Reproducibility of cardiovascular autonomic tests in diabetics with and without autonomic dysfunction and in normal controls

Summary The present study evaluates the reproducibility of five cardiovascular reflex tests, deep breathing (DB), Valsalva maneuver (VM), sustained hand-grip (SHG), postural hypotension (PH) and lying to standing (LS) in normal subjects and in insulin dependent (type I) diabetic patients. The study was carried out in 10 normal subjects, in 10 diabetics with autonomic neuropathy and in 10 diabetics without autonomic neuropathy. The five cardiovascular reflex tests were performed five times on five consecutive days by the same investigator and in identical basal conditions. The intraindividual variability of DB, LS and VM was significantly reduced in diabetics with autonomic neuropathy compared with normal controls, but there was no difference between diabetics without neuropathy and normal controls. The intraindividual variability of PH was significantly increased in diabetics with autonomic neuropathy compared with diabetics without autonomic neuropathy and with normal controls. There was no difference among the three groups in the reproducibility of SHG. In normal subjects the intraindividual variability only exceptionally produced a shift from normal to abnormal values or vice versa; in diabetics with autonomic neuropathy this shift was more frequent.     

Reduced intraindividual variability of repeated cardiovascular reflex tests: An additional marker of autonomic neuropathy in insulin-dependent (type I) diabetes mellitus?

Summary The particular questions asked in our study were: 1. does the individual reproducibility of the cardiovascular reflex tests differ between healthy controls and patients suffering from type I diabetes mellitus and 2. if there is a difference, do the different cardiovascular reflexes vary in this regard? Nine healthy controls (4 women, 5 men, age 31±2.1 years) and 11 type I diabetics (4 women, 7 men, age 30.9±5.6 years, duration of diabetes 3–23 years) underwent the following tests 6 times in a 12-h period (07⁰⁰ to 19⁰⁰): variation of heart rate during deep breathing (E/I ratio). variation of heart rate during lying and standing (tachycardia/bradycardia or 30/15 ratio), Valsalva maneuver (Valsalva ratio), response of diastolic blood pressure to sustained hand grip, and response of systolic blood pressure to posture. The test results did not indicate a diurnal fluctuation nor were they systematically influenced by antecedent insulin injections or meals, either in diabetic patients or in healthy, controls. The 11 diabetics had significantly lower intraindividual variations of E/I and Valsalva ratios than the controls (p<0.05, p<0.001, respectively). In the diabetics with parasympathetic failure the intraindividual variabilities of all cardiovascular reflex responses were lower than those of the patients with an intact autonomic nervous system as well as those of the control subjects. On the contrary, in the diabetic patients without autonomic neuropathy, only the intraindividual variability of the Valsalva maneuver was significantly attenuated (p<0.025), compared with the healthy volunteers. To conclude, the more pathological the single test result, the greater is its reproducibility and its clinical significance.     

Assessment of cardiovascular tests in the diagnosis of diabetic autonomic neuropathies

Eight tests for cardiovascular reflex function were evaluated in a group of 140 diabetic patients. The sensitivity, reproducibility and normal values of each test were previously assessed in a group of 70 normal controls. The measure of the R-R interval variation during six cycles of deep breathing (expiration/inspiration ratio) proved to be the most sensitive test, and was selected for screening. The Valsalva ratio, the bradycardia/tachycardia ratio post-standing and the blood pressure response to standing and to sustained handgrip served as a confirmatory test of autonomic neuropathy and were related to the severity of the lesion. The R-R interval variation during one deep breathing cycle, the post-standing tachycardia, and the R-R 30/15 standing ratio proved to be of little or not value in assessing cardiovascular neuropathy. Cardiovascular autonomic neuropathy was diagnosed in 38.5% of our diabetic population, predominantly in patients with other clinical evidence of autonomic neuropathy. In a few asymptomatic patients, abnormal cardiovascular responses were the first evidence of autonomic lesion.     

