This study aimed to investigate whether baroreflex sensitivity (BRS) could serve as a reliable metric for assessing cardiovascular autonomic neuropathy (CAN) and concurrently act as a surrogate biomarker for evaluating the severity of arterial stiffness and CAN in individuals diagnosed with type 2 diabetes mellitus (T2DM). Participants underwent brachial-ankle pulse wave velocity (baPWV) as well as autonomic function evaluations encompassing the Sudoscan-based modified composite autonomic scoring scale (CASS), baroreflex sensitivity, and heart rate variability in time domains and frequency domains. Linear regression analysis was performed to evaluate the influence of independent variables on baPWV and modified CASS. Participants with higher baPWV values were older, with longer diabetes duration, lower body weight, body mass index, waist circumference, elevated systolic and diastolic blood pressure, and mean arterial blood pressure. They also exhibited a higher prevalence of retinopathy as the underlying disease and reduced estimated glomerular filtration rate. Multiple linear regression analysis revealed that age and BRS were significantly associated with baPWV while diabetes duration, UACR, and BRS were significantly associated with modified CASS. Our study confirms the significant association of BRS with baPWV and modified CASS in T2DM, highlighting its pivotal role in linking microvascular and macrovascular complications. This supports BRS as a surrogate marker for assessing both the severity of arterial stiffness and cardiovascular autonomic neuropathy in T2DM, enabling the early identification of complications.

OBJECTIVE: The study aimed to explore risk stratification approaches for cardiovascular autonomic neuropathy (CAN) in individuals with prediabetes and type 2 diabetes (T2DM) over a three-year follow-up period.
METHODS: Participants underwent evaluations of autonomic function encompassing cardiovascular autonomic reflex tests (CARTs), baroreflex sensitivity (BRS), heart rate variability (HRV) in time domains (standard deviation of all normal RR intervals (SDNN)) and frequency domains (high frequency/low frequency ratio), and electrochemical skin conductance (ESC). The diagnosis of CAN relied on abnormal CART results. Subjects were categorized into 4 groups, based on their assessment of cardiac autonomic function at 3-year follow-up, relative to the presence or absence of CAN at baseline assessment: Persistent absence of CAN; Resolution of CAN; Progression to CAN; and Persistent CAN.
RESULTS: Participants with T2DM/prediabetes (n = 91/7) were categorized as: Persistent absence of CAN (n = 25), Resolution of CAN (n = 10), Progression to CAN (n = 18), and Persistent CAN (n = 45) groups. The Persistent absence of CAN group showed significant associations with SDNN. The Resolution of CAN group exhibited notable associations with mean HbA1C (follow-up), while the Progression to CAN group displayed a significant link with baseline estimated glomerular filtration rate. The Persistent CAN group demonstrated significant associations with SDNN and Sudoscan CAN risk score. Screening recommendations involve biennial to annual assessments based on risk levels, aiding in CAN detection and subsequent comprehensive and time-intensive autonomic function tests for confirmation. The study\'s findings offer improved risk categorization approaches for detecting CAN, which has relevance for shaping public health strategies.

Existing evidence supports an association between chemerin levels and cardiovascular risk, while reduced thiol levels are linked to diabetes mellitus. It is hypothesized that chemerin may contribute to autonomic dysfunction and cardiovascular risk in type 2 diabetes mellitus (T2DM), potentially mediated by the antioxidant capacity of patients with well-controlled T2DM and prediabetes. Comprehensive cardiovascular autonomic testing and biomarker assessments were conducted for all participants. The severity of cardiovascular autonomic neuropathy (CAN) was evaluated using the composite autonomic scoring scale (CASS). A mediation model was employed to explore the potential relationships among chemerin levels, antioxidant capacity (indicated by thiol levels), and CAN severity (indicated by CASS values). A total of 184 participants were enrolled in this study, comprising 143 individuals with T2DM and 40 individuals with prediabetes. The findings reveal a significant negative association between thiols levels (r = -0.38, p < 0.0001) and the CASS values, while a positive association is observed between chemerin levels (r = 0.47, p < 0.0001) and the CASS values. Linear regression analysis identified chemerin and thiols as independent variables significantly associated with CASS values. Subsequent mediation analysis elucidated that thiols levels act as mediators in the relationship between elevated chemerin levels and an increased CASS value. This study shows that poor cardiovascular function, higher chemerin levels, and reduced antioxidant capacity coexist in individuals with T2DM and prediabetes. Mediation analysis suggests a pathophysiological link between high chemerin levels and low antioxidant capacity, adversely impacting CAN severity.

