Diabetic Cardiac Autonomic Neuropathy Research Articles

Diabetic Cardiac Autonomic Neuropathy: A Review of NLRP3 Inflammasome Complicity

Debilitating and often misdiagnosed cardiac autonomic neuropathy affects people with diabetes. Damage to the biggest sympathetic trunk ganglion of autonomic nerve fibers that innervate the heart and blood vessels, the superior cervical ganglion (SCG), is the cause of aberrant heart rate and vascular dynamics in people with diabetic cardiac autonomic neuropathy (DCAN). Mediating host immunological responses to microbial infection and cellular damage, inflammasomes are a class of cytosolic protein complexes that include NLRP3. This review compiled the findings of experimental investigations on DCAN and discussed their connection to the NLRP3 inflammasome’s involvement. SCG P2X7 receptor expression can be boosted by inflammation brought on by hyperglycemia, leading to nerve injury. Unfortunately, there is a lack of research on DCAN-related inflammation in animal models, especially in inflammasome. Currently, only IncRNAUC.360+ shRNA and Schisandrin B, prove to alleviate the pathogenesis. Therefore, more research into the causes and potential remedies for DCAN is necessary.

Validation of Tele-HRV: A Novel Digital Health Solution for Cardiovascular Risk Detection in Diabetes

BackgroundHeart rate variability (HRV) in a sensitive test of Cardiac autonomic neuropathy (CAN) and predicts high mortality in diabetes subjects. Our innovative TeleHRV solution conforms to the HRV Task Force Standards and consists of mApp controlled battery powered handy device that uploads data to the cloud and delivers eReport. It eliminates all cost and technical constraints and makes HRV available for mass application. Aim of this study was to compare the computation accuracy of standard HRV indices using TeleHRV analysis software and its open-source equivalent software Kubios HRV which is considered the gold standard. MethodsData for this project was downloaded from Physionet.org. Standard Time domain indices (mean RR, SDNN, RMSSD, NN50) and Frequency Domain Indices (LF, HF and LF/HF) were calculated with TeleHRV analysis software and Kubios HRV software and Correlation Coefficient (CC) as well as Intra-Class Correlation Coefficient (ICCC) were computed for the indices obtained from the two software. ResultsThe Maximum of ICCC =1 (which is perfect agreement) was obtained for mean RR interval while the Minimum CC= 0.9976 was obtained for LF/HF which is extremely well correlated for a minimum observation; CC and ICCC for other indices were in between for the two software. ConclusionThe statistics strongly suggests that TeleHRV's analysis software faithfully matches the HRV indices values calculated by the gold standard Kubios HRV and support the validity of TeleHRV, which provides a cost effective, handy and user-friendly technology in a resource constrained and remote locations for early detection of CAN in diabetes.

Cardiac Autonomic Neuropathy in Newly Diagnosed Patients With Type 2 Diabetes Mellitus.

Cardiac autonomic neuropathy (CAN) is a debilitating complication in diabetes mellitus, leading to life-threatening arrhythmias and various impairments. Its prevalence varies widely, and early detection and management are crucial. This study investigates the prevalence of CAN in newly diagnosed type 2 diabetes mellitus patients in Central India, comparing them to a control group. This case-control study included 35 newly diagnosed type 2 diabetes mellitus patients and 35 age-matched healthy controls from the general population. Cardiac autonomic function testing (AFT) was done by heart rate variability (HRV), the deep breathing test (DBT), the cold pressor test (CPT), and the lying-to-standing test (LST). Parameters were recorded and analyzed usingstatistical tests. Patients with type 2 diabetes mellitus had significantly higher weight, BMI, fasting blood sugar, post-prandial blood sugar, urine albumin-creatinine ratios, and systolic and diastolic blood pressure than controls. Abnormalities in HRV and E: I ratio during the DBT and CPT were more prevalent in these patients. Parasympathetic dysfunction (delta HR) and a lower E: I ratio were also significantly highin this group. Also, LST results suggested a greater likelihood of orthostatic symptoms in the patients' group. This study highlights the importance of AFT in diagnosing early CAN in newly diagnosedpatients. Early diagnosis and management of diabetic CAN are essential to prevent complications.

