Monitoring of QTc interval is mandated in different clinical conditions. Nevertheless, intra-subject variability of QTc intervals reduces the clinical utility of QTc monitoring strategies. Since this variability is partly related to QT heart rate correction, 10 different heart rate corrections (Bazett, Fridericia, Dmitrienko, Framingham, Schlamowitz, Hodges, Ashman, Rautaharju, Sarma, and Rabkin) were applied to 452,440 ECG measurements made in 539 healthy volunteers (259 females, mean age 33.3 ± 8.4 years). For each correction formula, the short term (5-min time-points) and long-term (day-time hours) variability of rate corrected QT values (QTc) was investigated together with the comparisons of the QTc values with individually corrected QTcI values obtained by subject-specific modelling of the QT/RR relationship and hysteresis. The results showed that (a) both in terms of short-term and long-term QTc variability, Bazett correction led to QTc values that were more variable than the results of other corrections (p < 0.00001 for all), (b) the QTc variability by Fridericia and Framingham corrections were not systematically different from each other but were lower than the results of other corrections (p-value between 0.033 and < 0.00001), and (c) on average, Bazett QTc values departed from QTcI intervals more than the QTc values of other corrections. The study concludes that (a) previous suggestions that Bazett correction should no longer be used in clinical practice are fully justified, (b) replacing Bazett correction with Fridericia and/or Framingham corrections would improve clinical QTc monitoring, (c) heart rate stability is needed for valid QTc assessment, and (d) development of further QTc corrections for day-to-day use is not warranted.

Department of Internal Medicine and Cardiology Faculty of Medicine Masaryk University Jihlavská 20 625 00 Brno Czech Republic

Department of Internal Medicine and Cardiology Faculty of Medicine University Hospital Brno Masaryk University Jihlavská 20 625 00 Brno Czech Republic

Klinikum rechts der Isar Technische Universität München Ismaninger Straße 22 81675 Munich Germany

National Heart and Lung Institute Imperial College ICTEM Hammersmith Campus 72 Du Cane Rd Shepherd's Bush London W12 0NN England UK

Wilhelminenspital der Stadt Wien Montleartstraße 37 1160 Vienna Austria

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Vandael E, Vandenberk B, Vandenberghe J, Willems R, Foulon V. Risk factors for QTc-prolongation: Systematic review of the evidence. Int. J. Clin. Pharm. 2017;39:16–25. doi: 10.1007/s11096-016-0414-2. PubMed DOI

Drew BJ, et al. Prevention of torsade de pointes in hospital settings: A scientific statement from the American Heart Association and the American College of Cardiology Foundation. Circulation. 2010;121:1047–1060. doi: 10.1161/CIRCULATIONAHA.109.192704. PubMed DOI PMC

Buttà C, et al. Use of QT intervals for a more accurate diagnose of syncope and evaluation of syncope severity. Int. J. Clin. Pract. 2014;68:864–870. doi: 10.1111/ijcp.12387. PubMed DOI

Rometo AB, Beerman L, Arora G. Electrolyte screening in the evaluation of prolonged QTc interval. Cardiol. Young. 2015;25:398–399. doi: 10.1017/S1047951114000705. PubMed DOI

Genovesi S, et al. Electrolyte concentration during haemodialysis and QT interval prolongation in uraemic patients. Europace. 2008;10:771–777. doi: 10.1093/europace/eun028. PubMed DOI

Quenin P, et al. Clinical yield of familial screening after sudden death in young subjects: The French experience. Circ. Arrhythm. Electrophysiol. 2017;10:e005236. doi: 10.1161/CIRCEP.117.005236. PubMed DOI

Marcus FI. Electrocardiographic features of inherited diseases that predispose to the development of cardiac arrhythmias, long QT syndrome, arrhythmogenic right ventricular cardiomyopathy/dysplasia, and Brugada syndrome. J. Electrocardiol. 2000;33(Suppl):1–10. doi: 10.1054/jelc.2000.20360. PubMed DOI

Tisdale JE, et al. Development and validation of a risk score to predict QT interval prolongation in hospitalized patients. Circ. Cardiovasc. Qual. Outcomes. 2013;6:479–487. doi: 10.1161/CIRCOUTCOMES.113.000152. PubMed DOI PMC

Warnier MJ, et al. Are ECG monitoring recommendations before prescription of QT-prolonging drugs applied in daily practice? The example of haloperidol. Pharmacoepidemiol. Drug Saf. 2015;24:701–708. doi: 10.1002/pds.3792. PubMed DOI