OBJECTIVE: The relationship of CAN and BMD, fracture risk is still unclear in T2DM. The aim of the present study is to investigate the correlation between heart rate variability (HRV) and BMD in T2DM.
METHODS: The study included 276 patients with T2DM aged ≥ 50 years, and Cardiovascular Autonomic Reflex Tests (CARTs) were applied to divide patients into two groups: CAN ( ±). 24 h Ambulatory ECG was assessed for HRV, BMD was measured by dual-energy X-ray bone densitometry, and FRAX scores were calculated for 10-year hip fracture risk (HF1) and major osteoporotic fracture risk (MOF). Adjusted regression analysis was performed to investigate influence factors for BMD and fracture risk. ROC curve was used to analyze the optimal cut-off point of LF/HF for screening osteoporosis.
RESULTS: Baseline data showed significant differences in the duration of T2DM, insulin resistance index (HOMA-IR), 25-hydroxyvitamin D[25(OH)D], femoral neck BMD, hip BMD, lumbar BMD, HF1, and MOF between the CAN ( +) and CAN (-) groups. The proportion of patients with osteoporosis increased as the degree of CAN lesion increased. Correlation analysis showed that LF/HF was significantly correlated with BMD, especially with hip (r = - 0.534, p < 0.001). Regression analysis showed that LF/HF was a risk factor for reduced BMD and increased fracture risk. The optimal cut-point value for LF/HF to predict osteoporosis by ROC curve analysis was 3.17.
CONCLUSIONS: CAN is associated with reduced BMD and increased fracture risk in patients with T2DM, and LF/HF may have the potential to be a predictor of diabetic osteoporosis and have some clinical value in early diagnosis of diabetic osteoporosis and non-traumatic fractures in T2DM.

Cardiovascular autonomic neuropathy (CAN) is common in patients with type 2 diabetes mellitus (T2DM), mainly presented as decreased heart rate variability (HRV) which often leads to cardiac death. However, HRV measurement is not convenient in most clinics. Therefore, identifying high-risk patients for CAN in diabetes with easier measurements is crucial for the early intervention and prevention of catastrophic consequences.
In this cross-sectional study, 675 T2DM patients with normocalcemia were selected. Of these, they were divided into two groups: normal HRV group (n = 425, 100 ms≤ SDNN ≤180 ms) vs. declined HRV group (n = 250, SDNN <100 ms). All patients\' clinical data were collected and the correlation of clinical variables with HRV were analyzed by correlation and logistic regression analysis. The area below the ROC curve was used to evaluate the predictive performance of serum calcium on HRV.
In this study, declines in HRV were present in 37.0% of T2DM patients. Significant differences in albumin-adjusted serum calcium levels (CaA) (8.86 ± 0.27 vs. 9.13 ± 0.39 mg/dl, p <0.001) and E/A (0.78 ± 0.22 vs. 0.83 ± 0.26, p = 0.029) were observed between declined HRV and normal HRV groups. Bivariate linear correlation analysis showed that CaA and E/A were positively correlated with HRV parameters including SDNN (p < 0.001), SDNN index (p < 0.001), and Triangle index (p < 0.05). The AUC in the ROC curve for the prediction of CaA on HRV was 0.730 (95% CI (0.750-0.815), p < 0.001). The cutoff value of CaA was 8.87 mg/dl (sensitivity 0.644, specificity 0.814). The T2DM patients with CaA <8.87 mg/dl had significantly lower HRV parameters (SDNN, SDNN index, rMSSD, and triangle index) than those with CaA ≥8.87 mg/dl (p < 0.01, respectively). Multivariate logistic regression analysis showed a significantly increased risk of declined HRV in subjects with CaA level <8.87 mg/dl [OR (95% CI), 0.049 (0.024-0.099), p < 0.001].
Declined HRV is associated with a lower CaA level and worse cardiac function. The serum calcium level can be used for risk evaluation of declined HRV in T2DM patients even within the normocalcemic range.

