Increases in beat-to-beat variability of electrocardiographic QT interval duration have repeatedly been associated with increased risk of cardiovascular events and complications. The measurements of QT variability are frequently normalized for the underlying RR interval variability. Such normalization supports the concept of the so-called immediate RR effect which relates each QT interval to the preceding RR interval. The validity of this concept was investigated in the present study together with the analysis of the influence of electrocardiographic morphological stability on QT variability measurements. The analyses involved QT and RR measurements in 6,114,562 individual beats of 642,708 separate 10-s ECG samples recorded in 523 healthy volunteers (259 females). Only beats with high morphology correlation (r > 0.99) with representative waveforms of the 10-s ECG samples were analyzed, assuring that only good quality recordings were included. In addition to these high correlations, SDs of the ECG signal difference between representative waveforms and individual beats expressed morphological instability and ECG noise. In the intra-subject analyses of both individual beats and of 10-s averages, QT interval variability was substantially more strongly related to the ECG noise than to the underlying RR variability. In approximately one-third of the analyzed ECG beats, the prolongation or shortening of the preceding RR interval was followed by the opposite change of the QT interval. In linear regression analyses, underlying RR variability within each 10-s ECG sample explained only 5.7 and 11.1% of QT interval variability in females and males, respectively. On the contrary, the underlying ECG noise contents of the 10-s samples explained 56.5 and 60.1% of the QT interval variability in females and males, respectively. The study concludes that the concept of stable and uniform immediate RR interval effect on the duration of subsequent QT interval duration is highly questionable. Even if only stable beat-to-beat measurements of QT interval are used, the QT interval variability is still substantially influenced by morphological variability and noise pollution of the source ECG recordings. Even when good quality recordings are used, noise contents of the electrocardiograms should be objectively examined in future studies of QT interval variability.

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

Department of Internal Medicine and Cardiology University Hospital Brno 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

Zobrazit více v PubMed

Abreu R., Nunes S., Leal A., Figueiredo P. (2017). Physiological noise correction using ECG-derived respiratory signals for enhanced mapping of spontaneous neuronal activity with simultaneous EEG-fMRI. Neuroimage 154, 115–127. 10.1016/j.neuroimage.2016.08.008 PubMed DOI

Andršová I., Hnatkova K., Šišáková M., Toman O., Smetana P., Huster K. M., et al. . (2020). Heart rate influence on the QT variability risk factors. Diagnostics 10, 1096. 10.3390/diagnostics10121096 PubMed DOI PMC

Batchvarov V., Hnatkova K., Malik M. (2002). Assessment of noise in digital electrocardiograms. Pacing Clin. Electrophysiol. 25, 499–503. 10.1046/j.1460-9592.2002.00499.x 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

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

Browne K. F., Prystowsky E., Heger J. J., Chilson D. A., Zipes D. P. (1983). Prolongation of the Q-T interval in man during sleep. Am. J. Cardiol. 52, 55–59. 10.1016/0002-9149(83)90068-1 PubMed DOI

Chang K. M. (2010). Arrhythmia ECG noise reduction by ensemble empirical mode decomposition. Sensors 10, 6063–6080. 10.3390/s100606063 PubMed DOI PMC

Dobson C. P., Kim A., Haigney M. (2013). QT variability index. Prog. Cardiovasc. Dis. 56, 186–194. 10.1016/j.pcad.2013.07.004 PubMed 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

ERT (2020). Statistical Analysis Plan. Single-Dose and Randomized, Single-Center, Placebo- and Active Controlled, Crossover Study to Assess the Effect of Omecamtiv Mecarbil (OM) on QT/QTc Intervals in Healthy Subjects. Available online at: https://clinicaltrials.gov/ProvidedDocs/08/NCT04175808/SAP_002.pdf

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

Everss-Villalba E., Melgarejo-Meseguer F. M., Blanco-Velasco M., Gimeno-Blanes F. J., Sala-Pla S., Rojo-Álvarez J. L., et al. . (2017). Noise maps for quantitative and clinical severity towards long-term ECG monitoring. Sensors 17, 2448. 10.3390/s17112448 PubMed DOI PMC