Influence of Fibrinogen/Albumin Ratio and Fibrinogen/Pre-Albumin Ratio on Cardiac Autonomic Neuropathy in Type 2 Diabetes.

Subclinical inflammation may be involved in the pathogenesis of diabetic cardiac autonomic neuropathy (DCAN). The purpose of the study is to explore the relationship between novel inflammation biomarkers fibrinogen-albumin ratio (FAR), fibrinogen-prealbumin ratio (FPR), and DCAN in type 2 diabetes mellitus (T2DM). A total of 715 T2DM patients were enrolled in this retrospective study, divided into non-DCAN (n=565) and DCAN (n=150) groups by Ewing's test. Serum fibrinogen, albumin, prealbumin, routine inflammatory and other biochemical markers were measured. Patients with versus without DCAN had higher FAR (10.29 ± 4.83 vs 7.22 ± 2.56 g/g, P < 0.001) and FPR (2.19 ± 1.85 vs 1.43 ± 0.93 g/mg, P < 0.001). As FAR and FPR quartiles increased, the incidence of DCAN increased (Quartile 1 vs Quartile 4: 8.4 vs 42.7%, 9.6 vs 39.2%, respectively, P < 0.001), heart rate variability parameters decreased (P < 0.001); the incidence of diabetic nephropathy, retinopathy and peripheral neuropathy tended to be higher and inflammation factors were more active (P < 0.01). FAR (OR, 95% CI: 1.16, 1.08-1.25, P < 0.001) and FPR (OR, 95% CI: 1.22, 1.03-1.44, P = 0.021) were independent determinants of DCAN; the risk of DCAN increased by approximately 65% and 27% with each increase in the standard deviation (SD) of FAR (OR per SD, 95% CI: 1.65, 1.29-2.11, P < 0.001) and FPR (OR per SD, 95% CI: 1.27, 1.04-1.56, P = 0.021). FAR and FPR are independent risk factors and may influence DCAN development through inflammation.

Omega-3 polyunsaturated fatty acids: Effects on the arterial stiffness and heart rate variability in patients with diabetic cardiac autonomic neuropathy

Omega-3 polyunsaturated fatty acids: Effects on the arterial stiffness and heart rate variability in patients with diabetic cardiac autonomic neuropathy

Diabetic cardiac autonomic neuropathy: insulin resistance, lipid profile, and omega-3 polyunsaturated fatty acids

The significance of cardiac autonomic neuropathy (CAN) in patients with type 2 diabetes mellitus (T2DM) has been not fully appreciated and there is no unified treatment algorithm. Aim: The aim of study was to investigate the effects of -3 polyunsaturated fatty acids (-3 PUFAs) on blood lipid profile and insulin resistance (IR) parameters in patients with T2DM and definite CAN. The study involved 33 patients with T2DM and definite CAN. Patients were allocated into two treatment groups: 1st group - 15 patients received standard hypoglycaemic therapy - control (n = 15); 2nd group (n = 18) - standard hypoglycaemic therapy and 1 capsule/day of the ω-3 PUFAs (1 g, including 90 % ω-3 PUFAs) for three months. The concentrations of glucose, glycated haemoglobin A1c, immunoreactive insulin in the blood were determined. Lipid metabolism was assessed by the concentration of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG) measurements. The insulin resistance Homeostasis model assessment, atherogenic coefficient (AC), TG/LDL-C, TG/TC, TG/LDL-C and TG glucose (TyG) index were calculated. Obtained results of our study could witness that the prescription of -3 PUFAs was accompanied by a statistically significant decrease in TG concentration; AC, TG/LDL-C, TG/TC, TG/LDL-C, TyG index parameters and increase in HDL-C levels (compared to control). Conclusions. Obtained results justify the appropriateness of -3 PUFAs prescriptions to patients with T2DM and definite CAN.

