Cardiac autonomic neuropathy in patients with type 2 diabetes mellitus having peripheral neuropathy: A cross-sectional study

AimsThe aim was to see the frequency of CAN in type 2 diabetes mellitus patients with peripheral neuropathy, and its association with peripheral nerve conduction abnormalities.MethodsA cross-sectional study at BIRDEM was conducted in 62 patients with type 2 diabetes mellitus having electrophysiologically diagnosed peripheral neuropathy. CAN was detected by four clinical tests - heart rate response to deep breathing and valsalva maneuver, blood pressure response to standing and sustained handgrip.ResultThe study showed that all patients had CAN – 14.52% had early, 26.67% had definitive and 59.68% had severe CAN. Patients with severe CAN had significantly reduced nerve conduction velocity and amplitude of peripheral nerves (sural 4.36 ± 12.77 vs 9.65 ± 17.77 m/s, p = 0.009; 2.23 ± 1.89 vs 3.01 ± 2.76 mV, p = 0.001; peroneal 7 ± 4.23 vs 8.53 ± 5.99 mV, p = 0.047; tibial 0.008 ± 0.03 vs 0.026 ± 0.05 mV, p = 0.009) and higher serum triglyceride levels (221.17 ± 120.61 vs 197.76 ± 68.43 mg/dl, p = 0.033).ConclusionDiabetic patients with peripheral neuropathy have CAN, the severity of which increases with worsening neuropathy.     

Cardiac autonomic neuropathy in the diabetic patient

The importance of cardiac autonomic neuropathy (CAN) derives from its remarkable frequency and its clinical impact. The clinical features are postural hypotension and resting tachycardia, these abnormalities may be overlooked in a high number of patients asymptomatic. Although rarely life threatening, CAN causes considerable morbidity, which can be ameliorated by its identification and appropriate treatment. Circulatory reflexes were studied in 48 diabetic patients and 14 normal control subjects. Twenty-six of the diabetic patients had normal response. The remaining 22 had evidence of neuropathy and abnormal cardiac response during these tests. Only one patient had postural syncope but he had severe orthostatic hypotension. The others remained asymptomatic. All the control subjects had normal reflexes. Beat-to-beat variation with deep breathing (sinus arrhythmia), carotid body massage and mental stress, were important for the detection of CAN (86, 90 and 90% sensitivity respectively). The Valsalva maneuver and sinus arrhythmia showed 82 and 92% of specificity for the diagnosis of CAN. Our findings suggest that CAN in diabetic patients can be detected by these relatively simple test. We propose a rational approach to the diagnosis. Our method is applicable as a clinical routine examination for cardiac neuropathy.     

Cardiac autonomic neuropathy and QT interval length. A follow-up study in diabetic patients

For evaluating the clinical significance of QT interval prolongation in diabetics with cardiac autonomic neuropathy (CAN), 53 diabetic patients were followed-up for 5 years or to death and the results of cardiovascular function tests as well as the values of QT intervals were repeatedly determined. At baseline investigation, the QTc intervals were significantly longer in diabetics with definitive (456 +/- 5 ms, mean +/- SEM, n = 17) than those with early (435 +/- 5 ms, n = 13, p less than 0.01) and without (413 +/- 4 ms, n = 23, p less than 0.001) signs of CAN or in controls (414 +/- 5 ms, n = 15, p less than 0.001). Thirteen patients died during the follow-up period (1 without, 2 with early and 10 with definitive signs of CAN) but QTc intervals did not differ significantly between patients with cardiac (456 +/- 9 ms, n = 8) and non-cardiac (459 +/- 15 ms, n = 5) causes of death. At reinvestigation of 40 patients, the severity of CAN worsened in 22 patients, remained unchanged in 15 patients and improved in 3 patients. Accordingly, the mean values of autonomic function tests decreased (beat-to-beat variation from 15 +/- 2 to 9 +/- 1 beats/min, p less than 0.01; 30:15 ratio from 1.19 +/- 0.03 to 1.09 +/- 0.02, p less than 0.01) while QTc interval increased (from 424 +/- 3 to 431 +/- 4 ms, p less than 0.01). It was concluded that CAN carries a poor prognosis in diabetic patients. Nevertheless, QTc interval prolongation could be evaluated as rather an additional sign of CAN than the only explanation for mechanism in the pathogenesis of sudden cardiac death in diabetic patients.     

Cardiac autonomic neuropathy predicts renal function decline in patients with type 2 diabetes: a cohort study

Aims/hypothesis

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.

