Evidence for specific autoimmunity against sympathetic and parasympathetic nervous tissues in Type 1 diabetes mellitus and the relation to cardiac autonomic dysfunction

There is growing evidence for the involvement of immunological factors in the pathogenesis of cardiac autonomic dysfunction in Type 1 diabetes mellitus (DM). To evaluate the presence of autoantibodies against autonomic nervous tissues and their relationship with tests of autonomic function, 64 newly diagnosed and 142 long duration Type 1 DM patients were investigated for sympathetic and parasympathetic ganglia (CF-SG and CF-PSG) autoantibodies with a complement-fixing indirect immunofluorescence technique. Five cardiac reflex tests were performed to assess autonomic function. Fifty-seven patients with neurological diseases other than diabetic neuropathy and 131 healthy control subjects were also tested for CF-SG and CF-PSG autoantibodies. CF-SG autoantibodies were observed in 47 (23 %) and CF-PSG autoantibodies in 21 (10 %) of 206 Type 1 DM patients (p < 0.001). In contrast, these autoantibodies were detected in 3 (5 %) and 1 (2 %) of patients with non-diabetic neurological diseases and 3 (2 %) and 4 (3 %) of control subjects (p < 0.01, p < 0.05, p < 0.0001, p < 0.05 vs Type 1 DM patients). All except two Type 1 DM patients with CF-PSG autoantibodies also presented with CF-SG autoantibodies. In diabetic patients with long duration, CF-SG autoantibodies were more frequent in patients with ECG-based cardiac autonomic neuropathy (CAN; ≥2 of 5 cardiac reflex tests abnormal) compared to patients without CAN although this did not reach statistical significance (29 % vs 17 %, p = 0.06). However, 4 (80 %) of 5 newly diagnosed and 23 (32 %) of 73 established Type 1 DM patients with abnormalities in heart rate variation during deep breathing and/or standing from lying presented with CF-SG autoantibodies compared to 12 (25 %) of 58 newly diagnosed (p < 0.05) and 7 (11 %) of 63 established Type 1 DM patients (p < 0.01), in whom both tests were normal. The results suggest that autoimmune factors contribute to the pathogenesis of cardiac autonomic dysfunction in Type 1 DM and that autoantibodies against sympathetic and parasympathetic nervous tissues are relatively specific for Type 1 DM. © 1998 John Wiley & Sons, Ltd.     

Autonomic Mechanisms and Therapeutic Implications of Postural Diabetic Cardiovascular Abnormalities

Background

Cardiovascular autonomic neuropathy (CAN) is a disorder of progressive autonomic dysfunction (AD) associated with diabetes and other chronic diseases. Orthostatic hypotension (OH) is one of the most incapacitating symptoms of CAN and AD. AD in OH can include sympathetic withdrawal (SW). To detect and diagnose SW, parasympathetic and sympathetic changes must be clearly differentiated from each other. This is accomplished by means of the novel autonomic nervous system (ANS) method based on the simultaneous spectral analyses of respiratory activity (RA) and heart rate variability (HRV).

Methods

We performed autonomic profiling of 184 (142 females) consecutive, arrhythmia-free patients with type 2 diabetes using the ANX-3.0 autonomic monitoring system. The patient cohort included 86 (64 female) patients for whom an α₁-agonist was the only drug changed and increased from one test to the next; 37 (33 female) for whom the α₁-agonist was discontinued; and 61 (45 female) who were on an α₁-agonist, but for whom no drug changes were made. The tests averaged 3.1 ± 1.4 months apart; midodrine (ProAmatine) was the α₁-agonist prescribed. Of the group, 99 patients also had hypertension and 47 also had cardiovascular disease. No patient had supine hypertension.

Results

Changes in parameters from the HRV (without respiration) and ANS methods were compared with changes in heart rate and blood pressure (BP) as measured from one test (test N) to the next (test N + 1). SW with a BP drop of less than the clinical definition may be a trend that can be an early indicator of orthostasis. In this study, patients were treated with low-dose, short-term α₁-agonist (vasopressor) therapy, which tended to correct the abnormal trend of SW with a drop in BP. Included in the findings was a systolic BP trend in response to vasopressor therapy of an (expected) initial increase in BP followed by an eventual decrease in systolic BP as SW was reversed.

