vestimИзвестия Национальной академии наук Беларуси. Серия медицинских наукProceedings of the National Academy of Sciences of Belarus, Medical series1814-60232524-2350The Republican Unitary Enterprise Publishing House "Belaruskaya Navuka"10.29235/1814-6023-2022-19-4-351-363vestim-874Research ArticleКЛИНИЧЕСКАЯ И ЭКСПЕРИМЕНТАЛЬНАЯ МЕДИЦИНАCLINICAL AND EXPERIMENTAL MEDICINEГендерные особенности электрокардиограммы у пациентов с лекарственно-индуцированным синдромом удлиненного интервала QT на фоне антиаритмической терапииGender electrocardiographic features in patients with drug-induced long QT syndrome caused by antiarrhythmic therapyhttps://orcid.org/0000-0001-5211-709XКолоцейЛ. В.KalatseiL. V.

Колоцей Людмила Владимировна – аспирант, ассистент.

ул. Горького, 80, 230009, Гродно

Liudmila V. Kalatsei – Postgraduate student, Assistant, Grodno State Medical University.

80, Gorky Str., 230009, Grodno

lkolotsey@mail.ruhttps://orcid.org/0000-0002-1706-1243СнежицкийВ. А.SnezhitskiyV. A.

Снежицкий Виктор Александрович – член-корреспондент, доктор медицинских наук, профессор.

ул. Горького, 80, 230009, Гродно

Viktor A. Snezhitskiy – Corresponding Member, D. Sc. (Med.), Professor, Grodno State Medical University.

80, Gorky Str., 230009, Grodno

vsnezh@mail.ruГродненский государственный медицинский университетGrodno State Medical University202228112022194351363Copyright © Колоцей Л.В., Снежицкий В.А., 20222022Колоцей Л.В., Снежицкий В.А.Kalatsei L.V., Snezhitskiy V.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://vestimed.belnauka.by/jour/article/view/874

Женский пол традиционно относится к числу факторов риска удлинения интервала QT и развития полиморфной желудочковой тахикардии (ЖТ) типа «пируэт». Однако, несмотря на большое количество исследований, посвященных электрокардиографическим особенностям у пациентов с врожденным синдромом удлиненного интервала QT, имеется сравнительно немного информации о гендерных различиях показателей элекрокардиограмм (ЭКГ) на фоне лекарственно-индуцированного удлинения интервала QT.

Цель настоящего исследования ‒ оценка гендерных особенностей электрокардиографических показателей, характеризующих деполяризацию и реполяризацию миокарда, у пациентов с лекарственно-индуцированным удлинением интервала QT на фоне приема антиаритмических препаратов III класса.

Для достижения поставленной цели было обследовано 67 пациентов с лекарственно-индуцированным удлинением интервала QT на фоне  приема  антиаритмических препаратов  III класса  (амиодарон  либо  соталол),  из  них 38 (56,8 %) женщин и 29 (43,2 %) мужчин, средний возраст – 57,1 ± 9,5 года. Всем пациентам проводились клинико-лабораторные и неинвазивные электрофизиологические исследования, включавшие в себя запись ЭКГ в 12 отведениях и 24-часовое холтеровское мониторирование ЭКГ (ХМ-ЭКГ).

Пациенты исследуемых групп были сопоставимы по возрасту и клинико-нозологической характеристике, однако более  высокая  распространенность  фибрилляции  предсердий  отмечалась  у  мужчин  (82,7  %  против  52,6  %, p = 0,03). Общая продолжительность приема антиаритмических препаратов III класса у пациентов мужского пола составила 3,79 ± 1,49 сут, что значимо отличалось от аналогичного показателя у пациенток женского пола (3,11 ± 1,15 сут, p = 0,044). При анализе исходных показателей стандартных ЭКГ пациентов, записанных до начала приема антиаритмических препаратов, между группами не выявлено статистически достоверных различий, за исключением больших значений корригированного индекса кардиоэлектрофизиологического баланса (QTc/QRS)  у пациенток женского пола ( p = 0,037). На фоне приема антиаритмических препаратов III класса у женщин отмечались более высокая продолжительность интервалов QTс  ( p = 0,03) и JTс ( p = 0,023), а также дисперсия интервалов QT ( p = 0,012)  и JT ( p = 0,006). По данным ХМ-ЭКГ, у пациенток женского пола наблюдалась тенденция к повышенному риску развития неустойчивой полиморфной ЖТ ( p = 0,105).