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

Fossa A. A., DePasquale M. J., Raunig D. L., Avery M. J., Leishman D. J. (2002). The relationship of clinical QT prolongation to outcome in the conscious dog using a beat-to-beat QT-RR interval assessment. J. Pharmacol. Exp. Ther. 302, 828–833. 10.1124/jpet.102.035220 PubMed DOI

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

Funck-Brentano C., Jaillon P. (1993). Rate-corrected QT interval: techniques and limitations. Am. J. Cardiol. 72, 17B−22B. 10.1016/0002-9149(93)90035-B PubMed DOI

Garnett C. E., Zhu H., Malik M., Fossa A. A., Zhang J., Badilini F., et al. . (2012). Methodologies to characterize the QT/corrected QT interval in the presence of drug-induced heart rate changes or other autonomic effects. Am. Heart J. 163, 912–930. 10.1016/j.ahj.2012.02.023 PubMed 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

Guldenring D., Finlay D. D., Strauss D. G., Galeotti L., Nugent C. D., Donnelly M. P., et al. . (2012). Transformation of the Mason-Likar 12-lead electrocardiogram to the frank vectorcardiogram. Annu. Int. Conf. IEEE Eng. Med. Biol. Soc. 2012, 677–680. 10.1109/EMBC.2012.6346022 PubMed DOI

Hasan M. A., Abbott D. (2016). A review of beat-to-beat vectorcardiographic (VCG) parameters for analyzing repolarization variability in ECG signals. Biomed. Tech. 61, 3–17. 10.1515/bmt-2015-0005 PubMed DOI

Hasan M. A., Abbott D., Baumert M. (2012). Beat-to-beat spatial and temporal analysis for QRS-T morphology. Annu. Int. Conf. IEEE Eng. Med. Biol. Soc. 2012, 4193–4195. 10.1109/EMBC.2012.6346891 PubMed DOI

Hasan M. A., Abbott D., Baumert M. (2013). Beat-to-beat QT interval variability and T-wave amplitude in patients with myocardial infarction. Physiol. Meas. 34, 1075–1083. 10.1088/0967-3334/34/9/1075 PubMed DOI

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

Hnatkova K., Kowalski D., Keirns J. J., van Gelderen E. M., Malik M. (2013). Relationship of QT interval variability to heart rate and RR interval variability. J. Electrocardiol. 46, 591–596. 10.1016/j.jelectrocard.2013.07.007 PubMed DOI

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., Strauss D. G., Stockbridge N., et al. . (2019). Heart rate correction of the J-to-Tpeak interval. Sci. Rep. 9, 15060. 10.1038/s41598-019-51491-4 PubMed DOI PMC

Hwang B., You J., Vaessen T., Myin-Germeys I., Park C., Zhang B. T. (2018). Deep ECGNet: an optimal deep learning framework for monitoring mental stress using ultra short-term ECG signals. Telemed. J. E Health 24, 753–772. 10.1089/tmj.2017.0250 PubMed DOI

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

Jacquemet V., Cassani González R., Sturmer M., Dub,é B., Sharestan J., Vinet A., et al. . (2014). QT 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

Kautzner J., Yi G., Camm A. J., Malik M. (1994). Short- and long-term reproducibility of QT, QTc, and QT dispersion measurement in healthy subjects. Pacing Clin. Electrophysiol. 17, 928–937. 10.1111/j.1540-8159.1994.tb01435.x PubMed DOI

Kors J. A., van Herpen G. (1998). Measurement error as a source of QT dispersion: a computerised analysis. Heart 80, 453–458. 10.1136/hrt.80.5.453 PubMed DOI PMC

Lanfranchi P. A., Shamsuzzaman A. S., Ackerman M. J., Kara T., Jurak P., Wolk R., et al. . (2002). Sex-selective QT prolongation during rapid eye movement sleep. Circulation 106, 1488–1492. 10.1161/01.CIR.0000030183.10934.95 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

