Assessment of cardiac autonomic neuropathy (CAN) in Type I diabetic mice

Diabetic cardiovascular autonomic neuropathy (DCAN) is common in patients with diabetes mellitus, and causes abnormalities in heart rate control as well as central and peripheral nervous system dynamics. A good understanding of DCAN is not established yet. An effective way to detect diabetes mellitus at an early stage is still undiscovered, which method is highly desired by researchers and patients. One reason why the pathogenesis of DCAN is unclear is that non- invasive assessment of DCAN in humans and animals has been problematic. The non-stationary and non- linear natures of the interested physiological signals have placed great limitation on traditionally algorithms. To overcome this limitation, this work proposes a series of time- varying, nonlinear and non-invasive methods to assess cardiac autonomic dysregulation from ECG and PPG records. Including a non-stationary method called PDM, which is based on principal dynamic mode (PDM) analysis of heart rate variability (HRV), nonstationary power spectral density called TVOPS-VFCDM and also standard spectrum analysis method of HRV. We are also able to study and analyze a series of long term and short term ECG and PPG data. In a pilot study, ECG was measured via telemetry in conscious 4 month old C57/Bl6 controls and in Akita mice, a model of insulin- dependent type I diabetes, while PPG was measured via tail pulse oximetry system from 2 month old to 4 month old. The results indicate significant cardiac autonomic impairment in the diabetic mice in comparison to the controls at 4 month old and such impairment start to present at 3 month old. Further, both immunohistochemistry and Western blot analyses show a reduction in nerve density in Akita mice as compared to the control mice, thus, corroborating our data analysis records

Characterization of Murine Cardiac Cholinergic Innervation and Its Remodeling in Type 1 Diabetes.

Murine models have become increasingly popular to study various aspects of cardiovascular diseases due to their ease of genetic manipulation. Unfortunately, there has been little effort put into describing the distribution of autonomic nerves in the mouse heart, making it difficult to compare current findings from clinical and experimental models related to cardiovascular diseases. Furthermore, determination of the requirements for the development of this system and its maintenance in adult mice remains largely unexplored. This study represents the first detailed mapping of cholinergic neuroanatomy of the mouse heart based on immunohistochemical staining using true cholinergic markers. We found cholinergic innervation of the mouse heart to be largely focused in the atrium and conducting system. We investigated the involvement of the neurotrophic factor neurturin (NRTN) in the development of cholinergic innervation, because there was indirect evidence that implicated it as a crucial factor. Results from our work definitively demonstrate that NRTN plays a major role in the development of cardiac parasympathetic ganglia and cholinergic innervation of the mouse heart. Adult NRTN knockout mice exhibited a drastic reduction in the number of intracardiac neurons with decreased atrial acetylcholine, cholinergic nerve density at the sinoatrial node and negative chronotropic responses to vagal stimulation. The presence of NRTN and its receptors in hearts from adult wild-type mice suggests that this neurotrophic factor might also be required for maintenance of cardiac cholinergic innervation. Finally, we wanted to determine how intracardiac neurons and their processes change during diseased states, specifically type 1 diabetes. This work has shown that the cardiac cholinergic nervous system in the mouse undergoes structural and functional remodeling when challenged with streptozotocin-induced diabetes. Cholinergic nerves in diabetic hearts undergo extensive sprouting at the sinoatrial node with no change in the number of intracardiac neurons. Cholinergic function appears to be enhanced in diabetic mice, based on pharmacological testing, despite decreased response to direct vagal nerve stimulation. Evidence also suggests that diabetic mice have an imbalance in autonomic control of heart rate. The latter findings suggest that disruption of central input into intrinsic cardiac ganglia also contributes to the neuropathology of type 1 diabetes

Cardiac Autonomic Imbalance in Newly Diagnosed and Established Diabetes Is Associated with Markers of Adipose Tissue Inflammation

Introduction. Diabetics die from cardiovascular disease at a much greater rate than nondiabetics. Cardiac autonomic imbalance predicts increased cardiovascular risk and mortality. We studied the relationship between cardiac autonomic imbalance and adipose tissue-derived inflammation in newly diagnosed and established type 2 diabetes. Materials and Methods. Non-diabetics, newly diagnosed diabetics, and established diabetics were included. Anthropomorphic and biochemical measurements were obtained, and insulin resistance was approximated. Cardiac autonomic function was assessed using conventional measures and with power spectral analysis of heart rate. Results and Discussion. Heart rate variability was reduced in all diabetics. Interleukin-6 was higher in diabetics, as was the high molecular weight adiponectin-to-leptin ratio. Interleukin-6 correlated negatively with measures of autonomic balance. Ratios of adiponectin to leptin correlated positively with measures of autonomic balance. Cardiac autonomic imbalance and inflammation occur early in diabetes and are interrelated. Conclusions. Cardiac autonomic imbalance correlates with the adipose tissue-derived inflammation seen early in type 2 diabetes