323-OR: Association of Silent Myocardial Infarction with Cardiac Autonomic Neuropathy among Asymptomatic Patients with Type 2 Diabetes

Background: Silent myocardial infarction (SMI) is a severe cardiovascular disease among patients with DM. Nowadays, the mechanism of SMI is not clear, but diabetic cardiac autonomic neuropathy (CAN) is assumed to be the most probable reason. However, whether SMI is associated with CAN remains controversial. Therefore, we aimed to evaluate the relationship between SMI and CAN in asymptomatic patients with T2DM. Methods: This is a hospital-based observational study. 4055 T2DM patients who were screened for CAN by Holter monitoring were investigated. Q-waves SMI was detected by ECG. The sensitivity and specificity of ECG-detected SMI by computed tomography-coronary angiography (CTA). Results: A total of 4055 patients were screened. At last, we included 1015 patients with T2DM. In the included population, 508 cases (50%) had CAN. Patients with CAN were more likely to be older and have higher levels of TC, LDL-c, Cr, UA, and Hcy (p&amp;lt;0.05). A total of 466 cases of SMI were detected by ECG, and the prevalence of SMI was 45.9% in 1015 patients. Compared with T2DM patients without CAN, patients with CAN had a higher prevalence of SMI (73.4% vs 26.6%, p&amp;lt;0.001). Multivariate logistic regression analysis confirmed that concomitant CAN was an independent predictor of the risk of SMI in T2DM patients (OR=7.53, 95%CI:2.98-19.02, p&amp;lt;0.001). Among the 133 patients who underwent coronary CTA, 55 (41.0%) cases had SMI, and 36 of them had Q-waves on ECG. The sensitivity and specificity of SMI detected by ECG were 65.5% and 91.0%, respectively. In 133 T2DM patients, patients with CAN also had a higher risk of occurring SMI than those without CAN (65.5% vs 34.5%, p&amp;lt;0.001). Conclusion: In asymptomatic T2DM patients, the occurrence of SMI was independently associated with CAN. Therefore, we should pay attention to the possibility of SMI in asymptomatic T2DM patients clinically. In particular, the monitoring should be strengthened when patients combined with diabetic CAN. Disclosure Y.Fu: None. L.Wu: None. Y.Yang: None. B.Qin: None. Q.Luo: None. Y.Chen: None. Y.Zhu: None.

The potential role of CpG oligodeoxynucleotides on diabetic cardiac autonomic neuropathy mediated by P2Y12 receptor in rat stellate ganglia.

Cardiac autonomic neuropathy has a high prevalence in type 2 diabetes, which increases the risk of cardiovascular system disorders. CpG oligodeoxynucleotide (CpG-ODN), a Toll-like receptor 9 (TLR9) ligand, has been shown to have cardioprotection and cellular protection. Our previous work showed that P2Y12 in stellate ganglia (SG) is involved in the process of diabetic cardiac autonomic neuropathy (DCAN). Here, we aim to investigate whether CpG-ODN 1826 plays a protective role in DCAN and whether this beneficial protection involves regulation of the P2Y12-mediated cardiac sympathetic injury. Our results revealed that CpG-ODN 1826 activated TLR9 receptor, improved the abnormal blood pressure (BP), heart rate (HR), heart rate variability (HRV) and sympathetic nerve discharge (SND) activity in diabetic rats and reduced the up-regulated NF-κB, P2Y12 receptor, TNF-α and IL-1β in SG. Meanwhile, CpG-ODN 1826 significantly decreased the elevated ATP, nuclear receptor coactivator 4 (NCOA4), iron, ROS and MDA levels and increased GPX4 and GSH levels. In addition, CpG-ODN 1826 contributes to maintain normalization of mitochondrial structure in SG. Overall, CpG-ODN 1826 alleviates the sympathetic excitation and abnormal neuron-glial signal communication via activating TLR9 receptors to achieve a balance of autonomic activity and relieve the DCAN in rats. The mechanism may involve the regulation of P2Y12 receptor in SG by reducing ATP release and NF-κB expression, which counteract neuroinflammation and ferroptosis mediated by activated P2Y12 in SG.