Sharma S, et al. Providers' response to clinical decision support for QT prolonging drugs. J. Med. Syst. 2017;41:161. doi: 10.1007/s10916-017-0803-7. PubMed DOI

Pezo RC, Yan AT, Earle C, Chan KK. Underuse of ECG monitoring in oncology patients receiving QT-interval prolonging drugs. Heart. 2019;105:1649–1655. doi: 10.1136/heartjnl-2018-314674. PubMed DOI

Good MM, Riad FS, Good CB, Shalaby AA. Provider response to QTc prolongation on standard 12-Lead EKG: Do we notice or do we care? Pacing Clin. Electrophysiol. 2016;39:1174–1180. doi: 10.1111/pace.12951. PubMed DOI

Benjamin LN, et al. Recommendations for QTc monitoring: Rational or arbitrary? Prim. Care Comp. CNS Disord. 2018;20:18f02327. doi: 10.4088/PCC.18f02327. PubMed DOI

Gueta I, et al. Clinically significant incidental QTc prolongation is subject to within-individual variability. Ann. Noninvasive Electrocardiol. 2020;25:e12699. doi: 10.1111/anec.12699. PubMed DOI PMC

Genovesi S, et al. Acute effect of a peritoneal dialysis exchange on electrolyte concentration and QT interval in uraemic patients. Clin. Exp. Nephrol. 2019;23:1315–1322. doi: 10.1007/s10157-019-01773-y. PubMed DOI

Drew D, Baranchuk A, Hopman W, Brison RJ. The impact of fever on corrected QT interval. J. Electrocardiol. 2017;50:570–575. doi: 10.1016/j.jelectrocard.2017.04.006. PubMed DOI

Albert BB, Eckersley LG, Skinner JR, Jefferies C. QT prolongation in a child with thyroid storm. BMJ Case Rep. 2014;2014:bcr2013202595. doi: 10.1136/bcr-2013-202595. PubMed DOI PMC

Capparelli FJ, et al. QTc prolongation after brain surgery. Neurol. Res. 2013;35:159–162. doi: 10.1179/1743132813Y.0000000169. PubMed DOI

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

Garnett CE, et al. Methodologies to characterize the QT/corrected QT interval in the presence of drug-induced heart rate changes or other autonomic effects. Am. Heart J. 2012;163:912–930. doi: 10.1016/j.ahj.2012.02.023. PubMed DOI

Malik M. The imprecision in heart rate correction may lead to artificial observations of drug induced QT interval changes. Pacing Clin. Electrophysiol. 2002;25:209–216. doi: 10.1046/j.1460-9592.2002.00209.x. PubMed DOI

Rabkin SW, Cheng XB. Nomenclature, categorization and usage of formulae to adjust QT interval for heart rate. World J. Cardiol. 2015;7:315–325. doi: 10.4330/wjc.v7.i6.315. PubMed DOI PMC

Guideline ICH. Safety pharmacology studies for human pharmaceuticals S7A. Fed. Regist. 2001;66:36791–36792. PubMed

Hume R. Prediction of lean body mass from height and weight. J. Clin. Path. 1966;19:389–391. doi: 10.1136/jcp.19.4.389. PubMed DOI PMC

Malik M, et al. Thorough QT/QTc Study in patients with advanced Parkinson's disease: Cardiac safety of rotigotine. Clin. Pharmacol. Therap. 2008;84:595–603. doi: 10.1038/clpt.2008.143. PubMed DOI

Malik M, et al. Proarrhythmic safety of repeat doses of mirabegron in healthy subjects: A randomized, double-blind, placebo-, and active-controlled thorough QT study. Clin. Pharm. Therap. 2012;92:696–706. doi: 10.1038/clpt.2012.181. PubMed DOI

Hnatkova K, et al. Systematic comparisons of electrocardiographic morphology increase the precision of QT interval measurement. Pacing Clin. Electrophysiol. 2009;32:119–130. doi: 10.1111/j.1540-8159.2009.02185.x. PubMed DOI

Malik M. Errors and misconceptions in ECG measurement used for the detection of drug induced QT interval prolongation. J. Electrocardiol. 2004;37(Suppl):25–33. doi: 10.1016/j.jelectrocard.2004.08.005. PubMed DOI

Xue JQ. Robust QT interval estimation: From algorithm to validation. Ann. Noninvasive Electrocardiol. 2009;14(Suppl 1):S35–S41. doi: 10.1111/j.1542-474X.2008.00264.x. PubMed DOI PMC

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

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

Bazett JC. An analysis of time relations of electrocardiograms. Heart. 1920;7:353–367.

