Role of heart rate variability in the early diagnosis of diabetic autonomic neuropathy in children

BACKGROUND: Diabetic autonomic neuropathy (DAN) is a major complication of diabetes. DAN has been shown to be closely related to glycemic control. To contribute significantly to the morbidity and mortality of the disease, and to be indicative of an increased risk of cardiovascular events. Tests assessing the function of the autonomic nervous system, such as the response of heart rate and blood pressure to maneuvers stimulating the autonomic nervous system, including deep breathing. Valsalva maneuver and standing, allowed to detect signs of DAN in adolescents; however, the sensitivity of such tests in revealing an early impairment of the autonomic nervous system proved low. Several studies found heart rate variability (HRV) to be useful in assessing the dysfunction of the autonomic nervous system in diabetic children and adolescents, but only few HRV parameters were evaluated in most of them. OBJECTIVE: To study cardiac autonomic nervous system in diabetic children, and to investigate whether the duration of diabetes and the degree of metabolic control are determinants for the development of DAN in children. PATIENTS AND METHODS: We analyzed HRV in 50 asymptomatic patients with insulin-dependent diabetes mellitus (IDDM) and 30 healthy children matched for age and sex. RESULTS: Patients with a history of diabetes > 8 years showed significant alterations of the autonomic nervous system (significant reduction of r-MSSD, pNN50, HF and increase in LF/HF). Conversely, only a reduction in pNN50 was found in patients with a disease duration < 8 years. Furthermore, we also observed significant HRV abnormalities in patients with an impaired metabolic control of diabetes. Compared to controls, patients with glycosylated hemoglobin blood levels (HbA(1C)) > 8% showed a significant reduction of r-MSSD, pHH50 and total power spectrum, whereas no HRV abnormalities were detected in patients with an HbA(1C) < 8%. CONCLUSIONS: HRV analysis can detect early subclinical alterations of the autonomic nervous system in asymptomatic patients with IDDM, which seem to consist mainly in a parasympathetic impairment. Autonomic dysfunction is associated both with the duration and an inadequate metabolic control of the disease.     

Does Abnormal QT Interval Prolongation Reflect Autonomic Dysfunction in Diabetic Patients? QTc Interval Measure Versus Standardized Tests in Diabetic Autonomic Neuropathy

The question as to whether the QTc interval correlates with five cardiovascular tests (deep breathing test, 30/15 ratio test, lying to standing test, cough test, and postural blood pressure test) for the diagnosis of diabetic autonomic neuropathy (DAN) was investigated in 168 (38 Type 1, 130 Type 2) consecutive outpatients (mean age 54.9 ± 11.2 years). QT interval was measured on an ECG recorded at rest and QTc calculated according to Bazett's formula. The percentage of patients with a QTc greater than 0.440 s was: absent DAN = 11% (n = 7), probable DAN = 7% (n = 4), definite DAN = 23% (n = 12) (p < 0.05), and the mean (± SD) QTc values were 0.403 ± 0.028 s, 0.405 ± 0.023 s, and 0.421 ± 0.026 s, respectively. A significant correlation between QTc duration and DAN score of autonomic cardiovascular test results (r = 0.34, p < 0.0001) was observed. The calculated specificity, sensitivity, positive and negative predictive values were 89%, 15%, 70% and 37%, respectively. In conclusion, QTc can be considered as an additional specific test in the assessment of diabetic autonomic neuropathy, but cannot replace the standard battery of cardiovascular tests.     