Urinary albumin excretion rate is independently related to autonomic neuropathy in type 2 diabetes mellitus

OBJECTIVE: To evaluate if urinary albumin excretion rate (UAER) is independently related to subclinical autonomic neuropathy in type 2 diabetes. DESIGN: A controlled cross-sectional study. SETTING: Primary health care centre. SUBJECTS: Consecutive recently diagnosed (< 1 year) type 2 diabetic patients (group A, n = 150) and patients with long-standing (median 11 years) type 2 diabetes (group B, n = 146) chosen at random. A nondiabetic control group (group C, n = 150) matched for age and gender to group A. MAIN OUTCOME MEASURES: Neuropathy by cardiovascular reflex tests and UAER by nephelometry. METHODS: Univariate statistics in group A + B (t-test chi 2- or McNemars test) with Valsalva and breathing ratios as categorical grouping variables and the independent variables gender, smoking, systolic and diastolic blood pressure, fasting serum cholesterol, HDL cholesterol, triglycerides, haemoglobin A1c, glucagon stimulated C-peptide, fasting and postload 1 and 2 h blood glucose and serum insulin, UAER, coronary heart disease and congestive heart failure. Logistic regression analyses in group A + B with Valsalva and breathing ratios as dependent categorical variables and age, systolic blood pressure, congestive heart failure, coronary heart disease, fasting blood glucose, serum triglycerides and UAER as independent variables. RESULTS: Compared to nondiabetic subjects the diabetic patients of both groups were at increased risk of neuropathy as judged by the Valsalva ratio (P < 0.01). In known diabetic patients with a UAER > or = 30 mg 24-1 h neuropathy was more common than amongst their normoalbuminuric counterparts (Valsalva test P = 0.007, breathing test P = 0.02). In logistic regression analysis UAER independently explained abnormal Valsalva (P = 0.015) and breathing tests (P = 0.04) in the group A + B. CONCLUSIONS: UAER is independently related to subclinical autonomic neuropathy in type 2 diabetes.     

A comparison of peripheral vasoconstrictor responses and cardiovascular autonomic function tests in diabetic patients

Summary Venous occlusion plethysmography has been used to measure sympathetic vasoconstrictor responses in the feet and hands to a deep breath and body cooling and to assess blood flow variability. Measurements were made in 14 non-diabetic control subjects and 52 diabetic patients, 30 of whom had evidence of peripheral neuropathy. All the measurements were significantly reduced in the feet of patients with neuropathy. Vasoconstrictor responses were not significantly impaired in the hands of these patients. Cardiovascular autonomic function was assessed in the same subjects by standard tests of reflex heart rate responses and compared to sympathetic vasoconstrictor function as determined by the response to a deep breath. Eighteen of the 30 diabetic patients with peripheral neuropathy had impairment of both cardiovascular and sympathetic vasoconstrictor functon. Five had normal vasoconstrictor but impaired cardiovascular responses and two had normal cardiovascular but impaired vasoconstrictor function. It may therefore be important to assess both systems in diabetic patients.     

Diabetic autonomic neuropathy after pancreas and kidney transplantation

We have evaluated the effect of successful pancreatic and kidney transplantation on autonomic neuropathy in nine Type 1 (insulin-dependent) diabetic subjects. Cardiovascular reflex tests were performed before and at 6–24 months after transplantation. A control group of ten Type 1 diabetic patients after kidney grafting only was examined at the same time periods. For base-line comparisons results of the tests in ten healthy subjects were used. Advanced autonomic neuropathy was present in both groups of transplant recipients and no significant changes in test results could be found at post-transplant evaluation. Lack of autonomic nerve function improvement was confirmed in seven patients of the pancreatic and kidney transplantation group who were examined again after 2–4 years. Irreversible structural autonomic nerve damage is probably present in uraemic pancreatic transplantation candidates.     

