiol. 305, H1798–H1806. 10.1152/ajpheart.00577.2013 PubMed DOI PMC

Malik M., Hnatkova K., Novotny T., Schmidt G. (2008a). Subject-specific profiles of QT/RR hysteresis. Am. J. Physiol. Heart Circ. Physiol. 295, H2356–H2363. 10.1152/ajpheart.00625.2008 PubMed DOI

Malik M., Andreas J.-O., Hnatkova K., Hoeckendorff J., Cawello W., et al. . (2008b). Thorough QT/QTc Study in patients with advanced Parkinson's disease: cardiac safety of rotigotine. Clin. Pharmacol. Ther. 84, 595–603. 10.1038/clpt.2008.143 PubMed DOI

Malik M., Hnatkova K., Schmidt A., Smetana P. (2008c). Accurately measured and properly heart-rate corrected QTc intervals show little daytime variability. Heart Rhythm 5, 1424–1431. 10.1016/j.hrthm.2008.07.023 PubMed DOI

Malik M., Johannesen L., Hnatkova K., Stockbridge N. (2016). Universal correction for QT/RR hysteresis. Drug Saf. 39, 577–588. 10.1007/s40264-016-0406-0 PubMed DOI

Malik M., van Gelderen E. M., Lee J. H., Kowalski D. L., Yen M., Goldwater R., et al. . (2012). safety of repeat doses of mirabegron in healthy subjects: a randomized, double-blind, placebo-, and active-controlled thorough QT study. Clin. Pharm. Therap. 92, 696–706. 10.1038/clpt.2012.181 PubMed DOI

Maury P., Caudron G., Bouisset F., Fourcade J., Duparc A., Mondoly P., et al. . (2013). Slower heart rate and altered rate dependence of ventricular repolarization in patients with lone atrial fibrillation. Arch. Cardiovasc. Dis. 106, 12–18. 10.1016/j.acvd.2012.10.001 PubMed DOI

Pelchovitz D. J., Ng J., Chicos A. B., Bergner D. W., Goldberger J. J. Q. T.-. R. R. (2012). hysteresis is caused by differential autonomic states during exercise and recovery. Am. J. Physiol. Heart Circ. Physiol. 302, H2567–H2573. 10.1152/ajpheart.00041.2012 PubMed DOI PMC

Porta A., Cairo B., De Maria B., Bari V. (2020). Complexity of spontaneous QT variability unrelated to RR variations and respiration during graded orthostatic challenge. Comput. Cardiol. 47:9. 10.22489/CinC.2020.009 DOI

Porta A., Tobaldini E., Gnecchi-Ruscone T., Montano N. (2010). RT variability unrelated to heart period and respiration progressively increases during graded head-up tilt. Am. J. Physiol. Heart Circ. Physiol. 298, H1406–H1414. 10.1152/ajpheart.01206.2009 PubMed DOI

Rautaharju P. M., Mason J. W., Akiyama T. (2014). New age- and sex-specific criteria for QT prolongation based on rate correction formulas that minimize bias at the upper normal limits. Int. J. Cardiol. 174, 535–540. 10.1016/j.ijcard.2014.04.133 PubMed DOI

Robyns T., Willems R., Vandenberk B., Ector J., Garweg C., Kuiperi C., et al. . (2017). Individualized corrected QT interval is superior to QT interval corrected using the Bazett formula in predicting mutation carriage in families with long QT syndrome. Heart Rhythm 14, 376–382. 10.1016/j.hrthm.2016.11.034 PubMed DOI

Schmidt A. F., Finan C. (2018). Linear regression and the normality assumption. J. Clin. Epidemiol. 98, 146–151. 10.1016/j.jclinepi.2017.12.006 PubMed DOI

Taubel J., Ferber G., Lorch U., Batchvarov V., Savelieva I., Camm A. J. T. (2014). study of the effect of oral moxifloxacin on QTc interval in the fed and fasted state in healthy Japanese and Caucasian subjects. Br. J. Clin. Pharmacol. 77, 170–179. 10.1111/bcp.12168 PubMed DOI PMC

Toman O., Hnatkova K., Smetana P., Huster K. M., Šišáková M., Barthel P., et al. . (2020). Physiologic heart rate dependency of the PQ interval and its sex differences. Sci. Rep. 10:2551. 10.1038/s41598-020-59480-8 PubMed DOI PMC

Waller A. D. A.. (1887). demonstration on man of electromotive changes accompanying the heart's beat. J. Physiol. 8, 229–234. 10.1113/jphysiol.1887.sp000257 PubMed DOI PMC

Watanabe M. A.. (2007). Lissajous curves and QT hysteresis: a critical look at QT/RR slope analysis techniques. Heart Rhythm 4, 1006–1008. 10.1016/j.hrthm.2007.05.010 PubMed DOI

Yodogawa K., Aiba T., Sumitomo N., Yamamoto T., Murata H., Iwasaki Y. K., et al. . (2021). Differential diagnosis between LQT1 and LQT2 by QT/RR relationships using 24-hour Holter monitoring: a multicenter cross-sectional study. Ann. Noninvasive Electrocardiol. 26:e12878. 10.1111/anec.12878 PubMed DOI PMC

Zhang Y., Bao M., Dai M., Zhong H., Li Y., Tan T. (2014). QT hysteresis index improves the power of treadmill exercise test in the screening of coronary artery disease. Circ. J. 78, 2942–2949. 10.1253/circj.CJ-14-0697 PubMed DOI

Intra-subject stability of different expressions of spatial QRS-T angle and their relationship to heart rate