Lianmei Qiwu Decoction relieves diabetic cardiac autonomic neuropathy by regulating AMPK/TrkA/TRPM7 signaling pathway

This study investigated the effect of Lianmei Qiwu Decoction(LMQWD) on the improvement of cardiac autonomic nerve remodeling in the diabetic rat model induced by the high-fat diet and explored the underlying mechanism of LMQWD through the AMP-activated protein kinase(AMPK)/tropomyosin receptor kinase A(TrkA)/transient receptor potential melastatin 7(TRPM7) signaling pathway. The diabetic rats were randomly divided into a model group, an LMQWD group, an AMPK agonist group, an unloaded TRPM7 adenovirus group(TRPM7-N), an overexpressed TRPM7 adenovirus group(TRPM7), an LMQWD + unloaded TRPM7 adenovirus group(LMQWD+TRPM7-N), an LMQWD + overexpressed TRPM7 adenovirus group(LMQWD+TRPM7), and a TRPM7 channel inhibitor group(TRPM7 inhibitor). After four weeks of treatment, programmed electrical stimulation(PES) was employed to detect the arrhythmia susceptibility of rats. The myocardial cell structure and myocardial tissue fibrosis of myocardial and ganglion samples in diabetic rats were observed by hematoxylin-eosin(HE) staining and Masson staining. The immunohistochemistry, immunofluorescence, real-time quantitative polymerase chain reaction(RT-PCR), and Western blot were adopted to detect the distribution and expression of TRPM7, tyrosine hydroxylase(TH), choline acetyltransferase(ChAT), growth associated protein-43(GAP-43), nerve growth factor(NGF), p-AMPK/AMPK, and other genes and related neural markers. The results showed that LMQWD could significantly reduce the arrhythmia susceptibility and the degree of fibrosis in myocardial tissues, decrease the levels of TH, ChAT, and GAP-43 in the myocardium and ganglion, increase NGF, inhibit the expression of TRPM7, and up-regulate p-AMPK/AMPK and p-TrkA/TrkA levels. This study indicated that LMQWD could attenuate cardiac autonomic nerve remodeling in the diabetic state, and its mechanism was associated with the activation of AMPK, further phosphorylation of TrkA, and inhibition of TRPM7 expression.

Proprotein convertase subtilisin/kexin type 9 inhibitors: prospects for cholesterol-lowering therapy in type 2 diabetes

Diabetic dyslipoproteinemia (DLP), characterized by quantitative, qualitative, and kinetic changes in all major circulating lipids, contributes to an increased risk of atherosclerotic cardiovascular disease in patients with type 2 diabetes mellitus (DM). Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) by human monoclonal antibodies is a promising treatment for diabetic DLP. Several drugs differ in their mechanisms of inhibition of PCSK9 activity. The following groups are conditionally distinguished: PCSK9 monoclonal antibodies (anti-PCSK9 monoclonal antibodies): evolocumab, alirocumab, bococizumab (injectable); other injectable medications with different mechanism of actions (inclisiran, SPC4061, SPC5001, adnectin BMS-962476, LIB003, anti-PCSK9 vaccine; anti-PCSK9 vaccine (nanoparticle-based); orally administered drugs (PF-06446846, DS-9001a, SRT3025); cholesteryl ester transfer protein/PCSK9 inhibitors (anacetrapib, evacetrapib, torcetrapib, K-312). This review aims to discuss the role of alirocumab and evolocumab, fully humanized monoclonal antibodies, in the treatment of type 2 DM patients with DLP and to consider their effectiveness and safety. Strategy of search. Scopus, Science Direct (from Elsevier), and PubMed, including the Medline databases, were searched. The following keywords were used: autonomic nervous system, heart rate variability, baroreflex sensitivity, diabetic cardiac autonomic neuropathy, and MeSH terms. A manual search of the bibliography of publications was used to identify research results that could not be found with the online search. Statins are the first line of choice for treating DLP in patients with type 2 DM to reduce the risk of atherosclerotic cardiovascular disease. Ezetimibe is the next drug to be added if patients’ low-density lipoprotein cholesterol levels are higher than acceptable. In cases of failure of the combination of statins with ezetimibe, PCSK9 inhibitor is a reasonable and rational choice. Overall, clinical data suggest that PCSK9 inhibitors are well tolerated and provide a significant reduction in low-density lipoprotein cholesterol levels in type 2 DM patients with DLP in addition to high-intensity statin therapy. The use of PCSK9 inhibitors is not associated with impaired glycemic control or increased risk of diabetes development in individuals without previously diagnosed DM and may prevent or reduce subsequent cardiovascular events.

