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.

To evaluate whether heart rate variability (HRV) as a measure of cardiac autonomic neuropathy (CAN) is associated with chronic kidney disease (CKD) in Chinese adults with type 2 diabetes mellitus (T2DM) in China. 392 individuals of T2DM were entered in this study, all these subjects undertook the Holter electrocardiogram for 24 hours to get the HRV parameters. Of these T2DM patients, 126 (37.3%) had CKD, and most of the HRV parameters were lower in this group than in those without CKD. Decreased HRV parameters were strongly related with CKD in Spearman's correlation analysis. After adjustments for variables, the logistic regression showed that standard deviation of the averaged normal RR intervals for all 5-minute segments (SDANN) was independently associated with decreased estimated glomerular filtration rate (eGFR < 60 mL/min/1.73 m2) (OR = 0.988; 95% CI, 0.978-0.998; P = 0.015) and increased urine albumin : creatinine ratio (UACR) ≥ 30 mg/g Cr (OR = 0.992; 95% CI, 0.985-0.998; P = 0.015). A decreased 24-hour time domain HRV parameter, SDANN, was strongly associated with both eGFR and UACR among Chinese T2DM.

The purpose of this study was to determine the relationship between chronic kidney disease (CKD) and cardiovascular autonomic neuropathy (CAN).

From October 2008 to May 2011, we enrolled 218 patients with diabetes and 62 nondiabetic subjects. Heart rate variability was represented as the maximal heart rate minus the minimal heart rate (HR_max-min) during a one-minute deep breathing test. Normal, impaired cardiovascular autonomic function and CAN were defined as s HR_max-min > 15 beats/min, HR_max-min of 10-15 beats/min and HR_max-min < 10 beats/min, respectively. CKD was diagnosed if the estimated glomerular filtration rate (eGFR) was <60/min/1.73 m² or albuminuria.

In our sample, 19.4% of nondiabetic subjects and 49.5% of diabetic subjects had CKD. The prevalence of CAN was higher among patients with diabetes than among nondiabetic subjects (26.4 vs. 4.9%). A significant association was observed between eGFR and HR_max-min. CAN was independently associated with CKD with an adjusted odds ratio of 2.77 (95% CI, 1.15-6.68) in diabetic patients. A positive linear trend was observed for the odds of CAN with increasing CKD severity in diabetes. The areas under the curve (AUCs) for the predictive ability of eGFR for the risk of impaired cardiovascular autonomic function for nondiabetic group and CAN for the diabetic group were 0.734 and 0.703, respectively. Adding age, sex, body mass index, and albuminuria to the prediction model increased the AUCs to 0.852 and 0.791, respectively.

CKD is associated with the risk of CAN in both nondiabetic and diabetic subjects. eGFR and albuminuria improve the prediction of CAN.

The present study evaluates autonomic and somatic nerve function in different stages of glucose tolerance and its correlation with different cardio-metabolic parameters.

Four hundred seventy-eight subjects, mean age 49.3±13.7years and mean BMI 31.0±6.2kg/m2, divided according to glucose tolerance: 130 with normal glucose tolerance (NGT), 227 with prediabetes (125 with impaired fasting glucose (IFG) and 102 with isolated impaired glucose tolerance (iIGT)), and 121 with newly-diagnosed T2D (NDT2D), were enrolled. Glucose tolerance was studied during OGTT. Antropometric indices, blood pressure, HbA1c, serum lipids, hsCRP and albumin-to-creatinine ratio were assessed. Body composition was estimated by a bioimpedance method (InBody 720, BioSpace). Tissue AGEs accumulation was assessed by skin autofluorescence (AGE-Reader-DiagnOpticsTM). Electroneurography was performed by electromyograph Dantec Keypoint. Cardiovascular autonomic neuropathy (CAN) was assessed by ANX-3.0 method applying standard clinical tests.

CAN was found in 12.3% of NGT, 19.8% of prediabetes (13.2% of IFG and 20.6% of iIGT), and 32.2% of NDT2D. The prevalence of diabetic sensory polyneuropathy (DSPN) was 5.7% in prediabetes and 28.6% in NDT2D. The panel of age, QTc interval, waist circumference, diastolic blood pressure, and 120-min plasma glucose was related to sympathetic activity (F [5451]=78.50, p<0.001). The panel of age, waist circumference, and QTc interval was related to parasympathetic power (F [3453]=132.26, p<0.001). HbA1c and age were related to sural SNAP (F [2454]=15.12, p<0.001). HbA1c and AGEs were related to sural SNCV (F [2454]=12.18, p<0.001).