Conclusions

The ANS method enables quantitative assessment of CAN by independently and simultaneously quantifying the two branches of the ANS, sympathetic and parasympathetic. The ANS method modifies standard spectral analysis of HRV (without RA analysis) by incorporating spectral analysis of RA.The ANS method appears to model the normal and abnormal responses to upright posture and changes in vasopressor therapy with greater fidelity than the HRV method. Independent, simultaneous assessment of progressive parasympathetic and sympathetic dysfunction, autonomic imbalance, and responses of the two ANS branches to therapy seems to enable early detection and early intervention. Orthostasis, by way of example, illustrates that frequent, sensitive assessments of both ANS branches can improve the negative outcomes associated with CAN.     

Effects on heart rate variability of metoprolol supplementary to ongoing ACE-inhibitor treatment in Type I diabetic patients with abnormal albuminuria

AIMS/HYPOTHESIS: Diabetic nephropathy is associated with a high risk of cardiac mortality including sudden death. This is presumably related to an imbalance between sympathetic and parasympathetic tone resulting in a decreased heart rate variability (HRV). In non-diabetic patients a decreased HRV is known to be a strong predictor of cardiovascular death. Studies in non-diabetic patients have shown that beta-blockers improve HRV parameters known to reflect parasympathetic function. The aim of our study was to investigate effects of additional beta-blocker treatment on: cardiac autonomic function, blood pressure, and urine albumin excretion in ACE-inhibitor treated Type I (insulin-dependent) diabetes mellitus patients with abnormal albuminuria. METHODS: We studied the effects of 6 weeks treatment with metoprolol (100 mg once daily, zero order kinetics formulation) in 20 patients participating in a randomised, placebo controlled, double blind, crossover trial. Patients were simultaneously monitored under ambulatory conditions with 24-h Holter-monitoring, 24-h ambulatory blood pressure recording, and 24-h fractionated urine collections. Heart rate variability was assessed by four different methods; ambulatory HRV analysis was carried out by spectral and time domain analysis, and on days of investigation short-term spectral analysis and bed-side tests were carried out. RESULTS: Metoprolol treatment improved in vagal tone assessed by short-term spectral analysis. The 24-h ambulatory HRV analysis showed improvement in some parameters reflecting vagal function. A minor decrease in daytime diastolic blood pressure was shown, no alterations in diurnal variation of blood pressure or urine albumin excretion were observed. CONCLUSION/INTERPRETATION: These preliminary findings indicate that beta-blocker treatment could improve autonomic function in Type I diabetic patients with abnormal albuminuria and an associated high risk of cardiovascular disease.     

Assessing cardiovascular autonomic neuropathy in diabetes mellitus: how many tests to use?

The aim was to evaluate the relative importance of an established battery of five function tests used in the assessment of cardiovascular autonomic neuropathy (CAN) in diabetes employing spectral analysis of heart rate variability (HRV) as the reference test. In a population-based sample of 178 diabetic persons and 194 non-diabetic controls, five function tests (E/I ratio, Valsalva, 30:15 ratio, Orthostatic-BP, and sustained Handgrip) and power spectral analysis of a 24-h Holter recording were carried out. The high-frequency power during nighttime (LnHF(NIGHT)) was taken to express the parasympathetic function and the daytime low-frequency power (LnLF(DAY)) to express the sympathetic function. The readings were log transformation when appropriate, age-corrected, and standardized to units of standard deviation. Combinations of the three mainly parasympathetic tests and the two mainly sympathetic tests were computed by averaging the standardized readings. A high value of the mean sum of squares in LnHF(NIGHT) or LnLF(DAY) - explained in regression analysis - was assumed to represent the better test or combination of tests. The three parasympathetic function tests each correlated significantly to LnHF(NIGHT). The E/I ratio had a correlation to LnHF(NIGHT) similar to the combination of the three parasympathetic tests and the combination of all five function tests, whereas Valsalva and 30:15 ratio had a significantly poorer association. Sustained Handgrip-correlated significantly poorer to LnLF(DAY) compared to Orthostatic BP and the combination of the two sympathetic tests explained a significantly smaller part of the variation in LnLF(DAY) and LnHF(NIGHT) than did the combination of all five tests. This study indicates that: (1) no information is gained by adding the sympathetic function tests to the parasympathetic tests, (2) the most informative test is the E/I ratio, (3) and knowledge about the degree of CAN as defined by reduced HRV is not significantly increased when the four other function tests assessed are added to the E/I ratio.     