Lee J., McManus D. D., Merchant S., Chon K. H. (2012). Automatic motion and noise artifact detection in holter ECG data using empirical mode decomposition and statistical approaches. IEEE Trans. Biomed. Eng. 59, 1499–1506. 10.1109/TBME.2011.2175729 PubMed DOI

Li Q., Rajagopalan C., Clifford G. D. (2014). A machine learning approach to multi-level ECG signal quality classification. Comput. Methods Prog. Biomed. 117, 435–447. 10.1016/j.cmpb.2014.09.002 PubMed DOI

Malik M. (2004). Errors and misconceptions in ECG measurement used for the detection of drug induced QT interval prolongation. J. Electrocardiol. 37, 25–33. 10.1016/j.jelectrocard.2004.08.005 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., Andreas J.- O., Hnatkova K., Hoeckendorff J., Cawello W., Middle M., et al. . (2008a). 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., Batchvarov V. N. (2000). Measurement, interpretation, and clinical potential of QT dispersion. J. Am. Coll. Cardiol. 36, 1749–1766. 10.1016/S0735-1097(00)00962-1 PubMed DOI

Malik M., Camm A. J. (1990). Heart rate variability. Clin. Cardiol. 13, 570–576. 10.1002/clc.4960130811 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. (2012b). Importance of subject-specific QT/RR curvatures in the design of individual heart rate corrections of the QT interval. J. Electrocardiol. 45, 571–581. 10.1016/j.jelectrocard.2012.07.017 PubMed DOI

Malik M., Hnatkova K., Novotny T., Schmidt G. (2008b). 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., 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. . (2012a). Proarrhythmic safety of repeat doses of mirabegron in healthy subjects: a randomized, double-blind, placebo-, and active-controlled thorough QT study. Clin. Pharm. Ther. 92, 696–706. 10.1038/clpt.2012.181 PubMed DOI

Markendorf S., Lüscher T. F., Gerds-Li J. H., Schönrath F., Schmied C. M. (2018). Clinical impact of repolarization changes in supine versus upright body position. Cardiol. J. 25, 589–594. 10.5603/CJ.a2017.0138 PubMed DOI

Monasterio V., Martínez J. P., Laguna P., McNitt S., Polonsky S., Moss A. J., et al. . (2013). Prognostic value of average T-wave alternans and QT variability for cardiac events in MADIT-II patients. J. Electrocardiol. 46, 480–486. 10.1016/j.jelectrocard.2013.08.004 PubMed DOI

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

Noriega M., Martínez J. P., Laguna P., Bailón R., Almeida R. (2012). Respiration effect on wavelet-based ECG T-wave end delineation strategies. IEEE Trans. Biomed. Eng. 59, 1818–1828. 10.1109/TBME.2011.2157824 PubMed DOI

Nussinovitch U., Rubin S., Levy Y., Lidar M., Livneh A. (2018). QT variability index in patients with systemic sclerosis. Eur. J. Rheumatol. 6, 179–183. 10.5152/eurjrheum.2019.19074 PubMed DOI PMC

Orosz A., Baczkó I., Nagy V., Gavallér H., Csanády M., Forster T., et al. . (2015a). 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. 93, 765–772. 10.1139/cjpp-2014-0526 PubMed DOI

Orosz A., Csajbók É., Czékus C., Gavallér H., Magony S., Valkusz Z., et al. . (2015b). Increased short-term beat-to-beat variability of QT interval in patients with acromegaly. PLoS ONE 10, e0125639. 10.1371/journal.pone.0125639 PubMed DOI PMC

Panicker G. K., Kadam P., Chakraborty S., Kothari S., Turner J. R., Karnad D. R. (2018). Individual-specific QT interval correction for drugs with substantial heart rate effect using Holter ECGs extracted over a wide range of heart rates. J. Clin. Pharmacol. 58, 1013–1019. 10.1002/jcph.1258 PubMed DOI

Porta A., Baselli G., Caiani E., Malliani A., Lombardi F., Cerutti S. (1998a). Quantifying electrocardiogram RT-RR variability interactions. Med. Biol. Eng. Comput. 36, 27–34. 10.1007/BF02522854 PubMed DOI