Advanced glycation end-products in senile diabetic and non-diabetic patients with cardiovascular complications

Advanced glycation end products (AGEs) have been reported to contribute to aging and cardiovascular complications. In the present study, the immunoreactivity of AGEs in human serum samples of healthy older subjects (n = 31), senile diabetic patients without cardiovascular complications (n = 33), senile diabetic patients with cardiovascular complications (n = 32), senile non-diabetic patients with cardiovascular complications (n = 30) ,and healthy young subjects (n = 31) were investigated. The patients were selected on clinical grounds from the National Institute of Cardiovascular Disease, Karachi and the Jinnah Postgraduate Medical Centre, Karachi, Pakistan. Fasting blood glucose, HbA_1C and serum fructosamine levels were significantly (P < 0.001) increased in senile diabetic patients with and without cardiovascular complications as compared to non-diabetic senile patients with cardiovascular complications and healthy older subjects. Additionally, serum AGEs were found to be significantly (P < 0.001) increased in senile diabetic patients with cardiovascular complications and senile non-diabetic patients with cardiovascular complications, followed by diabetic patients without cardiovascular complications as compared to healthy older subjects and young control subjects. However, no significant difference was found in the senile diabetic patients without cardiovascular complications and senile non-diabetic patients with cardiovascular complications. In contrast to all four senile groups, serum AGEs were significantly (P < 0.001) lower in young control subjects. The AGEs distribution in the senile groups corroborates the hypothesis that the advanced glycation process might play a role in the development of cardiovascular complications, which are more severe in diabetic patients compared with non-diabetic patients with cardiovascular complications.     

Platelet activation in diabetic cardiovascular autonomic neuropathy.

AIMS: Platelet activation is known to be associated with arrhythmic effects in myocardial ischaemia. The present study attempts to clarify whether diabetic cardiovascular autonomic neuropathy (CAN) is associated with intravascular platelet activation. METHODS: Platelet activation was assessed by flow cytometry analysis in 30 patients with Type 1 diabetes mellitus screened for diabetic complications. Fifteen patients showed evidence of CAN as assessed by a battery of standard cardiovascular autonomic reflex tests. Fifteen patients without CAN were then selected as a matched control group. Platelet activation was assessed by flow cytometric detection of activation-dependent platelet membrane antigens (P-selectin (CD62), thrombospondin, lysosomal GP53 (CD63) and ligand-induced binding site-1 of GPIIb/IIIa (LIBS-1)). RESULTS: Significantly more activated platelets were detected in the patients with CAN showing 20.9% (coefficient of variation (CV) 44%) CD63+ (vs. 17.2% (CV 19%) in controls, P < or = 0.05), 6.4% (CV 87%) CD62+ (vs. 4.1% (CV 37%), P < or = 0.05), and 6.7% (CV 55%) thrombospondin+ (vs. 4.6% (CV 39%), P < or = 0.01) platelets, respectively. LIBS-1 on platelets was not significantly different between patients with and without CAN. No correlation was found between glucose metabolism and platelet activation. CONCLUSIONS: Cardiovascular autonomic neuropathy is associated with platelet activation in Type 1 diabetes mellitus. The high platelet activation may reflect an increased prothrombotic state in diabetic cardiovascular autonomic dysfunction.     

糖尿病性心自主神经、末梢神经病变与糖尿病微血管并发症的关系

目的 观察糖尿病性心自主神经病变和末梢神经病变的患病率及其与其他糖尿病慢性并发症的关系。方法 利用心自主神经功能检测系统和神经电生理检测仪测定308例糖尿病患者（平均年龄49岁，平均HbA1c9.8%。平均病程14年）的心自主神经功能和肢体的末梢神经传导速度，皮肤痛温觉，振动觉，同时检测24h尿白蛋白排泄率和眼底视网膜照相。结果 糖尿病患者心自主神经病变患病率为47.1%。末梢神经病变患病率为54.2%,两者呈显著正相关。并与病程和糖尿病控制状况呈显著正相关。并发糖尿病性神经病变患者并发其他糖尿病慢性并发症的机率增高。结论 糖尿病性神经病变患病率较高，并与糖尿病其他慢性并发症密切相关。     

Cardiovascular autonomic neuropathy associated with carotid atherosclerosis in Type 2 diabetic patients.

