Genetic markers of cardiac autonomic neuropathy in the Kazakh population.

BACKGROUND: Cardiac autonomic neuropathy (CAN) is a complication of diabetes mellitus (DM) that increases the risk of morbidity and mortality by disrupting cardiac innervation. Recent evidence suggests that CAN may manifest even before the onset of DM, with prediabetes and metabolic syndrome potentially serving as precursors. This study aims to identify genetic markers associated with CAN development in the Kazakh population by investigating the SNPs of specific genes. MATERIALS AND METHODS: A case-control study involved 82 patients with CAN (cases) and 100 patients without CAN (controls). A total of 182 individuals of Kazakh nationality were enrolled from a hospital affiliated with the RSE "Medical Center Hospital of the President's Affairs Administration of the Republic of Kazakhstan". 7 SNPs of genes FTO, PPARG, SNCA, XRCC1, FLACC1/CASP8 were studied. Statistical analysis was performed using Chi-square methods, calculation of odds ratios (OR) with 95% confidence intervals (CI), and logistic regression in SPSS 26.0. RESULTS: Among the SNCA gene polymorphisms, rs2737029 was significantly associated with CAN, almost doubling the risk of CAN (OR 2.03(1.09-3.77), p = 0.03). However, no statistically significant association with CAN was detected with the rs2736990 of the SNCA gene (OR 1.00 CI (0.63-1.59), p = 0.99). rs12149832 of the FTO gene increased the risk of CAN threefold (OR 3.22(1.04-9.95), p = 0.04), while rs1801282 of the PPARG gene and rs13016963 of the FLACC1 gene increased the risk twofold (OR 2.56(1.19-5.49), p = 0.02) and (OR 2.34(1.00-5.46), p = 0.05) respectively. rs1108775 and rs1799782 of the XRCC1 gene were associated with reduced chances of developing CAN both before and after adjustment (OR 0.24, CI (0.09-0.68), p = 0.007, and OR 0.43, CI (0.22-0.84), p = 0.02, respectively). CONCLUSION: The study suggests that rs2737029 (SNCA gene), rs12149832 (FTO gene), rs1801282 (PPARG gene), and rs13016963 (FLACC1 gene) may be predisposing factors for CAN development. Additionally, SNPs rs1108775 and rs1799782 (XRCC1 gene) may confer resistance to CAN. Only one polymorphism rs2736990 of the SNCA gene was not associated with CAN.

Autonomic Dysfunction from Diagnosis to Treatment.

Autonomic disorders can present with hypotension, gastrointestinal, genitourinary symptoms, and heat intolerance. Diabetes is the most common causes of autonomic failure, and management should focus on glucose control to prevent developing autonomic symptoms. The most prevalent cause of dysautonomia, or autonomic dysfunction, is Postural Orthostatic Tachycardia Syndrome (POTS). Autonomic testing characterizes causes for nonspecific symptoms but is not necessary in patients with classic presentations. Treatment for autonomic dysfunction and failure focus on discontinuing offending medications, behavioral modification, and pharmacologic therapy to decrease symptom severity. Autonomic failure has no cure; therefore, the focus remains on improving quality of life.

[Autoimmune Autonomic Ganglionopathy and Acute Autonomic Sensory Neuropathy].

Autoimmune autonomic ganglionopathy (AAG) and acute autonomic sensory neuropathy (AASN) are immune-mediated neuropathies that affect the autonomic and/or dorsal root ganglia. Autoantibodies against the nicotinic ganglionic acetylcholine receptor (gAChR) detected in the sera of patients with AAG play a key role in the pathogenesis of this condition. Notably, gAChR antibodies are not detected in the sera of patients with AASN. Currently, AAG and AASN are not considered to be on the same spectrum with regard to disease concept based on clinical symptoms and laboratory findings. However, extra-autonomic brain symptoms (including psychiatric symptoms and personality changes) and endocrine disorders occur in both diseases, which suggests shared pathophysiology between the two conditions.

Gastrointestinal symptom burden in diabetic autonomic and peripheral neuropathy - A Danes cohort study.