Methods

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.

Results

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.

Conclusions/interpretation

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.     

Diagnosis of diabetic autonomic neuropathy in young patients with diabetes mellitus type 1

Autonomic neuropathy, particularly cardiovascular autonomic neuropathy (CAN) is one of the complications of the diabetes mellitus both types. It leads to life comfort's declination but may also be the direct cause of death in diabetes mellitus patients. It seems that degree of metabolic control and duration of the disease is connected with prevalence and severity of CAN. The aim of our study was to assess cardiac autonomic function in young subjects suffered from insulin-dependent diabetes mellitus (IDDM) with relatively short duration time of the disease. We subdivided 25 (m-12, f-13) IDDM patients aged from 18 to 30 years: mean--26 +/- 38 years, with duration time of the disease up to 10 years, normotensive and without nephropathy and retinopathy. We created 25 healthy volunteers control group with similar age and sex. In all selected subjects full Ewing's battery tests were performed as well as the spectral analysis of power heart rate variability (HRV) was assessed with Finapress device (Ohmeda 2300) and automatically computed with special software. HRV in total spectrum power TP from 0.001-0.5 Hz, high frequency (HF) band from 0.15-0.3 Hz, low frequency (LF) band from 0.03-0.15 Hz and LF/HF ratio were examined both in supine and tilt. All assessed spectral values were significantly lower in IDDM patients then these in controls whereas LF/HF were respectively higher. Valsalva tests and deep breathing HR response tests were significantly differed among groups but within normal limits. We concluded that when spectral analyse was performed, in young IDDM patients with short duration time of the disease, impairment of cardiac autonomic function was observed.     

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     

Autonomic neuropathy in non-insulin-dependent diabetic patients: correlation with age, sex, duration and metabolic control of diabetes

The aim of this study has been to assess the prevalence of autonomic neuropathy among non-insulin dependent diabetic patients, and to determine whether a correlation could be found between autonomic impairment and the following: age, sex, duration of diabetes, body mass and metabolic control. Two hundred and twenty one non-insulin dependent patients were submitted to four cardiovascular tests: heart rate response to deep breathing and to standing up; blood pressure response to handgrip and to standing up. Sixty six percent of patients showed at least one abnormal cardiovascular response. The prevalence of autonomic impairment was higher in non-insulin dependent than in insulin-dependent diabetics. Patients were grouped according to the extent of autonomic impairment: absent (33.5%), early (27.6%), definite (3.6%), severe (4.5%). An atypical pattern (abnormality of blood pressure responses in absence of a definite abnormality of heart rate responses) was found in 30.8% of patients. Heart rate responses correlated significantly with age (p less than 0.001). No correlation between test results and duration was found in the multivariate analysis. The tests' results did not correlate with metabolic control or body mass index. Patients with symptoms of autonomic neuropathy had values for heart rate response to deep breathing and to standing significantly lower than those without (p less than 0.05).     

Glutamic acid decarboxylase antibodies,autonomic nerve antibodies and autonomic neuropathy in diabetic patients

Summary To clarify whether GAD-ab are associated with diabetic autonomic neuropathy and/or complement fixing antibodies against sympathetic ganglia, adrenal medulla, and vagus nerve, we examined 133 diabetic patients (95 with IDDM). GAD-ab were determined by a radioligand binding assay using in vitro expression of recombinant GAD-65 whereas sympathetic ganglia antibodies, adrenal medulla antibodies, vagus nerve, and ICA were evaluated by indirect immunofluorescence assays. Autonomic nerve function was evaluated by objective tests (heart rate reactions to deep breathing and to tilt). In the total material of 133 patients, GAD-ab were detected in 36 patients, all of whom had IDDM. The frequency of GADab was similar (38%) in IDDM patients with and without signs of autonomic neuropathy (21 of 55 vs 15 of 40). In addition, there were no significant associations between GAD-ab and autonomic nerve antibodies; GAD-ab were detected in 9 of 21 (43%) of patients with and in 27 of 112 (24%) of patients without sympathetic ganglia antibodies, in 5 of 15 (33%) of patients with and 31 of 118 (26%) without adrenal medulla antibodies, and in 5 of 15 (33%) with and 31 of 118 (26%) of patients without vagus nerve antibodies. The frequency of ICA, however, was significantly increased in patients with sympathetic ganglia antibodies compared with those without sympathetic ganglia antibodies (10 of 21 [48%] vs 21 of 112 [19%]; p<0.01). In conclusion, GAD-ab were neither associated with disturbed autonomic nerve function nor with antibodies against autonomic nerve structures.Abbreviations GAD Glutamic acid decarboxylase - ab antibodies - ICA islet cell antibodies - CF-ADM complement-fixing adrenal medulla antibodies - CF-SG complement-fixing sympathetic ganglia antibodies - CF-V complement-fixing vagal nerve antibodies - IDDM insulin-dependent diabetes mellitus - NIDDM non-insulin-dependent diabetes mellitus - JDF Juvenile Diabetes Foundation     

