Cardiovascular Autonomic Neuropathy Score Research Articles

Feasibility of combining heart rate variability and electrochemical skin conductance as screening and severity evaluation of cardiovascular autonomic neuropathy in type 2 diabetes.

Aims/IntroductionClinical studies show that either heart rate variability (HRV) or electrochemical skin conductance (ESC) alone can serve as a simple and objective method for screening cardiovascular autonomic neuropathy (CAN). We tested the hypothesis that combining these two quantitative approaches can not only reinforce accuracy in CAN screening but also provide a better estimate of CAN severity in patients with type 2 diabetes (T2DM) who had already had CAN in outpatient clinics.Materials and MethodsEach patient received a complete battery of cardiovascular autonomic reflex tests (CARTs), with ESC measured by SUDOSCAN, time domain of HRV measured by standard deviation of all normal RR intervals (SDNN) and frequency domain of HRV (low frequency [LF], high frequency [HF], and LF/HF ratio), and peripheral blood studies for vascular risk factors. Severity of CAN was measured by CAN score.ResultsThe 90 T2DM patients included 50 males and 40 females. Those with more severe CAN had lower values in feet ESC (P = 0.023) and SDNN (P < 0.0001). Multiple linear regression analysis also showed that feet ESC and SDNN value (P = 0.003 and P < 0.0001) were significantly associated with CAN score. Combining SDNN and feet ESC also can increase the diagnostic accuracy of CAN with respective to sensitivity and specificity by using receiver operating characteristic analysis.ConclusionsCombining the results of SDNN and feet ESC can not only assess, but also quantitatively reflect the progress or improvement of autonomic nerve function (including sympathetic and parasympathetic activity) in patients with T2DM.

Association of Urinary N-Acetyl-β-D-Glucosaminidase with Cardiovascular Autonomic Neuropathy in Type 1 Diabetes Mellitus without Nephropathy.

BackgroundCardiovascular autonomic neuropathy (CAN) is a common microvascular complication of diabetes and related to albuminuria in diabetic nephropathy (DN). Urinary N-acetyl-β-D-glucosaminidase (uNAG) is a renal tubular injury marker which has been reported as an early marker of DN even in patients with normoalbuminuria. This study evaluated whether uNAG is associated with the presence and severity of CAN in patients with type 1 diabetes mellitus (T1DM) without nephropathy.MethodsThis cross-sectional study comprised 247 subjects with T1DM without chronic kidney disease and albuminuria who had results for both uNAG and autonomic function tests within 3 months. The presence of CAN was assessed by age-dependent reference values for four autonomic function tests. Total CAN score was assessed as the sum of the partial points of five cardiovascular reflex tests and was used to estimatethe severity of CAN. The correlations between uNAG and heart rate variability (HRV) parameters were analyzed.ResultsThe association between log-uNAG and presence of CAN was significant in a multivariate logistic regression model (adjusted odds ratio, 2.39; 95% confidence interval [CI], 1.08 to 5.28; <i>P</i>=0.031). Total CAN score was positively associated with loguNAG (β=0.261, <i>P</i>=0.026) in the multivariate linear regression model. Log-uNAG was inversely correlated with frequency-domain and time-domain indices of HRV.ConclusionThis study verified the association of uNAG with presence and severity of CAN and changes in HRV in T1DM patients without nephropathy. The potential role of uNAG should be further assessed for high-risk patients for CAN in T1DM patients without nephropathy.

Time in Range, as a Novel Metric of Glycemic Control, Is Reversely Associated with Presence of Diabetic Cardiovascular Autonomic Neuropathy Independent of HbA1c in Chinese Type 2 Diabetes.

Objective The objective of this study is to investigate the relationship between time in range (TIR), a new metric of continuous glucose monitoring (CGM) and cardiovascular autonomic neuropathy (CAN) in individuals with type 2 diabetes mellitus (T2DM). Methods A total of 349 individuals with T2DM were enrolled in this study. Evaluating by the standard cardiac autonomic reflex tests (CARTs), there were 228 diabetic individuals without cardiovascular autonomic neuropathy (without confirmed CAN) including absent CAN (n = 83 cases) and early CAN (n = 83 cases) and early CAN (n = 83 cases) and early CAN (n = 83 cases) and early CAN (Results The total presence of CAN was 34.67% (definite CAN 31.23% and severe CAN 3.44%). Patients with more severe CAN had lower TIR (P < 0.001). With increasing quartiles of TIR, the presence of CAN by severity declined (P < 0.001). With increasing quartiles of TIR, the presence of CAN by severity declined (P < 0.001). With increasing quartiles of TIR, the presence of CAN by severity declined (P < 0.001). With increasing quartiles of TIR, the presence of CAN by severity declined (Conclusion TIR is associated with the presence of CAN independent of HbA1c and GV metrics in Chinese type 2 diabetes.