Полученные результаты свидетельствуют о сложном взаимодействии между полом и реполяризацией, которое требует дальнейшего исследования. Учитывая роль гендерных особенностей в процессе реполяризации миокарда, следует соблюдать осторожность не только при назначении антиаритмических препаратов III класса женщинам, но   и принимать во внимание вопросы гендерной специфичности на этапе доклинической и клинической разработки лекарственных препаратов, обладающих эффектом удлинения интервала QT.

Female gender is traditionally considered to be a risk factor for the QT interval prolongation and polymorphic ventricular tachycardia «torsades de pointes». However, despite a large number of studies on electrocardiographic features in patients with congenital long QT interval syndrome, there is relatively little information on gender ECG differences in the drug-induced QT interval prolongation.

The aim of this study is to evaluate the gender characteristics of electrocardiographic parameters characterizing myocardial depolarization and repolarization in patients with drug-induced QT interval prolongation induced by class III antiarrhythmic drugs.

67 patients with drug-induced QT interval prolongation induced class III antiarrhythmic drugs (amiodarone or sotalol) were examined, of which 38 (56.8 %) women and 29 (43.2 %) men, mean age – 57.1 ± 9.5 years. All patients underwent clinical laboratory and non-invasive electrophysiological studies, which included 12-lead ECG recording and 24-hour Holter monitoring. The patients of both genders were comparable in age and clinical characteristics, with the exception of a higher prevalence of AF in men (82.7 % vs 52.6 %, p = 0.03). The total duration of taking class III antiarrhythmic drugs in male patients was 3.79 ± 1.49 days, which significantly differed from female patients (3.11 ± 1.15 days, p = 0.044). When analyzing the initial standard ECG of patients recorded before starting antiarrhythmic drugs, there were no statistically significant differences between the groups, with the exception of large values of the corrected cardioelectrophysiological balance index (QTc/QRS) in female patients ( p = 0.037). While taking class III antiarrhythmic drugs, women had a higher duration of QTc ( p = 0.03) and JTc ( p = 0.023) intervals, as well as a dispersion of QT ( p = 0.012) and JT ( p = 0.006) intervals. According to Holter monitoring data, female patients were more likely to have an increased risk of developing non-sustained polymorphic VT ( p = 0.105).

These results suggest a complex interplay between gender and repolarization that needs further investigation. Considering the gender characteristics of the process of myocardial repolarization, it should be taken into account not only when prescribing class III antiarrhythmic drugs to women, but also during preclinical and clinical development of drugs that have the QT interval prolonging effect.

