METHOD FOR DETERMINING PROBABILITY OF PRESENCE OF LONG QT SYNDROME IN ATHLETES AGED 14-18 YEARS OF HIGH LEVEL SPORTS MASTERY AND SPORTS IMPROVEMENT WITH PROLONGATION OF CORRECTED QT INTERVAL (QTs GREATER THAN 460 MS) ON RESTING ECG

Abstract

FIELD: functional diagnostics; pediatrics.SUBSTANCE: clinical, anamnestic, electrocardiographic and laboratory parameters are determined, and points are assigned to the specified parameters according to the LQTS probability scale specified in Table 1 of the description. The points obtained are summed up and if the total points are less than 3.5, a low probability of LQTS syndrome is determined and the prolongation of the QT interval is secondary. With a score of 4–5, the probability of LQTS prolongation is uncertain, and the nature of the QT interval prolongation requires further clarification. If the total score is more than 6, LQTS is highly probable.EFFECT: this method enables the early clinical assessment of a young athlete to identify a high probability of LQTS, thereby: preventing the overlooking of patients with this life-threatening disease and avoiding the risk of sudden cardiac death in young athletes; optimizing and personalizing disease diagnostics; reducing the time it takes to make decisions regarding the athlete, taking into account the waiting time for genetic testing (up to six months or more) and the possibility of a negative or indeterminate result; and eliminating an unnecessary range of expensive laboratory, cardiological, neurological, endocrinological, and other examinations.1 cl, 4 dwg, 3 tbl, 2 ex

Description

[0001] Field of technology to which the invention relates: medicine.

[0002] For athletes aged 14-18 years of high athletic skill and athletic excellence (the level of Russian youth national teams and the nearest reserve), when conducting a 12-lead resting ECG in automatic mode, the corrected QT interval (QTc) is estimated in milliseconds (ms) using the Bazett formula:

[0003] QTc (ms) is equal to QT (ms) divided by the square root of the preceding RR interval (sec).

[0004] If the QTc interval is prolonged to more than 460 ms, the QTc interval value is confirmed by manual measurement. The QT interval value is determined by the slope or tangential method in standard lead II or chest (precordial) lead V5, followed by calculation of QTc (ms) using the Bazett formula [Sharma S, Drezner JA, Baggish A, Papadakis M, Wilson MG, Prutkin JM, et al. International recommendations for electrocardiographic interpretation in athletes. Eur Heart J 2017; 39:1466-80. https: / / doi.10.1093 / eurheartj / ehw631]. If confirmation of prolongation of the QTc interval of more than 460 ms is detected, CYIQT is excluded using the Scale developed by the authors at the Center for Syncope and Cardiac Arrhythmias of the Federal Scientific and Clinical Center for Children and Adolescents of the Federal Medical and Biological Agency of Russia (hereinafter referred to as the CSSSA Scale), Table 1. The scale was developed based on our own long-term experience in studying CYIQT [Makarov LM, Belokon NA, Laan MI, et al. Holter monitoring in the long QT syndrome of children and adolescents.Cor Vasa. 1990; 32(6):474-83. Makarov LM, Komoliatova BH, Miroshnikova EN, Kazantseva MA Physiological significance and normative parameters of frequency adaptation of the QT interval during Holter monitoring in healthy young individuals. Cardiology 2008; 48(4):54-8. Makarov L, Komoliatova V, Zaklyazminskaya E, et al. Ambulatory ECG Monitoring in Patients With Long QT Syndrome. Scientific Session AHA. Chicago 10-12 November 2018. https: / / doi:10.13140 / RG.2.2.32275.69921. Makarov LM, Komoliatova BH, Kiseleva II et al. Long QT syndrome - a disease with a high risk of sudden death. - M.: ID "Medpraktika-M", 2018, 24 p. ISBN 978-5-98803-402-5. L.M. Makarov, V.N. The Importance of QT Interval Prolongation in Children's and Youth Sports. Literature Review. Medicine of Extreme Conditions.2025 (in press)] and examination of young athletes at the highest level of sports mastery in the system of the Federal Medical and Biological Agency of Russia, where temporary or permanent exemptions from sports due to prolongation of the QT interval constitute one of the leading reasons [Makarov LM, Komolyatova VN, Aksenova NV Analysis of the reasons for exemptions from sports of young elite athletes. Russ. Vestn. Perinatol. i Pediatr 2020; 65:(6): 65-71. https: / / doi: 10.21508 / 1027-4065-2020-65-6-65-71], analysis of analogues existing in world practice.