OBJECTIVE: We investigated associations between gastrointestinal symptoms - evaluated as a combined weighted symptom score (CWSS) - Diabetic autonomic neuropathy (DAN), and distal symmetrical polyneuropathy (DSPN) in type 1 and type 2 diabetes. RESEARCH DESIGN AND METHODS: Cross-sectional study in a tertiary outpatient clinic. CWSS was calculated based on questionnaires: gastroparesis composite symptom index (GCSI) and gastrointestinal symptom rating score (GSRS). DAN and DSPN were addressed using the composite autonomic symptom score 31 (COMPASS-31) questionnaire, cardiac autonomic reflex tests (CARTs), electrochemical skin conductance (ESC), vibration perception threshold (VPT), Michigan Neuropathy Screening Instrument (MNSI), pain- and thermal sensation. Analyses were adjusted for age, sex, diabetes duration, smoking, LDL-cholesterol, HbA1C and systolic blood pressure. Type 1 and type 2 diabetes were evaluated separately. RESULTS: We included 566 with type 1 diabetes and 377 with type 2 diabetes. Mean ± SD age was 58 ± 15 years and 565 (59.9 %) were women. A high CWSS was present in 143 (25 %) with type 1 and 142 (38 %) with type 2 diabetes. The odds of DAN by COMPASS-31 (p < 0.001) were higher in the high score group. For type 1 diabetes, odds of cardiac autonomic neuropathy were higher in the high CWSS group. The odds of DSPN by VPT and MNSI in type 1 diabetes, and by ESC, VPT and pain sensation in type 2 diabetes were higher in the high CWSS group. CONCLUSIONS: A high symptom score was associated with neuropathy by COMPASS-31 and vibration perception. Gastrointestinal symptom burden associated inconsistently with other neuropathy tests between diabetes types.

Evaluation of cardiac autonomic dysfunctions in children with type 1 diabetes mellitus.

BACKGROUND: Cardiovascular autonomic neuropathy (CAN) is a serious complication of diabetes, impacting the autonomic nerves that regulate the heart and blood vessels. Timely recognition and treatment of CAN are crucial in averting the onset of cardiovascular complications. Both clinically apparent autonomic neuropathy and subclinical autonomic neuropathy, particularly CAN pose a significant risk of morbidity and mortality in children with type 1 diabetes mellitus (T1DM). Notably, CAN can progress silently before manifesting clinically. In our study, we assessed patients with poor metabolic control, without symptoms, following the ISPAD 2022 guideline. The objective is is to determine which parameters we can use to diagnose CAN in the subclinical period. METHODS: Our study is a cross-sectional case-control study that includes 30 children diagnosed with T1DM exhibiting poor metabolic control (average HbA1c > 8.5% for at least 1 year) according to the ISPAD 2022 Consensus Guide. These patients, who are under the care of the pediatric diabetes clinic, underwent evaluation through four noninvasive autonomic tests: echocardiography, 24-h Holter ECG for heart rate variability (HRV), cardiopulmonary exercise test, and tilt table test. RESULTS: The average age of the patients was 13.73 ± 1.96 years, the average diabetes duration was 8 ± 3.66 years, and the 1-year average HbA1c value was 11.34 ± 21%. In our asymptomatic and poorly metabolically controlled patient group, we found a decrease in HRV values, the presence of postural hypotension with the tilt table test, and a decrease in ventricular diastolic functions that are consistent with the presence of CAN. Despite CAN, the systolic functions of the ventricles were preserved, and the dimensions of the cardiac chambers and cardiopulmonary exercise test were normal. CONCLUSIONS: CAN is a common complication of T1DM, often associated with the patient's age and poor glycemic control. HRV, active orthostatic tests, and the evaluation of diastolic dysfunctions play significant roles in the comprehensive assessment of CAN. These diagnostic measures are valuable tools in identifying autonomic dysfunction at an early stage, allowing for timely intervention and management to mitigate the impact of cardiovascular complications associated with T1DM.

Chronotropic Incompetence in Parkinson's Disease: A Possible Marker of Severe Disease Phenotype?

Autonomic dysfunction is a prevalent feature of Parkinson's disease (PD), mediated by disease involvement of the autonomic nervous system. Chronotropic incompetence (CI) refers to inadequate increase of heart rate in response to elevated metabolic demand, partly dependent on postganglionic sympathetic tone. In a retrospective study, PD patients with/without CI were identified. We show that PD with CI was associated with a higher levodopa equivalent daily dose and Hoehn and Yahr stage, 5±2 years after motor onset. Our data support a putative role of CI as a clinical marker of a more severe disease phenotype, possibly reflecting more widespread alpha-synuclein pathology.

Paraneoplastic autonomic neuropathies and GI dysmotility.

