Standard Cardiovascular Reflex Tests Research Articles

Autonomic function and specific right atrial functions - Is there a relationship? Correlations from the three-dimensional speckle-tracking echocardiographic MAGYAR-Healthy Study.

Similarly to the ventricles, the atria are under sympathetic/parasympathetic neural regulation. Accordingly, correlations were investigated between Ewing's standard cardiovascular reflex tests (SCRTs) and three-dimensional speckle-tracking echocardiography (3DSTE)-derived right atrial (RA) volumes and strains in healthy subjects. The study comprised 45 healthy adults, but 5 subjects were excluded due to inferior image quality for 3DSTE-derived RA assessments. The remaining 40 individuals being in sinus rhythm had a mean age of 35.1 ± 3.5 years (20 men). Two-dimensional, Doppler, 3DSTE and SCRTs were performed in all cases. RA maximum volume and total and passive RA stroke volumes correlated with the Valsalva ratio. Active RA stroke volume and emptying fraction showed correlations with 30/15 ratio. Peak global and mean segmental RA circumferential (CS) and longitudinal strains (LS) showed correlation with the Valsalva ratio. At atrial contraction, global RA-LS and mean segmental RA-CS showed correlations with the Valsalva ratio. Moreover, mean segmental RA-CS correlated with 30/15 ratio and mean segmental RA radial strain showed correlations with systolic blood pressure in response to standing. Autonomic neuropathy score correlated with peak global RA-LS. Autonomic function parameters have significant associations with specific RA functions in healthy adults, making the latter possible indicators of autonomic dysregulation.

A three-month physical training program improves cardiovascular autonomic function in patients with metabolic syndrome with and without diabetes - a pilot study.

Vascular complications and neuropathy may develop in the presence of metabolic syndrome. The aim of our study was to measure the cardiovascular autonomic function following physical training in patients with metabolic syndrome with and without diabetes. 56 patients with metabolic syndrome (32 men/24 women, 40 non-diabetic patients (NDMetS)/16 diabetic patients (DMetS) [mean ± SD]: age: 50.35 ± 8.03 vs. 56.8 ± 9.30 years, p=0.023; baseline BMI: 32.2 ± 7.03 vs. 32.8 ± 5.94 kg/m2, p=0.739) were involved in our study. All tests and measurements were carried out before and following a 3-month physical training period. Autonomic function was assessed by means of five standard cardiovascular reflex tests. ECG repolarization parameters, including short-term QT variability and stress-ECG were also measured. In the whole population, Valsalva-ratio (VR) and the autonomic score (AS) improved following training (VR: 1.49 ± 0.24 vs. 1.64 ± 0.34, p=0.001; AS: 2.05 ± 1.73 vs. 1.41 ± 1.36, p=0.015) accompanied by the significant decrease of the systolic (150.3 ± 16.12 vs. 134.1 ± 16.67 mmHg, p<0.001) and diastolic (90.64 ± 12.8 vs. 82.79 ± 11.1 mmHg, p<0.001) blood pressure. An improvement in VR was detected in NDMetS patients following training (1.51 ± 0.24 vs. 1.67 ± 0.31, p= 0.002). No significant changes could be detected in autonomic tests' results in the DMetS patient group following training. The applied exercise training program did not lead to significant changes in ECG repolarization. The stress-ECG test in the whole study population yielded a significant increase in the test duration (12.9 ± 3.76 vs. 15.1 ± 2.96min, p<0.001) and in the test load (10.5 ± 2.78 vs. 11.6 ± 2.39 MET, p<0.001). The load capability improved significantly in both subgroups: 11.1 ± 2.04 vs. 12.1 ± 1.82, (p<0.001) and 9.0 ± 3.64 vs. 10.4 ± 3.05, (p=0.033) in subpopulations of NDMetS and DMetS, respectively. The DMetS patients achieved a significantly lower MET score at baseline (p=0.039) and following training (p=0.044) in comparison to the NDMetS patients. The three-month exercise program improved the Valsalva-ratio and the AN score in the MetS patients, that is potentially protective against cardiovascular events. The training had some beneficial effect on blood pressure and the results of the stress-ECG tests in both groups. The absence of significant change in the reflex tests in DMetS group reflects an impaired adaptation compared to the NDMestS group.