Impaired microvascular flow motion in subclinical diabetic feet with sudomotor dysfunction

Impaired cutaneous blood flow and sweating dysfunction might be among the earliest manifestations of diabetic autonomic neuropathy. This study assessed the pathophysiological basis underlying skin vasomotion changes and their relation with progressive sudomotor dysfunction and other autonomic and somatic measures in subclinical diabetic feet. Laser Doppler skin perfusion was assessed on 68 diabetic and 25 control subjects. The low-frequency vasomotion was transformed into three frequency intervals 0.0095-0.021, 0.021-0.052 and 0.052-0.145 Hz, respectively, for the investigation of endothelial, neurogenic and myogenic effects on microcirculatory alterations. The diabetic patients were categorized into three groups by increasing severity of sudomotor dysfunction: SSR+ (sympathetic skin response present; 27 patients), SSR- (SSR absent; 23 patients) and at-risk (SSR absent and of preulcerative cracked skin; 18 patients). All diabetic patients underwent nerve conduction and cardiovascular autonomic studies. The total spectral and endothelial activity was significantly decreased only in the at-risk group. The SSR- group had lower neurogenic vasomotion than the SSR+ group (p<0.05). Although no statistical difference was noted between any group in absolute myogenic spectrum, the SSR- group had higher normalized myogenic activity than the SSR+ group (p<0.01). The larger drop in orthostatic pressure was paralleled by a reduction in the myogenic amplitude (r=-0.33, p<0.01). These results suggested that early impairment of low-frequency flow motion correlated closely with the presence of sudomotor dysfunction of subclinical feet mainly in neurogenic and endothelial components. Impaired systemic vascular tone as manifested by orthostatic hypotension was proportional to the degree of myogenic dysregulation in diabetic patients.     

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。     

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。     

高血压和非高血压2型糖尿病患者心率变异性、压力反射敏感性和血压变异性频谱分析鉴定心脏自主神经病变

目的采用心率变异性（HRV）、压力反射敏感性（BRS）和血压变异性（BPV）频谱方法了解高血压和非高血压T2DM患者心血管自主神经病变的诊断价值。方法119例T2DM患者和101例非糖尿病对照者分别分为高血压（HT）和非高血压（NHT）亚组,均进行HRV、BRS和BPV检测。结果DM组中HT和NHT亚组的TV.rri、VLF.rri、LF.rri和HF．rri均显著低于对照组。DM-HT组的Total．brs和HF．brs明显下降,BPV无改变;DM-NHT组的TV．bp和VLF．bp显著增加。结论糖尿病患者（无论有无HT）HRV下降,反映基础状态下心血管自主神经功能张力异常可能不受血压影响;DM合并HT患者BRS降低,提示DM合并HT可使心血管反射调节能力减退;无高血压的DM患者BPV增大,提示DM患者血压调定和稳态早期受损。     

通心络胶囊对糖尿病自主神经病变的影响

目的观察通心络胶囊联合甲钴胺片对糖尿病自主神经病变（DAN）患者的影响。方法48例DAN患者均予通心络胶囊4老V次口服,3次／d,甲钴胺片500μg／次口服,3次／d,共2个月。观察服药前后患者心率变异性（HRV）的变化,并记录患者症状的积分情况。结果通心络胶囊治疗后患者多汗、腹泻、便秘、排尿障碍、直立性低血压症状减轻或消失,5项症状的积分均较治疗前减少达50％以上,与治疗前比较差异有统计学意义（P〈0．05）;HRV各指标中低频范围内的功率（LF）降低（32．8±11．4）ms^2,LF／高频范围内的功率（HF）降低（1．8±0．6）ms^2,余指标均增高,差异有统计学意义（P〈0．01）,且未见明显不良反应。结论通心络胶囊联合甲钴胺片对糖尿病自主神经病变有改善交感、迷走神经平衡失调的作用,是治疗DAN安全、有效的药物。     

Cardiovascular response to exercise in diabetic patients: influence of autonomic neuropathy of different severity