AIMS: To clarify if cardiovascular autonomic neuropathy is associated with carotid artery atherosclerotic plaques in Type 2 diabetic patients. METHODS: Cardiovascular autonomic nerve function was related to carotid artery ultrasound in 61 Type 2 diabetic patients 5-6 years after diagnosis of diabetes. RESULTS: Cardiovascular autonomic neuropathy [abnormal age corrected expiration/inspiration (E/I) ratio or acceleration index (AI)] was found in 13/61 (21%) patients. Patients with cardiovascular autonomic neuropathy showed increased degree of stenosis in the common carotid artery (24.6 +/- 13.2% vs. 14.7 +/- 9.2%; P = 0.014) and a tendency towards a higher plaque score (4.0 +/- 1.7 vs. 3.2 +/- 1.6; P = 0.064). Controlled for age, AI correlated inversely with degree of stenosis (r = -0.39; P = 0.005), plaque score (r = -0.39; P = 0.005), and mean (r = -0.33; P = 0.018) and maximum (r = -0.39; P = 0.004) intima-media thickness in the common carotid artery. In contrast, E/I ratio correlated only slightly with mean intima-media thickness in the common carotid artery (r = -0.28; P = 0.049). CONCLUSIONS: Cardiovascular autonomic neuropathy was associated with carotid atherosclerosis in Type 2 diabetic patients. Abnormal E/I ratios reflect efferent structural damage to parasympathetic nerves whereas abnormal AI reflects afferent autonomic dysfunction possibly due to impaired baroreceptor sensitivity secondary to carotid atherosclerosis.     

The significance of impaired pancreatic polypeptide and epinephrine responses to hypoglycemia in patients with insulin-dependent diabetes mellitus

The impaired epinephrine and glucagon responses to hypoglycemia often found in patients with insulin-dependent diabetes mellitus (IDDM) may be due to autonomic neuropathy. Since the pancreatic polypeptide response to hypoglycemia is mediated by cholinergic mechanisms, we used this response as an indicator of autonomic neuropathy to determine whether deficient epinephrine and glucagon responses in IDDM could be ascribed to an autonomic defect. The relationships between pancreatic polypeptide, epinephrine, and glucagon responses during insulin-induced hypoglycemia were assessed in 18 patients with IDDM who had no overt evidence of autonomic neuropathy, including normal standard cardiovascular reflex tests, and 11 age-matched nondiabetic subjects. All of the diabetic patients had impaired glucagon responses [19 +/- 3 (SEM) vs. 96 +/- 11 pg/ml, peak increment, P less than 0.001]. Ten of the 18 diabetic patients had either impairment of plasma epinephrine or plasma pancreatic polypeptide responses or both to hypoglycemia. Moreover, pancreatic polypeptide responses were significantly correlated with epinephrine responses (r = 0.53, P less than 0.003). There was no association between the plasma glucagon response and the epinephrine (r = 0.02, NS), norepinephrine (r = 0.03, NS), or pancreatic polypeptide (r = 0.35, NS) response. Last, there was no correlation between the plasma hormone responses and the cardiovascular reflex test results. Therefore, the association of impaired plasma pancreatic polypeptide responses with impaired plasma epinephrine responses suggests that the impaired epinephrine responses are due to autonomic neuropathy, whereas the dissociation of plasma glucagon responses with both plasma pancreatic polypeptide and epinephrine responses suggests that the impaired pancreatic alpha-cell response to hypoglycemia is not due to autonomic neuropathy. In addition, the plasma pancreatic polypeptide and epinephrine responses to hypoglycemia appear to be an earlier indicator of underlying autonomic dysfunction than standard cardiovascular reflex tests. Thus, the responses of plasma pancreatic polypeptide and epinephrine to insulin-induced hypoglycemia may be a useful test for the identification of early autonomic neuropathy in IDDM.     

Baroreflex sensitivity is depressed in microalbuminuric Type I diabetic patients at rest and during sympathetic manoeuvres