Cardiac autonomic neuropathy as risk factor of diabetic complications progression

Introduction. Diabetes mellitus (DM) is the most common and incapacitating endocrine disorder. Diabetic foot syndrome (DFS) is one of the most serious complications of DM, which is the main cause of nontraumatic lower-extremity amputations. Despite the efforts of the entire medical community, the survival rate of DFS patients with non-healing ulcers and after foot surgery does not exceed 50% over 5 years and is comparable to the survival rates of patients with colorectal cancer.Aim. It has been demonstrated that postsurgical diabetic foot wounds tend to chronization of inflammatory process. The diabetic autonomic neuropathy can be involved in diabetic foot damages. We hypothesized that progression of cardiovascular autonomic neuropathy (CAN) leads to aggressive microvascular complications of diabetes and delay the postsurgical wound healing in diabetic foot patients during 2 years of observation.Materials and methods. We examined 94 outpatients with postsurgical diabetic foot wounds and observation period of two years. The clinical neurological examination and standard cardiovascular autonomic reflex tests with identification of severe/advanced abnormalities were performed at baseline and after 2 years. The progression of CAN was diagnosed in cases of an increase in the amount of cardiovascular autonomic reflex tests by 1 score and more. The unsatisfactory result of wound treatment was detected in patients with wound healing delay and new cases of surgery debridement, foot amputations and Charcot foot during 2 years of observation.Results. The mean duration of diabetes was 10.7 year, HbA1c 8.3%, LDL-Chol 3.3 mmol/l, TG 1.8 mmol/l. The 51.1% patients had been amputated in the level of foot, 48.9% patients had surgery debridement. All patients had CAN, confirmed/severe forms in 57.4% cases. The progression of CAN was found in 22.3% patients, the most of them with functional stage at baseline. The aggressive course of CAN increased the risk of progression of diabetic sensomotor neuropathy (OR = 14.6; 95% CI 3.0–70.5; p = 0.0006), nephropathy (OR = 22.4; 95% CI 3.4–147.4; p = 0.0009) and unsatisfactory result of wound treatment (OR = 40; 95% CI 6.0–268.5; p = 0.0001).Conclusions. The patients with diabetic foot surgery wounds has high risk of confirmed/severe CAN and its progression during 2 years. The aggressive course of CAN associates with unsatisfactory result of wound treatment and progression of microvascular diabetic complications.

Cardiovascular reflex tests detect autonomic dysfunction in symptomatic and pre-symptomatic subjects with hereditary transthyretin amyloidosis.

Autonomic dysfunction is a distinctive but undervalued feature of hereditary transthyretin amyloidosis (ATTRv). It may predate the onset of polyneuropathy and cardiomyopathy, thereby providing crucial prognostic and therapeutic information. The objective of this study was to assess autonomic function by means of the standardized cardiovascular autonomic reflex tests (CRTs) in a cohort of subjects with genetically proven ATTRv from non-endemic areas who were in the symptomatic and pre-symptomatic stages. All subjects enrolled in this cross-sectional study had genetically proven ATTRv. They underwent the head-up tilt test, Valsalva manoeuvre, deep breathing test, cold face test and handgrip test while under continuous blood pressure and heart rate monitoring. Based on the results of the nerve conduction study, the subjects were divided into two groups: those with polyneuropathy (ATTRv-wPN) and those without polyneuropathy (ATTRv-woPN). Age- and sex-matched healthy controls (HC) were used for comparison. Thirty-seven ATTRv subjects (19 with ATTRv-wPN, 18 with ATTRv-woPN) and 41 HC performed the CRTs. Of these 37 subjects with ATTRv, four (11%) presented neurogenic orthostatic hypotension the during head-up tilt test. Based on the results of the CRTs, autonomic dysfunction characterized by either sympathetic or parasympathetic impairment was detected in 37% and 63% of ATTRv-wPN subjects, respectively. Subjects with ATTRv-woPN presented a significant impairment of autonomic responses to the Valsalva manoeuvre compared to the HC (overshoot p = 0.004; Valsalva ratio p = 0.001). Autonomic dysfunctions are frequent in subjectswith ATTRv when investigated by means of standardized CRTs, and are also relevant in the pre-symptomatic stage. Cardiovagal functions are the primary functions affected, among others. This may be crucial in defining the proper diagnostic workout for early diagnosis and improving the likelihood of providing the patient with prompt administration of disease-modifying treatments.

Cardiac Autonomic Neuropathy in Prediabetes: A Case-Control Study.

