Cardiovascular autonomic neuropathy in diabetes:Pathophysiology,clinical assessment and implications

Cardiovascular autonomic neuropathy(CAN)is a debilitating condition that mainly occurs in long-standing type 2 diabetes patients but can manifest earlier,even before diabetes is diagnosed.CAN is a microvascular complication that results from lesions of the sympathetic and parasympathetic nerve fibers,which innervate the heart and blood vessels and promote alterations in cardiovascular autonomic control.The entire mechanism is still not elucidated,but several aspects of the pathophysiology of CAN have already been described,such as the production of advanced glycation end products,reactive oxygen species,nuclear factor kappa B,and pro-inflammatory cytokines.This microvascular complication is an important risk factor for silent myocardial ischemia,chronic kidney disease,myocardial dysfunction,major cardiovascular events,cardiac arrhythmias,and sudden death.It has also been suggested that,compared to other traditional cardiovascular risk factors,CAN progression may have a greater impact on cardiovascular disease development.However,CAN might be subclinical for several years,and a late diagnosis increases the mortality risk.The duration of the transition period from the subclinical to clinical stage remains unknown,but the progression of CAN is associated with a poor prognosis.Several tests can be used for CAN diagnosis,such as heart rate variability(HRV),cardiovascular autonomic reflex tests,and myocardial scintigraphy.Currently,it has already been described that CAN could be detected even during the subclinical stage through a reduction in HRV,which is a non-invasive test with a lower operating cost.Therefore,considering that diabetes mellitus is a global epidemic and that diabetic neuropathy is the most common chronic complication of diabetes,the early identification and treatment of CAN could be a key point to mitigate the morbidity and mortality associated with this long-lasting condition.

Alpha-lipoic Acid:Effects on the Beat-to-Beat Vectorcardiographic Parameters in Type 2 Diabetes Mellitus Patients with Cardiac Autonomic Neuropathy

Objective:Relevance of cardiac autonomic neuropathy has not been fully recognized and there is no standardized treatment protocol.Aim:To evaluate the effects of alpha-lipoic acid on the beat-to-beat vectorcardiographic parameters,namely spatial QRS-T angle,QT dispersion(QTd)and corrected QT interval(QTc)in type 2 diabetes mellitus persons with cardiac autonomic neuropathy.Research designs and methods:Our study involved 33 persons with definite stage of cardiac autonomic neuropathy and diabetes mellitus type 2,which were assigned to each of two groups:one took standard antihyperglycaemic treatment(n=15,control group)and the other(n=18)in addition to standard therapy-600 mg of alpha-lipoic acid daily for three months.The analysis of vectorcardiographic parameters was performed.Results:It was found out that alpha-lipoic acid contributed to decrease of the vectorcardiographic parameters,namely QRS-T angle,QTd and QTc.Conclusions:The positive influences of alpha-lipoic acid suggest the usefulness of its prescription to type 2 diabetes mellitus persons with definite stage of cardiac autonomic neuropathy.The efficacy of alpha-lipoic acid is the result of its direct effect on the parameters of vectorcardiography.

Exercise Intolerance and Excessive Chronotropic Response Due to Possible Autonomic Dysfunction Post COVID-19 Infection

Introduction and Objectives: In patients with Post-Acute Sequelae of Coronavirus 2 infection (PASC), a post infectious autonomic dysfunction may be one of the underlying mechanisms. Patients often present with exercise intolerance and exaggerated heart rate response to exercise. We report a single centre experience of patients with PACS and suspected autonomic dysfunction. Methods: Forty-two patients evaluated in the Outpatient Cardiology Department with suspected PASC were included in the study. Patients complained of compromised exercise performance persisting >3 months after recovery from COVID-19 infection, compared to the pre-COVID-19 period. The patients were evaluated with 12-lead electrocardiogram, echocardiography, 24-hour ECG ambulatory monitoring and either exercise stress test or a 6-minute walk test. Results: All 42 patients demonstrated an exaggerated chronotropic response, defined as the inappropriate increase in heart rate before the 6th minute of exercise >100% of the age-predicted maximal heart rate value with reproduction of clinical symptoms. In addition, 24-hour ambulatory electrocardiography revealed an increased mean heart rate of 92 beats/minute and decreased mean standard deviation of sequential 5-minute N-N interval (SDNN) of 74.4 ms. Pharmaceutical treatment with b-blockers, ivabradine or both was administrated in 29 (69%) resulting in symptomatic improvement in 82.8% of those under treatment. However, residual symptoms persisted in 69% of patients after 3 months. Conclusions: In patients with “Post-acute COVID-19” syndrome, we found an excessive chronotropic response to exercise suggesting autonomic dysfunction as the underlying mechanism of symptoms. Treatment with beta blockers or ivabradine resulted in clinical improvement but a substantial proportion of patients remained symptomatic.