The Effects of Exercise Training on Indices of Cardiovascular Autonomic Neuropathy in STZ-Induced Type 1 Diabetic Rats Treated with Insulin

This study investigated whether regular aerobic exercise training could prevent the dysregulation of autonomic cardiovascular (CV) control in a streptozotocin (STZ)-diabetes model designed to represent clinical type 1 diabetes mellitus (T1DM). Rats were divided into control (C), control exercise (CX), diabetic (D) and diabetic exercise (DX) groups. Baroreflex sensitivity (BRS), heart rate variability (HRV) and vascular sympathetic tone (VST) were measured following 10 weeks of exercise. Parasympathetic-mediated bradycardia BRS was reduced in D compared to C and DX (

Prevalence of risk factors promoting Diabetic neuropathy .

Diabetic neuropathy is the worst consequence of diabetes mellitus leading to nerve dysfunction that is the cause of several complications such as pain, loss of sensitivity, damage to body systems, foot ulcers, morbidity and amputations etc. The aim of the present work was to study the prevalence of risk factors and occurrence of diabetic neuropathy in patients with diabetes, and how much diabetic neuropathy complications affect the life of diabetic patients

Temporal dystrophic remodeling within the intrinsic cardiac nervous system of the streptozotocin-induced diabetic rat model

INTRODUCTION: The pathogenesis of heart failure (HF) in diabetic individuals, called “diabetic cardiomyopathy”, is only partially understood. Alterations in the cardiac autonomic nervous system due to oxidative stress have been implicated. The intrinsic cardiac nervous system (ICNS) is an important regulatory pathway of cardiac autonomic function, however, little is known about the alterations that occur in the ICNS in diabetes. We sought to characterize morphologic changes and the role of oxidative stress within the ICNS of diabetic hearts. Cultured ICNS neuronal cells from the hearts of 3- and 6-month old type 1 diabetic streptozotocin (STZ)-induced diabetic Sprague-Dawley rats and age-matched controls were examined. Confocal microscopy analysis for protein gene product 9.5 (PGP 9.5) and amino acid adducts of (E)-4-hydroxy-2-nonenal (4-HNE) using immunofluorescence was undertaken. Cell morphology was then analyzed in a blinded fashion for features of neuronal dystrophy and the presence of 4-HNE adducts. RESULTS: At 3-months, diabetic ICNS neuronal cells exhibited 30% more neurite swellings per area (p = 0.01), and had a higher proportion with dystrophic appearance (88.1% vs. 50.5%; p = <0.0001), as compared to control neurons. At 6-months, diabetic ICNS neurons exhibited more features of dystrophy as compared to controls (74.3% vs. 62.2%; p = 0.0448), with 50% more neurite branching (p = 0.0015) and 50% less neurite outgrowth (p = <0.001). Analysis of 4-HNE adducts in ICNS neurons of 6-month diabetic rats demonstrated twice the amount of reactive oxygen species (ROS) as compared to controls (p = <0.001). CONCLUSION: Neuronal dystrophy occurs in the ICNS neurons of STZ-induced diabetic rats, and accumulates temporally within the disease process. In addition, findings implicate an increase in ROS within the neuronal processes of ICNS neurons of diabetic rats suggesting an association between oxidative stress and the development of dystrophy in cardiac autonomic neurons

Hemodynamic Considerations in the Pathophysiology of Peripheral Neuropathy

Peripheral neuropathic pain presents one of the greatest on going challenges to both acute and chronic pain management yet our understanding of the origins and pathogenesis of this complex disease state are severely lacking. The purpose of this chapter is to review the current literature regarding neuropathic pain as impacted by hemodynamic alterations. Because of the varied origins of neuropathy, this cannot be discussed as a single entity but we can seek to identify a final common pathway. We will for this reason examine each known pathogenetic category of neuropathy separately then discuss the effect of hemodynamic alterations through changes in blood pressure to determine any correlations between these alterations and specific effects upon neural structure and function. We have divided this chapter into sections which describe the more commonly known and encountered neuropathies. These are diabetes mellitus, neurotoxic medications, alcohol-related neuropathy, Vitamin B12 deficiency, end-stage renal disease, inflammatory bowel disease, and rheumatoid arthritis