Our results demonstrate a high prevalence of autonomic and sensory nerve dysfunction in early stages of glucose intolerance. Age, postprandial glycemia, central obesity, diastolic blood pressure and QTc interval outline as predictive markers of CAN; hyperglycemia, glycation and age of DSPN.

A well-established, comprehensive, and simple test battery was used here to re-evaluate risk factors for cardiovascular autonomic neuropathy (CAN) in type 2 diabetes. One hundred and seventy-four patients with type 2 diabetes were evaluated through the methods of deep breathing and Valsalva maneuver for correlation with factors that might influence the presence and severity of CAN. The Composite Autonomic Scoring Scale (CASS) was used to grade the severity of autonomic impairment, and CAN was defined as a CASS score ≥2. Results showed that nephropathy, duration of diabetes, blood pressure, uric acid, and the presence of retinopathy and metabolic syndrome significantly correlated with the CASS score. Age may not be a risk factor for diabetic CAN. However, the effects of diabetes on CAN are more prominent in younger patients than in older ones. Diabetic retinopathy is the most significant risk factor predictive of the presence of CAN in patients with type 2 diabetes.

The aim of this work was to assess the impact of cardiac autonomic neuropathy (CAN) on the development and progression of chronic kidney disease (CKD) in patients with type 2 diabetes.

We conducted a cohort study in adults with type 2 diabetes. Patients with end-stage renal disease were excluded. CKD was defined as the presence of albuminuria (albumin/creatinine ratio GFR > 3.4 mg/mmol) or an estimated (eGFR) < 60 ml min(-1) 1.73 m(-2). CKD progression was based on repeated eGFR measurements and/or the development of albuminuria. CAN was assessed using heart rate variability.

Two hundred and four patients were included in the analysis. At baseline, the prevalence of CKD and CAN was 40% and 42%, respectively. Patients with CAN had lower eGFR and higher prevalence of albuminuria and CKD. Spectral analysis variables were independently associated with eGFR, albuminuria and CKD at baseline. After a follow-up of 2.5 years, eGFR declined to a greater extent in patients with CAN than in those without CAN (-9.0 ± 17.8% vs -3.3 ± 10.3%, p = 0.009). After adjustment for baseline eGFR and baseline differences, CAN remained an independent predictor of eGFR decline over the follow-up period (β = -3.5, p = 0.03). Spectral analysis variables were also independent predictors of eGFR decline.

CAN was independently associated with CKD, albuminuria and eGFR in patients with type 2 diabetes. In addition, CAN was an independent predictor of the decline in eGFR over the follow-up period. CAN could be used to identify patients with type 2 diabetes who are at increased risk of rapid decline in eGFR, so that preventative therapies might be intensified.

Cardiac autonomic neuropathy (CAN) is an often overlooked and common complication of diabetes mellitus. CAN is associated with increased cardiovascular morbidity and mortality. The pathogenesis of CAN is complex and involves a cascade of pathways activated by hyperglycaemia resulting in neuronal ischaemia and cellular death. In addition, autoimmune and genetic factors are involved in the development of CAN. CAN might be subclinical for several years until the patient develops resting tachycardia, exercise intolerance, postural hypotension, cardiac dysfunction and diabetic cardiomyopathy. During its sub-clinical phase, heart rate variability that is influenced by the balance between parasympathetic and sympathetic tones can help in detecting CAN before the disease is symptomatic. Newer imaging techniques (such as scintigraphy) have allowed earlier detection of CAN in the pre-clinical phase and allowed better assessment of the sympathetic nervous system. One of the main difficulties in CAN research is the lack of a universally accepted definition of CAN; however, the Toronto Consensus Panel on Diabetic Neuropathy has recently issued guidance for the diagnosis and staging of CAN, and also proposed screening for CAN in patients with diabetes mellitus. A major challenge, however, is the lack of specific treatment to slow the progression or prevent the development of CAN. Lifestyle changes, improved metabolic control might prevent or slow the progression of CAN. Reversal will require combination of these treatments with new targeted therapeutic approaches. The aim of this article is to review the latest evidence regarding the epidemiology, pathogenesis, manifestations, diagnosis and treatment for CAN.