[0005] The CSSA Scale includes clinical, anamnestic, instrumental and laboratory criteria for the diagnosis of QT syndrome, the scoring of which determines the probability of congenital QT syndrome, which underlies the determination of further tactics for managing the athlete and the prognosis of his professional sports activities. The QT prolongation scale was formed on the basis of the examination algorithm for young athletes, which included: prolongation of the QT interval on the resting ECG (items 1-3, Table 1), during bicycle ergometry (item 4, Table 1), handgrip test and orthostasis (items 12, 13, Table 1), Holter monitoring (items 14-16, Table 1), assessment of heart rate, arrhythmias, morphology of the T wave and the QRS complex (items 5-11, Table 1), clarification of the athlete's training regimen (items 17, 18, Table 1) - the presence of possible cardiac events: loss of consciousness and its nature (items 19-22, Table 1), familial cases of QT syndrome and sudden death in family members at a young age (items24-26, Table 1), changes in blood laboratory parameters: decreased levels of electrolytes, free thyroxine and increased levels of creatine phosphokinase (paragraphs 27-29, Table 1).

[0006]

[0007]

[0008]

[0009] Result Interpretation:

[0010] Score less than 3.5 - diagnosis of QT prolongation is unlikely and prolongation of the QT interval is rather secondary;

[0011] Score 4-5 - the probability of the diagnosis of QT prolongation is uncertain, and the nature of the prolongation of the QT interval requires further clarification during observation and follow-up examinations;

[0012] A score of more than 6 means that the diagnosis of QT syndrome is highly probable and the issues of admission to sports training and treatment should be considered as in a patient with proven QT syndrome.

[0013] All athletes with a detected QTc prolongation of more than 460 ms on a resting ECG undergo a handgrip test using a method developed by the authors: without changing body position, the athlete rhythmically squeezes a handgrip with a resistance of 20 kg with his dominant hand for 20-30 seconds until the heart rate increases to more than 60 beats / min, after which a 12-lead ECG is recorded again and the QTc interval is calculated using the Besette formula. [Patent for invention No. 2759130 "Use of a hand expander in young athletes with sinus bradycardia (heart rate less than 60 beats / min) to increase the heart rate for the purpose of adequate assessment of the corrected QT interval (QTc) Authors: Makarov L.M., Komolyatova V.N., Akopyan A.G., Besportochny D.A. Application No. 2020140602. Priority of the invention December 09, 2020. Komolyatova V.N., Makarov L.M., Akopyan A.G. et al. Handgrip test in the diagnosis of long QT syndrome. Russian Journal of Cardiology. 2024; 29 (2S): 5762. doi: 10.15829 / 1560-4071-2024-5762]. Then the athlete is asked to stand up and immediately after changing the body position from horizontal to vertical, the ECG is recorded again, in which the RR and QT intervals are measured, and the QTc interval is calculated [Komolyatova V.N., Makarov L.M., Kiseleva I.I., Besportochny D.A., Dmitrieva A.V., Balykova L.A., et al. Change in the QT interval in orthostasis - a new diagnostic marker of long QT syndrome. Medical alphabet 2019; 22 (2): 18-21].