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。     

Clinical consequences of cardiovascular autonomic neuropathy in diabetic patients

A wide range of clinical consequences of cardiovascular autonomic neuropathy (CAN) can be observed in diabetic patients and contributes to the clinical picture of the diabetic heart. Resting heart rate and cardiovascular reflexes as well as circadian heart rate variability may be altered by CAN in diabetes. Moreover, blood pressure is also influenced by sympathovagal imbalance. Postural hypotension is a clinical characteristic in diabetic subjects with CAN. Painless myocardial infarction, ischaemia and left ventricular dysfunction are also observed in some cases. Impairment of cardiac parasympathetic and sympathetic innervation as well as QT-interval prolongation may play a partial role in the pathogenic mechanism of sudden unexpected death in diabetic patients. The risk of surgical intervention and that of anaesthesia are increased due to abnormal cardiovascular reactions. Clinical symptoms and signs of CAN should be assessed as severe diabetic complication and the therapy is difficult in some cases. Taken together, symptoms and signs of CAN carry a poor prognosis in diabetic patients.     

Cardiac autonomic dysfunction in patients with diabetic retinopathy

Summary Cardiac autonomic function was assessed by an on-line microcomputer technique in 67 patients with diabetic retinopathy. Sixteen patients had a resting tachycardia (92 beats/min or greater). R-R interval variations were abnormally low in 29 patients at rest, in 35 during deep breathing and in four in response to a Valsalva manoeuvre. The severity of retinopathy correlated significantly with the degree of autonomic dysfunction assessed by the interval variations at rest (p < 0.05), during deep breathing (p < 0.01), and with the Valsalva manoeuvre (p < 0.01). The results emphasise the important association between diabetic retinopathy and cardiac autonomic dysfunction.     

Relationship between autonomic neuropathy and thermogenesis in non diabetic and diabetic obese patients

Autonomic neuropathy is a well known complication of diabetes. Diabetes is often superimposed on obesity. A reduction in the variability of the heart rate in the resting state has been demonstrated in 16 obese diabetic subjects as well as in 34 obese non-diabetic subjects. The coefficient of variation (CV) of the heart rate during 30 minutes of resting was significantly decreased in both obese groups (3.9 +/- 0.2% for the diabetics; 5.2 +/- 0.2%, p less than 0.01 for the non diabetics) as compared to their own controls (4.5 +/- 0.6% and 6.5 +/- 0.4%, respectively). Age also contributes to decreased heart rate variability. Furthermore, this defect of autonomic function has been correlated with the blunted glucose-induced thermogenesis (GIT) seen in both obese groups (r = 0.52, p. less than 0.001): the increase in energy expenditure over basal values following a 100 g oral glucose load was only 4.8 +/- 0.8% for the diabetic obese group (p less than 0.001), and 8.5 +/- 0.7% for the non-diabetic obese group (p less than 0.001) as opposed to their own controls (12.4 +/- 1.3% and 13.3 +/- 0.6% respectively). Measurement of the variability of heart rate in obese individuals may be of predictive value in assessing blunted glucose-induced thermogenesis in non diabetic and diabetic obese patients.     

Clinical usefulness of corrected QT intervals in diabetic autonomic neuropathy in patients with type 2 diabetes

BACKGROUND: It is recognized that QTc intervals reflect autonomic nerve function. To investigate the clinical usefulness of corrected QT intervals (QTc) in assessing autonomic nerve function in type 2 diabetes, we measured QTc intervals using Bazett's formula in 58 type 2 diabetic patients and 20 age-matched healthy subjects. METHODS: We examined relationships between QTc intervals and the coefficient of variation of RR intervals (CV(RR)), systolic blood pressure response to standing, and sympathetic skin response (SSR) whose tests reflect autonomic nerve function. We also studied the correlation between QTc and blood pressure or serum lipid concentrations. RESULTS: QTc intervals in diabetic patients were significantly longer than those in healthy subjects and showed a significant but weak negative correlation with CV(RR), as well as systolic blood pressure response to standing. No significant difference in QTc intervals was observed between patients with and without a detectable SSR. QTc intervals showed a significant positive correlation with systolic and diastolic blood pressure although it did not correlate with serum lipid concentrations. QTc also tended to be long in obese diabetic subjects (body mass index > 25). CONCLUSION: QTc intervals might also be affected by other factors such as arteriosclerotic macroangiopathy and obesity, and not only autonomic nerve function. Therefore it might be considered as an overall index for complications, and not for pure autonomic impairment.     

