Cardiac Autonomic Neuropathy and Hypoglycemia as Independent Predictors of QTc Elongation at Night in Adolescents With Type 1 Diabetes: Cohort Study

Background. QTc elongation is the risk factor of sudden cardiac death. Patients with type 1 diabetes (T1D) can have QTc elongation due to hypoglycemia and cardiac autonomic neuropathy (CAN). The separate role of this two factors in QTc elongation development in T1D patients is still unknown.

Objective. The aim was to study the role of cardiac autonomic neuropathy and hypoglycemia as independent risk factors of QTc elongation at night in adolescents with T1D.

Methods. Patients at the age of 10-17 years old with T1D were enrolled in the cohort study. All patients have undergone simultaneous 24-hour monitoring of electrocardiogram and glycemia. Results of nocturnal monitoring (23:00-07:00) were estimated. QTc elongation > 450 ms was regarded pathological. CAN was diagnosed at decrease of ≥ 2 time domain parameters (SDNN < 101 ms, SDNNi < 48 ms, SDANN < 85 ms, rMSSD < 25 ms). Hypoglycemia was classified as 1st (≥ 3.0 and ≤ 3.9 mmol/L), 2nd (≥ 2.2 and < 3.0 mmol/L) or 3rd (≤ 3.9 mmol/L along with cognitive defects and the need of acute hypoglycemia treatment) level. We also have distinguished prolonged (< 3.0 mmol/L and ≥ 120 min) and asymptomatic (≤3.9 mmol/L and no adrenergic symptoms) nocturnal hypoglycemia. We didn’t analyse hypoglycemia periods with > 9.0 mmol/L.

Results. QTc elongation > 450 ms was revealed in 28 out of 100 patients. All patients with QTc > 450 ms were similar on gender, age, HbA1C level with patients without any QTc elongation but they have longer history of T1D and higher frequency of 2nd level hypoglycemia and asymptomatic nocturnal hypoglycemia. According to the data from multivariate regression analysis independent predictors of QTc elongation were the following: CAN — odds ratio (OR) 9.0 (95% confidential interval [CI] 3.3-24.2), 2nd level hypoglycemia — OR 4.4 (95% CI 1.4-14.2), asymptomatic nocturnal hypoglycemia — OR 2.9 (95% CI 1.1-7.7) and T1D duration — OR 1.3 (95% CI 1.0-1.5).

Conclusion. CAN and hypoglycemia (both clinically significant and asymptomatic nocturnal) are independent predictors of QTc elongation in adolescents with T1D.

1. DiMeglio LA, Acerini CL, Codner E, et al. SPAD Clinical Practice Consensus Guidelines 2018: Glycemic control targets and glucose monitoring for children, adolescents, and young adults with diabetes. Pediatr Diabetes. 2018;19 Suppl 27:105-114. doi: 10.1111/pedi.12737.

2. Ildarova RA, Shkolnikova MA. Modern approaches to hereditary life-threatening arrhythmias treatment in children. Pediatria. 2018;97(3):133-141. (In Russ). doi: 10.24110/0031-403X-2018-97-3-133-141.

3. Bokeria OL, Sanakoev MK. Long Q-T syndrome. Annaly aritmologii. 2015;12(2):114-126. (In Russ). doi: 10.15275/annaritmol.2015.2.7

4. Schwartz PJ, Stramba-Badiale M, Crotti L, et al. Prevalence of the congenital long-QT syndrome. Circulation. 2009;120(18): 1761-1767. doi: 10.1161/CIRCULATI0NAHA.109.863209.

5. Laptev DN, Shmushkovich IA. Arrhythmogenic effects of hypoglycemia. Diabetes mellitus. 2012;15(1):25-30. (In Russ.)

6. Veglio M, Giunti S, Stevens LK, et al. Prevalence of QT interval dispersion in type 1 diabetes and its relation with cardiac ischaemia: the EURODIAB IDDM Complications Study Group. Diabetes Care. 2002;25(4):702-707. doi: 10.2337/diacare.25.4.702.