Low heart rate variability (HRV) is a risk factor for adverse outcomes in the general population. We aimed to determine the factors associated with HRV and evaluate the association between low HRV and clinical outcomes in patients with chronic kidney disease (CKD).

A 10-second electrocardiogram was obtained at baseline in the Chronic Renal Insufficiency Cohort (CRIC) Study. HRV was measured by the standard deviation of all R-R intervals (SDNN) and the root mean square of successive differences between R-R intervals (RMSSD).

In 3,245 CRIC participants with available baseline SDNN and RMSSD, lower HRV was associated with older age, lack of exercise, heart failure, elevated phosphorus and hemoglobin A1c, and low estimated glomerular filtration rate. After a median follow-up of 4.2 years, in fully adjusted models, lower HRV was not associated with renal [SDNN: hazard rate, HR = 0.96 (95% confidence interval, CI 0.88-1.05); RMSSD: HR = 0.97 (95% CI 0.88-1.07)] or cardiovascular outcomes [SDNN: HR = 1.02 (95% CI 0.92-1.13); RMSSD: HR = 1.00 (95% CI 0.90-1.10)]. There was a nonlinear relationship between RMSSD and all-cause mortality with increased risk with both low and high RMSSD (p = 0.04).

In a large cohort of patients with CKD, multiple risk factors for renal and cardiovascular diseases were associated with lower HRV. Lower HRV was not associated with increased risk for renal or cardiovascular outcomes, but both low and high RMSSD were associated with increased risk for all-cause mortality. In conclusion, HRV measured by RMSSD may be a novel and independent risk factor for mortality in CKD patients.

Obstructive sleep apnea (OSA) has been hypothesized to cause a hypersympathetic state, which may be the mechanism for the increased incidence of cardiovascular disease in OSA. However, there is a high prevalence of hyperglycemia in OSA patients, which may also contribute to autonomic dysfunction.

Thirty-five patients with OSA and 11 controls with average body mass index (BMI) of 32.0 ± 4.6 underwent polysomnography, glucose tolerance testing, autonomic function tests, lying and standing catecholamines, overnight urine collection, and baseline ECG and continuous blood pressure measurements for spectral analysis. A linear regression model adjusting for age and BMI was used to analyze spectral data, other outcome measures were analyzed with Kruskal-Wallis test.

Twenty-three OSA patients and two control patients had hyperglycemia (based on 2001 American Diabetes Association criteria). Apnea-hypopnea index (AHI) correlated with total power and low frequency (LF) power (r = 0.138, 0.177, p = 0.031; and r = 0.013) but not with the LF/high frequency (HF) ratio (p = 0.589). Glucose negatively correlated with LF systolic power (r = -0.171, p = 0.038) but not AHI (p = 0.586) and was marginally associated with pnn50, total power, LF, and HF power (p ranged from 0.07 to 0.08).

These data suggest that patients with OSA and mild hyperglycemia have a trend towards lower heart rate variability and sympathetic tone. Hyperglycemia is an important confounder and should be evaluated in studies of OSA and autonomic function.

The aim of this study was to investigate the prevalence of cardiovascular autonomic neuropathy in persons with previously diagnosed impaired glucose tolerance and to characterize associations between components of metabolic syndrome and cardiovascular autonomic neuropathy in the Finnish Diabetes Prevention Study cohort.

Two hundred and sixty-eight individuals with impaired glucose tolerance at baseline in the Finnish Diabetes Prevention Study, but not diagnosed with diabetes during follow-up, were studied for cardiovascular autonomic neuropathy. At the second annual follow-up visit after the end of lifestyle intervention, we performed deep-breathing and active orthostatic tests to detect possible parasympathetic and sympathetic dysfunction. To describe metabolic characteristics, anthropometric measurements, an oral glucose tolerance test and assessments for HbA(1c,) serum lipids and blood pressure were carried out.

