Dynamics of heart rate variability in rats with streptozotocin-induced diabetes

Background: Diabetes mellitus (DM) has a negative impact on all organs. This is due to insufficiency of blood supply and the disruption of the trophic function of the nervous system. One of the most serious complication of DM is diabetic foot caused be vascular and neurological reasons. Correction of vascular disorders is effectively treated by modern therapeutic approaches, but the damage of nervous system has been studied insufficiently.

Aims: To investigate the dynamics of damage to the vegetative nervous system on the laboratory model of DM.

Materials and methods: DM in rats was induced by injection of streptozotocin at a dose of 65 mg/kg in citrate buffer (DM group). The control group of rats received a citrate buffer equivalent (CB group). Rats with DM were given a maintenance therapy with insulin in a dose of 2 units/kg/day. On 42 days of experience, a round wound with a diameter of 2 cm on the back of the animals was observed. Before the DM simulation, then on the 42, 50, 58 and 66 days of its development, an electrocardiogram (ECG) was recorded in the rats at a frequency of 2 kHz digitising in a state of calm wakefulness and after cold exposure. For 5 minutes ECG fragments, heart rate and heart rate variability (HRV) in the temporal domain were calculated, characterising: 1) the total heart rate variability (tHRV) according to SDRR, SDHR, KVRR and KVHR; 2) the effect of the parasympathetic department of the autonomic nervous system (aANS) for RMSSD and pNN3; 3) the contribution of the sympathetic department of the ANS (sANS) by SDAvgRR, SDAvgHR. The spectral parameters were estimated in the frequency domain: the total power of the spectrum is TR (range: 0–2.5 Hz), the powers in the low and high frequency ranges are LF (range: 0.2–0.8 Hz) and HF (range: 0.8–2.5 Hz) LF/HF. Weekly, the tail withdrawal time was measured in a temperature pain test (55°C).

Results: During the development of diabetes, the level of glucose in the blood increased 4–7 times compared with the normal level. The reaction time of the pain test in rats with DM increased by 20%–30% at the end of the experiment. At 42 days, the development of bradycardia (267 beats/min) was observed in rats with DM. The indicators of tHRV decreased by a factor of 2 due to a decrease in the contribution of sANS. The reaction to CP in the SD group differs from the norm by the severity of the individual components of the HRV structure, which indicates functional denervation of the heart and the development of diabetic neuropathy.

Conclusions: As the diabetes progressed, signs of neuropathy were observed. The overall HRV parameters decreased, the ratio of the contributions of sANS and pANS to the regulation of heart rate changed, and the temperature sensitivity decreased.

diabetes mellitus, neuropathy, streptozocin, heart rate variability, rats

1. Boulton AJ. Diabetic neuropathy and foot complications. Handb Clin Neurol. 2014;126:97-107. doi: 10.1016/B978-0-444-53480-4.00008-4

2. Болеева Г.С., Мочалов С.В., Тарасова О.С. Функциональные изменения артериальных сосудов при экспериментальном сахарном диабете 1 типа // Успехи физиологических наук. — 2014. — Т. 45. — №2. — С. 20-36. [Boleeva GS, Mochalov SM, Tarasova OS. Functional Alterations of Arterial Vessels in Experimental Models of Type l Diabetes Mellitus. Uspekhi fiziologicheskikh nauk. 2014;(2): 20-36. (In Russ.)]

3. Schmidt RE, Dorsey DA, Beaudet LN, et al. Experimental Rat Models of Types 1 and 2 Diabetes Differ in Sympathetic Neuroaxonal Dystrophy. J Neuropathol Exp Neurol. 2004;63(5):450-460. doi: 10.1093/jnen/63.5.450

4. Хаютин В.М., Лукошкова Е.В. Колебания частоты сердцебиений: спектральный анализ // Вестник аритмологии. — 2002.— №26. — С. 10-21. [Hayutin VM, Lyukoshkova EV, Kolebaniya chastoty serdtsebieniy: spektral’nyy analiz. Journal of arrhythmology. 2002;(26):10-21. (In Russ.)]

5. International diabetes federation. IDF atlas. 7th ed. Brussels: IDF; 2015.

6. McEwen TAJ, Sima AAF. Autonomic Neuropathy in BB Rat: Assessment by Improved Method for Measuring Heart-Rate Variability. Diabetes. 1987;36(3):251-255. doi: 10.2337/diab.36.3.251

7. Zhang WX, Chakrabarti S, Greene DA, Sima AAF. Diabetic Autonomic Neuropathy in BB Rats and Effect of ARI Treatment on Heart-Rate Variability and Vagus Nerve Structure. Diabetes. 1990;39(5):613-618. doi: 10.2337/diab.39.5.613

8. Fazan R, Ballejo G, Salgado MCO, et al. Heart Rate Variability and Baroreceptor Function in Chronic Diabetic Rats. Hypertension. 1997;30(3):632-635. doi: 10.1161/01.hyp.30.3.632