Summary We investigated cardiovascular function and plasma catecholamine response during incremental exercise and recovery in diabetic patients with (DAN+) and without autonomic neuropathy (DAN–). The former group was divided according to the presence of parasympathetic (DAN+PH–) or associated parasympathetic and sympathetic (DAN+PH+) damage to the autonomic nervous system. A group of healthy volunteers was studied as a control group. All the patients and control subjects underwent a submaximal or symptom-limited incremental exercise test using a cycle-ergometer. Air flow and respiratory gas fractions were sampled at the level of the mouth allowing a breath-by-breath analysis of oxygen consumption (VO₂). Heart rate and systolic blood pressure were recorded and venous blood samples were obtained from the patients at rest and during each minute of exercise and recovery to measure norepinephrine and epinephrine plasma levels. Haemodynamic parameters and plasma catecholamines were computed at rest and at 25, 50, 75 and 100% of the peak VO₂ (VO_{2 max}). The breath-by-breath relationships among VO₂, heart rate and VO₂/heart rate against work were assessed during exercise for patients and control subjects. While VO_{2 max} in absolute values was not significantly different among the diabetic groups, VO_{2 max} was much less in diabetic patients than in control subjects (p<0.01). During exercise the rate of heart rate, systolic blood pressure, norepinephrine and epinephrine increase was different among the diabetic groups, being significantly blunted in DAN+PH+. The VO₂/work relationship of the three diabetic groups was similar but markedly reduced in respect to that of control subjects (p<0.001). The relationship between oxygen pulse (VO₂/heart rate) and work showed no differences among the diabetic groups, whereas its slope was significantly steeper in control subjects (p<0.01 vs DAN–; p<0.05 vs DAN+PH– and DAN+PH+). In conclusion during incremental exercise both DAN+PH– and DAN+PH+ exhibit abnormal heart rate, systolic blood pressure and catecholamine responses which, however, appear clearly distinct between the two groups of DAN+. In DAN+ the VO₂ increment is reduced during exercise. Since DAN–show the same impairment, this particular finding seems most likely to be influenced by factors (i.e.: diabetic cardiomyopathy) other than overt autonomic neuropathy.Abbreviations C Control subjects - DAN– diabetic patients without autonomic neuropathy - DAN+ diabetic patients with autonomic neuropathy - DAN+PH– diabetic patients with autonomic neuropathy without postural hypotension - DAN+PH+ diabetic patients with autonomic neuropathy with postural hypotension - V_E minute ventilation - VO₂ oxygen consumption - VCO₂ carbon dioxide production - AT anaerobic threshold - SaO₂ arterial oxygen saturation - HR heart rate - SBP systolic blood pressure - CW cardiac work - VO_{2 max} peak VO₂     

Low prevalence of cardiac autonomic neuropathy in Type 1 diabetic patients without nephropathy.

AIM: To assess the prevalence of cardiac autonomic neuropathy (CAN) in Type 1 diabetic patients with and without nephropathy. METHODS: Sixty-six consecutive patients without nephropathy (n = 24), with incipient (n = 26) or overt nephropathy (n = 16) and a diabetes duration between 21 and 31 years were examined. Heart rate variability (HRV) as measure for CAN was investigated with short-term spectral analysis in the low-frequency (LF) band (0.06-0.15 Hz), reflecting sympathetic and vagal activity, and high-frequency (HF) band (0.15-0.50 Hz), reflecting vagal activity. HRV was expressed as spectral power (ms2, log-transformed). Normal, age-corresponding reference values were established in 184 controls. QTc intervals and dispersion were measured. RESULTS: After adjustment for age, there was no significant difference between healthy controls and patients without nephropathy. After further adjustment for diabetes duration, HbA1c, hypertension and treatment with beta-blockers, HRV in both frequency bands decreased with evidence of nephropathy. LF band (supine): patients without nephropathy 5.56 (4.89-6.21) (least squares means and 95% confidence interval (CI)), incipient nephropathy 5.72 (5.15-6.29) and overt nephropathy 4.11 (3.27-4.96). HF band (supine): without nephropathy 5.93 (5.26-6.60), incipient nephropathy 5.99 (5.41-6.57) and overt nephropathy 4.84 (4.00-5.68). Significant differences were found for patients without and with incipient nephropathy compared with those with overt nephropathy in the LF band and between patients with incipient nephropathy compared with those with overt nephropathy in the HF band. QTc intervals and QTc dispersion increased significantly with increasing nephropathy. CONCLUSIONS: Long-term Type 1 diabetes without nephropathy was not associated with impaired cardiac autonomic function in our study. However, in those with nephropathy, a loss of both vagal and sympathetic activity was present, and the severity of CAN correlated positively with more advanced nephropathy.     

