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24-h 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 b 0.05.
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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 i...
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... pm, 6 pm, 7 pm, 8 pm, 9 pm, 10 pm, and 11 pm in week 10; HR re- duced by an average of 38-98 bpm). A lower HR in STZ-treated mice was seen relatively consistently from weeks 8 to 11 (Supplemental Fig. 2). Temperature was not consistently reduced in parallel to HR. db/db and STZ-treated animals showed very low activity levels over the entire 24 h. Fig. 4 shows HRV data for 10-week-old animals. RMSSD and SD1, which are measures of short-term variability, differed little between groups, suggesting that parasympathetic control of HR may not be affected in these diabetic animals. db/db mice had reduced SDNN and SD2, which are measures of longer-term variability; together with the lack of ...
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... S.D. of HR increased from 19 ± 7 to an average of 52-61 bpm), but this did not occur in either db/db or STZ-treated mice (statistically significant for S.D. of HR for both db/db and STZ- treated after 4, 6, and 8 min). Upon treadmill running, all mice had rel- atively low HRV. The results were similar in db/db mice at week 16 (Supplemental Fig. 4). In summary, it appears that the diabetic mice had a reduced maximum HR, with the STZ group being most affected, but the HR remained close to this maximum throughout the treadmill test. Fig. 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 ...
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... 3). These findings indicate an alteration in circadi- an control. STZ-treated mice had lower HR across the entire 24 h cycle (reduced by an average of 38-98 bpm; Fig. 3). Short-term HRV mea- sures (related to parasympathetic control of HR) were not altered in ei- ther db/db or STZ-treated mice, suggesting that parasympathetic control is intact (Fig. 4). db/db mice had reduced HRV by longer-term variability measures (more influenced by sympathetic control), particularly during the early morning (2-5 am) and early afternoon (2-5 pm) (SDNN re- duced by an average of 4.9-8.6 ms, SD2 reduced by 18-47 units; Fig. 4). This, together with the lack of differences in parasympathetic control, ...
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... ther db/db or STZ-treated mice, suggesting that parasympathetic control is intact (Fig. 4). db/db mice had reduced HRV by longer-term variability measures (more influenced by sympathetic control), particularly during the early morning (2-5 am) and early afternoon (2-5 pm) (SDNN re- duced by an average of 4.9-8.6 ms, SD2 reduced by 18-47 units; Fig. 4). This, together with the lack of differences in parasympathetic control, indicates alteration in circadian patterns of sympathetic HR control in db/db mice, whereas in STZ-treated mice this longer-term variability was partially reduced throughout the 24-h period (reduced in SD2 (statistically significant at 6 am, 9 am, 12 pm, 5 pm, 7 ...
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... the lack of differences in parasympathetic control, indicates alteration in circadian patterns of sympathetic HR control in db/db mice, whereas in STZ-treated mice this longer-term variability was partially reduced throughout the 24-h period (reduced in SD2 (statistically significant at 6 am, 9 am, 12 pm, 5 pm, 7 pm, and 8 pm), but not in SDNN; Fig. 4). Both models had blunted HR response to stress and exercise (HR in upon placement on the stationary treadmill was 665 ± 8 bpm in db/db and 619 ± 21 in STZ-treated mice: sig- nificantly lower than the 740 ± 9 bpm in control; p b 0.05 for both; Fig. 5). Overall our data suggest impaired sympathetic control of HR in both diabetic mouse ...
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... of 38-98 bpm; statistically significant at 1 am, 2 am, 8 am, 11 am, 12 pm, 6 pm, 7 pm, 8 pm, 9 pm, 10 pm, and 11 pm in week 10; Fig. 3). At week 10, STZ-treated mice had relatively consistently lower levels of longer-term HRV as measured by SD2 (reduced by 13-54 units; statisti- cally significant at 6 am, 9 am, 12 pm, 5 pm, 7 pm, and 8 pm; Fig. 4), but no change in short-term HRV measures. This indicates that there is a rel- ative reduction in sympathetic control in these mice, which fits with their overall reduction in HR and agrees with most of the previously published studies in type-1 diabetic animal models ( Stables et al., 2013). However, the SDNN data (which reflects a ...