7. Suys BE, Huybrechts SJ, De Wolf D, et al. QTc interval prolongation and QTc dispersion in children and adolescents with type 1 diabetes. J Pediatr. 2002;141(1):59-63. doi: 10.1067/mpd.2002.125175

8. Malyuzhinskaya NV, Kozhevnikova KV, Polyakova OV. Factors affecting the QT interval duration in children with type 1 diabetes and the ability to predict its elongation. Journal of Volgograd State Medical University. 2016;58(2):132-135. (In Russ).

9. Laptev DN. Relationship of hypoglycemia and glycose variability with autonomic dysfunction in children and adolescents with type 1 diabetes. Diabetes mellitus. 2014;17(4):87-92. (In Russ). doi: 10.14341/DM2014487-92.

10. Ahmet A, Dagenais S, Barrowman NJ, et al. Prevalence of nocturnal hypoglycemia in pediatric type 1 diabetes: a pilot study using continuous glucose monitoring. J Pediatr. 2011;159(2): 297-302. doi: 10.1016/j.jpeds.2011.01.064.

11. Alimova IL, Demyanenko AN. Kharakteristika nochnykh gipoglikemii u detei s kardiovaskulyarnoi avtonomnoi neiropatiei. In: (Collection of theses) VIII (XXVI) Natsional'nogo kongressa endokrinologov s mezhdunarodnym uchastiem «Personalizirovannaya meditsina i prakticheskoe zdravo-okhranenie»; dated 22-25 May 2019. Moscow: UP PRINT; 2019. рр. 554-555. (In Russ).

12. Svetlova 0V, Gur'eva IV, Puzin SN, et al. Vzaimosvyaz' mezhdu avtonomnoi nevropatiei i bessimptomnymi gipoglikemiyami u pacientov s saharnym diabetom 1 tipa. Diabetes mellitus. 2008;11(4):76-79. (In Russ). doi: 10.14341/2072-0351-5596.

13. Vinik AI, Erbas T, Casellini CM. Diabetic cardiac autonomic neuropathy, inflammation and cardiovascular disease. J Diabetes Investig. 2013;4(1):4-18. doi: 10.1111/jdi.12042.

14. Popov KA, Tokmakova AY, Bondarenko IZ. Predictors of cardiac autonomic nervous dysfunction in patients with type 1 and 2 diabetes mellitus. Diabetes mellitus. 2017;20(3):185-193. (In Russ). doi: 10.14341/8156.

15. Alimova IL, Demyanenko AN. Functional condition of the cardiovascular system in children with type 1 diabetes depending on the level of glycemia. Russian bulletin of perinatology and pediatrics. 2018;63(5):69-74. (In Russ). doi: 10.21508/1027-4065-2018-63-5-69-74.

16. Makarov LM, Komolyatova VN, Kupriyanova 00. National Russian guidelines on application of the methods of Holter monitoring in clinical practice. Russian journal of cardiology. 2014;2:6-71. (In Russ).

17. American Diabetes Association and American Academy of Neurology. Consensus statement: report and recommendations of the San Antonio Conference on Diabetic Neuropathy. Diabetes Care. 1988;(11):592-597.

18. Danne T, Nimri R, Battelino T. International Consensus on Use of Continuous Glucose Monitoring. Diabetes Care. 2017;40: 1631-1640. doi: 10.2337/dc17-1600.

19. Laptev DN, Ryabykina GV, Sobolev AV, et al. The relationship between the level of glycemia, the length of the QT-interval, and locomotor activity in children and adolescents presenting with type 1 diabetes mellitus. Problems of endocrinology. 2010;56(6):24-31. (In Russ).

20. Klimontov VV. Impaired hypoglycemia awareness in diabetes: epidemiology, mechanisms and therapeutic approaches. Diabetes mellitus. 2018;21(6):513-523. (In Russ). doi: 10.14341/DM9597.

21. Popov KA, Tokmakova AYu, Bondarenko IZ. Predictors of cardiac autonomic nervous dysfunction in patients with type 1 and 2 diabetes mellitus. Diabetes mellitus. 2017;20(3):185-193. (In Russ). doi: 10.14341/8156.

22. Dedov II, Shestakova MV, Mayorov AYu. Standards of specialized diabetes care. Diabetes mellitus. 2019;22(S1):1-209. (In Russ).