Abstract Aims/hypothesis. To evaluate baroreflex sensitivity (BRS) in microalbuminuric and normoalbuminuric Type I (insulin-dependent) diabetic patients without autonomic neuropathy and in healthy control subjects. Methods. Microalbuminuric Type I diabetic patients (n = 15) were matched for age, sex, body mass index (BMI) and smoking habits with 15 normoalbuminuric patients and with 15 healthy control subjects. All subjects had a blood pressure less than 160/95 mmHg, a BMI less than 30 kg/m² and normal autonomic function on standard tests. Blood pressure and heart rate were measured non-invasively (Finapres) at rest and during sympathetic activation (handgrip, mental stress, standing). The baroreflex sensitivity was defined as the mean gain between blood pressure variability and heart rate variability in the 0.07–0.15 Hz frequency band. Results. Resting baroreflex sensitivity was decreased in the microalbuminuric patients (3.5 ± 0.4 ms/mmHg) compared with the normoalbuminuric patients and the healthy subjects (7.6 ± 1.6 and 9.5 ± 1.1 ms/mmHg, respectively, p < 0.001). The sympathetic tests reduced baroreflex sensitivity similarly in the groups without changing the between group differences. Conclusion/interpretation. Baroreflex sensitivity is reduced in Type I diabetic patients with microalbuminuria but without autonomic neuropathy. A prospective study should indicate whether this early abnormality in cardiovascular reflex function is a risk factor of cardiovascular mortality in these patients. [Diabetologia (1999) 42: 1345–1349] Received: 20 May 1999 and in revised form: 8 July 1999     

Twenty-four hour blood pressure and heart rate profiles of diabetic patients with abnormal cardiovascular reflexes

Twenty-four hour ambulatory blood pressure and heart rate profiles of 24 patients with diabetes were monitored in order to assess the effect of autonomic neuropathy on 24-h haemodynamic profiles. Eighteen patients had abnormal cardiovascular reflexes. Mean arterial pressure rose at night in six of the patients with autonomic neuropathy and fell by less than or equal to 5 mmHg in seven. In the remaining five patients with autonomic neuropathy and in the six diabetic patients with normal cardiovascular reflexes, the fall in nocturnal mean arterial pressure was comparable to that of 11 non-diabetic patients with essential hypertension. Median 24-h mean arterial pressure was similar in all four groups of diabetic patients. Prevalence of autonomic symptoms was not related to the change in blood pressure in those with autonomic neuropathy. Twenty-seven months after monitoring, three fatal and five severe non-fatal cardiovascular or renal events had occurred in four of the six patients with a rise in nocturnal blood pressure, compared with one non-fatal event in those with a small fall and no severe events in those with a pronounced fall (p = 0.02). Blood pressure rises at night in certain diabetic patients with abnormal cardiovascular reflexes and the nocturnal rise appears to be associated with a poor prognosis.     

2型糖尿病患者高血压与糖尿病性神经病变的关系

目的 探讨2型糖尿病患者高血压与糖尿病性神经病变的关系。方法 利用心自主神经功能检测系统和神经电生理检测仪对107例（高血压组52例,非高血压组55例）2型糖尿病患者的心自主神经功能和肢体的末梢神经传导速度、皮肤痛温觉、振动沉进行测定,以判断心自主神经病变和末梢神经病变。结果 两组间末梢神经功能和心自主神经功能各指标除心的是距频谱分析的高频值外差异均无显著性（P＜0.05）。Logistic回归分析显示高血压与心自主神经病变显著相关（P＜0.01）,而与末梢神经病变无显著相关。结论 2型糖尿病患者高血压是心自主神经病变发病的危险因素,而与末梢神经病变无明显关系。     

Autonomic neuropathy is associated with increased cardiovascular risk factors: the EURODIAB IDDM Complications Study.