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... of HRV measures that are particularly sensitive to artifacts and non-stationarity of signal ( Thireau et al., 2008) (i.e. fre- quency domain analysis by FFT). Thus, the FFT results (Supplemental Fig. 3) should only be considered in combination with the more robust (Kamen and Tonkin, 1995;Thireau et al., 2008) time-domain and Poincare plot data (Fig. ...
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Citations
... It can activate the cardiovascular system and kidney receptors to protect from DN in preclinical models 22 . Besides, the animal research has found that type 2 diabetic(db/db) mice showed altered circadian patterns of both heart rate (HR) and sympathetic control of HR variability (HRV) 23 . As cardiac autonomic dysfunction is a serious complication of diabetes, we assume that treatment based on rhythm regulation may prevent the occurrence of this complication. ...
... In the next study, on the basis of expanding the sample size, we plan to compare the efficacy and safety of different drugs, so as to further clarify the therapeutic differences among them. Third, the expression rhythms of some rhythm genes may be affected by psychotropics 23 . Unfortunately, we didn't detect gene expression in this study. ...
We aimed to explore a new treatment model for type 2 diabetes mellitus (DM) based on rhythm regulation under the framework of psychosomatic medicine. Using psychotropics as rhythm regulators, 178 patients with DM were evaluated and divided into three groups: the antidiabetic treatment group (AT group), psychotropic treatment group (PT group), and combined antidiabetic + psychotropic treatment group (combined group), for a course of 16 weeks. The West China Psychiatry Association (WCPA) Somatic Symptom Classification Scale (SSCS) was used to evaluate each patient. The levels of hormones in the hypothalamic–pituitary–adrenal (HPA) and hypothalamic-pituitary-thyroid axes and of blood glucose and glycosylated hemoglobin (HbA1c) were evaluated both before and after treatment. After the treatment, the blood glucose and HbA1c levels in all three groups were lower than those at baseline. Furthermore, the incidence of the abnormal HPA axis in the PT group was significantly decreased ( P = 0.003), while the incidence of the abnormal HPA axis in the combined group was 0.0%. The five factor scores of the SSCS in the PT and combined groups after treatment were both significantly low ( P < 0.01). Both the incidence of abnormal neuroendocrine axes and SSCS scores in the AT group showed no significant difference before and after treatment. “Blood glucose control + rhythm regulation” should be considered as optimised treatment goals for DM. Moreover, some psychotropics could be used as biorhythm regulators, which have good potential value for clinical application.
Clinical trial registration number: ChiCTR1800019064. Name of trial registration: Reinterpretation of mechanism and the optimization of treatment for non-infectious chronic diseases under the “stress-dysrhythmia” theory hypothesis. The full trial protocol can be accessed at the Chinese Clinical Trial Registry ( http://www.chictr.org.cn/ ).
... The following time domain measures of HRV were calculated for the Kcna1 -/mouse: the standard deviation of the beat-to-beat intervals (SDNN), which is an index of total autonomic variability; and the root mean square of successive beat-to-beat differences (RMSSD), which is an index of parasympathetic tone. 24 Using the signal acquisition software-generated R-R interval values for the Kcna1 -/mouse (Figure 9B), the HRV software calculated a heart rate of 737 beats/min ( Table 1), which is similar to WT mice in our previous studies 18 . The SDNN and RMSSD values were calculated to be 2.4 ms and 3.2 ms, respectively ( Table 1), which are about 2-to 3-fold higher than a normal WT mouse 18 . ...
In epilepsy, seizures can evoke cardiac rhythm disturbances such as heart rate changes, conduction blocks, asystoles, and arrhythmias, which can potentially increase risk of sudden unexpected death in epilepsy (SUDEP). Electroencephalography (EEG) and electrocardiography (ECG) are widely used clinical diagnostic tools to monitor for abnormal brain and cardiac rhythms in patients. Here, a technique to simultaneously record video, EEG, and ECG in mice to measure behavior, brain, and cardiac activities, respectively, is described. The technique described herein utilizes a tethered (i.e., wired) recording configuration in which the implanted electrode on the head of the mouse is hard-wired to the recording equipment. Compared to wireless telemetry recording systems, the tethered arrangement possesses several technical advantages such as a greater possible number of channels for recording EEG or other biopotentials; lower electrode costs; and greater frequency bandwidth (i.e., sampling rate) of recordings. The basics of this technique can also be easily modified to accommodate recording other biosignals, such as electromyography (EMG) or plethysmography for assessment of muscle and respiratory activity, respectively. In addition to describing how to perform the EEG-ECG recordings, we also detail methods to quantify the resulting data for seizures, EEG spectral power, cardiac function, and heart rate variability, which we demonstrate in an example experiment using a mouse with epilepsy due to Kcna1 gene deletion. Video-EEG-ECG monitoring in mouse models of epilepsy or other neurological disease provides a powerful tool to identify dysfunction at the level of the brain, heart, or brain-heart interactions.