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.     

Functional connectivity between parietal cortex and the cardiac autonomic system in uremics

Although the central autonomic network (CAN) has been well researched in animal models, the CAN in humans is still unclear, especially for cardiovascular control. This study aimed to investigate which areas of the cerebral cortices are associated with the peripheral cardiac autonomic control involved in the CAN in uremic patients with autonomic dysfunction and normal controls. The central and peripheral autonomic network in 19 uremic patients with significant autonomic dysfunction and 24 age- and sex-matched controls [mean age ± standard deviation (SD), 55.16 ± 10.45 years and 55.42 ± 5.42 years, respectively] were evaluated by simultaneous spectral analysis of electroencephalography (EEG) and electrocardiography recording (ECG), along with serial autonomic tests [autonomic questionnaire and orthostatic blood pressure (BP) change]. Only frequency-domain heart rate variability (f-HRV) during the deep-breathing stage could differentiate the two groups. Although there is no significant difference in f-HRV during the quiet-breathing stage, different patterns of central oscillation and their correlation with peripheral cardiac autonomic indices could be found for the two groups. Although the power of specific EEG bands under electrode T3 and T6 correlated significantly with the power of peripheral HRV indices in the control group, those under electrodes P3 and Pz had significant correlations in the uremic group suggesting a role of functional connectivity between them. In addition, sympathetic activity is correlated with slow wave EEG (theta/delta) power whereas parasympathetic activity is correlated with fast wave EEG (beta) power. In conclusion, there is functional connectivity between the parietal cortex and the peripheral cardiac autonomic system (PAN) in uremics and the pattern of central autonomic connectivity differs between uremic patients with autonomic dysfunction and normal controls.     

Autonomic nerve antibodies and autonomic nerve function in type 1 and type 2 diabetic patients

Complement-fixing adrenal medulla (CF-ADM), sympathetic ganglion (CF-SG), and vagal (CF-V) nerve antibodies were determined in diabetic patients. Among 74 patients with Type 1 diabetes, CF-ADM was detected in 7 (10%) cases, CF-SG in 14 (19%) cases, and CF-V in 8 (11%) cases. Among 38 patients with Type 2 diabetes, CF-ADM was detected in 5 (13%) cases, CF-SG in 4 (11%) cases, and CF-V in 6 (16%) cases. There were associations between autonomic nerve antibodies and autonomic nerve function. CF-ADM and/or CF-SG were significantly (P less than 0.002) less prevalent in Type 1 diabetic patients with autonomic neuropathy than in those without [5/44 (11%) vs. 14/30 (47%)] and, in agreement with this, the brake index, a sign of parasympathetic and sympathetic autonomic nerve function, was significantly (P less than 0.005) higher (more normal) in these patients (-0.56 +/- 0.13 vs. -1.04 +/- 0.12). In Type 2 diabetic patients, the E/I ratio, an index of parasympathetic nerve function, was significantly (P less than 0.03) lower (more abnormal) in those with CF-V than in those without (-1.81 +/- 0.17 vs. -1.20 +/- 0.11). In conclusion, the frequency of sympathetic nerve antibodies was decreased in Type 1 diabetic patients with autonomic neuropathy, while in Type 2 diabetic patients parasympathetic nerve antibodies were related to severe parasympathetic neuropathy.     