интервал QTлекарственно-индуцированный синдром удлиненного интервала QTантиаритмические препаратынеустойчивая полиморфная желудочковая тахикардияэлектрокардиографияреполяризациядисперсия интервала QTкорригированный индекс кардиоэлектрофизиологического балансаQT intervaldrug-induced long QT syndromeantiarrhythmic drugsnon-sustained polymorphic ventricular tachycardiaelectrocardiographyrepolarizationQT interval dispersioncorrected index of cardioelectrophysiological balanceReferencesBazett, H. C. An analysis of the time-relations of electrocardiograms / H. C. Bazett // Ann. Noninvasive Electrocardiol. ‒ 1997. – Vol. 2, N 2. – P. 177–194. https://doi.org/10.1111/j.1542-474X.1997.tb00325.xBazett H. C. An analysis of the time-relations of electrocardiograms. Annals of Noninvasive Electrocardiology, 1997, vol. 2, no. 2, pp. 177–194. https://doi.org/10.1111/j.1542-474X.1997.tb00325.xMoss, A. J. Gender differences in ECG parameters and their clinical implications / A. J. Moss // Ann. Noninvasive Electrocardiol. ‒ 2010. – Vol. 15, N 1. – P. 1–2. https://doi.org/10.1111/j.1542-474X.2009.00345.xMoss A. J. Gender differences in ECG parameters and their clinical implications. Annals of Noninvasive Electrocardiology, 2010, vol. 15 (1), pp. 1‒2. https://doi.org/10.1111/j.1542-474X.2009.00345.xSex 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 / C. Linde [et al.] // Europace. – 2018. – Vol. 20, N 10. – P. 1565–1565ao. https://doi.org/10.1093/europace/euy067.Linde C., Bongiorni M. G., Birgersdotter-Green U., Curtis A. B., Deisenhofer I., Furokawa T. [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, vol. 20, no. 10, pp. 1565‒1565ao. https://doi.org/10.1093/europace/euy067Sex and race differences in QRS duration / K. Hnatkova [et al.] // Europace. ‒ 2016. – Vol. 18, N 12. – P. 1842–1849. https://doi.org/10.1093/europace/euw065Hnatkova K., Smetana P., Toman O., Schmidt G., Malik M. Sex and race differences in QRS duration. Europace, 2016, vol. 18, no. 12, pp. 1842‒1849. https://doi.org/10.1093/europace/euw065Physiologic heart rate dependency 10.1093/europace/euw065 of the PQ interval and its sex differences / O. Toman [et al.] // Sci. Rep. ‒ 2020. – Vol. 10, N 1. – Art. 2551. https://doi.org/10.1038/s41598-020-59480-8Toman O., Hnatkova K., Smetana P., Huster K. M., Šišáková M., Barthel P., Novotný T., Schmidt G., Malik M. Physiologic heart rate dependency of the PQ interval and its sex differences. Scientific Reports, 2020, vol. 10, no. 1, art. 2551. https://doi.org/10.1038/s41598-020-59480-8Macfarlane, P. W. The Influence of Age and Sex on the Electrocardiogram / P. W. Macfarlane // Sex-Specific Analysis of Cardiovascular Function / eds. : P. L. M. Kerkhof, V. M. Miller. ‒ Cham, 2018. – P. 93–106.Macfarlane P. W. The Influence of Age and Sex on the Electrocardiogram. Sex-Specific Analysis of Cardiovascular Function. Cham, 2018, pp. 93‒106.Salama, G. Sex differences in the mechanisms underlying long QT syndrome / G. Salama, G. C. Bett // Am. J. Physiol. Heart Circ. Physiol. ‒ 2014. – Vol. 307, N 5. – P. H640–H648. https://doi.org/10.1152/ajpheart.00864.2013Salama G., Bett G. C. Sex differences in the mechanisms underlying long QT syndrome. American Journal of Physiology-Heart and Circulatory Physiology, 2014, vol. 307, no. 5, pp. H640‒H648. https://doi.org/10.1152/ajpheart.00864.2013Колоцей, Л. В. Методологические подходы к измерению и оценке длительности интервала QT стандартной электрокардиограммы / Л. В. Колоцей, В. А. Снежицкий // Журн. Гродн. гос. мед. ун-та. – 2019. – Т. 17, № 1. – С. 99–105.Kolotsei L. V., Snezhitskii V. A. Methodological approaches to measuring and estimating the duration of QT interval of a standard electrocardiogram. Zhurnal Grodnenskogo gosudarstvennogo meditsinskogo universiteta [Journal of the Grodno State Medical University], 2019, vol. 17, no. 1, pp. 99‒105 (Russian).Mechanisms of sex and age differences in ventricular repolarization in humans / J. Vicente [et al.] // Am. Heart J. ‒ 2014. – Vol. 