Differential impact of type-1 and type-2 diabetes on control of heart rate in mice

Abstract

Aims: Cardiac autonomic dysfunction is a serious complication of diabetes. One consequence is disruption of the normal beat-to-beat regulation of heart rate (HR), i.e. HR variability (HRV). However, our understanding of the disease process has been limited by inconsistent HR/HRV data from previous animal studies. We hypothesized that differences in the method of measurement, time of day, and level of stress account for the differing results across studies. Thus, our aim was to systematically assess HR and HRV in two common diabetic mouse models.

Methods: ECG radiotelemetry devices were implanted into db/db (type-2 diabetic), STZ-treated db/+ (type-1 diabetic), and control db/+ mice (n=4 per group). HR and HRV were analyzed over 24 h and during treadmill testing.

Results: 24 h analysis revealed that db/db mice had an altered pattern of circadian HR changes, and STZ-treated mice had reduced HR throughout. HRV measures linked to sympathetic control were reduced in db/db mice in the early morning and early afternoon, and partially reduced in STZ-treated mice. HR response to treadmill testing was blunted in both models.

Conclusions: It is important to consider both time of day and level of stress when assessing HR and HRV in diabetic mice. db/db mice may have altered circadian rhythm of sympathetic control of HR, whereas STZ-treated mice have a relative reduction. This study provides baseline data and a framework for HR analysis that may guide future investigations.

Keywords: Autonomic nervous system; Diabetes complications; Disease models, animal; Heart rate.

Figure 1. ECG telemetry experiment design

A) Experiment overview. Streptozotocin (STZ) or vehicle were injected at 5 weeks. Telemetry devices were implanted surgically at 7 weeks. ECG, temperature, and activity were recorded for three days each week. B) Treadmill test procotol. ECG traces (30 seconds duration) were analyzed at the time points indicated.

Figure 2. Characteristics of mice in the ECG telemetry study

(A) Weekly body weight. (B) Fasting blood glucose levels. (C) Survival curves. *p<0.05 db/db vs. control; # p<0.05 STZ vs. control.

Figure 3. 24-hour telemetry parameters

24-hour heart rate, temperature, and activity levels measured via implantable telemetry device. X-axis = time, with 0=midnight; lights on/off at 6am/6pm as indicated by dashed lines. * p<0.05

Figure 4. 24-hour Heart Rate Variability (HRV) at week 10

Measures of short-term HRV (RMSSD and SD1) and long-term HRV (SDNN and SD2). X-axis = time, with 0=midnight. *P<0.05.

Figure 5. Treadmill test at week 9

Treadmill tests conducted on telemetered mice at 9 weeks of age. All mice were placed on the stationary treadmill for 10 min acclimatization, then ran at 8 m/min for 10 min. For control and STZ mice this was followed by 10, 12 and 14 m/min for 2 minutes each. 30 second ECG traces were analyzed for HR and HRV at the time-points shown.*P<0.05.