Cardiac autonomic neuropathy and its correlation with QTc dispersion in type 2 diabetes

This study was conducted on 50 patients of diabetes mellitus type 2 and 20 healthy controls to correlate severity of diabetic cardiac autonomic neuropathy with QTc interval and QTc dispersion. Five standard cardiovascular response tests were carried out (i.e. Valsalva ratio, expiration-inspiration ratio, immediate heart rate response to standing, fall of systolic blood pressure on standing and sustained hand grip test) to determine the severity of cardiac autonomic neuropathy by scoring system. QTc dispersion was determined by subtracting heart rate-corrected minimum QTc interval (QTc min) from maximum QT interval (QTc max) from standard electrocardiogram. Severity of cardiac autonomic neuropathy strongly correlated with QTc dispersion (r = 0.760; p = 0.0001). Correlation of severity of cardiac autonomic neuropathy with QTc max and QTc mean was also found but weaker than with QTc dispersion (r = 0.663, r = 0.542, p = 0.0001 each) and no correlation was found with QTc min (r = 0.177; p = 0.17). This shows that QTc dispersion is a better predictor of cardiac autonomic neuropathy than any of above three QTc intervals. QTc max, QTc mean and QTc dispersion were significantly higher (p < 0.001) in diabetics with autonomic neuropathy (450 +/- 23, 423 +/- 22 and 57 +/- 12 msec; n = 30) than without neuropathy (407 +/- 14, 397 +/- 15 and 20 +/- 7 msec; n = 20) and control subjects (408 +/- 20, 399 +/- 19 and 19 +/- 7 msec; n = 20) but QTc min remained same in the three groups (393 +/- 21, 387 +/- 12, 388 +/- 19 msec, respectively) (p > 0.05). Correlation of QTc dispersion was stronger with QTc max (r = 0.781; p < 0.001) than QTc mean (r = 0.625; p = 0.001) but not with QTc min (r = 0.097; p = 1.0) which suggests that regional increase in QT interval due to regional autonomic denervation leads to increased QTc dispersion. Thus, QTc dispersion is a sensitive, non-invasive, simple and cost-effective predictor of cardiac dysautonomia.     

Prospective study of autonomic neuropathy as a predictor of mortality in patients with diabetes

To investigate the relationships between serum concentrations of soluble adhesion molecules and hyperglycemia, insulin resistance, or other conventional risk factors in type 2 diabetes, we measured soluble intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), E-selectin (sE-selectin), insulin sensitivity, and conventional risk factors in 150 Japanese type 2 diabetic patients without apparent diabetic macroangiopathy. High serum concentrations of sVCAM-1 and sE-selectin were observed in patients with type 2 diabetes. Serum concentrations of soluble adhesion molecules were not significantly influenced by sex, hypertension, dyslipidemia, or microangiopathy. Spearman correlation showed that sVCAM-1 concentrations correlated significantly with fasting plasma glucose (FPG), fasting C-peptide, and insulin sensitivity [K index of the insulin tolerance test (K(ITT))] (rho=0.19,0.23, and -0.23, respectively). Soluble E-selectin concentrations correlated significantly with body mass index (BMI), FPG, fasting C-peptide, insulin sensitivity, and triglyceride (rho=0.33,0.42,0.26,-0.48, and 0.29, respectively). Multiple regression analysis showed that FPG, fasting C-peptide, and total cholesterol were independent factors that correlated with sVCAM-1 levels. BMI, FPG, and insulin sensitivity were independent factors that correlated with sE-selectin levels. Serum concentrations of sE-selectin significantly increased associated with clustering of conventional risk factors those obesity, hypertension, dyslipidemia, and current smoking (P<0.01). Thus, sVCAM-1 and sE-selectin levels are related to both hyperglycemia and insulin resistance. Soluble E-selectin levels may be related to obesity, hyperglycemia, and insulin resistance and may reflect the presence of a multiple risk factor clustering syndrome.