Early detection and diagnosis of diabetic autonomic neuropathy, especially cardiac autonomic neuropathy (CAN), have gained attention recently because of their elevated cardiovascular mortality risk. Although the connection between type 2 diabetes mellitus and autonomic neuropathy is well established, evidence is emerging that the association might predate the stage of prediabetes. The present study was undertaken to compare the prevalence of CAN in prediabetes versus that in normoglycemic controls. The study population was selected by purposive sampling from individuals attending a tertiary care hospital from January 2018 to June 2019. Fifty individuals with prediabetes diagnosed by the American Diabetes Association's glycated haemoglobin criteria and 50 age- and gender-matched healthy controls were recruited. CAN was assessed by standard cardiovascular reflex tests, as described by Ewing and Clarke. Changes in R-R with deep breathing, Valsalva manoeuver, and changes in blood pressure (BP) in response to standing and sustained handgrip were evaluated. Three-time domains [standard deviation of normal-to-normal intervals (SDNN), root mean square of successive RR intervals (rMSSD) and percentage of successive normal to normal R-R (NN) intervals that differ by more than 50 ms (pNN50)] and four frequency domain indices [very low-frequency band (VLF), low-frequency band (LF), high-frequency band (HF), LF/HF ratio) of heart rate variability (HRV)] were examined. The mean heart rate was 71.37 ± 7.94 and 65.59 ± 8.73 beats/min in patients with prediabetes and controls, respectively (P < 0.05). All three-time-domain indices of HRV were significantly lower in persons with prediabetes compared to controls. The peak frequency of LF, peak power of LF, normalised unit of LF, and LF/HF ratio was significantly lower in subjects with prediabetes than in controls. There was no difference in the traditional cardiovascular autonomic reflex testing. Our study demonstrates the presence of subclinical autonomic dysfunction in persons with prediabetes. Early detection of CAN in prediabetes can have future implications for cardiovascular risk reduction.

Post-Acute Effect of SARS-CoV-2 Infection on the Cardiac Autonomic Function.

BackgroundRecent studies reported a long-lasting effect of COVID-19 infection that extends beyond the active disease and disrupts various body systems besides the respiratory system. The current study aims to investigate the post-acute effect of SARS-CoV-2 infection on cardiovascular autonomic activity, reactivity and sensitivity in patients who had the infection at least 3 months before.MethodsThis was a comparative cross-sectional observational study. Fifty-nine subjects were allocated into two groups, controls (n=31), who had no history of positive COVID-19 infection, and the post-COVID patients (n=28) who were recruited 3 to 8 months after testing positive for SARS-CoV-2 by reverse transcription polymerase chain reaction (RT-PCR). Baseline cardiovascular autonomic activity was evaluated through recording of baseline heart rate variability (HRV), autonomic reactivity was determined through standard cardiovascular autonomic reflex tests (CART), and cardiac autonomic sensitivity was assessed through cardiac baroreceptor sensitivity (cBRS).ResultsHigher incidence of orthostatic hypotension was observed in post-COVID patients compared to controls (39.3% and 3.2%, respectively, p <0.001). Additionally, significantly reduced handgrip test, and heart rate response to head-up tilt was illustrated in the post-COVID group (p <0.001). About 85.7% of post-COVID participants had at least one abnormal cardiovascular reflex test (CART) compared to the control group (p <0.001). Although HRV parameters (TP, LF, HF, SDRR, RMSSD, pRR50), and the cBRS were numerically lower in the post-COVID-19 group, this did not reach the level of significance.ConclusionThe results of the present study are suggestive of altered cardiovascular reactivity in post-acute COVID patients and demand further investigation and longer term follow up.

458-P: Inflammatory Markers and Cardiovascular Autonomic Neuropathy in Type 1 Diabetes