Alpha adrenoceptor agonist-induced microcirculatory oscillations are reduced in diabetic neuropathy

In diabetic patients small fiber neuropathy has been associated with impairment of 0.1 Hz microvascular vasomotion. The aim of this study was (1) to investigate whether vasoconstriction-induced microvascular oscillations in the skin are reduced in diabetic patients with peripheral and/or autonomic neuropathy, and (2) whether this method could be used as a non-invasive surrogate marker to assess diabetic small fiber neuropathy.Four matched groups were studied: diabetic patients without neuropathy (D), with peripheral neuropathy (DPN), with peripheral and autonomic neuropathy (DAN), and non-diabetic controls (Ctrl). All participants were evaluated for peripheral and autonomic neuropathy, microvascular endothelial function, and metabolic syndrome indicators. Laser Doppler flowmetry was used to measure oscillations after iontophoresis of the alpha one selective agonist phenylephrine.~ 0.1-Hz oscillations recorded at the foot were significantly attenuated in diabetic patients with peripheral and/or autonomic neuropathy (DPN and DAN groups) compared to diabetic patients without neuropathy or non-diabetic controls. In the forearm, microvascular oscillations were significantly reduced only in patients with autonomic neuropathy (DAN).Oscillation measures correlated significantly (P < 0.001) with all markers of peripheral neuropathy but not with markers of measurements of microvascular endothelial function, or metabolic syndrome markers. In a logistic regression model, reduced microvascular oscillations at the foot were a strong predictor for the presence of peripheral neuropathy.The measurement of phenylephrine-induced ~ 0.1-Hz microvascular oscillation may represent a useful non-invasive tool with which to study the effects of treatment strategies on the diabetic small fiber neuropathy.     

Skin blood flow in the upper and lower extremities of diabetic patients with and without autonomic neuropathy

BACKGROUND: Microvascular blood flow in the human skin is subject to rhythmic variations reflecting the influence of heartbeat, respiration, intrinsic myogenic activity, neurogenic factors and endothelial activity. The aim of our study was to test the hypothesis that basal skin blood flow (BSBF) and its dynamic components differ (1) among diabetic patients without autonomic neuropathy and with it and healthy control subjects, and (2) among the upper and lower extremities. PATIENTS AND METHODS: BSBF at four recording sites with predominantly nutritive capillary circulation (right and left caput ulnae, right and left medial malleolus) was measured by laser Doppler flowmetry in 25 diabetic patients without cardiovascular autonomic neuropathy (D), 18 neuropathic diabetic patients (DAN) and 36 healthy controls (C). Wavelet transform was applied to the laser Doppler signal. RESULTS: In absolute terms, mean flow, mean amplitude of the total spectrum and mean amplitudes at all frequency intervals were highest in C, followed by DAN and lowest in D. However, these differences were statistically significant only in the left arm. Within all three groups, mean flow and spectral amplitudes were significantly higher in the arms than in the legs, besides there was a significant difference between the two arms in D. CONCLUSION: We have confirmed the differences in BSBF among D, DAN and C, and demonstrated differences among the four recording sites which have not been previously described. The latter indicates an uneven progression of autonomic neuropathy and allows for speculation that the left arm is the latest to be affected.     