Fridericia LS. Die Systolendauer im Elekrokardiogramm bei normalen Menschen und bei Herzkranken. Acta Med. Scand. 1920;53:469–486. doi: 10.1111/j.0954-6820.1920.tb18266.x. DOI

Dmitrienko AA, et al. Electrocardiogram reference ranges derived from a standardized slinical trial population. Drug Inf. J. 2005;39:395–405. doi: 10.1177/009286150503900408. DOI

Sagie A, Larson MG, Goldberg RJ, Bengtson JR, Levy D. An improved method for adjusting the QT interval for heart rate (the Framingham study) Am. J. Cardiol. 1992;70:797–801. doi: 10.1016/0002-9149(92)90562-D. PubMed DOI

Schlamowitz I. An analysis of time relationship within cardiac cycle in electrocardiogram in normal men: The duration of the QT interval and its relationship to the cycle length (RR interval) Am. Heart J. 1946;31:329–342. doi: 10.1016/0002-8703(46)90314-6. PubMed DOI

Hodges M, Salerno D, Erlien D. Bazett’s QT correction reviewed: Evidence that a linear QT correction for heart rate is better. J Am Coll Cardiol. 1983;1:694.

Ashman R. The normal duration of the Q-T interval. Am. Heart J. 1942;28:522–534. doi: 10.1016/S0002-8703(42)90297-7. DOI

Rautaharju PM, Warren JW, Calhoun HP. Estimation of QT prolongation: A persistent, avoidable error in computer electrocardiography. J. Electrocardiol. 1990;23(Suppl):111–117. doi: 10.1016/0022-0736(90)90085-G. PubMed DOI

Sarma JSM, Sarma RJ, Bilitch M, Katz D, Song SL. An exponential formula for heart rate dependence of QT interval during exercise and pacing in humans: Reevaluation of Bazett’s formula. Am. J. Cardiol. 1984;54:103–108. doi: 10.1016/0002-9149(84)90312-6. PubMed DOI

Rabkin SW, Szefer E, Thompson DJS. A new QT interval correction formulae to adjust for increases in heart rate. JACC Clin. Electrophysiol. 2017;3:756–766. doi: 10.1016/j.jacep.2016.12.005. PubMed DOI

https://ars.els-cdn.com/content/image/1-s2.0-S2405500X16305199-mmc1.pdf

Täubel J, et al. Single doses up to 800 mg of E-52862 do not prolong the QTc interval: A retrospective validation by pharmacokinetic-pharmacodynamic modelling of electrocardiography data utilising the effects of a meal on QTc to demonstrate ECG assay sensitivity. PLoS ONE. 2015;10:e0136369. doi: 10.1371/journal.pone.0136369. PubMed DOI PMC

Hnatkova K, Kowalski D, Keirns JJ, van Gelderen EM, Malik M. Reproducibility of QTc interval changes after meal intake. J. Electrocardiol. 2015;48:194–202. doi: 10.1016/j.jelectrocard.2015.01.006. PubMed DOI

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

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

Malik M, Hnatkova K, Kowalski D, Keirns JJ, van Gelderen EM. Importance of subject-specific QT/RR curvatures in the design of individual heart rate corrections of the QT interval. J. Electrocardiol. 2012;45:571–581. doi: 10.1016/j.jelectrocard.2012.07.017. PubMed DOI

Vandenberk B, et al. Which QT correction formulae to use for QT monitoring? J. Am. Heart Assoc. 2016;5:e003264. doi: 10.1161/JAHA.116.003264. PubMed DOI PMC

Malik M, Hnatkova K, Batchvarov V. Differences between study-specific and subject-specific heart rate corrections of the QT interval in investigations of drug induced QTc prolongation. Pacing Clin. Electrophysiol. 2004;27:791–800. doi: 10.1111/j.1540-8159.2004.00530.x. PubMed DOI

Malik M, et al. Implications of individual QT/RR profiles-part 1: Inaccuracies and problems of population-specific QT/heart rate corrections. Drug Saf. 2019;42:401–414. doi: 10.1007/s40264-018-0736-1. PubMed DOI PMC

Malik M, Färbom P, Batchvarov V, Hnatkova K, Camm AJ. Relation between QT and RR intervals is highly individual among healthy subjects: Implications for heart rate correction of the QT interval. Heart. 2002;87:220–228. doi: 10.1136/heart.87.3.220. PubMed DOI PMC

Linde C, et al. 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. 2018;20:1565ao–1565. doi: 10.1093/europace/euy067. PubMed DOI

Fujiki A, Yoshioka R, Sakabe M. Evaluation of repolarization dynamics using the QT-RR regression line slope and intercept relationship during 24-h Holter ECG. Heart Vessels. 2015;30:235–240. doi: 10.1007/s00380-014-0471-1. PubMed DOI