Objective: We aimed to assess the role of chronic inflammation in the pathogenesis of cardiovascular autonomic neuropathy (CAN) , a serious complication of type 1 diabetes (T1D) . Methods: We leveraged an ongoing randomized, placebo-controlled clinical trial targeting inflammation with salsalate in individuals with T1D, to measure a panel of 40 inflammatory markers (Figure) in baseline samples. Measures of CAN included standardized cardiovascular autonomic reflex tests (CARTs) (E/I, Valsalva, 30/15 ratios) and indices of heart rate variability (HRV) . We used Spearman-rank to assess the correlations between inflammatory markers and CAN measures, and linear regression to adjust for age and hemoglobin A1c. Results: The Figure displays the correlation between biomarkers and CAN measures in 58 T1D participants (mean age 51 ± 13 years, and HbA1c 8.4 ± 1.8%) . Amongst all biomarkers, we noted a singular negative correlation between soluble urokinase plasminogen activator receptor (suPAR) and measures of CAN, which remained significant in multivariable analysis (E/I ratio p=0.005, Valsalva p=0.037, RFA p=0.019, LFA p=0.023) . Conclusion: Amongst a large panel of inflammatory markers, we found suPAR to have a notable association with CAN. SuPAR is an immune-mediated signaling glycoprotein which levels are strong predictors of risk in patients with diabetes, thus its role in CAN warrants further exploration. Disclosure L.Ang: None. L.Zhao: None. E.L.Feldman: None. S.Hayek: n/a. R.Pop-busui: Advisory Panel; Averitas Pharma, Inc., Boehringer Ingelheim International GmbH, Nevro Corp., Novo Nordisk, Reata Pharmaceuticals, Inc., Regenacy Pharmaceuticals, Inc. S.V.G.Gunaratnam: None. Y.Huang: None. K.R.Mizokami-stout: None. C.Martin: Advisory Panel; Nevro Corp. J.Reiss: n/a. A.Burant: None. A.Vasbinder: None. C.Launius: None. Funding NIH/NIDDK-1-R01-DK-107956-01

Leisure-Time Physical Activity and Glycemic Control Independently Predicts Cardiac Autonomic Neuropathy in Type 2 Diabetes Mellitus.

Though cardiac autonomic neuropathy (CAN) is a common complication of type 2 diabetes mellitus (T2DM); still, there is lack of clarity on pathophysiological correlates for its onset and progression. Therefore, the purpose of this study was to investigate the predictive ability of lifestyle and cardiometabolic risk factors for CAN in T2DM patients. A total of 105 Indian T2DM patients were recruited in the present study. Cardiometabolic risk factors, such as glycemic control, lipids, resting heart rate, systolic and diastolic blood pressure, and lifestyle risk parameters, such as physical activity levels and sleep quality were assessed. Standard cardiovascular autonomic reflex tests were performed for diagnosing CAN by Ewing's criteria. Leisure-time physical activity and glycosylated hemoglobin were significant independent predictors of CAN in T2DM. Leisure-time physical activity and glycosylated hemoglobin predicted the occurrence of CAN at cutoff values ≤4.68 metabolic equivalent-hours per week (P = .007) and >7.5% (P = .002), respectively. The T2DM patients should be encouraged to engage in leisure-time physical activity of at least 4.68 metabolic equivalent-hours per week (equivalent to 1.2h of walk or 0.6h of jog per week) and therapeutic strategies for controlling hyperglycemia in T2DM should aim to reduce glycosylated hemoglobin below 7.5% to reduce CAN occurrence.

Peripheral and Autonomic Neuropathy Status of Young Patients With Type 1 Diabetes Mellitus at the Time of Transition From Pediatric Care to Adult-Oriented Diabetes Care

IntroductionThe prevalence of neuropathic lesions in young patients with type 1 diabetes mellitus (T1DM) at the time of transition from pediatric care to adult-oriented diabetes care is poorly studied. A comparative study with healthy volunteers to assess the possible neuropathic condition of this special population and to identify the potential early screening needs has not been performed yet. The results may provide important feedback to pediatric diabetes care and a remarkable baseline reference point for further follow up in adult diabetes care.Patients and MethodsTwenty-nine young patients with T1DM [age: 22.4 ± 2.9 years; HbA1c: 8.5 ± 2.1%, diabetes duration: 12.2 ± 5.8 years; (mean ± SD)] and 30 healthy volunteers (age: 21.5 ± 1.6 years; HbA1c: 5.3 ± 0.3%) were involved in the study. Autonomic function was assessed by standard cardiovascular reflex tests. Complex peripheral neuropathic testing was performed by Neurometer®, Neuropad®-test, Tiptherm®, Monofilament®, and Rydel-Seiffer tuning fork tests.ResultsT1DM patients had significantly higher diastolic blood pressure than controls (80 ± 9 vs. 74 ± 8 mmHg, p < 0.01), but there was no significant difference in systolic blood pressure (127 ± 26 vs. 121 ± 13 mmHg). Cardiovascular reflex tests had not revealed any significant differences between the T1DM patients and controls. No significant differences with Neurometer®, Neuropad®-test, and Monofilament® were detected between the two groups. The vibrational sensing on the radius on both sides was significantly impaired in the T1DM group compared to the controls with Rydel-Seiffer tuning fork test (right: 7.5 ± 1.0 vs. 7.9 ± 0.3; left: 7.5 ± 0.9 vs. 7.9 ± 0.3, p < 0.05). The Tiptherm®-test also identified a significant impairment in T1DM patients (11 sensing failures vs. 1, p < 0.001). In addition, the neuropathic complaints were significantly more frequently present in the T1DM patient group than in the controls (9 vs. 0, p < 0.01).ConclusionIn this young T1DM population, cardiovascular autonomic neuropathy and cardiac morphological alterations could not be found. However, Rydel-Seiffer tuning fork and Tiptherm®-tests revealed peripheral sensory neurological impairments in young T1DM patients at the time of their transition to adult diabetes care.