Melatonin levels decrease in type 2 diabetic patients with cardiac autonomic neuropathy

The present study has been designed to determine melatonin levels in type 2 diabetic patients and test the relationship between the autonomic nervous system and melatonin dynamics. Thirty-six type 2 diabetic patients and 13 age-matched healthy subjects were recruited for the study. Circadian rhythm of melatonin secretion was assessed by measuring serum melatonin concentrations between 02:00-04:00 and 16:00-18:00 hr. Melatonin dynamics were re-evaluated with respect to autonomic nervous system in diabetic patients with autonomic neuropathy who were diagnosed by the cardiovascular reflex tests, heart rate variability (HRV), and 24-hr blood pressure monitoring. Nocturnal melatonin levels and the nocturnal melatonin surge were low in the diabetic group (P = 0.027 and 0.008 respectively). Patients with autonomic neuropathy revealed decreased melatonin levels both at night and during day when compared with healthy controls (P < 0.001 and 0.004 respectively) while the melatonin dynamics were similar to controls in patients without autonomic neuropathy. Nocturnal melatonin level was positively correlated with nocturnal high and low frequency components of HRV (P = 0.005 and 0.011 respectively) and systolic and diastolic blood pressures at night (P = 0.002 and 0.004 respectively) in patients with autonomic neuropathy. We found a negative correlation between nocturnal melatonin levels and the degree of systolic blood pressure decrease at night (r = -0.478, P = 0.045). As a conclusion this study has shown that circadian rhythm of melatonin secretion is blunted in type 2 diabetic patients and there is a complex relationship between various components of autonomic nervous system and melatonin secretion at night. Among the patients with autonomic neuropathy those with more preserved HRV and the systolic nondippers (<10% reduction in blood pressure during the night relative to daytime values) have more pronounced melatonin surge at night.     

Heart Rate Variability in Young Women with Polycystic Ovary Syndrome

Background: Limited data are available related to the effects of sex hormones on cardiac autonomic function. Few studies investigated the heart rate variability (HRV) parameters during regular menstrual cycle or in postmenopausal women using hormone replacement therapy, but the results were contradictory. The aim of the study was to compare the characteristics of the autonomic innervation of the heart in polycystic ovary syndrome (PCOS) patients with regularly cycling controls. Methods: Thirty PCOS patients and 30 healthy regularly cycling controls were included in the study. Groups were compared with respect to age and various cardiovascular risk factors. Characteristics of autonomic innervation of the heart were evaluated with HRV. Power spectral analysis of HRV was performed to calculate the low frequency peak (LF 0.04–0.15 Hz), high‐frequency peak (HF 0.15–0.40 Hz), LF in normalized unit (LF nu), HF in normalized unit (HF nu) and LF/HF ratio. Results: PCOS patients had adverse cardiovascular risk profile than controls. As the HRV parameters, PCOS patients had significantly higher LF nu (P = 0.005) and LF/HF ratio (P = 0.001) and significantly lower HF (P = 0.006) and HF nu (P < 0.001) compared to controls. Conclusion: Autonomic innervation of the heart can be affected in PCOS with increased sympathetic and decreased parasympathetic components of HRV. As a result, sympathetic to parasympathetic ratio may increase in PCOS. This finding should be confirmed with larger studies also evaluating the clinical implications of altered HRV parameters.     

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.     

A Novel Method for the Assessment of Autonomic Neuropathy in Type 2 Diabetic Patients: a Comparative Evaluation of 123I-MIBG Myocardial Scintigraphy and Power Spectral Analysis of Heart Rate Variability