Prevalence of parasympathetic dysfunction was 25% and prevalence of sympathetic dysfunction was 6%, with no difference between the former intervention and control group participants or between men and women. Subjects with parasympathetic dysfunction were older, more obese (weight, waist circumference, body mass index) and had higher triglyceride concentration compared with those with normal parasympathetic function (P<0.01 for all). Parasympathetic dysfunction was not significantly associated with other characteristics of metabolic syndrome; for example, high cholesterol, glucose and insulin levels or HbA(1c) . Correlations between the Expiration/Inspiration (E/I) ratio (the longest heart beat duration in expiration divided by the shortest heart beat duration in inspiration) and measures reflecting obesity were statistically significant in the pooled population and in men but not in women.

Cardiovascular autonomic neuropathy is common in persons with impaired glucose tolerance. Obesity, especially among men, seems to play an important role in the early pathogenesis of cardiovascular autonomic neuropathy.

Autonomic nervous system dysfunction is observed in Type 2 diabetes. As gestational diabetes is a potent risk factor of later Type 2 diabetes, we set out to determine whether autonomic nervous system imbalance could already be observed in women with this condition. Because activity of the sympathetic nervous system tends to be relatively stable in the nocturnal hours, we performed the study at night.

We studied 41 women with gestational diabetes, 22 healthy pregnant controls and 14 non-pregnant controls. We assayed plasma noradrenaline at 24.00, 04.00 and 07.00 h and performed an overnight Holter recording for heart rate variability analysis. In addition, we assayed plasma adrenomedullin, a cardiovascular protective hormone.

Compared with non-pregnant controls, plasma noradrenaline levels were increased at 04.00 and 07.00 h in the gestational diabetic (P = 0.003) and pregnant control (P = 0.002) groups, with no difference between them. Heart rate variability, very-low-frequency and low-frequency power were lower in pregnant groups compared to the non-pregnant controls. Heart rate variability remained unchanged between specified sampling times in the gestational diabetic group, in contrast to fluctuation seen in the control groups.

Gestational diabetes, compared with normal pregnancy, seems not to be a state of overall sympathetic nervous system activation. At the heart level, however, an inhibitory effect on autonomic nervous system modulation was seen. Plasma noradrenaline and heart rate variability correlated well, supporting the use of this function in future studies of overall sympathetic activity during pregnancy.

Microalbuminuria is associated with cardiovascular mortality, particularly among individuals with type 2 diabetes, but the mechanisms underlying this association are not completely understood. Microalbuminuria is known to be associated with cardiovascular autonomic dysfunction (C-AD), and C-AD in turn is associated with cardiovascular mortality. The purpose of this study, therefore, was to investigate whether C-AD can explain the relationship between microalbuminuria and cardiovascular mortality.

We studied 490 individuals from a population-based cohort of individuals aged 50-75 years who were followed for a median period of 13.6 years. Microalbuminuria was defined as an albumin-to-creatinine ratio > or =2.0 mg/mmol in an early-morning spot-urine sample. Ten parameters reflecting different aspects of cardiovascular autonomic function were measured and compiled into a total score of C-AD (mean of separate z scores). The association between C-AD and microalbuminuria was estimated by multiple linear regression, and relative risks (RRs) for cardiovascular mortality were estimated by Cox proportional hazards analyses.

After adjustments for age, sex, glucose tolerance status, and other risk factors, C-AD was associated with microalbuminuria (beta = 0.16 [95% CI 0.01-0.33]), and both microalbuminuria (RR 2.09 [1.07-4.08]) and C-AD (1.74 [1.04-2.89]) were associated with cardiovascular mortality. These associations did not change after further mutual adjustment for C-AD (2.13 [1.09-4.17]) or microalbuminuria (1.76 [1.05-2.94]), respectively.

Both microalbuminuria and C-AD are independently associated with cardiovascular mortality, and the excess mortality attributable to microalbuminuria cannot be explained by C-AD.

To determine the relationships between cardiovascular autonomic neuropathy (CAN) and autonomic symptoms, clinical parameters and diabetic complications in type 2 diabetes (T2DM).

The results of autonomic symptoms, clinical parameters, diabetes complications and cardiovascular reflex (CVR) tests of 674 T2DM were analyzed.