[0014] If the QTc interval after the handgrip test is prolonged by more than 480 ms and in orthostasis by more than 500 ms, the athlete is temporarily suspended from sports until the results of further examination are obtained. This includes stopping the use of medications (www.crediblemeds.org). Echocardiography (ECHO-CG) should be performed to exclude structural (heart defects) and organic (cardiomyopathy, myocarditis) heart disease. Bradycardia, which is one of the diagnostic criteria for QTc in children (0.5 points according to Schwartz), often occurs in athletes, especially those involved in endurance training (cross-country skiing, cycling, swimming, rowing, long-distance running, etc.) [Gademan MG et al. Eur J Prev Cardiol. 2012:19:126-138. doi: 10.1177 / 1741826710392669) and cannot be considered as a criterion for CYIQT.Patients with CYIQT have characteristic changes in the T wave on the ECG: a double-humped T wave in more than 2 leads, often accompanying the 2 molecular genetic variant of the syndrome and included in the Schwartz criteria [Schwartz PJ, Crotti L, Insolia R. Long-QT syndrome: from genetics to management. Circ Arrhythm Electrophysiol. 2012 Aug 1; 5(4):868-77.] and a late onset of the T wave, which occurs in patients with the 3 molecular genetic variant, a criterion added by the authors of the Scale to the diagnostic table. In recent years, another ECG criterion has been described in patients with the 3 molecular genetic variant - alternans of the QRS complex [Makarov LM, Komolyatova VN, Zaklyazminskaya EV, et al. 2 Cases of New Electrocardiographic Patterns in Patients With Long QT Syndrome. JACC Case Rep. 2025 Jun 18; 30(15): 103753. https: / / doi: 10.1016 / j.jaccas.2025.103753].

[0015] All athletes with prolongation of the QT interval undergo exercise testing (bicycle ergometry) and Holter monitoring (HM) with additional assessment of the QT interval. Bicycle ergometry is performed on a bicycle ergometer according to the PWC 170 protocol. Heart rate (HR) and QT, QTc intervals are determined at the 4th minute of the recovery period; an increase in the QTc interval of more than 480 ms at the 4th minute of recovery is included in the diagnostic criteria for QT and can also be used in young athletes, as well as macroscopic T-wave alternans and polymorphic ventricular tachycardia Torsade de Pointes with a specific weight of 1 point for each criterion [Schwartz PJ, Crotti L, Insolia R. Long-QT syndrome: from genetics to management. Circ Arrhythm Electrophysiol. 2012 Aug 1; 5(4):868-77. https: / / doi:10.1161 / CIRCEP.111.962019].Additionally, during HM in young athletes with a QT prolongation greater than 460 ms on a resting ECG, the following QT interval parameters added by the authors are assessed: QT prolongation during HM at the minimum heart rate greater than 530 ms with manual analysis, average daily QTc greater than 460 ms with automatic analysis or greater than 65% of the recording time with automatic analysis, and maximum QT greater than 530 ms with automatic analysis. An increase in each of these parameters adds 0.5 points to the probability of QT prolongation in an athlete according to the CSSA Scale.

[0016] Prolongation of the QT interval is often accompanied by electrolyte disturbances and thyroid pathology, therefore, such items as electrolyte imbalance (decreased levels of K, Ca, Mg, Fe in the blood) have been added to the QT scale.

[0017] An increase in the CPK level may indicate that the athlete is overtraining, which may also be the cause of QT prolongation.

[0018] If the score on the CSSSA Scale is 6 points or more, the athlete is referred for molecular genetic testing to identify mutations in the genes responsible for CYIQT.

[0019] As part of the development and validation of the Scale, 32 athletes aged 14-18 (16±2) years, at the level of the highest sports mastery and sports improvement (members of the Russian youth teams and the nearest reserve), with a detected QTc prolongation of more than 460 ms on the resting ECG, 23 (72%) girls, were examined. The conducted analysis according to the CSSA Scale revealed that 5 (15%) of 32 were determined to have 6 points, 6 (19%) received 4 points, and 21 (66%) the results of 3 points. The conducted molecular genetic analysis revealed a high probability of congenital syndrome in 3 of 5 (more than 6 points) and in 1 athlete with uncertain results according to the CSSA Scale (4-5 points).