Utility of using electrocardiogram measures of heart rate variability as a measure of cardiovascular autonomic neuropathy in type 1 diabetes patients.

Aims/IntroductionCardiovascular autonomic neuropathy (CAN) is a predictor of cardiovascular disease and mortality. Cardiovascular reflex tests (CARTs) are the gold standard for the diagnosis of CAN, but might not be feasible in large research cohorts or in clinical care. We investigated whether measures of heart rate variability obtained from standard electrocardiogram (ECG) recordings provide a reliable measure of CAN.Materials and MethodsStandardized CARTs (R‐R response to paced breathing, Valsalva, postural changes) and digitized 12‐lead resting ECGs were obtained concomitantly in Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications participants (n = 311). Standard deviation of normally conducted R‐R intervals (SDNN) and the root mean square of successive differences between normal‐to‐normal R‐R intervals (rMSSD) were measured from ECG. Sensitivity, specificity, probability of correct classification and Kappa statistics evaluated the agreement between ECG‐derived CAN and CARTs‐defined CAN.ResultsParticipants with CARTs‐defined CAN had significantly lower SDNN and rMSSD compared with those without CAN (P < 0.001). The optimal cut‐off points of ECG‐derived CAN were <17.13 and <24.94 ms for SDNN and rMSSD, respectively. SDNN plays a dominant role in defining CAN, with an area under the curve of 0.73, indicating fair test performance. The Kappa statistic for SDNN was 0.41 (95% confidence interval 0.30–0.51) for the optimal cut‐off point, showing fair agreement with CARTs‐defined CAN. Combining SDNN and rMSSD optimal cut‐off points does not provide additional predictive power for CAN.ConclusionsThese analyses are the first to show the agreement between indices of heart rate variability derived from ECGs and the gold standard CARTs, thus supporting potential use as a measure of CAN in clinical research and clinical care.

Cardiovascular autonomic neuropathy in patients with schizophrenia

Background Cardiovascular autonomic neuropathy (CAN) is an independent predictor of cardiovascular disease (CVD) in patients with diabetes as well as in patients with pre-diabetes and metabolic syndrome. Patients with schizophrenia have an increased rate of metabolic syndrome, pre-diabetes and diabetes as compared to the general population. Despite of this, occurrence CAN has not been investigated in patient with schizophrenia. Therefore, the aims of this study were (1) to evaluate the feasibility testing for CAN with a new clinical tool and (2) report the prevalence of early and manifest CAN in patients with schizophrenia. Methods and results Patients with diagnosed schizophrenia and with a disease duration ≥10 years were matched 1:1 on age and gender at screening with psychiatric healthy controls. CAN was defined as ≥ two abnormal standard cardiovascular autonomic reflex tests (lying-to-standing, deep breathing, and Valsalva maneuver) using the VagusTM device. A total of 46 patients with schizophrenia were included and matched to psychiatric healthy controls. Manifest CAN were more frequently presented in patients with schizophrenia (39% vs. 6% for controls, p<.0001). Sensitivity analysis of 41 subjects with schizophrenia without diabetes matched to 41 psychiatric healthy controls, showed similar results (37% vs. 5% for controls, p<.0001). Conclusion CAN is highly prevalent in patients with schizophrenia. Testing for CAN is feasible and might be a new clinically tool for detecting early stages of CVD in patients with schizophrenia.

Correlations between left ventricular rotational mechanics and parasympathetic autonomic function-results from the three-dimensional speckle-tracking echocardiographic MAGYAR-Healthy Study.