Transient Receptor Potential Canonical 5 (TRPC5) Channels Activator, BTD [N-{3-(adamantan-2-yloxy)-propyl}-3-(6-methyl-1,1-dioxo-2H-1λ6,2,4- benzothiadiazin-3-yl)-propanamide)] Ameliorates Diabetic Cardiac Autonomic Neuropathy in Rats.

Diabetic cardiac autonomic neuropathy (DCAN) is a serious diabetic complication with no approved pharmacological agents for its treatment. Parasympathetic system dysfunction characterized by vagal nerve damage is one of the major drivers of DCAN. The TRPC5 or transient receptor potential canonical 5 channel is a promising target in autonomic dysfunction; however, its role in vagal nerve damage and subsequent DCAN has not yet been elucidated. The present study investigated the role of the TRPC5 channel in DCAN using [N-{3-(adamantan-2-yloxy)-propyl}-3-(6-methyl-1,1-dioxo-2H-1λ6,2,4-benzothiadiazin-3-yl) propanamide)] or BTD, which is a potent TRPC5 activator. The role of the TRPC5 channel and its activator, BTD, was investigated in the treatment of parasympathetic dysfunction associated with DCAN. Type 1 diabetes was induced in male Sprague-Dawley rats using streptozotocin. The alterations in cardiac autonomic parameters in diabetic animals were assessed by heart rate variability, hemodynamic parameters, and baroreflex sensitivity. TRPC5's role in DCAN was investigated by treating diseased rats with BTD (1 and 3 mg/kg, i.p. for 14 days). BTD's beneficial effects in parasympathetic dysfunction were assessed by western blotting, estimating oxidative stress and inflammatory markers in the vagus nerve. BTD treatment (3 mg/kg, i.p.) once daily for 14 days ameliorated heart rate variability, hemodynamic dysfunction, and baroreflex sensitivity in diseased rats. BTD treatment down regulated TRPC5 expression by increasing the activity of protein kinase C in the vagus nerve. It also down-regulated the apoptotic marker CASPASE-3 and also exerted potent anti-inflammatory action on pro-inflammatory cytokines levels in the vagus. BTD ameliorated parasympathetic dysfunction associated with DCAN by virtue of its TRPC5 modulatory, anti-inflammatory, and anti-apoptotic properties.

CORRELATION BETWEEN MICROALBUMINURIA AND CORRECTED QT INTERVAL PROLONGATION IN PATIENTS WITH DIABETES MELLITUS

Background and Objectives: Diabetic cardiac autonomic neuropathy is a severe and common complication of diabetes. QTc prolongation is a predictor of Cardiac Autonomic Neuropathy (CAN), and microalbuminuria is a predictor of nephropathy. The main aim of the present study is to nd the association between prolonged QTc interval and microalbuminuria in Type 2 Diabetes Mellitus(T2DM). Methods: Sixty patients of type 2 diabetics, attending RLJH hospital in Kolar, were included in the study. We divided these patients into two groups, each with thirty patients. One group consists of patients with microalbuminuria and the other with normoalbuminuria. All these patients were tested for microalbuminuria and looked for QTc interval prolongation in ECG. A chi-square test was used to analyze t h e two sample proportions. Most of the p Results: atients were in the 50 to 70 years of age group. There is a signicant associa n between QTc prolongation with microalbuminuria, as evidenced by (66.6%, P-Value &lt;0.0001). The male-tofemale ratio is 3.8:1, and as the duration of diabetes increases, there is an increase in the incidence of QTc interval prolongation andmicroalbuminuria. There was also a signicant association with retinopathy and neuropathy with cardiac autonomic neuropathy(CAN). Interpretation and Conclusion: There was a signicant association between CAN(QTc prolongation) and microalbuminuria. Microalbuminuria per se doesn't cause QTc prolongation, and the reason for this is not clearly understood. QTc prolongation is one of the independent cause of mortality seen in microalbuminuria patients, which is preventable. Hence the aim is to prevent and reduce the mortality in T2DM patients

Schisandrin B Alleviates Diabetic Cardiac Autonomic neuropathy Induced by P2X7 Receptor in Superior Cervical Ganglion via NLRP3.