AIMS: To assess the prevalence of and risk factors for autonomic neuropathy in the EURODIAB IDDM Complications Study. METHODS: The study involved the examination of randomly selected Type I (insulin-dependent) diabetic patients from 31 centres in 16 European countries. Neuropathic symptoms and two tests of autonomic function (changes in heart rate and blood pressure from lying to standing) were assessed and data from 3007 patients were available for the present analysis. Autonomic neuropathy was defined as an abnormality of at least one of the tests. RESULTS: The prevalence of autonomic neuropathy was 36% with no sex differences. The frequency of one and two abnormal reflex tests was 30% and 6%, respectively. The R-R ratio was abnormal in 24% of patients while 18% had orthostatic hypotension defined as a fall in systolic blood pressure > 20 mmHg on standing. Significant correlations were observed between autonomic neuropathy and age (P < 0.01), duration of diabetes (P < 0.0001), HbA1c (P < 0.0001), diastolic blood pressure (P < 0.05), lower HDL-cholesterol (P < 0.01), the presence of retinopathy (P < 0.0001) and albuminuria (P < 0.0001). New associations have been identified from the study: the strong relationship of autonomic neuropathy to cigarette smoking (P < 0.01), total cholesterol/HDL-cholesterol ratio (P < 0.05) and fasting triglyceride (P < 0.0001). As a key finding, autonomic neuropathy was related to the presence of cardiovascular disease (P < 0.0001). All analyses were adjusted for age, duration of diabetes and HbA1c. However, data have been only partly confirmed by logistic regression analyses. Frequency of dizziness on standing up was 18%, while only 4% of patients had nocturnal diarrhoea and 5% had problems with bladder control. CONCLUSION: Cardiovascular reflex tests, even in the form of the two tests applied, rather than a questionnaire, seem to be appropriate for the diagnosis of autonomic neuropathy. The study has identified previously known and new potential risk factors for the development of autonomic neuropathy, which may be important for the development of risk reduction strategies. Our results may support the role of vascular factors in the pathogenesis of autonomic neuropathy.     

Cardiac repolarization interval in end-stage diabetic and nondiabetic renal disease

Background and hypothesis: QT interval length is influenced by autonomic nervous activity. In patients with diabetic autonomic neuropathy, both prolongation and shortening of ventricular repolarization has been reported. We studied diabetic and nondiabetic uremic patients to assess the effects of autonomic neuropathy on QT interval length. Methods: 24-hour electrocardiogram recordings were performed in 12 diabetic and 11 nondiabetic renal transplantation patients, and in 12 control patients. Mean and corrected QT interval (QTc) during the 24-h period and intervals at predetermined heart rates at day and night periods were determined. The degree of autonomic neuropathy was assessed with cardiovascular autonomic function tests and measurement of heart rate variability. Results: In the diabetic group, severe autonomic neuropathy was present; in nondiabetic uremic patients, abnormalities were less severe. Mean QTc interval during 24 h was 444 ± 24,447 ± 21, and 442 ± 19 ms in the diabetic and nondiabetic uremic patients, and in the control groups, respectively, without any between-group difference. QT and QTc interval length did not differ among the groups when measured at heart rates of 70, 80, 90, or 100 beats/min. Conclusions: In patients with autonomic failure caused by diabetes and/or uremia, QT interval length cannot be used as a diagnostic indicator of cardiac autonomic neuropathy.     

Assessment of cardiovascular autonomic function: age-related normal ranges and reproducibility of spectral analysis, vector analysis, and standard tests of heart rate variation and blood pressure responses.

To establish normal ranges for assessment of autonomic dysfunction, a battery of cardiovascular reflex tests was performed in 120 healthy subjects aged 15-67 years using a computer-based technique. Tests of heart rate variation (HRV) included 8 measures at rest: coefficient of variation (CV), root mean squared successive difference (RMSSD), spectral analysis of HRV in the low frequency, mid frequency, and high frequency bands in the supine and standing postures; 5 measures during deep breathing: CVb, RMSSDb, Expiration-Inspiration (E-I) difference, E/I ratio, and mean circular resultant of vector analysis; Valsalva ratio, and max/min 30:15 ratio. In addition, the change in systolic and diastolic blood pressure in response to standing and the diastolic blood pressure response to sustained handgrip were determined. The results of all measures, the blood pressure tests excepted, declined significantly with increasing age (r = -0.16 to -0.59; p less than 0.05). Moreover, RMSSD, RMSSDb, and E-I difference decreased considerably with increasing heart rate (r = -0.37 to -0.52; p less than 0.001). The longest and shortest R-R intervals in response to standing were distributed within beats 21-39 and 6-24, respectively. All tests were independent of sex. Log transformation was used to define the age-related lower limits of normal at the 2.3 centile for all tests of HRV, except for the E/I, Valsalva, and max/min 30:15 ratios. The results of these tests had to be analysed using a log(y-1) transformation. The intra-individual reproducibility determined on two consecutive days in 20 healthy subjects and 21 diabetic patients indicated that there were no major differences between the two groups regarding the day-to-day variation of test results, which was highest for the Valsalva ratio. We conclude that: (1) all indices of spectral and vector analyses of HRV are age-dependent and have the advantage of being independent of heart rate; (2) RMSSD, E-I difference, and the 30:15 ratio as it was used previously are not suitable for evaluation of autonomic dysfunction in diabetes; (3) log(y-1) transformation is required to determine age-dependent normal ranges and reproducibility for the three ratios.     