Myocardial ischemia reperfusion injury and cardioprotection in the presence of sensory neuropathy: therapeutic options

During the last decades, mortality of acute myocardial infarction has been dramatically improved, however, the incidence of post-infarction heart failure is still increasing. Cardioprotection by ischemic conditioning have been discovered more than 3 decades ago, however, its clinical translation is still an unmet need, mainly due to the disrupted cardioprotective signalling pathways in the presence of different cardiovascular risk factors and comorbidities and their medications. Sensory neuropathy is one of the comorbidities that has been shown to interfere with cardioprotection. In the present review we summarize the diverse aetiology of sensory neuropathies and the mechanisms by which neuropathies may interfere with ischemic heart disease and cardioprotective signalling. Moreover, we suggest future therapeutic options targeting ischemic heart and sensory neuropathy simultaneously

Cardiac dysfunction in the ZDF rat: Possible mechanisms and benefits of exercise

Cardiovascular disease has resulted in an increased risk of premature deaths for the 104 million Americans with prediabetes or diabetes and has accounted for approximately 65% of total diabetic deaths annually. Clinical manifestations of diabetic heart disease include left ventricular hypertrophy, diastolic and systolic dysfunction, and diabetic cardiac autonomic neuropathy, which are regularly observed at varying severities in persons with type 2 diabetes. The Zucker diabetic fatty (ZDF) rat has shown promise as a model of diabetic heart disease since it resembles the blending of cardiac diseases seen in humans and as such can be utilized to investigate diabetic heart disease and therapeutic interventions. We chose to investigate the impact of exercise on diabetic heart disease in the ZDF rat, and to explore a novel mechanism. The objectives of the dissertation were to investigate the cardiac dysfunction in the ZDF model, determine whether aerobic exercise training can reverse electrocardiographic (ECG) and hemodynamic changes induced by diabetes, and identify whether cardiac edema may be one of the factors contributing to diabetic heart disease and a possible target of exercise. Myocardial edema is an imbalance between vascular permeability, lymphatic vessels, lymph flow, and cardiac function. It is unknown if diabetes causes myocardial edema. Little is known about the impact of diabetes on the lymphatic system and its receptors, vascular endothelial growth factor receptor 3 (VEGFR-3) and lymphatic endothelial receptor 1(LYVE-1). These receptors are responsible for the uptake of their respective ligands, VEGF-C and hyaluronan. Each receptor's expression is regulated by prospero homeobox protein 1(PROX-1), which is the master switch for the lymphangiogenesis. Myocardial fluid imbalances have been implicated in the fibrosis and hypertrophy associated with common cardiovascular diseases, which makes edema a suitable target for possible interventions. Diabetes in the ZDF rat caused crucial changes in R wave amplitudes (p<0.001), heart rate variability (p<0.01), QT intervals (p<0.001) and QTc intervals (p<0.001). R wave amplitude augmentation in sedentary diabetic rats from baseline to termination was ameliorated by exercise, resulting in R wave amplitude changes in exercised diabetic rats similar to control rats. Of these changes, aerobic exercise training was only able to correct R wave amplitude changes. In addition, exercise had beneficial effects in this diabetic rat model with regards to ECG correlates of left ventricular mass. Of the 24 hemodynamic parameters tested, 15 were negatively affected by diabetes. The debility of diabetic heart disease was evident in the diastolic filling, isovolumic contraction, ejection, and isovolumic relaxation phases. Importantly, exercise training restored 13 of the 15 hemodynamic parameters affected by diabetes. However, we did not observe differences in left ventricular weights, a direct measure of myocardial edema, or alterations in the levels of VEGF-C, VEGFR-3, LYVE-1, or hyaluronan. We were able to observe systemic differences in plasma interleukin (IL)-2 levels, reductions in dP/dtmax, and differences in PROX-1 protein levels and DNA binding activity that were suggestive of the presence of myocardial edema in the ZDF rat. However, these alterations are indirect measures of myocardial edema, therefore we were unable to conclude in the 19 week old ZDF rat if myocardial edema exists and plays a role in diabetic heart disease