Diabetic cardiovascular autonomic neuropathy (DCAN) is a common complication of diabetes mellitus which brings about high mortality, high morbidity, and large economic burden to the society. Compensatory tachycardia after myocardial ischemia caused by DCAN can increase myocardial injury and result in more damage to the cardiac function. The inflammation induced by hyperglycemia can increase P2X7 receptor expression in the superior cervical ganglion (SCG), resulting in nerve damage. It is proved that inhibiting the expression of P2X7 receptor at the superior cervical ganglion can ameliorate the nociceptive signaling dysregulation induced by DCAN. However, the effective drug used for decreasing P2X7 receptor expression has not been found. Schisandrin B is a traditional Chinese medicine, which has anti-inflammatory and antioxidant effects. Whether Schisandrin B can decrease the expression of P2X7 receptor in diabetic rats to protect the cardiovascular system was investigated in this study. After diabetic model rats were made, Schisandrin B and shRNA of P2X7 receptor were given to different groups to verify the impact of Schisandrin B on the expression of P2X7 receptor. Pathological blood pressure, heart rate, heart rate variability, and sympathetic nerve discharge were ameliorated after administration of Schisandrin B. Moreover, the upregulated protein level of P2X7 receptor, NLRP3 inflammasomes, and interleukin-1β in diabetic rats were decreased after treatment, which indicates that Schisandrin B can alleviate the chronic inflammation caused by diabetes and decrease the expression levels of P2X7 via NLRP3. These findings suggest that Schisandrin B can be a potential therapeutical agent for DCAN.

Pathophysiological and clinical aspects of the circadian rhythm of arterial stiffness in diabetes mellitus: A minireview.

Several cross-sectional trials have revealed increased arterial stiffness connected with the cardiac autonomic neuropathy in types 2 and 1 diabetic patients. The pathophysiological relationship between arterial stiffness and autonomic dysfunction in diabetes mellitus is still underinvestigated and the question whether the presence of cardiac autonomic neuropathy leads to arterial stiffening or increased arterial stiffness induced autonomic nervous system impairment is still open. Both arterial stiffness and dysfunction of the autonomic nervous system have common pathogenetic pathways, counting state of the chronic hyperinsulinemia and hyperglycemia, increased formation of advanced glycation end products, activation of protein kinase C, development of endothelial dysfunction, and chronic low-grade inflammation. Baroreceptor dysfunction is thought to be one of the possible reasons for the arterial wall stiffening development and progression. On the contrary, violated autonomic nervous system function can affect the vascular tone and by this way alter the large arteries walls elastic properties. Another possible mechanism of attachment and/or development of arterial stiffness is the increased heart rate and autonomic dysfunction corresponding progression. This minireview analyzes the current state of the relationship between the diabetes mellitus and the arterial stiffness. Particular attention is paid to the analysis, interpretation, and application of the results obtained in patients with type 2 diabetes mellitus and diabetic cardiac autonomic neuropathy.

Beneficial Effects of lncRNA-UC.360+ shRNA on Diabetic Cardiac Sympathetic Damage via NLRP3 Inflammasome-Induced Pyroptosis in Stellate Ganglion.

Hyperglycemia is one of the common symptoms of diabetes, and it produces excessive reactive oxygen species (ROS). This study investigated whether the long noncoding RNA (lncRNA) UC.360+ is involved in diabetic cardiac autonomic neuropathy (DCAN) mediated by NLRP3 inflammasome-induced pyroptosis in the stellate ganglion (SG). Using a rat type 2 diabetes model, we found that lncRNA UC.360+ short hairpin RNA (shRNA) ameliorated the dyslipidaemia of type 2 diabetic rats and reduced serum adrenaline and ROS production in SG under hyperglycemia. In addition, UC.360+ shRNA also reduced the expression of nuclear factor kappa-B (NF-κB), NLRP3, ASC, caspase-1, interleukin-1β (IL-1β), and IL-18 in the SG of diabetic rats and inhibited the phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK). Therefore, lncRNA-UC.360+ shRNA may modulate the NLRP3 inflammasome/inflammatory pathway in the SG, which in turn alleviates diabetic heart sympathetic nerve damage.