Screening for diabetic cardiac autonomic neuropathy using a new handheld device

Background

Cardiac autonomic neuropathy (CAN) is a serious complication of longstanding diabetes and is associated with an increased morbidity and reduced quality of life in patients with diabetes. The present study evaluated the prevalence of CAN diagnosed by reduced heart rate variability (HRV) using a newly developed device in a large, unselected, hospital-based population of patients with diabetes.

Methods

The study examined 323 patients consisting of 206 type 1 diabetes (T1DM) patients and 117 type 2 diabetes (T2DM) patients. The new handheld prototype Vagus™ was used to screen for CAN. Three different standardized cardiac reflex tests were performed to calculate HRV: 30:15 ratio, E:I ratio, and the Valsalva maneuver. An abnormal HRV in one test is indicative of early CAN, and if two or more tests show abnormal HRV, the diagnosis of CAN is established.

Results

In total, 86% of examined patients completed all three tests. Each test was completed by more than 90% of the patients. The prevalence of established CAN was 23%, whereas 33% of the patients had early signs of CAN. The prevalence was higher in T2DM patients (27.8%) than in T1DM patients (20.6 %), p = .02. Patients with CAN were older and had a longer duration of diabetes, higher systolic blood pressure, more nephropathy and retinopathy, and a higher vibration threshold.

Conclusions

Cardiac autonomic neuropathy is frequent in both T2DM and T1DM patients, especially in those with other late diabetes complications. Screening for CAN with the new device is feasible.     

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.     

The connection between QT dispersion and autonomic neuropathy in patients with type 2 diabetes.

It is controversial whether an increase in the QT dispersion (QTd) on the electrocardiogram (ECG) reflects cardiac autonomic neuropathy in diabetic patients. In the current study, the QTd was compared in 60 type 2 diabetic patients and in 30 healthy subjects, and its association with autonomic neuropathy in diabetic patients was investigated. An increased QTd was found in diabetic patients, compared to healthy subjects. The QTd had significant negative associations with the log of the low and high frequency power (log LF and HF, respectively) of the power spectral analyses (PSA) of heart rate variations and the systolic blood response during standing (Delta BP). There was no significant difference in the QTd between patients with and without sympathetic skin response (SSR), reflecting peripheral sympathetic function. A significant positive correlation was also found between QTd and the systolic blood pressure (SBP). On the other hand, there was no correlation between QTd and serum total cholesterol (TC), triglycerides (TG), fasting plasma glucose (FPG), hemoglobin (Hb) A (1C) concentrations or body mass index (BMI). By multiple regression analysis, the log HF, which reflects cardiac parasympathetic function, and the SBP alone were significantly associated with QTd as the dependent variable. The Delta BP and log LF, which partially reflect sympathetic nerve function, had no significant associations with QTd. These findings suggest that QTd reflects cardiac autonomic neuropathy (relative parasympathetic neuropathy) and that the QTd is also influenced by SBP, independent of autonomic neuro-function.     

Comparative value of 24-hour ECG monitoring and standardized maneuvers in the detection and exploration of cardiac autonomic neuropathy in diabetics

24-hour continuous electrocardiographic ECG monitoring and standardized tests were performed to detect cardiac autonomic neuropathy in diabetic patients. Thirty-eight patients, with a mean duration of diabetes of 10 years, twenty-five IDDM and thirteen NIDDM, and thirty-two controls, with no illness or treatment which could alter the heart rate (HR), were studied. Five standardized tests were performed. Three tests investigated parasympathetic function: variations of HR during Valsalva manoeuvre, deep breathing and standing. The other two tests investigated sympathetic function: detection of orthostatic hypotension and blood pressure response to sustained handgrip. Parasympathetic HR control was impaired in twenty-nine patients, together with impaired sympathetic cardiovascular control in seven. According to the 6 indices studied, 24-hour ECG monitoring detected abnormalities in only eight patients. Mean minimum 24-hour HR and mean sleeping HR were elevated in the group of patients whose five standardized tests were normal and in the group of patients with impairment of both parasympathetic and sympathetic cardiovascular control, but not in the group of patients with only impaired parasympathetic HR control. This study suggests that 24-hour ECG monitoring is a less sensitive test of cardiac autonomic neuropathy than standardized tests. Moreover, it shows HR abnormalities that are not specific to cardiac autonomic neuropathy.     