[0020] Field of application to which the invention relates

[0021] The invention relates to the field of medicine, more precisely pediatrics, sports medicine, pediatric cardiology, functional diagnostics, namely, to the early detection of the likelihood of the presence of long QT syndrome (LQTS) in children and adolescent athletes aged 14-18 years, a disease with a high risk of arrhythmogenic life-threatening conditions and sudden cardiac death.

[0022] Prior art (analogues of the invention)

[0023] Preferred to близким аналогом, к заявляемоу мособу можно считать [Schwartz P., Stramba-Badiale М., Crotti L., Pedrazzini М, et al. Prevalence of congenital long-QT syndrome. Circulation. 2009. 120(18): 1761–7. https: / / doi: 10.1161 / circulationha. 109.863209. [ PubMed ] Wilde AAM, Amin AS, Postema PG. Diagnosis, management, and therapeutic strategies for congenital long QT syndrome. Heart. 2022 Mar; 108(5):332-338. https: / / doi:10.1136 / cardiovascular-2020-318259. Priory SG, Wilde AA, Horie M, et al. HRS / EHRA / APHRS Expert Consensus Statement on the Diagnosis and Management of Patients With Inherited Primary Arrhythmia Syndromes: Document Endorsed by HRS, EHRA, and APHRS. 2013; 10:1932-6 https: / / doi:10.1016 / j.hrthm.2013.05.014] However, the traditional Schwartz criteria do not take into account the specific electrophysiological features of the heart of a trained athlete, which affect the duration of the QT interval (large myocardial mass, increased vagal influences, etc.). According to the current global criteria for assessing the duration of the QT interval in adult elite athletes, the normal duration of the QTc interval, calculated using the Bazett formula, is proposed to be QTc values ​​of up to 470 ms in men, and up to 480 ms in women [Sharma S, Drezner JA, Baggish A, Papadakis M, Wilson MG, Pratkin JM, et al. International recommendations for electrocardiographic interpretation in athletes. Eur. Heart J. 2017;39:1466^80. https: / / doi.10.1093 / eurheartj / ehw631]. In the Schwartz criteria, QTc interval values ​​at the level of 460-180 ms already contribute from 2 to 3.5 points to the diagnosis of QT syndrome.Bradycardia, which is often recorded in athletes, adds another 0.5 points to the probability of CYIQT diagnosis, and the Bazett formula itself, when calculated in athletes with bradycardia, can give a false-negative result of QT prolongation [Schnell F, Behar N, Carre F. Long-QT Syndrome and Competitive Sports. Arrhythm Electrophysiol Rev. 2018 Aug;7(3): 187-192. https: / / doi: 10.15420 / aer.2018.39.3] and lead to missing CYIQT.

[0024] Syncope, as the leading clinical signs of QT syndrome (2 and 1 points in the Schwartz criteria), does not take into account that syncopal states in athletes are widespread (up to 5%) and are practically not associated with QT syndrome, but have a vasovagal (reflex) nature, do not threaten the health and life of the athlete and do not require suspension from sports [Makarov LM, Komolyatova VN, Kiseleva II, Aksenova NV, Besportochny DA, Balykova LA et al. Epidemiology of attacks of loss of consciousness in children and adolescents in high-performance sports (EPIZOD-S study). Russian Bulletin of Perinatology and Pediatrics. 2019; 64(6):62-67. The nature of syncope can be fairly reliably differentiated based on the clinical picture, which is included in the CSSA Scale.

[0025] Intensive training can increase the duration of the QT interval, while temporary detraining, on the contrary, can decrease it, which does not take into account the traditional Schwartz criteria, as well as the influence of specific characteristics of sports activity (training intensity, experience, type of sport) on the heart rate and QT interval in athletes.