Prospects for the application of transcranial magnetic stimulation in diabetic neuropathy

Encouraging results have been reported for the use of transcranial magnetic stimulationbased nerve stimulation in studies of the mechanisms of neurological regulation,nerve injury repair,and nerve localization.However,to date,there are only a few reviews on the use of transcranial magnetic stimulation for diabetic neuropathy.Patients with diabetic neuropathy vary in disease progression and show neuropathy in the early stage of the disease with mild symptoms,making it difficult to screen and identify.In the later stage of the disease,irreversible neurological damage occurs,resulting in treatment difficulties.In this review,we summarize the current state of diabetic neuropathy research and the prospects for the application of transcranial magnetic stimulation in diabetic neuropathy.We review significant studies on the beneficial effects of transcranial magnetic stimulation in diabetic neuropathy treatment,based on the outcomes of its use to treat neurodegeneration,pain,blood flow change,autonomic nervous disorders,vascular endothelial injury,and depression.Collectively,the studies suggest that transcranial magnetic stimulation can produce excitatory/inhibitory stimulation of the cerebral cortex or local areas,promote the remodeling of the nervous system,and that it has good application prospects for the localization of the injury,neuroprotection,and the promotion of nerve regeneration.Therefore,transcranial magnetic stimulation is useful for the screening and early treatment of diabetic neuropathy.transcranial magnetic stimulation can also alleviate pain symptoms by changing the cortical threshold and inhibiting the conduction of sensory information in the thalamo-spinal pathway,and therefore it has therapeutic potential for the treatment of pain and pain-related depressive symptoms in patients with diabetic neuropathy.Additionally,based on the effect of transcranial magnetic stimulation on local blood flow and its ability to change heart rate and urine protein content,transcranial magnetic stimulation has potential in the treatment of autonomic nerve dysfunction and vascular injury in diabetic neuropathy.Furthermore,oxidative stress and the inflammatory response are involved in the process of diabetic neuropathy,and transcranial magnetic stimulation can reduce oxidative damage.The pathological mechanisms of diabetic neuropathy should be further studied in combination with transcranial magnetic stimulation technology.

Studies on the apoptosis of autonomic neuron in streptozotocin-induced diabetic rats

Objective： The aim of the study was to investigate apoptosis of the autonomic neuron in streptozotocin-induced diabetic rats, and observe the effect of intervention with nerve growth factor （NGF） on the apoptosis. Methods： A total of 29 male Sprague-Dawley rats were divided into three groups, i.e. normal control （NC, n = 12）, untreated diabetic （DM, n = 9） and diabetic treated with NGF daily of 500 μg/kg for 30 days （DM＋NGF, n = 8）. The diabetic rat models were produced by intraperitoneal injection with streptozotocin （65 mg/kg ）. Over 3 months since the diabetes were setup, the superior cervical sympathetic ganglions（SCG） and the celiac ganglions（CG） were removed and fixed with 10% paraformaldchyde. Apoptosis was measured using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling（TUNEL）. Apoptotic index （AI） was calculated by computer image analysis system. Results： The AI of SCG and CG in DM and DM＋NGF group were significant higher than those of NC group （P 〈 0.001） respectively. There was no difference of AI of SCG and CG between DM group and DM＋NGF group （both P 〉 0.05）. Conclusion： Neuron apoptosis may contribute to the pathophysiology of diabetic autonomic neuropathy and NGF can not prevent the apoptosis of autonomic neuron in diabetic rats.

Can the change of vasomotor activity in irritable bowel syndrome patients be detected via color Doppler ultrasound?