High prevalence and early onset of cardiac autonomic neuropathy among South Indian type 2 diabetic patients with nephropathy

OBJECTIVE: This study was conducted to assess the adverse effects of diabetic nephropathy on cardiovascular autonomic neuropathy (CAN) in South Indian Type 2 diabetic patients. METHODS: Comparison was made between Type 2 diabetic patients with nephropathy (group 1, n=25), Type 2 diabetic patients without nephropathy (group 2, n=25) and non-diabetic, non-hypertensive control subjects (n=20). All had a detailed clinical and biochemical work-up and cardiac assessment by ECG. Cardiac dysautonomia was assessed by a battery of five non-invasive autonomic function tests (ANF) as recommended by Ewing and Clarke [D.J. Ewing, B.F. Clarke, Diagnosis and Management of autonomic neuropathy. Br. Med. J. 285 (1982) 916-918]. RESULTS: Group 1 patients showed a higher percentage of abnormal CAN function and a more severe form of CAN compared with patients in group 2. Group 1 patients showed early development of the abnormalities. They also had a higher prevalence of peripheral neuropathy compared with the patients without nephropathy. CONCLUSIONS: The present study showed that the presence of nephropathy was associated with the risk of cardiac autonomic neuropathy in Type 2 diabetic patients and it probably had an earlier onset also in them.     

Cardiac sympathetic dysinnervation in Type 2 diabetes mellitus with and without ECG-based cardiac autonomic neuropathy

To evaluate the presence and extent of global and regional distributions of cardiac sympathetic dysinnervation in Type 2 diabetes mellitus I-123-metaiodobenzylguanidine (I-123-MIBG) scintigraphy was applied to 15 Type 2 (noninsulin-dependent) diabetic patients with ECG-based cardiac autonomic neuropathy (> or = two of five age-related cardiac reflex tests abnormal) and 15 clinically comparable Type 2 diabetic patients without ECG-based cardiac autonomic neuropathy. Myocardial perfusion abnormalities were excluded by 99 m-Tc-methoxyisobutylisonitrile (99 m-MIBI) scintigraphy. Both in Type 2 diabetic patients with and without, ECG-based autonomic neuropathy, only one patient (7%) was found to have a normal homogeneous uptake of I-123-MIBG compared to 14 patients (93%) with a reduced I-123-MIBG uptake. The uptake of I-123-MIBG in the posterior myocardium of diabetic patients was smaller than in the anterior, lateral, and septal myocardium (P< .001, P< .001, P< .001, respectively). Diabetic patients with ECG-based cardiac autonomic neuropathy demonstrated a more pronounced reduction of the posterior I-123-MIBG myocardial uptake than diabetic patients without (P< .01). The mean global and the anterior, lateral, septal, and apical myocardial I-123-MIBG uptake was comparable between the two groups. The uptake of the posterior myocardial region correlated with all indices of heart rate variation at rest and during deep breathing. A correlation between global or regional myocardial I-123-MIBG uptake and QT interval was not observed. The study demonstrates that cardiac sympathetic dysinnervation is common in Type 2 diabetes mellitus both with and without ECG-based cardiac autonomic neuropathy. In Type 2 diabetes mellitus, the posterior myocardium is predominantly affected and the extent of dysinnervation is more pronounced in the presence of ECG-based cardiac autonomic neuropathy.     