Significant correlations were found between CAN risk and age (p=0.019), duration of diabetes (p=0.008), HbA1c (p<0.001), systolic blood pressure (p=0.006), nephropathy (p<0.001), retinopathy (p<0.001), and QTc interval (p<0.001), but not BMI and hyperlipidemia. Patients with retinopathy or proteinuria had increase risk of CAN, and proliferative diabetic retinopathy (PDR) was the most significant risk factor (odds ratio: 6.85; 95% CI: 2.32-20.20) for CAN. Eighty-three percent of patients complained of autonomic symptoms; and the more symptoms complained, the higher the prevalence of CAN. Impotence was the only single symptom associated with CAN risk. Additional CAN risks were also observed when patients with multiple symptoms and/or complications in combinations.

Our results implied that patients with multiple symptoms and/or complications in combinations have increased CAN risk, and this may provide additional information for clinicians to identify T2DM at risk of having CAN.

Interaction of vascular and metabolic factors appears to contribute to the pathogenesis of diabetic neuropathy. The aim of the study was to assess the impact of arterial stiffening and thickness on diabetic neuropathy in Type 2 diabetes.

In 294 patients with Type 2 diabetes, neuropathy was assessed by four components: the presence of neuropathic symptoms, the absence of ankle tendon reflexes, perception of vibration scores and heart rate variation. We measured intima-media thickness (IMT) of carotid arteries to assess arterial thickening, and brachial-ankle pulse-wave velocity (PWV) and brachial pulse pressure (PP) which reflect arterial stiffening.

Diabetic neuropathy, defined as > or = two of the four components, was significantly associated with age, duration, glycated haemoglobin (HbA(1c)), systolic blood pressure, diastolic blood pressure, PP, hypertension, retinopathy, urinary albumin excretion rate, nephropathy stages, PWV and IMT. PWV and PP were significantly associated with neuropathy independent of conventional cardiovascular risk factors. Multiple logistic regression analysis revealed that PWV, retinopathy, age, and HbA(1c), were significant independent determinants of neuropathy.

The present cross-sectional study indicates that markers for vascular wall properties such as PWV, IMT and PP are significantly associated with diabetic neuropathy. PWV and PP are significant determinants of neuropathy independent of conventional cardiovascular risk factors. Multifactorial intervention to inhibit progression of the atherosclerotic process may slow progression of neuropathy.

Antihypertensive treatment in diabetes mellitus, especially in diabetics known to have cardiac autonomic neuropathy, may have to consider the status of the autonomic nervous system. In diabetic subjects with cardiac autonomic neuropathy, vagal activity during the night is often reduced. The reduction results in relative or absolute sympathetic activation, which could increase cardiovascular risk. Pathophysiological and clinical data suggests that antihypertensive treatment should reduce rather than induce sympathetic activity in this setting. Beta blocking agents, ACE inhibitors, calcium antagonists of verapamil or diltiazem type and selective imidazoline receptor agonists reduce sympathetic activity and, therefore, may have a beneficial effect in diabetic patients with disturbed sympathovagal balance.

Autonomic dysfunction has been theorized to be responsible for the increased risk of cardiovascular disease in obstructive sleep apnea (OSA). Previous studies did not control for the presence of impaired glucose regulation (IGR, comprising impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and diabetes) which is also associated with abnormalities in autonomic function.

Thirty-two patients were recruited for the study. Patients underwent autonomic testing consisting of heart rate response to deep breathing, valsalva maneuver, tilt-up, and quantitative sudomotor axon reflex testing. Polysomnography (PSG) and a 2-h oral glucose tolerance test were performed. Results were analyzed with logistic regression, with age, race, body mass index (BMI), and gender as covariates.

Nineteen of 24 patients with OSA had abnormal glucose (79%, p=0.04) compared to two of nine patients without OSA. The correlation between IGR, OSA and total autonomic dysfunction was similar (p=.10 for IGR, p=0.06 for OSA). However, cardiac autonomic function was more strongly associated with IGR than OSA (p=.10 vs. 0.50). Age was a significant confounder, as glucose correlated with adrenergic autonomic dysfunction significantly when age was removed from the model (p=0.006).

The presence of IGR may be a confounding factor in studies of autonomic function in OSA. Larger studies are needed to delineate whether OSA is directly associated with autonomic dysfunction or whether the previously described association between dysautonomia and OSA may have been due to glucose dysregulation.

Cardiac autonomic neuropathy is a common dysfunction in manifest diabetes mellitus and is associated with duration of diabetes and/or an inadequate glycaemic control. Heart rate variability (HRV) reflects autonomic heart function. The aim of the present study was to investigate whether in women with prior gestational diabetes (GD; pre-type 2 diabetes) alterations of cardiac autonomic function can be observed after delivery in relation to insulin sensitivity and glycaemic control.