The correlation between the degree of sympathetic denervation measured through ¹²³I-MIBG Myocardial Scintigraphy and Power Spectral Analysis of consecutive R-R records was investigated in order to evaluate their potential application for the assessment of myocardial autonomic neuropathy in patients with diabetes mellitus. This study comprised 42 patients with Type 2 diabetes. Low frequency (0.02–0.09 Hz) components of the power spectral density were measured as markers of sympathetic activity. The myocardial uptake of ¹²³I-MIBG was measured by using the single photon emission computed tomography (SPECT) and the early and delayed images were recorded. Scoring from 0 to 3 of the ¹²³I-MIBG uptake of various cardiac segments (7) was performed and the total uptake was calculated. The washout rate inthe whole myocardium was determined. The values obtained in the group with diabetic autonomic neuropathy (DAN) without orthostatic hypotension (OH) were significantly lower as compared to those of the (DAN (−)) group in the delayed images. The washout rate of the OH (−) group was also significantly higher than the DAN (−) group. There was significant difference between the images and the washout rate of OH (+) and OH(−) groups. There was a significant correlation between Power Spectral Analysis and SPECT (early, delayed images, and washout rate). Of these, the delayed image showed the strongest correlation (r = 0.55, p < 0.01). Further, the QTc interval showed a significant inverse correlation with the delayed image (r = −0.44, p < 0.05). In conclusion, these results suggest that the cardiac ¹²³I-MIBG scintigraphy could be a useful method for the assessment of the myocardial autonomic neuropathy in patients with diabetes mellitus.     

Detecting and treating the protean manifestations of diabetic autonomic neuropathy

The manifestations of diabetic autonomic neuropathy (DAN) are protean and clinically involve multiple systems, including the cardiovascular system, the gastrointestinal system, the genitourinary system as well as the sweat glands (sudomotor dysfunction) and the gallbladder. In addition, cardiac autonomic neuropathy (CAN) is associated with a correctible inability to appreciate and correct hypoglycaemia. While not a clinical problem, pupillary involvement should be the clue and the catalyst to investigate for other manifestations of DAN. This review outlines a practical approach to detecting and investigating the manifestations of DAN. Of particular importance is early detection of cardiovascular involvement where prompt therapy through glycaemic control can decrease the severity of CAN and decelerate the frequency and severity of retinopathy and nephropathy in addition to decreasing cardiovascular events and mortality. CAN also plays a role in accelerating other diabetic complications such as acute ischaemic stroke, heart failure, medial artery calcinosis, foot ulcers, peripheral artery disease and Charcot joints. Many therapies of DAN are available, which should not only decrease morbidity and mortality from DAN, but also improve the patient's quality of life. However, the therapies available are largely symptomatic.     

The relationship between glycaemic variability and cardiovascular autonomic dysfunction in patients with type 1 diabetes: A systematic review

Rigorous glycaemic control—reflected by low HbA1c goals—is of the utmost importance in the prevention and management of complications in patients with type 1 diabetes mellitus (T1DM). However, previous studies suggested that short‐term glycaemic variability (GV) is also important to consider as excessive glucose fluctuations may have an additional impact on the development of diabetic complications. The potential relationship between GV and the risk of cardiovascular autonomic neuropathy (CAN), a clinical expression of cardiovascular autonomic dysfunction, is of increasing interest. This systematic review aimed to summarize existing evidence concerning the relationship between GV and cardiovascular autonomic dysfunction in T1DM. An electronic database search of Medline (PubMed), Web of Science and Embase was performed up to October 2019. There were no limits concerning year of publication. Methodological quality was evaluated using the Newcastle Ottawa Scale for observational studies. Six studies (four cross‐sectional and two prospective cohorts) were included. Methodological quality of the studies varied from level C to A2. Two studies examined the association between GV and heart rate variability (HRV), and both found significant negative correlations. Regarding cardiovascular autonomic reflex tests (CARTs), two studies did not, while two other studies did find significant associations between GV parameters and CART scores. However, associations were attenuated after adjusting for covariates such as HbA1c, age and disease duration. In conclusion, this systematic review found some preliminary evidence supporting an association between GV and cardiovascular autonomic dysfunction in T1DM. Hence, uncertainty remains whether high GV can independently contribute to the onset or progression of CAN. The heterogeneity in the methodological approach made it difficult to compare different studies. Future studies should therefore use uniformly evaluated continuous glucose monitoring‐derived parameters of GV, while standardized assessment of HRV, CARTs and other potential cardiac autonomic function parameters is needed for an unambiguous definition of CAN.     