BACKGROUND Irritable bowel syndrome(IBS)is one of the most frequently referred conditions to the gastrointestinal outpatient clinic.The pathophysiology of IBS has not been determined with certainty.Visceral hypersensitivity is indicated as one of the pathophysiologies.The sympathetic nervous system is primarily in charge of controlling the arteries,and its effect is vasospasm in the medium and large arteries,resulting in decreased blood flow.AIM To demonstrate,using Doppler evaluation of the brachial artery,that sympathetic activity impairs vasomotor performance due to autonomic neuropathy,which we believe is associated with IBS.METHODS There were 58 participants in the study.The control group consisted of 29 healthy patients,while the remaining 29 patients had been diagnosed with IBS.Patients who met the Rome IV criteria and had IBS were included in the study.People with known polyneuropathy or non-IBS chronic conditions that can progress were excluded from the trial,as were those with essential hypertension,diabetes mellitus,cardiovascular disease,or peripheral arterial disease,and patients diagnosed with anxiety or depression.Those with moderate to severe carpal tunnel syndrome or a median nerve lesion due to trauma were also excluded from the trial.A Doppler probe was used to measure the baseline diameter and flow rates of the brachial artery from 2 cm superior to the antecubital fossa.The Doppler probe remained stationary throughout the experiment,allowing for continuous measurements.Then,to activate the sympathetic fibers,an electrical stimulus for 5 s with an intensity of 10 mA and a frequency of 1 Hz was applied to the median nerve at the wrist level via the bipolar stimulus electrode.The artery diameter and flow rates were measured again immediately following the fifth stimulus.RESULTS In healthy persons with no history of chronic illness,there was a statistically significant decrease in flow rate after stimulation(P<0.001).In addition,stimulation resulted in a statistically significant reduction in the diameter of the brachial artery(P<0.001).Patients diagnosed with IBS had statistically significant vasodilation and an increase in flow rate.CONCLUSION Sympathetic stimulation causes a reduction in vascular diameter and blood flow,whereas it has the reverse effect on IBS patients.In investigating the involvement of autonomic neuropathy in the development of IBS,significant changes in brachial artery Doppler parameters were observed before and after stimulation of the median nerve with low-current sensory stimulation.This method is thought to be more user-friendly and comfortable than other methods described in the literature.

Impaired contractility and remodeling of the upper gastrointestinal tract in diabetes mellitus type-1

AIM: To investigate that both the neuronal function of the contractile system and structural apparatus of the gastrointestinal tract are affected in patients with longstanding diabetes and auto mic neuropathy. METHODS: The evoked esophageal and duodenal contractile activity to standardized bag distension was assessed using a specialized ultrasound-based probe. Twelve type-1 diabetic patients with autonomic neuropathy and severe gastrointestinal symptoms and 12 healthy controls were studied. The geometry and biomechanical parameters (strain, tension/stress, and stiffness) were assessed. RESULTS: The diabetic patients had increased frequency of distension-induced contractions (6.0 ± 0.6 vs 3.3 ± 0.5, P < 0.001). This increased reactivity was correlated with the duration of the disease (P = 0.009). Impaired coordination of the contractile activity in diabetic patients was demonstrated as imbalance between the time required to evoke the first contraction at the distension site and proximal to it (1.5 ± 0.6 vs 0.5 ± 0.1, P = 0.03). The esophageal wall and especially the mucosa-submucosa layer had increased thickness in the patients (P < 0.001), and the longitudinal and radial compressive stretch was less in diabetics (P <0.001). The esophageal and duodenal wall stiffness and circumferential deformation induced by the distensions were not affected in the patients (all P > 0.14). CONCLUSION: The impaired contractile activity with an imbalance in the distension-induced contractions likely reflects neuronal abnormalities due to autonomic neuropathy. However, structural changes and remodeling of the gastrointestinal tract are also evident and may add to the neuronal changes. This may contribute to the pathophysiology of diabetic gut dysfunction and impact on future management of diabetic patients with gastrointestinal symptoms.

Prevalence and determinants of delayed gastric emptying in hospitalised Type 2 diabetic patients

AIM: To determine the prevalence of delayed gastric emptying (GE) in older patients with Type 2 diabetes mellitus. METHODS: One hundred and forty seven patients with Type 2 diabetes, of whom 140 had been hospitalised, mean age 62.3 ± 8.0 years, HbA1c 9.1% ± 1.9%, treated with either oral hypoglycemic drugs or insulin were studied. GE of a solid meal (scintigraphy), autonomic nerve function, upper gastrointestinal symptoms, acute and chronic glycemic control were evaluated. Gastric emptying results were compared to a control range of hospitalised patients who did not have diabetes. RESULTS: Gastric emptying was delayed (T50 > 85 min) in 17.7% patients. Mean gastric emptying was slower in females (T50 72.1 ± 72.1 min vs 56.9 ± 68.1 min, P = 0.02) and in those reporting nausea (112.3 ± 67.3 vs 62.7 ± 70.0 min, P < 0.01) and early satiety (114.0 ± 135.2 vs 61.1 ± 62.6 min, P = 0.02). There was no correlation between GE with age, body weight, duration of diabetes, neuropathy, current glycemia or the total score for upper gastrointestinal symptoms. CONCLUSION: Prolonged GE occurs in about 20% of hospitalised elderly patients with Type 2 diabetes when compared to hospitalised patients who do not have diabetes. Female gender, nausea and early satiety areassociated with higher probability of delayed GE.