Forty-eight healthy women with prior GD were consecutively admitted to the study. HRV was analysed by both time, as well as frequency, domain methods using 24-h Holter monitoring. In addition, 20 women with normal glucose tolerance during and after pregnancy were investigated as control subjects. All women underwent a frequently sampled intravenous glucose tolerance test (FSIGT) for measurement of insulin sensitivity.

Time domain analysis (standard deviation of normal RR intervals; SDNN) showed a reduced HRV in 25 out of the 48 (52%) women with prior GD. Frequency domain analysis revealed that in these 25 subjects both low and high frequency components of power spectral density (reflecting mainly sympathetic respectively parasympathetic activity) were reduced, indicating that sympathetic as well as parasympathetic functional impairment may be assumed. However, a relative predominance of the sympathetic over parasympathetic cardiac function was observed. The impairment of cardiac autonomic function (reduced SDNN) was correlated with HbA1c values and the 2-h blood glucose concentration (oral glucose tolerance test) but not with insulin sensitivity.

The present results demonstrate that in 52% of the women examined who had prior GD, an impairment of cardiac sympathetic as well as parasympathetic function was present, which related to glycaemic control, but not to insulin sensitivity. This infers that functional autonomic changes could be an early prognostic indicator in pre-type 2 diabetes.

Microalbuminuria is a strong and independent indicator of increased cardiovascular risk among individuals with and without diabetes. Therefore, microalbuminuria can be used for stratification of risk for cardiovascular disease. Once microalbuminuria is present, cardiovascular risk factor reduction should be more "aggressive." The nature of the link between microalbuminuria and cardiovascular risk, however, remains poorly understood. There is no strong evidence that microalbuminuria causes atherothrombosis or that atherothrombosis causes microalbuminuria. Many studies have tested the hypothesis that a common risk factor underlies the association between microalbuminuria and cardiovascular disease but, again, have found no strong evidence in favor of this contention. At present, the most likely possibility is that a common pathophysiologic process, such as endothelial dysfunction, chronic low-grade inflammation, or increased transvascular leakage of macromolecules, underlies the association between microalbuminuria and cardiovascular disease, but more and prospective studies of these hypotheses are needed.

This study compares the cardiovascular autonomic function in type 2 diabetes with and without microalbuminuria, in order to identify the possible links between early nephropathy and diabetic autonomic neuropathy (DAN).

Cardiovascular reflex tests were performed to determine the cardiovascular autonomic function. Thirty cases of type 2 diabetes with microalbuminuria were studied for evidence of DAN to compare with a normoalbuminuric group of 56 diabetic patients.

There was an increased prevalence of autonomic dysfunction in patients with microalbuminuria (63.3% in the microalbuminuria group vs. 40.0% in the normoalbuminuric controls, p = 0.001). These patients had lower heart rate variability during single breathing tests (6.9 +/- 4.3 vs. 9.6 +/- 3.6 beats/minute, p = 0.005), during 6 consecutive breathings (5.8 +/- 3.6 vs. 8.2 +/- 3.3 beats/minute, p = 0.005), after standing up (12.2 +/- 4.6 vs. 15.0 +/- 5.2 beats/ minute, p = 0.012), and during the Valsalva maneuver (11.3 +/- 3.5 vs. 13.2 +/- 3.6 beats/minute, p = 0.022). The heart rate variability with these stresses was revealed to be less favorable in subjects with microalbuminuria. However, blood pressure (BP) changes from the sitting to standing position were not significantly different for systolic BP (11.5 +/- 10.7 vs. 10.7 +/- 7.8 mmHg, p = 0.741) and diastolic BP (5.2 +/- 4.4 vs. 5.9 +/- 4.0 mmHg, p = 0.451) between the 2 groups.

Type 2 diabetic patients with microalbuminuria have diminished heart rate variability in response to deep breathing, change of position and the Valsalva maneuver, but they preserve BP response to postural change. Therefore, microalbuminuria seems to be associated with early DAN, but not with advanced DAN.