Left ventricular (LV) twist is calculated from the net difference of counterclockwise apical and clockwise basal rotation during systole. The current study was designed to evaluate correlations between autonomic function and LV rotational mechanics in healthy subjects. The present study comprised 18 healthy subjects (mean age: 36±12 years, 12 men). Three-dimensional speckle tracking echocardiography (3DSTE) could be used for non-invasive evaluation of LV rotation and twist. Autonomic function was assessed by means of 5 standard cardiovascular reflex tests. During 3DSTE, basal LV rotation proved to be -3.24±2.02 degree, while apical LV rotation was 9.08±3.04 degree, therefore LV twist was 11.70±6.80 degree. Valsalva test showed significant correlations with LV basal (r=0.529, P=0.019) and apical rotations (r=-0.534, P=0.022), and LV twist (r=-0.467, P=0.044). Heart rate response to deep breathing significantly correlated with LV twist, as well (r=-0.452, P=0.052). The other tests had no any relationship with rotational characteristics. Correlations exist between parasympathetic autonomic function and 3DSTE-derived LV rotation and twist in healthy subjects.

Peripheral sensory nerve hyperaesthesia in women with polycystic ovary syndrome.

Dysfunction of the nervous system is well-known in diabetes and also among patients with prediabetes, obesity and hypertension. However, there is only a limited amount of data available on the changes in neuronal function in polycystic ovary syndrome (PCOs), despite the fact that this condition is also accompanied by metabolic and vascular abnormalities. The aim of our study was to assess the cardiovascular autonomic and peripheral sensory function in patients with PCOs. The study involved 27 women with PCOs, and 24 healthy women as control subjects. Autonomic neuropathy (AN) was assessed using the four standard cardiovascular reflex tests. Peripheral sensory function was determined using the Neurometer. Electric stimulation was applied transcutaneously and the current perception threshold (CPT) values were determined on the median and peroneal nerves. No significant differences were found between the PCOs patients and the control group regarding the cardiovascular autonomic reflex tests and the AN scores. The CPT values of PCOs patients in the median and peroneal nerves were lower at all frequencies in comparison to controls. Conclusions: The cardiovascular autonomic nerve function was normal in the patients with PCOs. The current perception thresholds were consequently lower in the PCOs patients both in the upper and lower extremities at all frequencies, which serves as an early sign of neuropathy. As a novel observation, our results suggest that early neuronal damage manifests in the form of sensory hyperaesthesia in patients with PCOs.

Association of serum CTRP9 levels with cardiac autonomic neuropathy in patients with type 2 diabetes mellitus.

AimsCardiac autonomic neuropathy (CAN) is a serious complication of diabetes and is associated with adipokines. The C1q tumor necrosis factor‐related protein 9 (CTRP9) is a newly discovered adipokine. This study aimed to evaluate the association of serum CTRP9 levels with the prevalence and severity of CAN in patients with type 2 diabetes mellitus.Materials and MethodsWe enrolled 262 patients (aged ≥18 years) with type 2 diabetes mellitus into this study. Standard cardiovascular autonomic reflex tests (CARTs) were used to assess CAN and patients were divided into three groups accordingly: a non‐CAN group, an early CAN group, and a definite CAN group. Serum CTRP9 levels were measured by enzyme‐linked immunosorbent assay, and the tertiles were calculated.ResultsSerum CTRP9 levels decreased significantly in the early CAN and definite CAN groups (P < 0.05). The percentage of definite CAN was the highest at the minimum tertile of serum CTRP9 level (T1; P < 0.05). Additionally, serum CTRP9 levels were negatively correlated with age, DM duration, hemoglobin A1c (HbA1c), and fasting plasma glucose (FPG) while positively correlated with high‐density lipoprotein cholesterol (HDL; P < 0.05). The level of CTRP9 was also significantly associated with the four indexes of CARTs (P < 0.05). Furthermore, CTRP9 was a protective factor for definite CAN (P < 0.05). Compared with the maximum tertile (T3) of the serum CTRP9 levels, a decreased level of serum CTRP9 in T1 significantly increased the prevalence ratio of definite CAN in patients with type 2 diabetes mellitus (P < 0.05).ConclusionSerum CTRP9 levels were independently associated with definite CAN. CTRP9 represents a reliable biomarker for exploring CAN in patients with type 2 diabetes mellitus.

