QT interval variability, mostly expressed by QT variability index (QTVi), has repeatedly been used in risk diagnostics. Physiologic correlates of QT variability expressions have been little researched especially when measured in short 10-second electrocardiograms (ECGs). This study investigated different QT variability indices, including QTVi and the standard deviation of QT interval durations (SDQT) in 657,287 10-second ECGs recorded in 523 healthy subjects (259 females). The indices were related to the underlying heart rate and to the 10-second standard deviation of RR intervals (SDRR). The analyses showed that both QTVi and SDQT (as well as other QT variability indices) were highly statistically significantly (p < 0.00001) influenced by heart rate and that QTVi showed poor intra-subject reproducibility (coefficient of variance approaching 200%). Furthermore, sequential analysis of regression variance showed that SDQT was more strongly related to the underlying heart rate than to SDRR, and that QTVi was influenced by the underlying heart rate and SDRR more strongly than by SDQT (p < 0.00001 for these comparisons of regression dependency). The study concludes that instead of QTVi, simpler expressions of QT interval variability, such as SDQT, appear preferable for future applications especially if multivariable combination with the underlying heart rate is used.

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

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

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

National Heart and Lung Institute Imperial College 72 Du Cane Road Shepherd's Bush London W12 0NN UK

Wilhelminenspital der Stadt Wien Montleartstraße 37 1160 Vienna Austria

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US Preventive Services Task Force. Curry S.J., Krist A.H., Owens D.K., Barry M.J., Caughey A.B., Davidson K.W., Doubeni C.A., Epling J.W., Jr., Kemper A.R., et al. Screening for cardiovascular disease risk with electrocardiography: US Preventive Services Task Force recommendation statement. JAMA. 2018;319:2308–2314. PubMed

Somsen G.A. The role of ECG screening in primary care; a call for collaboration between general practitioner and cardiologist. Neth. Heart J. 2020;28:190–191. doi: 10.1007/s12471-020-01410-4. PubMed DOI PMC

Campbell M.J., Zhou X., Han C., Abrishami H., Webster G., Miyake C.Y., Sower C.T., Anderson J.B., Knilans T.K., Czosek R.J. Pilot study analyzing automated ECG screening of hypertrophic cardiomyopathy. Heart Rhythm. 2017;14:848–852. doi: 10.1016/j.hrthm.2017.02.011. PubMed DOI

Lyons M.M., Kraemer J.F., Dhingra R., Keenan B.T., Wessel N., Glos M., Penzel T., Gurubhagavatula I. Screening for obstructive sleep apnea in commercial drivers using EKG-derived respiratory power index. J. Clin. Sleep Med. 2019;15:23–32. doi: 10.5664/jcsm.7562. PubMed DOI PMC

Yao X., McCoy R.G., Friedman P.A., Shah N.D., Barry B.A., Behnken E.M., Inselman J.W., Attia Z.I., Noseworthy P.A. ECG AI-guided screening for low ejection fraction (EAGLE): Rationale and design of a pragmatic cluster randomized trial. Am. Heart J. 2020;219:31–36. doi: 10.1016/j.ahj.2019.10.007. PubMed DOI

Proietti M., Farcomeni A., Goethals P., Scavee C., Vijgen J., Blankoff I., Vandekerckhove Y., Lip G.Y., Mairesse G.H. Belgian Heart Rhythm Week Investigators. Cost-effectiveness and screening performance of ECG handheld machine in a population screening programme: The Belgian Heart Rhythm Week screening programme. Eur. J. Prev. Cardiol. 2019;26:964–972. doi: 10.1177/2047487319839184. PubMed DOI

Baumert M., Porta A., Vos M.A., Malik M., Couderc J.P., Laguna P., Piccirillo G., Smith G.L., Tereshchenko L.G., Volders P.G. QT interval 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. 2016;18:925–944. PubMed PMC

Fischer C., Seeck A., Schroeder R., Goernig M., Schirdewan A., Figulla H.R., Baumert M., Voss A. QT variability improves risk stratification in patients with dilated cardiomyopathy. Physiol. Meas. 2015;36:699–713. doi: 10.1088/0967-3334/36/4/699. PubMed DOI