A number of the well-recognized autoimmune and paraneoplastic neurologic syndromes commonly involve the autonomic nervous system. In some cases, the autonomic nerves or ganglia are primary targets of neurologic autoimmunity, as in immune-mediated autonomic ganglionopathies. In other disorders such as encephalitis, autonomic centers in the brain may be affected. The presence of autonomic dysfunction (especially gastrointestinal dysmotility) is sometimes overlooked even though this may contribute significantly to the symptom burden in these paraneoplastic disorders. Additionally, recognition of autonomic features as part of the clinical syndrome can help point the diagnostic evaluation toward autoimmune and paraneoplastic etiologies. As with other paraneoplastic disorders, the clinical syndrome and the presence and type of neurologic autoantibodies help to secure the diagnosis and direct the most appropriate investigation for malignancy. Optimal management for these conditions typically includes aggressive treatment of the neoplasm, immunomodulatory therapy, and symptomatic treatments for orthostatic hypotension and gastrointestinal dysmotility.

The Degree of Cardiovascular Autonomic Dysfunction is not Different in GBA-Related and Idiopathic Parkinson's Disease Patients: A Case-Control Instrumental Evaluation.

Background: Increased prevalence of cardiovascular autonomic failure might play a key role on Parkinson's disease (PD) progression of glucocerebrosidase gene (GBA)-mutated patients, determining a malignant phenotype of disease in these patients. Objective: To objectively characterize, for the first time, the cardiovascular autonomic profile of GBA-mutated patients compared to idiopathic PD patients by means of cardiovascular reflex tests (CRTs). Methods: This is a case-control (1 : 2) study on PD patients belonging to well-characterized prospective cohorts. For each PD patient carrying GBA variants, two idiopathic PD patients, matched for sex and disease duration at CRTs, were selected. Patients recruited in these cohorts underwent a complete clinical and instrumental evaluation including specific autonomic questionnaires, CRTs and extensive genetic analysis. Results: A total of 23 GBA-PD patients (19 males, disease duration 7.7 years) were included and matched with 46 non-mutated PD controls. GBA-mutated patients were younger than controls (59.9±8.1 vs. 64.3±7.2 years, p = 0.0257) and showed a more severe phenotype. Despite GBA-mutated patients reported more frequently symptoms suggestive of orthostatic hypotension (OH) than non-mutated patients (39.1% vs 6.5%, p = 0.001), the degree of cardiovascular autonomic dysfunction, when instrumentally assessed, did not differ between the two groups, showing the same prevalence of neurogenic OH, delayed OH and cardiovascular reflex impairment (pathological Valsalva maneuver). Conclusion: GBA-PD patients did not show different instrumental cardiovascular autonomic pattern than non-mutated PD. Our findings suggested that symptoms suggestive of OH should be promptly investigated by clinicians to confirm their nature and improve patient care and management.

Setting the clinical context to non-motor symptoms reflected by Park-pain, Park-sleep, and Park-autonomic subtypes of Parkinson's disease.

Non-motor symptoms (NMS) of Parkinson's disease (PD) are well described in both clinical practice and the literature, enabling their management and enhancing our understanding of PD. NMS can dominate the clinical pictures and NMS subtypes have recently been proposed, initially based on clinical observations, and later confirmed in data driven analyses of large datasets and in biomarker-based studies. In this chapter, we provide an update on what is known about three common subtypes of NMS in PD. The pain (Park-pain), sleep dysfunction (Park-sleep), and autonomic dysfunction (Park-autonomic), providing an overview of their individual classification, clinical manifestation, pathophysiology, diagnosis, and potential treatments.

Autoimmune Autonomic Neuropathy: From Pathogenesis to Diagnosis.

Autoimmune autonomic ganglionopathy (AAG) is a disease of autonomic failure caused by ganglionic acetylcholine receptor (gAChR) autoantibodies. Although the detection of autoantibodies is important for distinguishing the disease from other neuropathies that present with autonomic dysfunction, other factors are important for accurate diagnosis. Here, we provide a comprehensive review of the clinical features of AAG, highlighting differences in clinical course, clinical presentation, and laboratory findings from other neuropathies presenting with autonomic symptoms. The first step in diagnosing AAG is careful history taking, which should reveal whether the mode of onset is acute or chronic, followed by an examination of the time course of disease progression, including the presentation of autonomic and extra-autonomic symptoms. AAG is a neuropathy that should be differentiated from other neuropathies when the patient presents with autonomic dysfunction. Immune-mediated neuropathies, such as acute autonomic sensory neuropathy, are sometimes difficult to differentiate, and therefore, differences in clinical and laboratory findings should be well understood. Other non-neuropathic conditions, such as postural orthostatic tachycardia syndrome, chronic fatigue syndrome, and long COVID, also present with symptoms similar to those of AAG. Although often challenging, efforts should be made to differentiate among the disease candidates.

Association between autonomic dysfunction with motor and non-motor symptoms in patients with Parkinson's disease.