Neu initiierte Insulintherapie und kardiale autonome Funktion bei Typ-2-Diabetes

BACKGROUND AND AIM: There is scintigraphic evidence that insulin improves cardiac autonomic innervation in diabetic patients. The aim of the study was to assess the effects of insulin therapy on parameters of cardiac reflex tests in type 2 diabetic patients. PATIENTS AND METHODS: 30 type 2 diabetic patients with an HbA(1c) of > 7.5% under oral antidiabetic agents were included into the 4-month follow-up. Insulin therapy was performed according to standardized clinical guidelines. Parameters of five cardiac reflex tests were assessed to study cardiac autonomic function: Coefficient of variation (CV) of heart rate variation (HRV) at rest and during deep breathing, HRV in response to standing (max./min. 30:15-ratio), Valsalva ratio, systolic blood pressure response (> 1 test abnormal = cardiac autonomic neuropathy [CAN]). QT(QTc)-interval was also assessed in the patients. RESULTS: At 4-months follow-up, mean insulin dosage in the patients was 25 +/- 8 IU/day. HbA(1c) was decreased from 9,2 +/- 0,7 to 7.2 +/- 0.6 % (p < 0.001). Three parameters of cardiac autonomic function were significantly improved: CV of HRV at rest 2.79 +/- 0.84 versus 2.96 +/- 0.85 (p < 0,001), CV of HRV during deep breathing 4.15 +/- 1.46 versus 4.38 +/- 1.68 (p = 0.002), 30:15 ratio 1.06 +/- 0.05 versus 1.09 +/- 0.04 (p < 0.05). Length of QTc- Interval changed significantly from 417 +/- 12 ms at month 0 to 398 +/- 11 ms at month 4 (p<0.05). CONCLUSIONS: The study demonstrates that insulin therapy with regular insulin optimizes cardiac autonomic function in type 2 diabetes mellitus. It emphasizes the value of cardiac reflex tests with regrad to follow-up of cardiac autonomic function in diabetes.     

Autonomic dysfunction in psoriatic arthritis

Autonomic nervous system (ANS) involvement has been studied in systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, Sjogren’s syndrome, and ankylosing spondylitis but still has not been studied in psoriatic arthritis (PsA). The aim of this study was to investigate the prevalence and the nature of autonomic neuropathy in patients with PsA. Sixteen patients of PsA and 15 age and sex matched control subjects were studied prospectively using a battery of noninvasive tests. Cardiovascular autonomic neuropathy (CAN) was diagnosed by applying four cardiovascular reflex tests, and peripheral sympathetic autonomic function was assessed by Sudoscan. Patients with PsA had significantly higher heart rate response to standing (p?=?0.01), blood pressure response to standing (p?=?0.02), and Sudoscan (p?=?0.01) when compared with healthy controls. Fifty percent (n?=?8) of the patients with PsA had at least two or more abnormal CAN parasympathetic dysfunction; of these, 18.75 % (n?=?3) of the patients had abnormal parasympathetic and sympathetic dysfunction, 68.7 % (n?=?11) and 25 % (n?=?4) of the patients had at least one abnormal parasympathetic and sympathetic parameters, respectively, and 37.5 % (n?=?6) of the patients had moderate sudomotor dysfunction. About 18.7 % (n?=?3) of our parasympathetic dysfunction patients had autonomic symptoms. None of healthy volunteers had abnormal ANS dysfunction. Heart rate response significantly correlated with erythrocyte sedimentation rate (p?<?0.05) and C-reactive protein (p?<?0.05) levels. In conclusion, cardiovascular autonomic and peripheral sympathetic neuropathy occurs in PsA. Parasympathetic function is more commonly found to be abnormal than sympathetic function. There is no correlation of peripheral sympathetic dysfunction with cardiovascular autonomic neuropathy.     