Orosz A., Baczkó I., Nagy V., Gavallér H., Csanády M., Forster T., Papp J.G., Varró A., Lengyel C., Sepp R. Short-term beat-to-beat variability of the QT interval is increased and correlates with parameters of left ventricular hypertrophy in patients with hypertrophic cardiomyopathy. Can. J. Physiol. Pharmacol. 2015;93:765–772. doi: 10.1139/cjpp-2014-0526. PubMed DOI

Porta A., Girardengo G., Bari V., George A.L., Jr., Brink P.A., Goosen A., Crotti L., Schwartz P.J. Autonomic control of heart rate and QT interval variability influences arrhythmic risk in long QT syndrome type 1. J. Am. Coll. Cardiol. 2015;65:367–374. doi: 10.1016/j.jacc.2014.11.015. PubMed DOI PMC

Seethala S., Singh P., Shusterman V., Ribe M., Haugaa K.H., Němec J. QT adaptation and intrinsic QT variability in congenital long QT syndrome. J. Am. Heart Assoc. 2015;4:e002395. doi: 10.1161/JAHA.115.002395. PubMed DOI PMC

Monasterio V., Martínez J.P., Laguna P., McNitt S., Polonsky S., Moss A.J., Haigney M., Zareba W., Couderc J.P. Prognostic value of average T-wave alternans and QT variability for cardiac events in MADIT-II patients. J. Electrocardiol. 2013;46:480–486. doi: 10.1016/j.jelectrocard.2013.08.004. PubMed DOI

Smoczyńska A., Loen V., Sprenkeler D.J., Tuinenburg A.E., Ritsema van Eck H.J., Malik M., Schmidt G., Meine M., Vos M.A. Short-term variability of the QT interval can be used for the prediction of imminent ventricular arrhythmias in patients with primary prophylactic implantable cardioverter defibrillators. J. Am. Heart Assoc. 2020;9:e018133. doi: 10.1161/JAHA.120.018133. PubMed DOI PMC

Orosz A., Csajbók É., Czékus C., Gavallér H., Magony S., Valkusz Z., Várkonyi T.T., Nemes A., Baczkó I., Forster T., et al. Increased short-term beat-to-beat variability of QT interval in patients with acromegaly. PLoS ONE. 2015;10:e0125639. doi: 10.1371/journal.pone.0125639. PubMed DOI PMC

Viigimae M., Karai D., Pilt K., Pirn P., Huhtala H., Polo O., Meigas K., Kaik J. QT interval variability index and QT interval duration during different sleep stages in patients with obstructive sleep apnea. Sleep Med. 2017;37:160–167. doi: 10.1016/j.sleep.2017.06.026. PubMed DOI

Nussinovitch U., Rubin S., Levy Y., Lidar M., Livneh A. QT variability index in patients with systemic sclerosis. Eur. J. Rheumatol. 2018;6:179–183. PubMed PMC

Niemeijer M.N., van den Berg M.E., Eijgelsheim M., van Herpen G., Stricker B.H., Kors J.A., Rijnbeek P.R. Short-term QT variability markers for the prediction of ventricular arrhythmias and sudden cardiac death: A systematic review. Heart. 2014;100:1831–1836. doi: 10.1136/heartjnl-2014-305671. PubMed DOI

Feeny A., Han L., Tereshchenko L.G. Repolarization lability measured on 10-second ECG by spatial TT’ angle: Reproducibility and agreement with QT variability. J. Electrocardiol. 2014;47:708–715. doi: 10.1016/j.jelectrocard.2014.06.003. PubMed DOI PMC

van den Berg M.E., Kors J.A., van Herpen G., Bots M.L., Hillege H., Swenne C.A., Stricker B.H., Rijnbeek P.R. Normal values of QT variability in 10-s electrocardiograms for all ages. Front. Physiol. 2019;10:1272. doi: 10.3389/fphys.2019.01272. PubMed DOI PMC

Bazett J.C. An analysis of time relations of electrocardiograms. Heart. 1920;7:353–367. doi: 10.1111/j.1542-474X.1997.tb00325.x. DOI