[0026] The Schwartz criteria for Holter monitoring (HM) include only T-wave alternans and Torsade de Pointes ventricular tachycardia, but not the assessment of the QT interval itself. The CSSA Scale includes parameters for assessing the QT interval during HM, based on our own experience [Makarov L, Komoliatova V, Zaklyazminskaya E, Dmitrieva A. Ambulatory ECG Monitoring in Patients With Long QT Syndrome. Scientific Session AHA. Chicago 10-12 November 2018. https: / / doi:10.13140 / RG.2.2.32275.69921. Makarov LM Holter monitoring. 4th Edition. - M., "Medpraktika-M". - 2017. - pp. 111-119 ISBN 978-5-98803-362-362-2], and a number of similar studies in non-athlete patients of different ages [Page A, Aktas MK, Soyata T, et al. "QT clock" to improve detection of QT prolongation in long QT syndrome patients. Heart Rhythm 2016 Jan; 13(1): 190-8. https: / / doi:10.1016 / j.hrthm.2015.08.037. Follansbee CW, Beerman L, Arora G.Automated QT analysis on Holter monitors in pediatric patients can differentiate long QT syndrome from controls. Pacing Clin Electrophysiol. Jan 2018; 41(l):50-56. https: / / doi:10.1111 / pace.l3244].

[0027] Essence of the invention

[0028] The main task, which the claimed invention is aimed at solving, is to determine, at the stages of clinical examination, the probability of the presence of QT prolongation in young elite athletes with a prolongation of the QT interval of more than 460 ms on the resting ECG, which makes it possible to determine whether this ECG phenomenon (QT prolongation) is either relatively benign and reversible, or associated with a high probability of the presence of congenital QT prolongation with the risk of developing cardiac events (ventricular tachycardia, syncope and cardiac arrest).

[0029] Characteristics of the implementation of the proposed method

[0030] Filling in the data for assessing the CSSSA Scale is carried out based on the results of an in-depth medical examination (IME), which includes all methods of clinical, instrumental and laboratory examination specified in the CSSSA Scale and which is regularly (at least once every 6 months) undergone by all young athletes aged 14-18 years of high sportsmanship and sports improvement level.

[0031] Technical result

[0032] Using this method allows for the early clinical examination of a young athlete to determine the high probability of the presence of QT syndrome, which allows for:

[0033] • To avoid missing real patients with life-threatening diseases and to avoid the risk of sudden cardiac death in young athletes;

[0034] • Optimize and personalize disease diagnostics, reduce the time it takes to make decisions about an athlete, taking into account the waiting period for genetic analysis (up to six months or more) and the possibility of a negative or indeterminate result;

[0035] • Eliminate an unjustified range of unnecessary expensive laboratory, cardiological and neurological, endocrinological and other examinations;

[0036] • Taking into account the contingent of those examined (professional young athletes who are fully supported by the state), optimize the costs of their support, with the exclusion of unjustified, even temporary, suspensions from sports, which, in the conditions of a tough training and competition schedule of the national youth teams, can lead not only to a decrease in the team's results, but also to financial and reputational losses at the national level, in the event of the sudden death of a young athlete. Examples of implementation

[0037] EXAMPLE 1

[0038] Athlete A., 16 years old. Has been playing hockey professionally for 12 years, 12 hours a week. During a routine in-depth medical examination, an ECG revealed moderate bradycardia (heart rate 53 bpm), prolongation of the QT interval, the QTc interval was 478 ms. Denies syncope. Family history: his father died suddenly at the age of 28 (cause unspecified). A handgrip test was performed - the QTc interval was 490 ms, in the early period of orthostasis - 612 ms (Fig. 1A, 1B).

[0039] During echocardiography, the heart size and contractility were within normal limits. Bicycle ergometry was performed: at the 4th minute of recovery, the QTc interval was 458 ms. Holter monitoring revealed sinus bradycardia, the QT interval at a minimum heart rate of 35 bpm was 560 ms. The average daily QTc interval according to automatic analysis was 495 ms, the maximum QT interval was 592 ms (Fig. 2).