Hnatkova K, Malik M. "Optimum" formulae for heart rate correction of the QT interval. Pacing Clin. Electrophysiol. 1999;22:1683–1687. doi: 10.1111/j.1540-8159.1999.tb00390.x. PubMed DOI

Malik M, et al. Sample size, power calculations, and their implications for the cost of thorough studies of drug induced QT interval prolongation. Pacing Clin. Electrophysiol. 2004;27:1659–1669. doi: 10.1111/j.1540-8159.2004.00701.x. PubMed DOI

Indik JH, Pearson EC, Fried K, Bazett WRL. Fridericia QT correction formulas interfere with measurement of drug-induced changes in QT interval. Heart Rhythm. 2006;3:1003–1007. doi: 10.1016/j.hrthm.2006.05.023. PubMed DOI

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

Hnatkova K, Johannesen L, Vicente J, Malik M. Heart rate dependency of JT interval sections. J. Electrocardiol. 2017;50:814–824. doi: 10.1016/j.jelectrocard.2017.08.005. PubMed DOI

Andršová I, et al. Problems with Bazett QTc correction in paediatric screening of prolonged QTc interval. BMC Pediatr. 2020;20:558. doi: 10.1186/s12887-020-02460-8. PubMed DOI PMC

Johannesen L, et al. Quantitative understanding of QTc prolongation and gender as risk factors for torsade de pointes. Clin. Pharmacol. Therap. 2018;103:304–309. doi: 10.1002/cpt.783. PubMed DOI

Wolbrette D. Antiarrhythmic drugs: Age, race, and gender effects. Card Electrophysiol. Clin. 2010;2:369–378. doi: 10.1016/j.ccep.2010.06.007. PubMed DOI

Gonzalez R, et al. Sex and age related differences in drug induced QT prolongation by dofetilide under reduced repolarization reserve in simulated ventricular cells. Annu. Int. Conf. IEEE Eng. Med. Biol. Soc. 2010;2010:3245–3248. PubMed

Pueyo E, et al. Characterization of QT interval adaptation to RR interval changes and its use as a risk-stratifier of arrhythmic mortality in amiodarone-treated survivors of acute myocardial infarction. IEEE Trans. Biomed. Eng. 2004;51:1511–1520. doi: 10.1109/TBME.2004.828050. PubMed DOI

Batchvarov VN, et al. QT-RR relationship in healthy subjects exhibits substantial intersubject variability and high intrasubject stability. Am. J. Physiol. Heart Circ. Physiol. 2002;282:H2356–H2363. doi: 10.1152/ajpheart.00860.2001. PubMed DOI

Hnatkova K, et al. Errors of fixed QT heart rate corrections used in the assessment of drug-induced QTc changes. Front Physiol. 2019;10:635. doi: 10.3389/fphys.2019.00635. PubMed DOI PMC

Cirincione B, Sager PT, Mager DE. Influence of meals and glycemic changes on QT interval dynamics. J. Clin. Pharmacol. 2017;57:966–976. doi: 10.1002/jcph.933. PubMed DOI PMC

Sampedro-Puente DA, et al. Time course of low-frequency oscillatory behavior in human ventricular repolarization following enhanced sympathetic activity and relation to arrhythmogenesis. Front Physiol. 2020;10:1547. doi: 10.3389/fphys.2019.01547. PubMed DOI PMC

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

Andršová I, et al. Heart rate influence on the QT variability risk factors. Diagnostics. 2020;10:1096. doi: 10.3390/diagnostics10121096. PubMed DOI PMC

Copie X, et al. Predictive power of increased heart rate versus depressed left ventricular ejection fraction and heart rate variability for risk stratification after myocardial infarction: Results of a two-year follow-up study. J. Am. Coll. Cardiol. 1996;27:270–276. doi: 10.1016/0735-1097(95)00454-8. PubMed DOI

Seravalle G, Grassi G. Heart rate as cardiovascular risk factor. Postgrad. Med. 2020;132:358–367. doi: 10.1080/00325481.2020.1738142. PubMed DOI

Pueyo E, Smetana P, Laguna P, Malik M. Estimation of the QT/RR hysteresis lag. J. Electrocardiol. 2003;36(Suppl):187–190. doi: 10.1016/j.jelectrocard.2003.09.056. PubMed DOI

Halámek J, et al. Use of a novel transfer function to reduce repolarization interval hysteresis. J. Interv. Card Electrophysiol. 2010;29:23–32. doi: 10.1007/s10840-010-9500-x. PubMed DOI

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

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