To investigate the association between autonomic dysfunction (AutD) and motor as well as non-motor symptoms (NMS) in patients with Parkinson's disease (PD). Fifty-three PD patients were divided into two groups based on the number of domains affected by AutD: a multi-domain AutD group (AutD-M) and a single-domain AutD group (AutD-S), as evaluated using the Scale for Outcomes in Parkinson's disease-Autonomic (SCOPA-AUT), which assesses autonomic symptoms, one of the NMS. A comprehensive comparison was conducted between the two groups, including clinical measures such as clinical scales, quantitative evaluations of motor function and exercise capacity. Spearman correlation analysis was employed to investigate the relationship between AutD severity and PD symptoms. Additionally, we performed multiple linear regression model analysis to determine whether associations between SCOPA-AUT scores and clinical assessments remained significant after adjusting for Hoehn and Yahr stage, sex, and age. PD patients in the AutD-M group exhibited significantly more severe NMS and motor symptoms compared to those in the AutD-S group. In correlation analysis, SCOPA-AUT scores showed significant correlations with multiple clinical symptoms, such as most of the NMS, 10-MWT and CPET parameters. Furthermore, regression analysis also revealed that more pronounced fatigue, anxiety, depressive symptoms, worse walking speed and impaired exercise capacity were associated with higher SCOPA-AUT scores. The presence of AutD is correlated with emotional disturbances, decreased exercise endurance, and impaired gait function in patients with PD. Early management of AutD may prove beneficial in alleviating some NMS and motor symptoms in PD.

The handgrip test - A historical test for diabetic autonomic neuropathy or a marker of something else?

Cardiovascular autonomic neuropathy (CAN) is a frequent complication of diabetes mellitus and is associated with increased morbidity and mortality in patients with diabetes. Hence, early and correct diagnosis of CAN is crucial. Standard cardiovascular reflex rests (CARTs) have been the gold standard of CAN assessment. Originally, CARTs consisted of five reflex tests, but measuring diastolic blood pressure response to sustained handgrip exercise has no longer been suggested as an established clinical test. Increasing body of evidence suggests that isometric handgrip test should no longer be used for the evaluation of sympathetic dysfunction during cardiovascular autonomic neuropathy assessment in diabetic patients. The associations of isometric handgrip test results with parameters of hypertension and markers of hypertension-related target-organ damage in diabetic and non-diabetic individuals point toward its potential role as a screening tool to identify patients with high cardiovascular risk. The current review summarizes historical view of standard cardiovascular reflex tests and latest data on isometric handgrip test.

Orthostatic Hypotension in Adults With Hypertension: A Scientific Statement From the American Heart Association.

Although orthostatic hypotension (OH) has long been recognized as a manifestation of autonomic dysfunction, a growing body of literature has identified OH as a common comorbidity of hypertension. This connection is complex, related to pathophysiology in blood pressure regulation and the manner by which OH is derived as the difference between 2 blood pressure measurements. While traditional therapeutic approaches to OH among patients with neurodegenerative disorders focus on increasing upright blood pressure to prevent cerebral hypoperfusion, the management of OH among patients with hypertension is more nuanced; resting hypertension is itself associated with adverse outcomes among these patients. Although there is substantial evidence that intensive blood pressure treatment does not cause OH in the majority of patients with essential hypertension, some classes of antihypertensive agents may unmask OH in patients with an underlying autonomic impairment. Practical steps to manage OH among adults with hypertension start with (1) a thorough characterization of its patterns, triggers, and cause; (2) review and removal of aggravating factors (often pharmacological agents not related to hypertension treatment); (3) optimization of an antihypertensive regimen; and (4) adoption of a tailored treatment strategy that avoids exacerbating hypertension. These strategies include countermaneuvers and short-acting vasoactive agents (midodrine, droxidopa). Ultimately, further research is needed on the epidemiology of OH, the impact of hypertension treatment on OH, approaches to the screening and diagnosis of OH, and OH treatment among adults with hypertension to improve the care of these patients and their complex blood pressure pathophysiology.

Unveiling autonomic failure in synucleinopathies: Significance in diagnosis and treatment.