[0040] No ventricular arrhythmias, tachycardia, T-wave alternans, or QRS complexes were detected. Electrolyte levels, thyroid hormone levels, and CPK, CPK-MB, and Fe levels were normal. The probability of QT syndrome is presented in Table 2.

[0041]

[0042]

[0043]

[0044] According to the proposed scale, the total score is 6.0, making it highly likely that the athlete has congenital long QT syndrome. Subsequently (4 months later), molecular genetic testing revealed a mutation in the KCNH2 gene, confirming the diagnosis.

[0045] EXAMPLE 2

[0046] Female athlete S, 15 years old. Has been practicing judo for 5 years, training 6 times a week for 4 hours, for a total of up to 24 hours per week. Denies syncope, family history is unremarkable. An ECG showed a heart rate of 62 bpm, and a QTc interval of -464 ms. A wrist expander test revealed a QTc interval of -485 ms, and in the early period of orthostasis, 508 ms (Figs. 3A, 3B).

[0047] When tested on a bicycle ergometer at the 4th minute of recovery, the QTc interval was 456 msec (Fig. 4).

[0048] Holter monitoring revealed a prolongation of the QT interval: QT at a minimum heart rate of 41 bpm to 584 ms, the maximum QT interval was 568 ms, and the average daily QTc interval was 465 ms. No ventricular arrhythmias, tachycardia, T-wave alternans, or QRS complexes were detected. Blood potassium levels decreased to 2.7 mmol / L, while thyroid hormones, CPK, and CPK-MB levels were normal.

[0049] The probability assessment of QT syndrome in athlete S. is presented in Table 3.

[0050]

[0051]

[0052]

[0053] According to the proposed algorithm, the athlete's final score is 0.5 points, making the likelihood of a diagnosis of congenital long QT syndrome low. The girl is currently receiving potassium supplements, her QT interval on the ECG has normalized, and she is undergoing examination by a nephrologist for severe hypokalemia.

[0054] Brief description of drawings

[0055] Fig. 1A shows the ECG of athlete A. with prolongation of the QT interval on a standard ECG: sinus rhythm, heart rate 51 beats / min, QT interval 520 ms, QTc - 478 ms.

[0056] Fig. 1B shows the ECG of athlete A. in the early period of orthostasis: heart rate increases to 83 beats / min, QT interval is 520 ms, QTc is 612 ms. A double-humped T wave is recorded in leads II, V5, V6.

[0057] Fig. 2 shows a fragment of Holter monitoring of athlete A., 16 years old. Prolongation of the QT interval at a minimum heart rate of 35 bpm, QT interval 560 msec.

[0058] Fig. 3A shows the ECG of athlete C, with prolongation of the QT interval on a standard ECG: sinus rhythm, heart rate 62 beats / min, QT interval 458 ms, QTc - 464 ms.

[0059] Fig. 3B shows the ECG of athlete S, with an increase in the QT interval after the test with a wrist expander: sinus rhythm, increased heart rate to 78 beats / min, QT interval 400 ms, QTc - 485 ms.

[0060] Figure 4 shows a fragment of the stress test results for athlete S. with a prolongation of the QT interval. At the 4th minute of recovery, the heart rate is 78 bpm, the duration of the QT interval is 400 ms, and QTc is 456 ms.

Claims

A method for determining the probability of the presence of long QT syndrome (LQS) in athletes aged 14-18 years with a prolongation of the corrected QT interval (QTc) greater than 460 ms on a resting ECG, characterized in that clinical, anamnestic, electrocardiographic and laboratory parameters are determined according to the LQS probability scale specified in Table 1 of the description, points are assigned to the specified parameters, the obtained points are summed up and if the sum of points is less than 3.5, a low probability of LQS is determined and the prolongation of the QT interval is secondary in nature; if the sum of points is 4-5, the probability of LQS is uncertain and the nature of the prolongation of the QT interval requires further clarification; if the sum of points is more than 6, LQS is highly probable.

Images