168, N 5. – P. 749–756. https://doi.org/10.1016/j.ahj.2014.07.010Vicente J., Johannesen L., Galeotti L., Strauss D. G. Mechanisms of sex and age differences in ventricular repolarization in humans. American Heart Journal, 2014, vol. 168, no. 5, pp. 749‒756. https://doi.org/10.1016/j.ahj.2014.07.010Influence of steroid hormones on ventricular repolarization / J. E. Salem [et al.] // Pharmacol. Ther. – 2016. – Vol. 167. – P. 38–47. https://doi.org/10.1016/j.pharmthera.2016.07.005Salem J. E., Alexandre J., Bachelot A., Funck-Brentano C. Influence of steroid hormones on ventricular repolarization. Pharmacology and Therapeutics, 2016, vol. 167, pp. 38‒47. https://doi.org/10.1016/j.pharmthera.2016.07.005Coker, S. J. Drugs for men and women – how important is gender as a risk factor for TdP? / S. J. Coker // Pharmacol. Ther. ‒ 2008. – Vol. 119, N 2. – P. 186–194. https://doi.org/10.1016/j.pharmthera.2008.03.005Coker S. J. Drugs for men and women – how important is gender as a risk factor for TdP? Pharmacology and Therapeutics, 2008, vol. 119, no. 2, pp. 186‒194. https://doi.org/10.1016/j.pharmthera.2008.03.005Are women more susceptible than men to drug-induced QT prolongation? Concentration-QTc modelling in a phase 1 study with oral rac-sotalol / B. Darpo [et al.] // Br. J. Clin. Pharmacol. ‒ 2014. – Vol. 77, N 3. – P. 522–531. https://doi.org/10.1111/bcp.12201Darpo B., Karnad D. R., Badilini F., Florian J., Garnett C. E., Kothari S., Panicker G. K., Sarapa N. Are women more susceptible than men to drug-induced QT prolongation? Concentration-QTc modelling in a phase 1 study with oral rac-sotalol. British Journal of Clinical Pharmacology, 2014, vol. 77, no. 3, pp. 522‒531. https://doi.org/10.1111/bcp.12201A new biomarker-index of cardiac electrophysiological balance (iCEB)–plays an important role in drug-induced cardiac arrhythmias: beyond QT-prolongation and Torsades de Pointes (TdPs) / H. R. Lu [et al.] // J. Pharmacol. Toxicol. Methods. – 2013. – Vol. 68, N 2. – P. 250–259. https://doi.org/10.1016/j.vascn.2013.01.003Lu H. R., Yan G. X., Gallacher D. J. A new biomarker-index of cardiac electrophysiological balance (iCEB) – plays an important role in drug-induced cardiac arrhythmias: beyond QT-prolongation and Torsades de Pointes (TdPs). Journal of Pharmacological and Toxicological Methods, 2013, vol. 68, no. 2, pp. 250‒259. https://doi.org/10.1016/j.vascn.2013.01.003Evaluation of Index of Cardio-Electrophysiological Balance (iCEB) as a New Biomarker for the Identification of Patients at Increased Arrhythmic Risk / T. Robyns [et al.] // Ann. Noninvasive Electrocardiol. – 2016. – Vol. 21, N 3. – P. 294–304. https://doi.org/10.1111/anec.12309Robyns T., Lu H. R., Gallacher D. J., Garweg C., Ector J., Willems R., Janssens S., Nuyens D. Evaluation of Index of Cardio-Electrophysiological Balance (iCEB) as a New Biomarker for the Identification of Patients at Increased Arrhythmic Risk. Annals of Noninvasive Electrocardiology, 2016, vol. 21, no. 3, pp. 294‒304. https://doi.org/10.1111/anec.12309CredibleMeds [Electronic resource]. – Mode of access: https://crediblemeds.org. – Date of access: 20.02.2022.CredibleMeds [Electronic resource]. Available at: https://crediblemeds.org (accessed 20.02.2022).Age and sex estimation using artificial intelligence from standard 12-lead ECGs / Z. I. Attia [et al.] // Circ. Arrhythm. Electrophysiol. – 2019. – Vol. 12, N 9. – P. e007284. https://doi.org/10.1161/CIRCEP.119.007284Attia Z. I., Friedman P. A., Noseworthy P. A., Lopez-Jimenez F., Ladewig D. J., Satam G. [et al.]