Urinary albumin excretion/microalbuminuria and cardiovascular autonomic dysfunction are associated with high mortality in type 2 diabetic patients. We tested the hypothesis that the presence of microalbuminuria would correlate with cardiovascular autonomic dysfunction and insulin resistance in type 2 diabetic patients. The study group consisted of 15 Japanese patients with type 2 diabetes and microalbuminuria (age: 56 +/- 10 years, mean +/- SD). The control group consisted of 19 age-matched patients with normalbuminuria (56 +/- 7 years). Cardiovascular autonomic function was assessed by baroreflex sensitivity (BRS), heart rate variability, plasma norepinephrine concentration, and cardiac 123I-metaiodobenzylguanidine (MIBG) scintigraphy. BRS was lower in the microalbuminuria group than in the normalbuminuria group (P < .05). Early and delayed 123I-MIBG myocardial uptake values were lower (P < .05 and P < .005, respectively) and the percent washout rate of 123I-MIBG was higher (P < .0005) in the microalbuminuria group than in the normalbuminuria group. Fasting plasma glucose (P < .05) and insulin concentrations (P < .05), and the homeostasis model assessment (HOMA) index (P < .01) were higher in the microalbuminuria group than in the normalbuminuria group. Multiple regression analysis showed that urinary albumin excretion was independently predicted by the myocardial uptake of 123I-MIBG at delayed phase, fasting plasma insulin concentration, and the HOMA index. Our results indicate that the presence of microalbuminuria in our Japanese patients with type 2 diabetes is characterized by depressed cardiovascular autonomic function and insulin resistance, and that the myocardial uptake of 123I-MIBG at delayed phase, fasting plasma insulin, and HOMA index are independent predictors of urinary albumin excretion.

Prospective studies of autonomic nerve function are rare. We have followed the progression of autonomic dysfunction in relation to nephropathy over 14 years in Type 1 diabetic patients.

Autonomic nerve function was assessed by heart-rate responses to deep breathing (E/I ratio) and tilting (acceleration and brake indices) and by the postural blood pressure reaction in 58 patients, 43 of whom were reassessed after 14 years. Nephropathy was evaluated by the degree of albuminuria (albuminuria > 20 micro g/min or > 0.03 g/24 h) and glomerular filtration rate ((51)Cr-EDTA plasma clearance). The acceleration index had deteriorated after 7 years (P = 0.0155), whereas the E/I ratio (P = 0.0070) and the diastolic postural blood pressure reaction (P = 0.0054) had deteriorated 14 years after the baseline examination (age-corrected values). All those with albuminuria at the third examination showed signs of autonomic neuropathy at baseline (10 of 10) compared with only nine of 22 without (P = 0.0016). Multiple regression analysis showed that the association between autonomic dysfunction and future albuminuria was due to the E/I ratio. In addition, individuals with an abnormal postural diastolic blood pressure fall (n = 7) at baseline showed a greater fall in glomerular filtration rate more than others 7-14 years later [29 (16.5) ml/min/1.72 m(2) vs. 11 (9) ml/min/1.72 m(2); P = 0.0074].

Autonomic nerve function had deteriorated after 14 years. Autonomic neuropathy and abnormal postural diastolic blood pressure falls at baseline were associated with future renal complications.

Cardiovascular autonomic neuropathy is associated with microalbuminuria in young and middle-aged patients with type 2 diabetes. We examined this relationship and the potential mediating role of blood pressure in older patients.

At least two of three components of cardiovascular autonomic testing were completed by 132 patients (mean age 70 +/- 5.6 years). Relative rankings on each of the components were averaged to create a summary heart rate variability (HRV) measure. The urine microalbumin-to-creatinine ratio (milligrams albumin/grams creatinine) was calculated. Blood pressure was measured at rest and by 24-h ambulatory recording.

Urine microalbumin-to-creatinine ratio was higher in those with lower HRV (mean urine microalbumin-to-creatinine ratio 28, 56, and 191 mg/g from the highest to lowest tertile of HRV; P < 0.0001). Resting and ambulatory blood pressure levels were negatively correlated with HRV and positively correlated with urine microalbumin-to-creatinine ratio. In multivariate analysis adjusting for age, duration of diabetes, HbA(1c), and HDL cholesterol, HRV and blood pressure were both independently associated with urine microalbumin-to-creatinine ratio, with no evidence that either mediates the effect of the other.