9. Hashimoto M, Harada T, Ishikawa T, et al. Investigation on diabetic autonomic neuropathy assessed by power spectral analysis of heart rate variability in WBN/Kob rats. J Electrocardiol. 2001;34(3):243-250. doi: 10.1054/jelc.2001.25130

10. Sanyal SN, Wada T, Yamabe M, et al. Synaptic degradation of cardiac autonomic nerves in streptozotocin-induced diabetic rats. Pathophysiology. 2012;19(4):299-307. doi: 10.1016/j.pathophys.2012.08.002

11. Li X, Jiang YH, Jiang P, et al. Analysis of Heart Rate Variability and Cardiac Autonomic Nerve Remodeling in Streptozotocin-induced Diabetic Rats. Exp Clin Endocrinol Diabetes. 2015;123(5):272-281. doi: 10.1055/s-0035-1547258

12. Xuan YL, Wang Y, Xue M, et al. In rats the duration of diabetes influences its impact on cardiac autonomic innervations and electrophysiology. Auton Neurosci. 2015;189:31-36. doi: 10.1016/j.autneu.2015.01.003

13. Nath Sanyal S, Arita M, Ono K. Inhomogeneous Derangement of Cardiac Autonomic Nerve Control in Diabetic Rats. Circulation J. 2002;66(3):283-283. doi: 10.1253/circj.66.283

14. Валеева Ф.В., Шайдуллина М.Р. Диагностика диабетической автономной кардиальной нейропатии у больных сахарным диабетом 1 типа // Сахарный диабет. — 2009. — Т. 12. — №4. — С. 55-60. [Valeyeva FV, Shaydullina MR. Diagnosis of diabetic autonomous cardioneuropathy in patients with type 1 diabetes mellitus. Diabetes mellitus.2009;12(4):55-60. (In Russ.)] doi: 10.14341/2072-0351-5706

15. Мухарямова Р.Р., Маянская С.Д., Валеева Ф.В., и др. Диагностика нарушений вариабельности сердечного ритма у пациентов, страдающих сахарным диабетом 1-типа // Инновационные технологии в медицине. — 2014. — №4-1. — С. 83-87. [Mukharyamova RR, Mayanskaya SD, Valeyeva FV, et al. Diagnosing of heart rate variability disorders in patients with diabetes mellitus of type 1. Innovatsionnie tekhnologii v meditsine. 2014;(4-1):83-87. (In Russ.)]

16. Онучина Е.Л., Соловьев О.В., Чапурных А.В., и др. Нарушения ритма сердца у пациентов с сахарным диабетом 2 типа // Сахарный диабет. — 2008. — Т. 11. — №1. — С. 25-27. [Onuchina LL, Solov'ev OV, Chapurnykh AV, et al. Narusheniya ritma serdtsa u patsientov s sakharnym diabetom 2 tipa. Diabetes mellitus. 2008;11(1):25-27. (In Russ.)] doi: 10.14341/2072-0351-5940

17. Franca da Silva AK, Penachini da Costa de Rezende Barbosa M, Marques Vanderlei F, et al. Application of Heart Rate Variability in Diagnosis and Prognosis of Individuals with Diabetes Mellitus: Systematic Review. Ann Noninvasive Electrocardiol. 2016;21(3):223-235. doi: 10.1111/anec.12372

18. Istenes I, Körei AE, Putz Z, et al. Heart rate variability is severely impaired among type 2 diabetic patients with hypertension. Diabetes Metab Res Rev. 2014;30(4):305-312. doi: 10.1002/dmrr.2496

19. Tadic M, Vukomanovic V, Cuspidi C, et al. Left atrial phasic function and heart rate variability in asymptomatic diabetic patients. Acta Diabetol. 2017;54(3):301-308. doi: 10.1007/s00592-016-0962-x

20. Souza NM, Giacon TR, Pacagnelli FL, et al. Dynamics of heart rate variability analysed through nonlinear and linear dynamics is already impaired in young type 1 diabetic subjects. Cardiol Young. 2016;26(7):1383-1390. doi: 10.1017/S104795111500270X

21. Arroyo-Carmona RE, Lopez-Serrano AL, Albarado-Ibanez A, et al. Heart Rate Variability as Early Biomarker for the Evaluation of Diabetes Mellitus Progress. J Diabetes Res. 2016;2016:8483537. doi: 10.1155/2016/8483537

22. Seyd A., Joseph P. K., Jacob J. Automated diagnosis of diabetes using heart rate variability signals. J Med Syst. 2012;36(3):1935-1941. doi: 10.1007/s10916-011-9653-x

23. Kou ZZ, Li CY, Hu JC, et al. Alterations in the neural circuits from peripheral afferents to the spinal cord: possible implications for diabetic polyneuropathy in streptozotocin-induced type 1 diabetic rats. Front Neural Circuits. 2014;8:6. doi: 10.3389/fncir.2014.00006