Porta A., Baselli G., Lombardi F., Cerutti S., Antolini R., Del Greco M., et al. . (1998b). Performance assessment of standard algorithms for dynamic R-T interval measurement: comparison between R-Tapex and R-T(end) approach. Med. Biol. Eng. Comput. 36, 35–42. 10.1007/BF02522855 PubMed DOI

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. 10.22489/CinC.2020.009 DOI

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

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

Rahola J. T., Kiviniemi A. M., Ukkola O. H., Tulppo M. P., Junttila M. J., Huikuri H. V., et al. . (2021). Temporal variability of T-wave morphology and risk of sudden cardiac death in patients with coronary artery disease. Ann. Noninvasive Electrocardiol. 26, e12830. 10.1111/anec.12830 PubMed DOI PMC

Rautaharju P. M. (1999). QT and dispersion of ventricular repolarization: the greatest fallacy in electrocardiography in the 1990s. Circulation 99, 2477–2478. 10.1161/circ.99.18.2476/c PubMed DOI

Sadiq I., Perez-Alday E. A., Shah A. J., Clifford G. D. (2021). Breathing rate and heart rate as confounding factors in measuring T wave alternans and morphological variability in ECG. Physiol. Meas. 42, 015002. 10.1088/1361-6579/abd237 PubMed DOI PMC

Sagie A., Larson M. G., Goldberg R. J., Bengtson J. R., Levy D. (1992). An improved method for adjusting the QT interval for heart rate (the framingham heart study). Am. J. Cardiol. 70, 797–801. 10.1016/0002-9149(92)90562-D PubMed DOI

Schmidt M., Baumert M., Malberg H., Zaunseder S. T. (2016). Wave amplitude correction of QT interval variability for improved repolarization lability measurement. Front. Physiol. 7, 216. 10.3389/fphys.2016.00216 PubMed DOI PMC

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

Smoczyńska A., Loen V., Sprenkeler D. J., Tuinenburg A. E., Ritsema van Eck H. J., Malik M., et al. . (2020). 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, e018133. 10.1161/JAHA.120.018133 PubMed DOI PMC

Täubel J., Ferber G., Van Langenhoven L., Del Bianco T., Fernandes S., Djumanov D., et al. . (2019). The cardiovascular effects of a meal: J-Tpeak and tpeak-tend assessment and further insights into the physiological effects. J. Clin. Pharmacol. 59, 799–810. 10.1002/jcph.1374 PubMed DOI PMC

Tayel M. B., Eltrass A. S., Ammar A. I. (2018). A new multi-stage combined kernel filtering approach for ECG noise removal. J. Electrocardiol. 51, 265–275. 10.1016/j.jelectrocard.2017.10.009 PubMed DOI

Tereshchenko L. G., Cygankiewicz I., McNitt S., Vazquez R., Bayes-Genis A., Han L., et al. . (2012). Predictive value of beat-to-beat QT variability index across the continuum of left ventricular dysfunction: competing risks of noncardiac or cardiovascular death and sudden or nonsudden cardiac death. Circ. Arrhythm. Electrophysiol. 5, 719–727. 10.1161/CIRCEP.112.970541 PubMed DOI PMC

van den Berg M. E., Kors J. A., van Herpen G., Bots M. L., Hillege H., Swenne C. A., et al. . (2019). Normal values of QT variability in 10-s electrocardiograms for all ages. Front. Physiol. 10, 1272. 10.3389/fphys.2019.01272 PubMed DOI PMC

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

Viigimae M., Karai D., Pirn P., Pilt K., Meigas K., Kaik J. (2015). QT interval variability index and QT Interval duration in different sleep stages: analysis of polysomnographic recordings in nonapneic male patients. Biomed. Res. Int. 2015, 963028. 10.1155/2015/963028 PubMed DOI PMC

Xue J. Q. (2009). Robust QT interval estimation - from algorithm to validation. Ann. Noninvasive Electrocardiol. 14 (Suppl. 1), S35–S41. 10.1111/j.1542-474X.2008.00264.x PubMed DOI PMC

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