Streptozotocin-induced type 1 and 2 diabetes in rodents: a model for studying diabetic cardiac autonomic neuropathy.

BACKGROUND: Several animal models are continually being developed to study diabetic complication. Several conflicting regimen for diabetes induction exist in the literature with varying dose strength and regimen for different study interest in diabetes. This study aims to show the effect of high dose streptozotocin (STZ) on the one hand compared with multiple low doses after high fat diet induction on diabetic cardiac autonomic neuropathy (DCAN). METHODOLOGY: Eighty-four Wistar rats were used to demonstrate DCAN induction using 2 approaches one for T1DM (STZ 50mg/kg) and the other for T2DM (HFD for 8 weeks with STZ 25mg/Kg daily for five days). DCAN features were assessed using invasive biomarkers, histology patterns and cardiac nerve densities. RESULTS: Diabetes induction rate was 76% and 89% in T1DM and T2DM model respectively. T1DM group had significant weight loss, reduced c-peptide, and insulin level post induction. The T2DM additionally showed significantly higher total cholesterol and Homeostatic model assessment (HOMA) compared with control. Serum levels of catecholamine, choactase, nerve growth factor and cardiac nerve density confirms development of DCAN. CONCLUSION: High single dose of STZ and HFD with multiple low doses of STZ may be recommended for DCAN study in T1DM and T2DM rat model respectively.

Carvedilol improves heart rate variability indices, biomarkers but not cardiac nerve density in streptozotocin-induced T2DM model of diabetic cardiac autonomic neuropathy.

OBJECTIVES: There has been increasing recognition of the significant relationship between the autonomic nervous system and cardiovascular sequel in diabetes mellitus (DM) patients. Diabetic cardiac autonomic neuropathy (DCAN) still poses a treatment challenge in the clinical settings despite several research interventions. This study was designed to investigate the effect of carvedilol on experimentally induced DCAN in type 2 DM rat model. METHODS: DCAN was induced in 42 Wistar rats using high fat diet (HFD) for eight weeks, thereafter streptozotocin (STZ) at 25 mg/kg daily for five days. DCAN features were then assessed using non-invasive time and frequency varying holter electrocardiogram (ECG), invasive biomarkers, cardiac histology and cardiac nerve density. RESULTS: Carvedilol significantly ameliorated the effects of DCAN on noradrenaline (p=0.010) and advanced glycated end products (AGEs) (p<0.0001). Similarly, carvedilol reversed the reduction in levels of antioxidants, sorbitol dehydrogenase (SD) activity (p=0.009) nerve growth factors (p<0.0001) and choline acetyl-transferase (p=0.031) following DCAN induction. Furthermore, heart rate variability (HRV) indices which were also reduced with DCAN induction were also ameliorated by carvedilol. However, carvedilol had no significant effect on cardiac neuronal dystrophy and reduced cardiac nerve densities. CONCLUSIONS: Carvedilol improves physiological HRV indices and biomarkers but not structural lesions. Early detection of DCAN and intervention with carvedilol may prevent progression of autonomic neurologic sequel.

Assessment of Ventricular Repolarization in Sickle Cell Anemia Patients: The Role of QTc Interval, Tp-e Interval and Tp-e/QTc Ratio and Its Gender Implication.

BACKGROUND: Many specific and non-specific electrocardiographic abnormalities including ventricular arrhythmias have been reported in subjects with sickle cell anemia (SCA). In SCA patients, cardiac electrical abnormalities may be the leading cause of increased risk of arrhythmias. The corrected QT (QTc) interval, peak to the end of the T wave (Tp-e) interval and associated Tp-e/QTc ratio are promising measures of altered ventricular repolarization and increased arrhythmogenesis risk. AIM: This study assessed ventricular repolarization abnormalities in subjects with SCA using the QTc interval, Tp-e interval and Tp-e/QTc ratio, and also evaluated the gender differences in these parameters, as well as their determinants. METHODS: Sixty subjects with SCA and 60 healthy control subjects, matched for age and gender, were studied. All participants underwent physical examination, hematological and biochemical evaluation, and 12-lead electrocardiography (ECG) recording. QT and Tp-e intervals were measured from the ECG, and the QTc interval was calculated using Bazett's formula. Tp-e/QT and Tp-e/QTc ratios were also derived. RESULTS: QT and QTc intervals were prolonged in subjects with SCA. Tp-e interval, Tp-e/QT ratio and Tp-e/QTc ratio were prolonged in male SCA subjects, with a paradoxical shortening in female SCA subjects. Plasminogen activator inhibitor-1 (PAI-1) was an independent determinant of QTc, while body mass index (BMI) was an independent determinant of both Tp-e interval and Tp-e/QTc ratio. CONCLUSION: Our results suggest an elevated risk for ventricular arrhythmogenesis in male SCA subjects. Furthermore, increased BMI and PAI-1 level are possible markers of ventricular repolarization abnormalities in SCA subjects.

Heart rate variability indices, biomarkers, and cardiac nerve density: Independent surrogate markers for diagnosis of diabetic cardiac autonomic neuropathy in type 2 diabetes mellitus animal model.

OBJECTIVES: Heart rate variability (HRV) has been shown to represents a promising quantitative marker of autonomic activity. Studies have shown that diabetic patients and animal models have derangements in certain biochemical parameters with reduced cardiac nerve density following development of diabetic cardiac autonomic neuropathy (DCAN). This study, therefore, aims to correlate HRV indices, cardiac histology, and cardiac nerve density with selected biochemical markers in the DCAN rat model using high fat diet (HFD) and streptozotocin (STZ) induction. METHODS: DCAN was induced in Wistar rats using HFD for 8 weeks with 25 mg/kg STZ daily for 5 days. DCAN features were then assessed using Holter electrocardiography (ECG), invasive biomarkers, and cardiac histology. RESULTS: DCAN group had significantly higher advanced glycated end product levels (P < 0.0001), noradrenaline (P = 0.010), and insulin resistance (P = 0.016) compared with controls. The level of antioxidants, sorbitol dehydrogenase activity (P = 0.009), nerve growth factors (P < 0.0001), and choline acetyl-transferase (P = 0.031) was, however, significantly reduced. Furthermore, HRV indices which were also reduced with DCAN induction correlated significantly with levels of biomarkers and cardiac nerve density. CONCLUSION: HRV is a cheap and easy tool for assessing DCAN that significantly correlates with markers of autonomic activity. Holter ECG and HRV evaluation should be considered early in patients with diabetes.