BACKGROUND: The clinical characteristics and outcomes of small fiber neuropathy (SFN) in Chinese patients with type 2 diabetes mellitus (T2DM) have not been thoroughly described. In this study, we investigated the metabolic and neurological indexes and the prognosis of patients with T2DM based on skin biopsy.
METHODS: A total of 34 healthy Chinese volunteers were recruited for skin biopsy to establish the reference range of intra-epidermal nerve fiber density (IENFD), and 89 patients with T2DM attending the Nanjing Drum Tower Hospital were evaluated at baseline. Of these 89 patients, 17 with pure SFN and nine with mixed diabetic polyneuropathy (DPN) were reassessed at the end of the follow-up.
RESULTS: Glycated hemoglobin and postprandial blood glucose levels were lower (P = 0.005 and P = 0.041, respectively) and postprandial C-peptide and insulin levels were higher (P = 0.001 and P = 0.019, respectively) in the pure SFN group than in the mixed DPN group. A partial correlation study showed that there was a negative correlation between IENFD of the distal leg and cardiovascular autonomic reflex test (CART) scores (r = - 0.513, P = 0.001) after adjusting for age and duration of diabetes. Only vitamin B12 level (P = 0.028) and motor nerve conduction velocity (MCV) of the common peroneal nerve (P = 0.045) were increased in the patients with pure SFN at the final visit while MCVs of the common peroneal nerve (P = 0.025) and tibial nerve (P = 0.047) were decreased in the mixed DPN group at the final visit.
CONCLUSIONS: Better islet function and cardiovascular autonomic function were observed in patients with pure SFN compared with mixed DPN. The metabolic and neurological indexes remained relatively stable in the patients with pure SFN during the follow-up.

OBJECTIVE: Cardiovascular autonomic neuropathy (CAN) is one of the most serious types of diabetic autonomic neuropathy and is a class of small fibre neuropathy. Among many inspection methods, quantitative sensory testing is an effective and convenient method for diagnosing diabetic small fibre neuropathy. This cross-sectional study aimed to identify the correlation between the development of cardiovascular autonomic neuropathy and quantitative sensory testing parameters in patients with type 2 diabetes mellitus.
METHODS: A total of 266 participants with type 2 diabetes mellitus from Nanjing Drum Tower Hospital were enrolled in this study, and each of them received cardiovascular reflex tests (CARTs) and quantitative sensory testing, including testing of cold, warm, cold pain, and heat pain detection thresholds (CDT, WDT, CPT, and HPT, respectively). The results of CARTs were compared with the thermal detection thresholds in quantitative sensory testing by using SPSS 26.0.
RESULTS: A total of 266 participants were divided into the CAN group, early CAN (ECAN) group, and without CAN (NCAN) group. There were significant differences in quantitative sensory testing parameters among three groups, and CARTs presented a positive correlation with the WDT and HPT and a negative correlation with the CDT. Moreover, after adjusting for age, sex, diabetes duration, and other influencing factors, WDT, HPT, and CDT were independent risk factors for cardiovascular autonomic neuropathy.
CONCLUSIONS: The thermal detection thresholds, including cold, warm, and heat pain detection thresholds, in quantitative sensory testing were found to be significantly related to the results of CARTs. Some thermal detection thresholds were independent risk factors for cardiovascular autonomic neuropathy. Therefore, this study showed that quantitative sensory testing has a reliable predictive ability for the occurrence and development of cardiovascular autonomic neuropathy.