Fridericia L.S. 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

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

Malik M., Andreas J.-O., Hnatkova K., Hoeckendorff J., Cawello W., Middle M., Horstmann R., Braun M. Thorough QT/QTc Study in patients with advanced Parkinson’s disease: Cardiac safety of rotigotine. Clin. Pharmacol. Ther. 2008;84:595–603. doi: 10.1038/clpt.2008.143. PubMed DOI

Malik M., van Gelderen E.M., Lee J.H., Kowalski D.L., Yen M., Goldwater R., Mujais S.K., Schaddelee M.P., de Koning P., Kaibara A., 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. Ther. 2012;92:696–706. doi: 10.1038/clpt.2012.181. PubMed DOI

Hnatkova K., Smetana P., Toman O., Bauer A., Schmidt G., Malik M. 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;37:25–33. doi: 10.1016/j.jelectrocard.2004.08.005. PubMed DOI

Xue J.Q. 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

Berger R.D., Kasper E.K., Baughman K.L., Marban E., Calkins H., Tomaselli G.F. Beat-to-beat QT interval variability: Novel evidence for repolarization lability in ischemic and nonischemic dilated cardiomyopathy. Circulation. 1997;96:1557–1565. doi: 10.1161/01.CIR.96.5.1557. PubMed DOI

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

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

Guldenring D., Finlay D.D., Strauss D.G., Galeotti L., Nugent C.D., Donnelly M.P., Bond R.R. Transformation of the Mason-Likar 12-lead electrocardiogram to the Frank vectorcardiogram. Annu. Int. Conf. IEEE Eng. Med. Biol. Soc. 2012;2012:677–680. PubMed

Hiromoto K., Shimizu H., Mine T., Masuyama T., Ohyanagi M. Correlation between beat-to-beat QT interval variability and impaired left ventricular function in patients with previous myocardial infarction. Ann Noninvasive Ann. Noninvasive Electrocardiol. 2006;11:299–305. doi: 10.1111/j.1542-474X.2006.00121.x. PubMed DOI PMC

Oosterhoff P., Tereshchenko L.G., van der Heyden M.A., Ghanem R.N., Fetics B.J., Berger R.D., Vos M.A. Short-term variability of repolarization predicts ventricular tachycardia and sudden cardiac death in patients with structural heart disease: A comparison with QT variability index. Heart Rhythm. 2011;8:1584–1590. doi: 10.1016/j.hrthm.2011.04.033. PubMed DOI

Haigney M.C., Zareba W., Gentlesk P.J., Goldstein R.E., Illovsky M., McNitt S., Andrews M.L., Moss A., Jr. Multicenter Automatic Defibrillator Implantation Trial II investigators. QT interval variability and spontaneous ventricular tachycardia or fibrillation in the Multicenter Automatic Defibrillator Implantation Trial (MADIT) II patients. J. Am. Coll. Cardiol. 2004;44:1481–1487. doi: 10.1016/j.jacc.2004.06.063. PubMed DOI

Dobson C.P., Kim A., Haigney M. QT Variability Index. Prog. Cardiovasc. Dis. 2013;56:186–194. doi: 10.1016/j.pcad.2013.07.004. PubMed DOI

Heravi A.S., Etzkorn L.H., Urbanek J.K., Crainiceanu C.M., Punjabi N.M., Ashikaga H., Brown T.T., Budoff M.J., D’Souza G., Magnani J.W., et al. HIV infection is associated with variability in ventricular repolarization: The Multicenter AIDS Cohort Study (MACS) Circulation. 2020;141:176–187. doi: 10.1161/CIRCULATIONAHA.119.043042. PubMed DOI PMC

Copie X., Hnatkova K., Staunton A., Fei L., Camm A.J., Malik M. 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

Malik M., Hnatkova K., Huikuri H.V., Lombardi F., Schmidt G., Zabel M. CrossTalk proposal: Heart rate variability is a valid measure of cardiac autonomic responsiveness. J. Physiol. 2019;597:2595–2598. doi: 10.1113/JP277500. PubMed DOI PMC