Naringin Relieves Diabetic Cardiac Autonomic Neuropathy Mediated by P2Y14 Receptor in Superior Cervical Ganglion.

Diabetes mellitus (DM), an emerging chronic epidemic, contributes to mortality and morbidity around the world. Diabetic cardiac autonomic neuropathy (DCAN) is one of the most common complications associated with DM. Previous studies have shown that satellite glial cells (SGCs) in the superior cervical ganglia (SCG) play an indispensable role in DCAN progression. In addition, it has been shown that purinergic neurotransmitters, as well as metabotropic GPCRs, are involved in the pathophysiological process of DCAN. Furthermore, one traditional Chinese medicine, naringin may potently alleviate the effects of DCAN. Ferroptosis may be involved in DCAN progression. However, the role of naringin in DCAN as well as its detailed mechanism requires further investigation. In this research, we attempted to identify the effect and relevant mechanism of naringin in DCAN mitigation. We observed that compared with those of normal subjects, there were significantly elevated expression levels of P2Y14 and IL-1β in diabetic rats, both of which were remarkably diminished by treatment with either P2Y14 shRNA or naringin. In addition, abnormalities in blood pressure (BP), heart rate (HR), heart rate variability (HRV), sympathetic nerve discharge (SND), and cardiac structure in the diabetic model can also be partially returned to normal through the use of those treatments. Furthermore, a reduced expression of NRF2 and GPX4, as well as an elevated level of ROS, were detected in diabetic cases, which can also be improved with those treatments. Our results showed that naringin can effectively relieve DCAN mediated by the P2Y14 receptor of SGCs in the SCG. Moreover, the NRF2/GPX4 pathway involved in ferroptosis may become one of the principal mechanisms participating in DCAN progression, which can be modulated by P2Y14-targeted naringin and thus relieve DCAN. Hopefully, our research can supply one novel therapeutic target and provide a brilliant perspective for the treatment of DCAN.

Novel Application of Multiscale Cross-Approximate Entropy for Assessing Early Changes in the Complexity between Systolic Blood Pressure and ECG R-R Intervals in Diabetic Rats.

Cardiac autonomic neuropathy (CAN) is a common complication of diabetes mellitus, and can be assessed using heart rate variability (HRV) and the correlations between systolic blood pressure (SBP) and ECG R-R intervals (RRIs), namely baroreflex sensitivity (BRS). In this study, we propose a novel parameter for the nonlinear association between SBP and RRIs based on multiscale cross-approximate entropy (MS-CXApEn). Sixteen male adult Wistar Kyoto rats were equally divided into two groups: streptozotocin-induced diabetes and age-matched controls. RRIs and SBP were acquired in control rats and the diabetic rats at the onset of hyperglycemia and insulin-treated euglycemia to determine HRV by the ratio of low-frequency to high-frequency power (LF/HF) and Poincaré plot as SSR (SD1/SD2), BRS, and MS-CXApEn. SSR and BRS were not significantly different among the three groups. The LF/HF was significantly higher in the hyperglycemic diabetics than those in the controls and euglycemic diabetic rats. MS-CXApEn was higher in the diabetic hyperglycemic rats than the control rats from scales 2 to 10, and approached the values of controls in diabetic euglycemic rats at scales 9 and 10. Conclusions: We propose MS-CXApEn as a novel parameter to quantify the dynamic nonlinear interactions between SBP and RRIs that reveals more apparent changes in early diabetic rats. Furthermore, changes in this parameter were related to correction of hyperglycemia and could be useful for detecting and assessing CAN in early diabetes.