OBJECTIVE: Clinical studies show that either heart rate variability (HRV) or electrochemical skin conductance (ESC) alone can serve as a simple and objective method for screening cardiovascular autonomic neuropathy (CAN). We tested the hypothesis that combining these two quantitative approaches can not only reinforce accuracy in CAN screening but also provide a better estimate of CAN severity in patients with type 2 diabetes (T2DM) who had already had CAN in outpatient clinics.
METHODS: Each patient received a complete battery of cardiovascular autonomic reflex tests (CARTs), with ESC measured by SUDOSCAN, time domain of HRV measured by standard deviation of all normal RR intervals (SDNN) and frequency domain of HRV (low frequency [LF], high frequency [HF], and LF/HF ratio), and peripheral blood studies for vascular risk factors. Severity of CAN was measured by CAN score.
RESULTS: The 90 T2DM patients included 50 males and 40 females. Those with more severe CAN had lower values in feet ESC (P = 0.023) and SDNN (P < 0.0001). Multiple linear regression analysis also showed that feet ESC and SDNN value (P = 0.003 and P < 0.0001) were significantly associated with CAN score. Combining SDNN and feet ESC also can increase the diagnostic accuracy of CAN with respective to sensitivity and specificity by using receiver operating characteristic analysis.
CONCLUSIONS: Combining the results of SDNN and feet ESC can not only assess, but also quantitatively reflect the progress or improvement of autonomic nerve function (including sympathetic and parasympathetic activity) in patients with T2DM.

Autonomic disorders have been recognized as an important non-motor feature in Parkinson\'s disease (PD). However, there is a paucity of information on the presence and severity of cardiovascular autonomic neuropathy (CAN) among different motor phenotypes. The aims of this study were to examine the feasibility of electrochemical skin conductance (ESC) measured by Sudoscan as a screening service for CAN in patients with PD and investigate the severity of CAN among different motor phenotypes. Design: This was a cross-sectional observational study that enrolled 63 patients with PD. Patients were divided into three phenotypes, postural instability/gait difficulty (PIGD), tremor-dominant (TD), and akinetic-rigid (AR), according to their motor symptoms. Cardiovascular autonomic function was measured, and the presence and severity of CAN was determined according to the composite autonomic scoring scale (CASS). Functional scores were measured by the Hoehn and Yahr (HY) stage and the Unified Parkinson\'s Disease Rating Scale (UPDRS). The median HY stage was 2.0 [1.5, 3.0]. Median UPDRS total score was 23.0 (17.5, 30.5), 10.0 (6.0, 11.0) and 14.0 (6.3, 23.8) in groups of PIGD, TD and AR, respectively (p = 0.001). Mean CASS was 1.7 ± 1.3, 0.6 ± 0.4, and 1.8 ± 1.5 in groups of PIGD, TD and AR, respectively (p = 0.204). Although the ESC was not strongly associated with the cardiovascular autonomic parameters, the CAN risk score provided by Sudoscan significantly correlated with parameters of cardiovascular autonomic function, including heart rate response to deep breathing (HR_DB), Valsalva ratio (VR), and baroreflex sensitivity (BRS). By receiver-operating characteristic (ROC) analysis, if a patient\'s CAN risk score is higher than 33.5 (%), it is recommended to be aware of the presence of CAN even in PD patients who are asymptomatic. The area under ROC curve was 0.704. Based on our results, CAN risk score may be used for screening of CAN in patients with PD before resorting to the more sophisticated and specific, but ultimately more time-consuming, complete autonomic function testing.

Evidences support the view that central obesity is an independently cardiovascular risk. It is thought that leptin contributes to autonomic dysfunction and cardiovascular risks in type 1 and type 2 diabetes mellitus (T1DM and T2DM). This raises the possibility that leptin might mediate the relationship between central obesity and the severity of cardiovascular autonomic neuropathy (CAN) in patients with well-controlled T2DM and prediabetes.
The complete cardiovascular reflex tests and biomarkers were assessed for each patient. The severity of CAN was assessed using composite autonomic scoring scale (CASS). A single-level three-variable mediation model was used to investigate the possible relationships among central obesity [as indicated by waist circumference (WC)], leptin level, and severity of CAN (as indicated by CASS value).
A total of 107 patients were included in this study: 90 with diabetes and 17 with prediabetes. The results demonstrate that increased WC is associated with increased severity of CAN (r = 0.242, P = 0.017). We further discovered that leptin level is positively correlated with WC (r = 0.504, P < 0.0001) and the CASS value (r = 0.36, P < 0.0001). Further mediation analysis shows that leptin level serves as mediators between higher WC and higher CASS.
Our results highlighted the relationship among leptin, central obesity, and severity of CAN. As the leptin level serves as mediator between central obesity and severity of CAN, a longitudinal study is needed to confirm that control of WC can decrease leptin levels and can be effective in reducing CAN progression.