Diabetic heart disease:A clinical update

Diabetes mellitus(DM) significantly increases the risk of heart disease,and DMrelated healthcare expenditure is predominantly for the management of cardiovascular complications.Diabetic heart disease is a conglomeration of coronary artery disease(CAD),cardiac autonomic neuropathy(CAN),and diabetic cardiomyopathy(DCM).The Framingham study clearly showed a 2 to 4-fold excess risk of CAD in patients with DM.Pathogenic mechanisms,clinical presentation,and management options for DM-associated CAD are somewhat different from CAD among nondiabetics.Higher prevalence at a lower age and more aggressive disease in DM-associated CAD make diabetic individuals more vulnerable to premature death.Although common among diabetic individuals,CAN and DCM are often under-recognised and undiagnosed cardiac complications.Structural and functional alterations in the myocardial innervation related to uncontrolled diabetes result in damage to cardiac autonomic nerves,causing CAN.Similarly,damage to the cardiomyocytes from complex pathophysiological processes of uncontrolled DM results in DCM,a form of cardiomyopathy diagnosed in the absence of other causes for structural heart disease.Though optimal management of DM from early stages of the disease can reduce the risk of diabetic heart disease,it is often impractical in the real world due to many reasons.Therefore,it is imperative for every clinician involved in diabetes care to have a good understanding of the pathophysiology,clinical picture,diagnostic methods,and management of diabetes-related cardiac illness,to reduce morbidity and mortality among patients.This clinical review is to empower the global scientific fraternity with up-to-date knowledge on diabetic heart disease.

Influence of cardiac nerve status on cardiovascular regulation and cardioprotection

Neural elements of the intrinsic cardiac nervous system transduce sensory inputs from the heart, blood vessels and other organs to ensure adequate cardiac function on a beat-to-beat basis. This inter-organ crosstalk is critical for normal function of the heart and other organs; derangements within the nervous system hierarchy contribute to pathogenesis of organ dysfunction. The role of intact cardiac nerves in development of, as well as protection against, ischemic injury is of current interest since it may involve recruitment of intrinsic cardiac ganglia. For instance, ischemic conditioning, a novel protection strategy against organ injury, and in particular remote conditioning, is likely mediated by activation of neural pathways or by endogenous cytoprotective bloodborne substances that stimulate different signalling pathways. This discovery reinforces the concept that inter-organ communication, and maintenance thereof, is key. As such, greater understanding of mechanisms and elucidation of treatment strategies is imperative to improve clinical outcomes particularly in patients with comorbidities. For instance, autonomic imbalance between sympathetic and parasympathetic nervous system regulation can initiate cardiovascular autonomic neuropathy that compromises cardiac stability and function. Neuromodulation therapies that directly target the intrinsic cardiac nervous system or other elements of the nervous system hierarchy are currently being investigated for treatment of different maladies in animal and human studies.

Holmes-Adie syndrome, autoimmune hepatitis and celiac disease: A case report

A 35-year-old female patient presented with the following symptoms of Holmes-Adie syndrome： photophobia, enlargement of the left pupil unresponsive to light, Achilles areflexia. The pilocarpine test was positive. No tumor or other neurological abnormality was found. She had a 19-year history of autoimmune hepatitis. Flares up were observed following each 3 deliveries. At age of 31 she presented with diarrhea and weight loss. Abdominal tumor was detected by ultrasound. The surgically removed tumor was histologically a benign mesenteric multicystic lymphangioma. Simultaneously, celiac disease was diagnosed. Gluten-free diet resulted in a significant improvement of celiac disease, but not of autoimmune hepatitis. Autonomic neuropathy was proven by standard cardiovascular tests. The patient was a homozygous carrier for HLA DQ2 antigen characteristic for celiac disease and heterozygous for HLA DR3 B8 frequent in autoimmune liver diseases. Our novel observation on association of Holmes-Adie syndrome with autoimmune hepatitis and celiac disease is suggestive for a common immunological background for all three entities present in a patient with mesenteric multicystic lymphangioma.

Congenital insensitivity to pain with anhidrosis and progressing acro-osteolysis:a case report with 7-year follow-up

Congenital insensitivity to pain is a rare disorder, first described by Dearborn in 1932. Since the discovery of congenital insensitivity to pain with anhidrosis or hereditary sensory neuropathy type Ⅳ in 1983, fewer than 60 cases have been reported. Congenital insensitivity to pain with anhidrosis and progressing acro-osteolysis is a very rare disorder characterized by absence of painful perception after birth. Severe problems may arise if pain sensation is absent, causing injury to oral structures as teeth, lips and the tongue by self mutilation. The patient is at a risk of late presentation with systemic illnesses associated with pain, such as fracture and joint dislocation. Importantly, the patient may suffer from acro-osteolysis with growth, for instance, osteolysis of the distal extremities.