Measurable deficit of autonomic and sensory nerve function in asymptomatic diabetic patients.

In a group of 46 consecutive outpatients attending the diabetic clinic of our Metabolic Department, 30 insulin-dependent and 16 non-insulin-dependent diabetic patients in stable metabolic control, and in 38 age-matched controls, we measured vibration perception threshold with biothesiometer and autonomic function, by means of the five classical cardiovascular tests: R-R interval variations during deep breathing, Valsalva ratio, lying-to-standing, postural hypotension, and sustained handgrip. None of the patients complained of symptoms related to diabetic autonomic neuropathy (DAN) or sensory polyneuropathy. Vibration perception threshold positively correlated with Valsalva ratio (p < 0.05) and deep breathing (p < 0.01), and all of them correlated with age (p < 0.001), but not with duration of diabetes and metabolic control. Patients scored significantly lower than controls in vibration perception threshold and all of the autonomic function tests. According to the outcomes of cardiovascular tests ["Autonomic Score" (AS)] patients were divided into two different groups: presence (DAN+ = AS > or = 3) or absence (DAN- = AS < 3) of autonomic neuropathy. The DAN- group (n = 28, 60.9%) showed no significant differences from the DAN+ group (n = 18, 39.1%) in age, duration of diabetes, glycated hemoglobin, or body mass index. DAN+ patients had vibration perception threshold measured at the first toe tip and at external malleolus significantly higher than DAN- patients (p < 0.01 and p < 0.001, respectively) and controls (p < 0.005), as well as all the other cardiovascular tests except sustained handgrip. No difference in any of these items was observed between DAN- patients and controls.(ABSTRACT TRUNCATED AT 250 WORDS)     

Diabetic autonomic neuropathy

Summary The use of heart rate monitoring in the diagnosis of diabetic autonomic neuropathy, and its value in observing the natural history of this disorder, has been assessed. Two tests were used: measurement of heart rate variation during deep breathing and of heart rate change on standing up. Two hundred and eighty seven diabetics aged between 20 and 49 years were studied, and 21 of them were observed repeatedly over 3 to 5 years. Heart rate variation (HRV) on deep breathing proved to be the more sensitive diagnostic index of autonomic neuropathy and was abnormal or borderline in 62 of 64 patients with established autonomic symptoms. Autonomic abnormalities were also detected in some diabetics without autonomic symptoms especially in those with peripheral neuropathy, 30% of whom had abnormal HRV on deep breathing. Abnormal tests appeared to represent permanent autonomic damage and may be present for years without the development of autonomic symptoms, occasionally (7%) preceding any other manifestation of diabetic neuropathy. Serial observations of HRV on deep breathing over 3 to 5 years showed little change, although overall there was a small deterioration of autonomic function, with a decrease of HRV score of 1.0 per year. The tests used are simple, and provide quantitative bedside measurements of autonomic function. When heart rate variation is normal, autonomic neuropathy is virtually excluded.     

心率变异评价Ⅱ型糖尿病患者自主神经功能

目的 研究Ⅱ型糖尿病患者心率变异（ＨＲＶ）与自主神经病及心、肾脏器受损的关系。方法 ５７例Ⅱ型糖尿病患者,分３组：单纯糖尿病组２９例,糖尿病合并冠心病组（糖冠组）１７例,糖尿病肾病组（糖肾组）１１例,正常对照组１５例,全部进行心血管反射试验及ＨＲＶ分析。结果 糖尿病患者合并自主神经病变为４５．６％,各组在ＨＲＶ时域指标及非线性定量分析指标上均较对照组降低,以糖肾组最为显著。比较Ｒ－Ｒ间期散点图,对