Retracted: Association of QT interval indices with cardiac autonomic neuropathy in diabetic patients

Background. Cardiovascular autonomic neuropathy (CAN) is a severely debilitating yet underdiagnosed condition in patients with diabetes mellitus. The prevalence can range from 2.5% (based on the primary prevention cohort in the Diabetes Control and Complications Trial) to as high as 90% of diabetic patients. Clinical manifestations range from orthostasis to myocardial infarction. The diagnosis is made using multiple autonomic function tests to assess both sympathetic and parasympathetic function. This study was conducted to assess the relationship between Cardiac autonomic neuropathy and QT interval. Material and methods. This was a cross-sectional study conducted in 100 patients attending a tertiary care hospital in India. Deep breathing test, Valsalva ratio, immediate heart rate response to standing 30 : 15, BP rise with sustained hand grip and postural hypotension were evaluated. Scoring was done for cardiac autonomic neuropathy. QT interval and QTc interval were determined and association with CAN was obtained. Results. Out of 100 type 2 diabetic patients, 60% were males and 40% were females. 25 patients having no cardiac autonomic neuropathy and had no prolonged QTc interval. While, 75 patients had QTc prolonged were associated with early and severe CAN cardiac autonomic neuropathy. The prolonged QTc was significantly associated with CAN in diabetic patients when compared without CAN and controls (P &lt; 0.0001). The grading score for CAD showed that 75% cases were having score &gt; 2 were 25% of cases had score &lt; 2. Out of 75 patients 44 were between score 2–4 and 31 were above score 4. A significant association between QTc and Diabetic CAN patients observed when compared non CAN and controls. Conclusions. Diabetic cardiac autonomic neuropathy is associated with increase in prolongation of QTc intervals. Hence, there is need for regular checkup of autonomic nervous system in diabetic patient to prevent further complications.

DIABETIC CARDIAC AUTONOMIC NEUROPATHY: SIMVASTATIN, INSULIN RESISTANCE AND LIPIDS

Treatment of diabetic cardiac autonomic neuropathy (CAN) is a complex process, that includes: lifestyle modification; reducing of insulin resistance (IR); optimal glycemic control; management of diabetic dyslipidemia; antioxidants; vitamins; treatment of myocardial metabolic abnormalities; thrombosis and others. The aim of study was to investigate the effects of simvastatin on insulin resistance and blood lipid profile parameters in patients with type 2 diabetes mellitus (T2DM) and the definite stage of cardiac autonomic neuropathy. The study involved 107 patients with T2DM among them 16 patients without CAN, 19 with subclinical stage of CAN and 72 with definite CAN. Median age of patients was 53.6 ± 0.41 yrs, disease duration - 4.12 ± 0.24 yrs and median glycated hemoglobin (HbA1c) - 7.01% ± 0.09%. The control group included 14 almost healthy people without DM. Patients with definite CAN were allocated into two treatment groups: 1st group - 22 patients received standard hypoglycemic therapy and simvastatin 20 mg/day; 2nd group - control (n = 15). The duration of the study was 3 mos. The concentrations of glucose, HbA1c, immunoreactive insulin (IRI) in the blood were determined. Lipid metabolism was assessed by the concentration of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG) measurements. The IR index (HOMA-IR), atherogenic coefficient (AC), TG/HDL-C parameters, and TG-glucose (TyG) index were calculated. It was established that in patients with T2DM with subclinical stage of CAN there was statistically significant increase in the parameters of HbA1c, IRI, TC, TG and HOMA-IR, AC, TyG indices and decrease of TG/HDL-C and HDL-C compared to control; increase of IRI, TG, TG/HDL-C and TyG indices compared to patients with T2DM without CAN. The definite stage of CAN is characterized by an increase of HbA1c, IRI, TC, LDL-C levels and HOMA-IR, AC indices and a significant decrease in the concentration of HDL-C (compared to patients with subclinical CAN). As a result of our study, we found out that prescription of simvastatin to patients with definite stage of CAN was accompanied by a statistically significant decrease in the concentration of TC, LDL-C, TG and an increase in the content of HDL-C (compared to 2nd, control group). Obtained results justify the appropriateness of statins prescription to patients with T2DM and the definite stage of CAN.

The association between diabetic retinopathy and cardiac autonomic neuropathy in patients with type 2 diabetes

The association between diabetic retinopathy and cardiac autonomic neuropathy in patients with type 2 diabetes