Cardiovascular autonomic neuropathy and blood pressure are independently associated with microalbuminuria in older patients with type 2 diabetes.

Currently, three categories of cardiovascular autonomic nervous function measures are used: classic Ewing-test measures, measures of heart-rate variability (HRV), and measures of baroreflex sensitivity (BRS). Little is known about the agreement between these measures, and reference and reproducibility values for these measures have not been reported within the same group.

As part of the Hoorn Study, 631 subjects aged 50 to 75 participated in a study of autonomic nervous function. Cardiac cycle duration (RR interval) and continuous finger arterial pressure were measured under three conditions: during spontaneous breathing, during six deep breaths over 1 min, and during an active change in position from lying to standing. From these readings, ten measures of autonomic function were assessed (mean heart rate, three Ewing test measures, five HRV measures and one BRS measure).

Regression analysis in a healthy subgroup (n=191) showed sex differences for two of the ten measures and seven measures decreased with age. Therefore, appropriate age-specific and sex-specific reference values were calculated. Reproducibility (n=39) of most measures was moderate, with a reliability coefficient of around 50%. Agreement between the measures of autonomic nervous function varied greatly, between 0% and 87%. The HRV-power ratio measure and the blood pressure changes in the lying-to-standing test showed the lowest agreement with all other measures.

This study provides age-specific and sex-specific reference values for a wide range of different autonomic function measures in an elderly population. Agreement among the different measures varied widely and reproducibility was only moderate.

To examine the association of heart-rate variability with cardiovascular risk factors and coronary calcification in type 1 diabetic and nondiabetic subjects without a history of cardiovascular disease. Reduced heart-rate variability is associated with increased risk of coronary events. Whether it is associated with coronary atherosclerosis is unknown.

Power spectral analysis was used to define heart-rate variability in a cross-sectional study of 160 type 1 diabetic patients and 163 randomly selected nondiabetic adults from the general population aged 30-55 years. Coronary artery calcification was measured using electron beam-computed tomography.

Reduced heart-rate variability was associated with similar risk factors in the diabetic and nondiabetic subjects, namely higher HbA(1c), triglycerides, systolic blood pressure, BMI, and albumin excretion rate. Reduced heart-rate variability was significantly associated with coronary artery calcification in all subjects (odds ratio per tertile lower total power = 1.5, P = 0.01). This association was not independent of blood pressure or BMI (odds ratio on adjustment = 1.3, P = 0.1).

Reduced heart-rate variability clusters with other cardiovascular disease risk factors, especially those that are more common in the insulin resistance syndrome, and is associated with increased coronary calcification in asymptomatic young adults. Whether reduced heart-rate variability leads to other risk factor disturbances or mediates the effects of other risk factors on atherosclerosis deserves further study.

The aim of this study was to examine the impact of parental type 2 diabetes on the autonomic nervous system and to determine whether autonomic neuropathy is present and associated with changes in 24-h ambulatory blood pressure (AMBP) and urinary albumin excretion rate (UAER) in nondiabetic subjects with parental type 2 diabetes. We examined 223 nondiabetic offspring of type 2 diabetic subjects and a control group of 258 offspring of nondiabetic subjects. The autonomic nervous system was assessed by three cardiovascular reflex tests, 24-h AMBP was measured with an oscillometric recorder (90207; Spacelabs, Redmond, WA), and UAER was determined through three overnight urine samples. The subjects with parental type 2 diabetes had significantly lower heart rate variation in all three bedside tests (P < 0.01) than subjects without parental diabetes. The prevalence of autonomic neuropathy in the nondiabetic offspring with parental type 2 diabetes (6.7%) was significantly (P < 0.01) higher compared with the control group (1.6%). Autonomic neuropathy was associated with a higher fasting insulin level (P < 0.05), higher UAER (P < 0.001), higher 24-h mean AMBP (P < 0.01), and reduced diurnal blood pressure variation (P < 0.001) after adjustment for age, sex, and BMI. In conclusion, parental type 2 diabetes was found to be associated with alterations in the autonomic nervous system in nondiabetic subjects. The presence of autonomic neuropathy in subjects with parental type 2 diabetes was associated with higher UAER, fasting insulin level, and 24-h AMBP and a reduced diurnal blood pressure variation. This study indicates that parental type 2 diabetes has an impact on the cardiac autonomic function in nondiabetic subjects.