... Kcna1 -/mice also exhibit ictal bradycardia and improved survival following vagotomy, suggesting underlying parasympathetic dysfunction that may contribute to their premature death (14,15). To assess the influence of the parasympathetic branch of the autonomic nervous system on cardiac function, heart rate variability (HRV) was calculated in the time domain for each genotype using the following measures: the standard deviation of the beat-to-beat intervals (SDNN), which is an index of total autonomic variability; and the root mean square of successive beat-to-beat differences (RMSSD), which is an index of parasympathetic tone (35). Mean heart rates were similar between all genotypes (one-way ANOVA, P ¼ 0.39; Fig. 5C). ...
People with epilepsy have greatly increased probability of premature mortality due to sudden unexpected death in epilepsy (SUDEP). Identifying which patients are most at risk of SUDEP is hindered by a complex genetic etiology, incomplete understanding of the underlying pathophysiology, and lack of prognostic biomarkers. Here we evaluated heterozygous Scn2a gene deletion (Scn2a+/–) as a protective genetic modifier in the Kcna1 knockout mouse (Kcna1–/–) model of SUDEP, while searching for biomarkers of SUDEP risk embedded in electroencephalography (EEG) and electrocardiography (ECG) recordings. The human epilepsy gene Kcna1 encodes voltage-gated Kv1.1 potassium channels that act to dampen neuronal excitability whereas Scn2a encodes voltage-gated Nav1.2 sodium channels important for action potential initiation and conduction. SUDEP-prone Kcna1–/– mice with partial genetic ablation of Nav1.2 channels (i.e., Scn2a+/–; Kcna1–/–) exhibited a two-fold increase in survival. Classical analysis of EEG and ECG recordings separately showed significantly decreased seizure durations in Scn2a+/–; Kcna1–/– mice compared to Kcna1–/– mice, without substantial modification of cardiac abnormalities. Novel analysis of the EEG and ECG together revealed a significant reduction in EEG-ECG association in Kcna1–/– mice compared to wild types, which was partially restored in Scn2a+/–; Kcna1–/– mice. The degree of EEG-ECG association was also proportional to the survival rate of mice across genotypes. These results show that Scn2a gene deletion acts as protective genetic modifier of SUDEP and suggest measures of brain-heart association as potential indices of SUDEP susceptibility.
Genetically or surgically altered mice are commonly used as models of human cardiovascular diseases. Electrocardiography (ECG) is the gold standard to assess cardiac electrophysiology as well as to identify cardiac phenotypes and responses to pharmacological and surgical interventions. A variety of methods are used for mouse ECG acquisition under diverse conditions , making it difficult to compare different results. Non-invasive techniques allow only short-term data acquisition and are prone to stress or anesthesia related changes in cardiac activity. Telemetry offers continuous long-term acquisition of ECG data in conscious freely moving mice in their home cage environment. Additionally, it allows acquiring data 24/7 during different activities, can be combined with different challenges and most telemetry systems collect additional physiological parameters simultaneously. However, telemetry transmitters require surgical implantation, the equipment for data acquisition is relatively expensive and analysis of the vast number of ECG data is challenging and time-consuming. This review highlights the limits of non-invasive methods with respect to telemetry. In particular, primary screening using non-invasive methods can give a first hint; however, subtle cardiac phenotypes might be masked or compensated due to anesthesia and stress during these procedures. In addition, we detail the key differences between the mouse and human ECG. It is crucial to consider these differences when analyzing ECG data in order to properly translate the insights gained from murine models to human conditions.