Goldenberg I., Goldkorn R., Shlomo N., Einhorn M., Levitan J., Kuperstein R., Klempfner R., Johnson B. Heart rate variability for risk assessment of myocardial ischemia in patients without known coronary artery disease: The HRV-DETECT (Heart Rate Variability for the Detection of Myocardial Ischemia) study. J. Am. Heart Assoc. 2019;8:e014540. doi: 10.1161/JAHA.119.014540. PubMed DOI PMC

Dobson C.P., La Rovere M.T., Pinna G.D., Goldstein R., Olsen C., Bernardinangeli M., Veniani M., Midi P., Tavazzi L., Haigney M. GISSI-HF Investigators. QT variability index on 24-hour Holter independently predicts mortality in patients with heart failure: Analysis of Gruppo Italiano per lo Studio della Sopravvivenza nell’Insufficienza Cardiaca (GISSI-HF) trial. Heart Rhythm. 2011;8:1237–1242. doi: 10.1016/j.hrthm.2011.03.055. PubMed DOI

ESC/NASPE Task Force Heart rate variability—Standards of measurement, physiological interpretation, and clinical use. Circulation. 1996;93:1043–1065. doi: 10.1161/01.CIR.93.5.1043. PubMed DOI

Schmidt G., Malik M., Barthel P., Schneider R., Ulm K., Rolnitzky L., Camm A.J., Bigger J.T., Jr., Schömig A. Heart rate turbulence after ventricular premature beats as a predictor of mortality after acute myocardial infarction. Lancet. 1999;353:1390–1396. doi: 10.1016/S0140-6736(98)08428-1. PubMed DOI

Bauer A., Malik M., Schmidt G., Barthel P., Bonnemeier H., Cygankiewicz I., Guzik P., Lombardi F., Müller A., Oto A., et al. Heart rate turbulence: Standards of measurement, physiological interpretation, and clinical use. International Society for Holter and Noninvasive Electrophysiology Consensus. J. Am. Coll. Cardiol. 2008;52:1353–1365. doi: 10.1016/j.jacc.2008.07.041. PubMed DOI

Bauer A., Kantelhardt J.W., Barthel P., Schneider R., Mäkikallio T., Ulm K., Hnatkova K., Schömig A., Huikuri H., Bunde A., et al. Deceleration capacity of heart rate as a predictor of mortality after myocardial infarction: Cohort study. Lancet. 2006;367:1674–1681. doi: 10.1016/S0140-6736(06)68735-7. PubMed DOI

Verrier R.L., Klingenheben T., Malik M., El-Sherif N., Exner D.V., Hohnloser S.H., Ikeda T., Martinez J.P., Narayan S.M., Nieminen T., et al. Microvolt T-wave alternans: Physiological basis, methods of measurement, and clinical utility consensus guideline by International Society for Holter and Noninvasive Electrocardiology. J. Am. Coll. Cardiol. 2011;58:1309–1324. doi: 10.1016/j.jacc.2011.06.029. PubMed DOI PMC

Hnatkova K., Šišáková M., Smetana P., Toman O., Huster K.M., Novotný T., Schmidt G., Malik M. Sex differences in heart rate responses to postural provocations. Int. J. Cardiol. 2019;297:126–134. doi: 10.1016/j.ijcard.2019.09.044. PubMed DOI PMC

Linde C., Bongiorni M.G., Birgersdotter-Green U., Curtis A.B., Deisenhofer I., Furokawa T., Gillis A.M., Haugaa K.H., Lip G.Y.H., Van Gelder I., et al. ESC Scientific Document Group. 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;20:1565–1565ao. doi: 10.1093/europace/euy067. PubMed DOI

Garnett C.E., Zhu H., Malik M., Fossa A.A., Zhang J., Badilini F., Li J., Darpö B., Sager P., Rodriguez I. 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., Hnatkova K., Batchvarov V., Gang Y., Smetana P., Camm A.J. 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

Short-Term Beat-to-Beat QT Variability Appears Influenced More Strongly by Recording Quality Than by Beat-to-Beat RR Variability

Influence of heart rate correction formulas on QTc interval stability