Cardiac autonomic neuropathy in diabetic patients: influence of diabetes duration,obesity, and microangiopathic complications--the French multicenter study

The current study sought to examine in a large series of diabetic patients the prevalence of symptoms of autonomic neuropathy and subclinical cardiac autonomic neuropathy (CAN) and their determinants, particularly the influence of diabetes duration, obesity, and microangiopathic complications. Three hundred ninety-six patients, 245 type 1 and 151 type 2, were recruited in 7 French departments of diabetology. CAN was detected by measuring heart rate variability during 3 standardized tests: deep-breathing, Valsalva, and lying-to-standing tests. At least 24.5% of the patients had one or more symptoms suggesting overt autonomic neuropathy. They were older than those free of dysautonomic symptom (P<.001). The deep-breathing test correlated negatively with body mass index (BMI) in type 2 diabetic patients (P<.0001). In the whole population, the deep-breathing and Valsalva tests correlated negatively with diabetes duration (P=.0004 and.019, respectively) and the log urinary albumin/creatinine ratio (P<.002 and.001, respectively). The prevalence of CAN (51%) was higher than the prevalence of other diabetic complications. The rate of moderate and severe CAN (defined by 2 or 3 abnormal CAN function tests) was higher in type 1 than in type 2 diabetic patients (P=.031). It correlated with diabetes duration (P=.026) and was higher in the patients with retinopathy than in those without (P=.035). Among type 2 diabetic patients, the prevalence of CAN was higher in the obese ones (P=.033); in a logistic regression taking age, diabetes duration, and obesity as independent variables, CAN was associated independently with obesity (P=.034). Mild or moderate CAN was found in 33.8% and 13.0% of the 80 patients with diabetes duration less than 18 months. We conclude that CAN is found early in the course of diabetes and should be considered as a prognostic marker of microangiopathic complications. Obesity could be involved in the impairment of CAN function in type 2 diabetics and body weight control could provide an approach to reducing neuropathic complications.     

Squatting, a posture test for studying cardiovascular autonomic neuropathy in diabetes

Cardiovascular autonomic neuropathy (CAN) is a frequent complication of diabetes mellitus, which is associated with increased morbidity and mortality. It involves both the parasympathetic and sympathetic nervous systems, and may be diagnosed by classical dynamic tests with measurements of heart rate (HR) and/or arterial blood pressure (BP). An original squat test (1-min standing, 1-min squatting, 1-min standing) was used with continuous monitoring of HR and BP, using a Finapres^® device. This active test imposes greater postural stress than the passive head-up tilt test, and provokes large changes in BP and HR that can be analyzed to derive indices of CAN. In healthy subjects, squatting is associated with BP increases and HR decreases (abolished by atropine: SqTv index), whereas the squat–stand transition is accompanied by a deep but transient drop in BP associated with sympathetic-driven tachycardia (abolished by propranolol: SqTs index). In diabetic patients with CAN, BP increases are accentuated during squatting whereas reflex bradycardia is reduced. When standing from squatting position, the fall in BP tends to be more pronounced and orthostatic hypotension more prolonged, while reflex tachycardia is markedly dampened. The baroreflex gain, similar to that calculated during pharmacological testing with vasodilator/vasopressor agents, can be derived by plotting pulse intervals (R–R) against systolic BP levels during the biphasic response following the squat–stand transition. The slope, which represents baroreflex sensitivity, is significantly reduced in patients with CAN. This discriminatory index allows study of the natural history of CAN in a large cohort of diabetic patients.     

Abnormal heart rate variability in adults with growth hormone deficiency

GH-deficient (GHD) patients have increased risk of cardiovascular death and may have cardiac structural abnormalities. In non-GHD patients these are associated with cardiac autonomic dysfunction, and it is possible that autonomic dysfunction is also present in GHD patients. Power spectral analysis (PSA) of heart rate variability (HRV) indirectly measures cardiac autonomic tone and generates peaks at 3 frequency bands, very low frequency (VLF), low frequency (LF) and high frequency (HF). The area under the LF curve is considered to reflect predominantly cardiac sympathetic activity, whereas HF indicates parasympathetic activity. PSA of HRV was performed in 14 normotensive GHD patients (5 men and 9 women; mean age, 35.2 yr) and 19 healthy controls (9 men and 10 women; mean age, 38.3 yr). GHD patients had 26% lower normalized LF power (P < 0.004), 39% higher normalized HF power (P < 0.001), 28% lower normalized VLF power (P < 0.046), and 51% lower LF/HF ratio (an index of sympathovagal balance; P < 0.001) compared to controls. These data indicate that heart rate variability is abnormal in patients with GHD. The decreased sympathetic tone could be a consequence of reduced central sympathetic tone or altered cardiac responsiveness to autonomic control and may contribute to the increased cardiovascular risk in GHD patients.     