. Age and sex estimation using artificial intelligence from standard 12-lead ECGs. Circulation: Arrhythmia and Electrophysiology, 2019, vol. 12, no. 9, p. e007284. https://doi.org/10.1161/CIRCEP.119.007284Gender differences in the long QT syndrome: effects of beta-adrenoceptor blockade / C. E. Conrath [et al.] // Cardiovasc. Res. – 2002. – Vol. 53, N 3. – P. 770–776. https://doi.org/10.1016/s0008-6363(01)00477-1Conrath C. E., Wilde A. A., Jongbloed R. J., Alders M., van Langen I. M., van Tintelen J. P., Doevendans P. A., Opthof T. Gender differences in the long QT syndrome: effects of beta-adrenoceptor blockade. Cardiovascular Research, 2002, vol. 53, no. 3, pp. 770‒776. https://doi.org/10.1016/s0008-6363(01)00477-1Larger dispersion of Ina in female dog ventricle as a mechanism for gender-specific incidence of cardiac arrhythmias / H. Barajas-Martinez [et al.] // Cardiovasc. Res. – 2009. – Vol. 81, N 1. – P. 82–89. https://doi.org/10.1093/cvr/cvn255Barajas-Martinez H., Haufe V., Chamberland C., Roy M.-J. B., Fecteau M. H., Cordeiro J. M., Dumaine R. Larger dispersion of Ina in female dog ventricle as a mechanism for gender-specific incidence of cardiac arrhythmias. Cardiovascular Research, 2009, vol. 81, no. 1, pp. 82‒89. https://doi.org/10.1093/cvr/cvn255Sex-specific IKAS activation in rabbit ventricles with drug-induced QT prolongation / A. Z. Vu [et al.] // Heart Rhythm. – 2021. – Vol. 18, N 1. – P. 88–97. https://doi.org/10.1016/j.hrthm.2020.07.020Wu A. Z., Chen M., Yin D., Everett T. H., Chen Z., Rubart M., Weiss J. N., Qu Z., Chen P.-S. Sex-specific IKAS activation in rabbit ventricles with drug-induced QT prolongation. Heart Rhythm, 2021, vol. 18, no. 1, pp. 88‒97. https://doi.org/10.1016/j.hrthm.2020.07.020Sex differences in repolarization and slow delayed rectifier potassium current and their regulation by sympathetic stimulation in rabbits / Y. Zhu [et al.] // Pflugers Archiv. – 2013. – Vol. 465, N 6. – P. 805–818. https://doi.org/10.1007/s00424-012-1193-9Zhu Y., Ai X., Oster R. A., Bers D. M., Pogwizd S. M. Sex differences in repolarization and slow delayed rectifier potassium current and their regulation by sympathetic stimulation in rabbits. Pflügers Archiv, 2013, vol. 465, no. 6, pp. 805‒818. https://doi.org/10.1007/s00424-012-1193-9Female gender as a risk factor for torsades de pointes associated with cardiovascular drugs / R. R. Makkar [et al.] // JAMA. – 1993. – Vol. 270, N 21. – P. 2590–2597. https://doi.org/10.1001/jama.270.21.2590Makkar R. R., Fromm B. S., Steinman R. T., Meissner M. D., Lehmann M. H. Female gender as a risk factor for torsades de pointes associated with cardiovascular drugs. JAMA, 1993, vol. 270, no. 21, pp. 2590‒2597. https://doi.org/10.1001/jama.270.21.2590Sex difference in risk of torsade de pointes with d,l-sotalol / M. H. Lehmann [et al.] // Circulation. – 1996. – Vol. 94, N 10. – P. 2535–2541. https://doi.org/10.1161/01.cir.94.10.2535Lehmann M. H., Hardy S., Archibald D., Quart B., MacNeil D. J. Sex difference in risk of torsade de pointes with d,l-sotalol. Circulation, 1996, vol. 94, no. 10, pp. 2535‒2541. https://doi.org/10.1161/01.cir.94.10.2535Cardiac actions of erythromycin: influence of female sex / M. D. Drici [et al.] // JAMA. – 1998. – Vol. 280, N 20. – P. 1774–1776. https://doi.org/10.1001/jama.280.20.1774Drici M. D., Knollmann B. C., Wang W. X., Woosley R. L. Cardiac actions of erythromycin: influence of female sex. JAMA, 1998, vol. 280, no. 20, pp. 1774‒1776. https://doi.org/10.1001/jama.280.20.1774Mechanism of cardiotoxicity of halofantrine / D. L. Wesche [et al.] // Clin. Pharmacol. Ther. – 2000. – Vol. 67, N 5. – P. 521–529. https://doi.org/10.1067/mcp.2000.106127Wesche D. L., Schuster B. G., Wang W. X., Woosley R. L. Mechanism of cardiotoxicity of halofantrine. Clinical Pharmacology and Therapeutics, 2000, vol. 67, no. 5, pp. 521‒529. https://doi.org/10.1067/mcp.2000.106127Nachimuthu, S. Drug-induced QT interval prolongation: mechanisms and clinical management. / S. Nachimuthu, M. D. Assar, J. M. Schussler // Ther. Adv. Drug Saf. – 2012. – Vol. 3, N 5. – P. 241–253. https://doi.org/10.1177/2042098612454283Nachimuthu S., Assar M. D., Schussler J. M. Drug-induced QT interval prolongation: mechanisms and clinical management. Therapeutic Advances in Drug Safety, 2012, vol. 3, no. 5, pp. 241‒253. https://doi.org/10.1177/2042098612454283

The authors declare that there are no conflicts of interest present.