Autonomic failure is frequently encountered in synucleinopathies such as multiple system atrophy (MSA), Parkinson's disease (PD), Lewy body disease, and pure autonomic failure (PAF). Cardiovascular autonomic failure affects quality of life and can be life threatening due to the risk of falls and the increased incidence of myocardial infarction, stroke, and heart failure. In PD and PAF, pathogenic involvement is mainly post-ganglionic, while in MSA, the involvement is mainly pre-ganglionic. Cardiovascular tests exploring the autonomic nervous system (ANS) are based on the analysis of continuous, non-invasive recordings of heart rate and digital blood pressure (BP). They assess facets of sympathetic and parasympathetic activities and provide indications on the integrity of the baroreflex arc. The tilt test is widely used in clinical practice. It can be combined with catecholamine level measurement and analysis of baroreflex activity and cardiac variability for a detailed analysis of cardiovascular damage. MIBG myocardial scintigraphy is the most sensitive test for early detection of autonomic dysfunction. It provides a useful measure of post-ganglionic sympathetic fiber integrity and function and is therefore an effective tool for distinguishing PD from other parkinsonian syndromes such as MSA. Autonomic cardiovascular investigations differentiate between certain parkinsonian syndromes that would otherwise be difficult to segregate, particularly in the early stages of the disease. Exploring autonomic failure by gathering information about residual sympathetic tone, low plasma norepinephrine levels, and supine hypertension can guide therapeutic management of orthostatic hypotension (OH).

Chronotropic Incompetence During Exercise Testing as a Marker of Autonomic Dysfunction in Individuals with Early Parkinson's Disease.

BACKGROUND: An attenuated heart rate response to exercise, termed chronotropic incompetence, has been reported in Parkinson's disease (PD). Chronotropic incompetence may be a marker of autonomic dysfunction and a cause of exercise intolerance in early stages of PD. OBJECTIVE: To investigate the relationship between chronotropic incompetence, orthostatic blood pressure change (supine - standing), and exercise performance (maximal oxygen consumption, VO2peak) in individuals with early PD within 5 years of diagnosis not on dopaminergic medications. METHODS: We performed secondary analyses of heart rate and blood pressure data from the Study in Parkinson's Disease of Exercise (SPARX). RESULTS: 128 individuals were enrolled into SPARX (63.7±9.3 years; 57.0% male, 0.4 years since diagnosis [median]). 103 individuals were not taking chronotropic medications, of which 90 had a normal maximal heart rate response to exercise testing (155.3±14.0 bpm; PDnon-chrono) and 13 showed evidence of chronotropic incompetence (121.3±11.3 bpm; PDchrono, p < 0.05). PDchrono had decreased VO2peak compared to PDnon-chrono (19.7±4.5 mL/kg/min and 24.3±5.8 mL/kg/min, respectively, p = 0.027). There was a positive correlation between peak heart rate during exercise and the change in systolic blood pressure from supine to standing (r = 0.365, p < 0.001). CONCLUSIONS: A subgroup of individuals with early PD not on dopaminergic medication had chronotropic incompetence and decreased VO2peak, which may be related to autonomic dysfunction. Evaluation of both heart rate responses to incremental exercise and orthostatic vital signs may serve as biomarkers of early autonomic impairment and guide treatment. Further studies should investigate whether cardiovascular autonomic dysfunction affects the ability to exercise and whether exercise training improves autonomic dysfunction.

Associations of age-adjusted coefficient of variation of R-R intervals with autonomic and peripheral nerve function in non-elderly persons with diabetes.

AIMS/INTRODUCTION: Early diagnosis of diabetes-associated cardiac autonomic neuropathy using the coefficient of variation of R-R intervals (CVRR) may improve outcomes for individuals with diabetes. The present study examined the associations of decreased CVRR at rest and during deep breathing (DB) with other autonomic nerve function parameters. MATERIALS AND METHODS: The electronic records of 141 inpatients with diabetes (22-65 years) admitted to our hospital between March 2015 and March 2019 were analyzed retrospectively. After assessment by exclusion criteria, 51 inpatients were included. All inpatients were assessed for peripheral and autonomic nerve function, clinical characteristics, and physical abilities. RESULTS: Inpatients with decreased CVRR at rest (n = 9 (17.6%)) and during DB (n = 12 (23.5%)) had a longer duration of known diabetes, a higher prevalence of diabetic retinopathy, lower body mass index (BMI), skeletal mass index (SMI), and knee extension strength, and a higher proportion of impaired standing balance. Decreased CVRR at rest was associated with a greater fall in diastolic BP from supine to standing, higher resting HR, longer QTc, longer time of voiding, and sensory symptoms. CONCLUSIONS: Decreased CVRR at rest and during deep breathing was associated with lower BMI, SMI, and knee strength and a higher proportion of impaired standing balance among non-elderly inpatients with diabetes. Decreased CVRR at rest appeared more strongly associated with a greater orthostatic BP decline, higher resting heart rate, longer QTc, lower urinary tract dysfunction, and sensory symptoms than a decreased CVRR during deep breathing.