Environmental enrichment (EE) can reduce anxiety and stress in experimental animals, while little is known about the influence on autonomic nervous activity especially in disease animal models. Diabetes mellitus (DM) is associated with cardiovascular autonomic dysfunction, which can be characterized by a higher resting heart rate and a lower heart rate variability (HRV). We hypothesized that EE can enhance parasympathetic nervous activity while reducing disease progression in type 2 diabetic mice. A telemetry transmitter was implanted in NSY mice to continuously record electrocardiograms (ECG). Animals were kept in a cage with or without a nest box as EE. The autonomic nervous activity was evaluated using power spectral analysis of HRV. Four weeks of EE could increase high frequency (HF) power, but no change was observed in the absence of EE. Although animals showed impaired glucose tolerance at 48 weeks of age regardless of EE, a worsen case was observed in control. These results indicate that EE can be necessary for long-term housing of experimental animals and may reduce the risk of impaired glucose tolerance in NSY mice by enhancing parasympathetic nervous activity. In future, it is demanded whether increasing parasympathetic nervous activity, whatever the method is, can prevent diabetes from worsening.
Background:
Patients with type 2 diabetes mellitus (T2DM) have a greater risk of developing life-threatening cardiac arrhythmias. Since the underlying mechanisms and potential influence of diabetic autonomic neuropathy are not well understood, we aimed to assess the relevance of a dysregulation in cardiac autonomic tone.
Methods and results:
Ventricular arrhythmia susceptibility was increased in Langendorff-perfused hearts isolated from mice with T2DM (db/db). Membrane properties and synaptic transmission were similar at cardiac postganglionic parasympathetic neurons from diabetic and control mice; however, a greater asynchronous neurotransmitter release was present at sympathetic postganglionic neurons from the stellate ganglia of db/db mice. Western blot analysis showed a reduction of tyrosine hydroxylase (TH) from the ventricles of db/db mice, which was confirmed with confocal imaging as a heterogeneous loss of TH-immunoreactivity from the left ventricular wall but not the apex. In-vivo stimulation of cardiac parasympathetic (vagus) or cardiac sympathetic (stellate ganglion) nerves induced similar changes in heart rate in control and db/db mice and the kinetics of pacing-induced Ca2+ transients, recorded from isolated cardiomyocytes, were similar in control and db/db cells. Antagonism of cardiac muscarinic receptors did not affect the frequency or severity of arrhythmias in db/db mice, but sympathetic blockade with propranolol completely inhibited arrhythmogenicity.
Conclusion:
Collectively, these findings suggest that the increased ventricular arrhythmia susceptibility of type 2 diabetic mouse hearts is due to dysregulation of the sympathetic ventricular control.
Echocardiography is the most commonly applied technique for non-invasive assessment of cardiac function in small animals. Manual tracing of endocardial borders is time consuming and varies with operator experience. Therefore, we aimed to evaluate a novel automated two-dimensional software algorithm (Auto2DE) for small animals and compare it to the standard use of manual 2D-echocardiographic assessment (2DE). We hypothesized that novel Auto2DE will provide rapid and robust data sets, which are in agreement with manually assessed data of animals.
2DE and Auto2DE were carried out using a high-resolution imaging-system for small animals. First, validation cohorts of mouse and rat cine loops were used to compare Auto2DE against 2DE. These data were stratified for image quality by a blinded expert in small animal imaging. Second, we evaluated 2DE and Auto2DE in four mouse models and four rat models with different cardiac pathologies.
Automated assessment of LV function by 2DE was faster than conventional 2DE analysis and independent of operator experience levels. The accuracy of Auto2DE-assessed data in healthy mice was dependent on cine loop quality, with excellent agreement between Auto2DE and 2DE in cine loops with adequate quality. Auto2DE allowed for valid detection of impaired cardiac function in animal models with pronounced cardiac phenotypes, but yielded poor performance in diabetic animal models independent of image quality.
Auto2DE represents a novel automated analysis tool for rapid assessment of LV function, which is suitable for data acquisition in studies with good and very good echocardiographic image quality, but presents systematic problems in specific pathologies.
Electronic supplementary material
The online version of this article (10.1186/s12947-019-0156-0) contains supplementary material, which is available to authorized users.