The effect of α-lipoic acid treatment on plasma asymmetric dimethylarginine, a biomarker of endothelial dysfunction in diabetic neuropathy

IntroductionDiabetic neuropathy may develop on a background of hyperglycaemia and is associated with increased oxidative stress. Elevated asymmetric dimethylarginine (ADMA) levels are linked to oxidative stress reducing the synthesis of nitric oxide (NO) by uncoupling NO synthase. Oxidative stress induces considerable changes in nerve conduction velocity in diabetic patients. There is strong evidence that α-lipoic acid (ALA) as an antioxidant may improve nerve conduction and relieve neuropathic symptoms. We aimed to investigate the relationship between endothelial dysfunction and NO synthesis in type 2 diabetic patients with peripheral neuropathy after ALA treatment.Material and methodsFifty-four type 2 diabetic patients with neuropathy were included in the study. Serum ADMA concentration, ICAM-1, VCAM-1, oxidised low-density lipoprotein (oxLDL), and TNF-α levels were determined with Enzyme-Linked Immunosorbent Assay (ELISA). Nitric oxide concentration was measured by Griess reaction. Peripheral sensory nerve function was assessed by current perception threshold (CPT) testing. Autonomic function was assessed by Ewing’s five standard cardiovascular reflex tests composite autonomic score (CAS).ResultsAsymmetric dimethylarginine levels were significantly decreased (0.62 ±0.11 vs. 0.53 ±0.11 µmol/l, p &lt; 0.001), as well as TNF-α concentrations (1.21 ±0.42 pg/ml vs. 1.05 ±0.5 pg/ml, p &lt; 0.05), while NO levels were significantly increased (16.78 ±11.1 vs. 21.58 ±8.84 µmol/l, p &lt; 0.05) after six-months of 600 mg/day ALA treatment. VCAM-1, ICAM-1, and oxLDL levels did not change significantly. The CPT and CAS significantly improved after ALA treatment. The improvement of CPT values was correlated positively with the change of ADMA levels (r = 0.58, p &lt; 0.001). The change in ADMA level was more pronounced in responder patients based on both CPT and CAS.ConclusionsOur results suggest that ALA supplementation improves endothelial function characterised by serum levels of ADMA and TNF-α in patients with diabetic neuropathy. Changes in serum ADMA levels may predict the clinical response to ALA treatment.

Cardiac vagal tone as a novel screening tool to recognize asymptomatic cardiovascular autonomic neuropathy: Aspects of utility in type 1 diabetes

AimsTo test the performance of the cardiac vagal tone (CVT) derived from a 5-minute ECG recording compared with the standardized cardiovascular autonomic reflex tests (CARTs). MethodsCross-sectional study included 56 well-phenotyped adults with type 1 diabetes (19–71 years, 2–54 years disease-duration). Autonomic testing included: standardized CARTs obtained with the VAGUS™, CVT, and indices of heart rate variability (HRV) obtained at 24- and 120-hour, and electrochemical skin conductance assessed with SUDOSCAN®. ROC AUC and cut-off values were calculated for CVT to recognize CAN based on ≥ 2 (established CAN, n = 7) or 1 (borderline CAN, n = 9) abnormal CARTs and compared to HRV indices and electrochemical skin conductance. ResultsEstablished CAN: The cut-off CVT value of 3.2LVS showed 67% sensitivity and 87% specificity (p = 0.01). Indices of HRV at either 24-hour (AUC > 0.90) and 120-hour (AUC > 0.88) performed better than CVT. Borderline CAN: The cut-off CVT value of 5.2LVS indicated 88% sensitivity and 63% specificity (p = 0.07). CVT performed better than HRV indices (AUC < 0.72). Electrochemical skin conductance (AUC:0.63–0.72) had lower sensitivity and specificity compared with CVT. ConclusionsImplementation of CVT with a clinically applicable cut-off value may be considered a quicker and accessible screening tool which could ultimately decrease the number of unrecognized CAN and initiate earlier prevention initiatives.

Risk Factors for Diabetic Peripheral Neuropathy and Cardiovascular Autonomic Neuropathy in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study.

The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study demonstrated that intensive glucose control reduced the risk of developing diabetic peripheral neuropathy (DPN) and cardiovascular autonomic neuropathy (CAN). We evaluated multiple risk factors and phenotypes associated with DPN and CAN in this large, well-characterized cohort of participants with type 1 diabetes, followed for >23 years. DPN was defined by symptoms, signs, and nerve conduction study abnormalities in ≥2 nerves; CAN was assessed using standardized cardiovascular reflex tests. Generalized estimating equation models assessed the association of DPN and CAN with individual risk factors measured repeatedly. During DCCT/EDIC, 33% of participants developed DPN and 44% CAN. Higher mean HbA1c was the most significant risk factor for DPN, followed by older age, longer duration, greater height, macroalbuminuria, higher mean pulse rate, β-blocker use, and sustained albuminuria. The most significant risk factor for CAN was older age, followed by higher mean HbA1c, sustained albuminuria, longer duration of type 1 diabetes, higher mean pulse rate, higher mean systolic blood pressure, β-blocker use, estimated glomerular filtration rate <60 mL/min/1.73 m2, higher most recent pulse rate, and cigarette smoking. These findings identify risk factors and phenotypes of participants with diabetic neuropathy that can be used in the design of new interventional trials and for personalized approaches to neuropathy prevention.