Haemodynamic response to an isometric exercise test in obese patients: influence of autonomic dysfunction.

OBJECTIVE: To investigate blood pressure (BP) and heart rate (HR) responses to an isometric exercise test in obese non diabetic patients and to correlate the results with vagal function and plasma insulin concentration. SUBJECTS: 63 obese patients, 36 of whom had abnormal cardiac parasympathetic control (PS+), and 35 healthy control subjects. METHODS: Analysis of HR variations during three standardized tests: deep-breathing, lying-to-standing and Valsalva. Isometric contraction (handgrip) for 5 min. RESULTS: In the PS+ obese patients, resting HR and body mass index (BMI) were significantly higher than in the PS- subjects and there was a trend to higher plasma insulin concentrations. Age-matched comparison showed that during the handgrip test, the increase in HR at the first minute was significantly higher in the PS- obese patients than in the controls. The increase in BP was significantly lower in the PS+ obese patients than in age-and-BMI-matched PS- obese patients. CONCLUSION: These data suggest that 1) there is an increase in cardiac vagal tone in PS- obese patients, since the early increase in HR at 1 min of the handgrip test, results from the withdrawal of vagal tone; 2) BP response to an isometric contraction is impaired in PS+ obese patients due to a lower sympathetic activation; 3) high plasma insulin concentrations may also contribute to limiting the BP response; and 4) autonomic disorders may account for alterations in the haemodynamic changes during exercise.     

QT dispersion: comparison between participants with Type 1 and 2 diabetes and association with microalbuminuria in diabetes

BACKGROUND AND AIMS: The interlead variation of QT duration in surface electrocardiogram [ECG; QT dispersion (QTd)] has been shown to predict mortality in both diabetic and general population. Diabetic cardiac autonomic neuropathy (CAN) is a common complication of diabetes, and it is also associated with worse prognosis among the diabetic population. In this study, we investigated the association between QTd duration and CAN, as well as other complications of diabetes in participants with Types 1 and 2 diabetes. METHODS: A total of 184 patients with either Type 1 (n=63) or 2 (n=121) diabetes, as well as 100 control participants, matched for age and sex with the diabetic individuals, were studied. QT and RR intervals were measured on 12 leads of resting ECG tracing. QTd was calculated semiautomatically using a computer program as the difference between the maximum and the minimum QT in any of the 12 leads. CAN was diagnosed when two out of the four classical tests were abnormal. RESULTS: QTd was not significantly different between controls and patients with either Type 1 or 2 diabetes. Age-adjusted QTd intervals were not significantly different between patients with Types 1 and 2 diabetes (P=.86). For both types of diabetes, no significant differences were found in QTd between patients with and without CAN. Multivariable linear regression analysis, after adjustment for a number of confounding factors, demonstrated a positive association between QTd and duration of diabetes (P=.02) in the group of the patients with Type 1 diabetes. In those with Type 2 diabetes, QTd was associated with age (P=.006) and presence of microalbuminuria (P=.001). In addition, no significant association was found with retinopathy or blood pressure levels. CONCLUSIONS: Age-adjusted QTd interval was not different between patients with Types 1 and 2 diabetes. CAN is not associated with QTd interval in both types of diabetes. Furthermore, microalbuminuria was found to be the strongest predictor of QTd in patients with Type 2 diabetes. Because long QTd interval predicts cardiac mortality in participants with diabetes, it is suggested that it may be a useful adjuvant index in the evaluation of cardiovascular risk in participants with Type 2 diabetes and microalbuminuria.