Erythropoietin response to anemia and its association with autonomic neuropathy in type 2 diabetic patients without advanced renal failure

AimWe aim to investigate erythropoietin (EPO) response to anemia and its association with autonomic neuropathy in type 2 diabetic patients without advanced renal failure.MethodsA cross-sectional study was conducted on 211 type 2 diabetes mellitus patients without advanced renal failure [estimated glomerular filtration rate (eGFR) >40 ml/min/1.73 m²]. The response of EPO to anemia of type 2 diabetic patients without advanced renal failure was compared with those of nondiabetic control subjects. Autonomic nerve function was assessed using three cardiovascular tests (deep breathing, the Valsalva maneuver, and lying-to-standing). The results of each test were scored as 0 if normal, 1 if borderline, and 2 if abnormal. Autonomic neuropathy was diagnosed when a total score of the tests was 2 or more.ResultsFifty-eight patients were anemic; compared with nonanemic patients, they had a longer duration of diabetes (16.69±10.11 vs. 10.67±8.41 years, P<.001), lower eGFR (66.43±16.30 vs. 81.74±19.49 ml/min/1.73 m², P<.001), and higher cardiovascular autonomic neuropathy score (3.17±1.95 vs. 1.79±1.72, P<.001). Serum EPO level was weakly correlated with hemoglobin (Hb) level (r=?.085, P<.001). However, the slopes of regression lines between EPO and Hb levels differed significantly between type 2 diabetic patients and nondiabetic control subjects (?0.0085 vs. ?0.255, P=.008). Multiple linear regression analysis revealed that cardiovascular autonomic neuropathy score was independently related to Hb (P<.001) or EPO level (P=.052).ConclusionsAutonomic neuropathy is associated with a blunted EPO response to anemia in type 2 diabetic patients without advanced renal failure.     

Prevalence of cardiovascular autonomic dysfunction assessed by spectral analysis, vector analysis, and standard tests of heart rate variation and blood pressure responses at various stages of diabetic neuropathy.

To establish a test battery for the detection and characterization of cardiovascular autonomic neuropathy (CADN) and to evaluate its prevalence, a number of autonomic function tests based on spectral analysis, vector analysis, and standard tests of heart rate variation and blood pressure responses were performed in 261 diabetic patients aged 11-76 years with various stages of peripheral neuropathy. The percentages of abnormal results in the individual tests based on heart rate variation were 6-31% in 115 patients without peripheral neuropathy, 16-45% in 61 patients with subclinical neuropathy, 22-59% in 73 patients with symptomatic peripheral neuropathy, and 67-100% in 12 patients with the latter in conjunction with autonomic symptoms (p < 0.05). The most frequently abnormal indices, each representing a different physiological basis, were the coefficient of variation, low-frequency and mid-frequency power spectrum at rest, mean circular resultant, postural change in systolic blood pressure, and, in particular, the max/min 30:15 ratio and Valsalva ratio. CADN, defined as the presence of > or = 3 abnormalities among these seven parameters was detected in none of 120 control subjects, 13.0% of the patients without peripheral neuropathy, 34.4% of those with subclinical neuropathy, 49.3% of those with symptomatic peripheral neuropathy, and in 100% of the subjects with the latter and concomitant autonomic symptoms (p < 0.05). The overall prevalence of CADN in 103 patients completing all parameters was 46.6%. The corresponding rate of CADN defined as > or = 2 abnormalities among the five tests included in an optimized version of the battery proposed by Ewing and Clarke was 38.8%.(ABSTRACT TRUNCATED AT 250 WORDS)