Role of Heart Rate Response to Standing and Valsalva Manoeuvre Measurement in Diagnosing Cardiovascular Autonomic Neuropathy in Patients With Diabetes Mellitus.

Diabetes is an iceberg disease with many complications like cardiovascular disease &diabetic neuropathy. One of the most overlooked of all serious complications of diabetes is cardiovascular autonomic neuropathy (CAN), Autonomic nervous system dysfunction is one of the significant complications of diabetes mellitus and this is generally associated with a poor prognosis. Standard cardiovascular reflex tests are used to assess cardiovascular autonomic function. These include changes in heart rate during standing up and, Valsalva manoeuvre to assess cardiac parasympathetic activity. Aim: To analyse the role of heart rate during standing up and , Valsalva manoeuvre in diagnosing Cardiac Autonomic Neuropathy.

Cardiac autonomic neuropathy in nonobese young adults with type 1 diabetes.

PurposeThe aim of this study was to evaluate the prevalence and risk factors for cardiac autonomic neuropathy (CAN) in nonobese nonobese young type 1 diabetes mellitus (T1DM) patients without micro- or macrovascular complications.MethodsCAN was assessed in 95 patients with T1DM, aged 18–29 years, using standard cardiovascular reflex tests – heart rate response to deep breathing, standing, and the Valsalva maneuver and blood pressure response to standing. Furthermore, power spectral analyses of overall heart rate variability (HRV), standard deviation of NN intervals (SDNN), and total power (TP) were tested with DiCAN. CAN was defined as abnormal results for at least 1 of the 4 cardiovascular reflex tests.ResultsThe prevalence of CAN was 12.6%. The frequency of one and 2 abnormal reflex tests was 10.5% and 2.1%, respectively. No significant differences were observed in age, sex, mean hemoglobin A1c (HbA1c) level, and duration of diabetes with respect to presence of CAN. Patients with CAN exhibited lower overall HRV parameters (SDNN and TP) compared with those without CAN even though there was no statistical significance. In multivariable analyses, higher mean HbA1c level was significantly associated with lower overall HRV (β=-44.42, P=0.002 for SDNN and β=-2.82, P<0.001 for TP).ConclusionsCAN can be detected in 12.6% of young adult T1DM patients even without other micro- or macrovascular complications. Glycemic control is the main determinant to maintain overall HRV and prevent CAN.

Impaired Amino Acid and TCA Metabolism and Cardiovascular Autonomic Neuropathy Progression in Type 1 Diabetes.

While diabetes is characterized by hyperglycemia, nutrient metabolic pathways like amino acid and tricarboxylic acid (TCA) cycle are also profoundly perturbed. As glycemic control alone does not prevent complications, we hypothesized that these metabolic disruptions are responsible for the development and progression of diabetic cardiovascular autonomic neuropathy (CAN). We performed standardized cardiovascular autonomic reflex tests and targeted fasting plasma metabolomic analysis of amino acids and TCA cycle intermediates in subjects with type 1 diabetes and healthy control subjects followed for 3 years. Forty-seven participants with type 1 diabetes (60% female and mean ± SD age 35 ± 13 years, diabetes duration 13 ± 7 years, and HbA1c 7.9 ± 1.2%) had lower fumarate levels and higher threonine, serine, proline, asparagine, aspartic acid, phenylalanine, tyrosine, and histidine levels compared with 10 age-matched healthy control subjects. Higher baseline fumarate levels and lower baseline amino acid levels—asparagine and glutamine—correlate with CAN (lower baseline SD of normal R-R interval [SDNN]). Baseline glutamine and ornithine levels also associated with the progression of CAN (lower SDNN at 3 years) and change in SDNN, respectively, after adjustment for baseline HbA1c, blood glucose, BMI, cholesterol, urine microalbumin-to- creatinine ratio, estimated glomerular filtration rate, and years of diabetes. Therefore, significant changes in the anaplerotic flux into the TCA cycle could be the critical defect underlying CAN progression.