The Association between Urinary N-Acetyl-ß-D-Glucosaminidase and Cardiovascular Autonomic Neuropathy in Patients with Diabetes

Background: Cardiovascular autonomic neuropathy (CAN) is a microvascular complication of diabetes, which involves autonomic nerve fibers innervating the heart and vessels, resulting in increased cardiovascular morbidity and mortality. Previous studies reported that diabetic CAN is related to microalbuminuria. However, it is unclear whether CAN is related with urinary N-acetyl-β-D-glucosaminidase (uNAG), which was suggested as an early marker of renal tubular injury in diabetic nephropathy recently. Methods: Cross-sectional data of 1052 patients with diabetes were analyzed who had tests for uNAG and autonomic function test at outpatient clinic. The presence and severity of CAN were assessed by the five autonomic function tests. Results: The association between uNAG and the presence of CAN in patients with type 1 diabetes (T1D) (n=161) was significant in multivariate analysis (OR 1.20, 95% CI 1.03-39; p = 0.018) after correction of variables including age, duration of diabetes, glycemic index and albuminuria, but it was insignificant in patients with type 2 diabetes (T2D) (n=891). Among quartile groups divided by uNAG levels, prevalence of CAN was significantly increased across with higher quartiles of uNAG level only in patients with T1D (p = 0.013). The association between uNAG and the total CAN score, assessed as the severity of CAN, was significant in both patients with T1D (p = 0.033) and T2D (p = 0.006) in multivariate analyses. Conclusion: Elevated uNAG is associated with the prevalence of CAN only in patients with T1D, and it is also related to the severity of CAN in both patients with T1D and T2D. It suggests that elevated uNAG might be a potential marker for the development and progression of CAN in patients with diabetes. Disclosure M. Choi: None. J. Jun: None. G. Kim: None. S. Jin: None. K. Hur: None. M. Lee: None. J. Kim: None.

Association between a MIR499A polymorphism and diabetic neuropathy in type 2 diabetes

AimsDiabetic polyneuropathy (DPN) and cardiovascular autonomic neuropathy (CAN) affect a large percentage of diabetic people and impact severely on quality of life. As it seems that miRNAs and their variations might play a role in these complications, we investigated whether the rs3746444 SNP in the MIR499A gene could be associated with susceptibility to DPN and/or CAN. MethodsWe analyzed 150 participants with type 2 diabetes. DNA was extracted from peripheral blood samples and genotyping was performed by TaqMan genotyping assay. Cardiovascular tests, MNSI-Q and MDNS for neuropathic symptoms and signs, VPT, and thermal thresholds were used for CAN and DPN assessment. We performed a genotype-phenotype correlation analysis. ResultsWe observed that the GG genotype was associated with a higher risk of developing CAN (P=0.002 and OR=16.08, P=0.0005 and OR=35.02, for early and confirmed CAN, respectively) and DPN (P=0.037 and OR=6.56), after correction for BMI, sex, age, HbA1c and disease duration. Moreover, the GG genotype was associated with worse values of MDNS (P=0.017), VPT (P=0.01), thermal thresholds (P=0.01), and CAN score (P<0.001). A logistic multivariate analysis confirmed that MIR499A GG genotype, disease duration and HbA1c contributed to early CAN (R2=0.26), while the same variables and age contributed to DPN (R2=0.21). With a multiple linear regression, we observed that GG genotype (P=0.001) and disease duration (P=0.035) were the main variables contributing to the CAN score (R2=0.35). ConclusionsWe described for the first time that the MIR499A genetic variation could be involved in diabetic neuropathies susceptibility. In particular, patients carrying the rs3746444 GG genotype had a higher risk of CAN development, together with a more severe form of CAN.

Common polymorphisms in MIR146a, MIR128a and MIR27a genes contribute to neuropathy susceptibility in type 2 diabetes

Diabetic polyneuropathy (DPN) and cardiovascular autonomic neuropathy (CAN) are common type 2 diabetes complications with a large inter-individual variability in terms of clinical manifestations and severity. Our aim was to evaluate a possible involvement of genetic polymorphisms in miRNA regions in the susceptibility to DPN and CAN. Nine polymorphisms in miRNA genes were studied in a sample of 132 type 2 diabetes patients (T2D) analysed for DPN and 128 T2D patients analysed for CAN. A genotype-phenotype correlation analysis was performed. The T allele of rs11888095 single nucleotide polymorphism (SNP) in MIR128a was significantly associated with a higher risk (ORadj=4.89, P adj=0.02), whereas the C allele of rs2910164 SNP in MIR146a was associated with a lower risk to develop DPN (ORadj=0.49, P adj=0.09), respectively. A multivariate logistic regression analysis confirmed that both SNPs contribute to DPN (p<0.001 and p=0.01 for MIR128a and MIR146a, respectively). MIR128a SNP significantly contributed also to DPN score (p=0.026). Rs895819 SNP in MIR27a was significantly associated with a higher risk to develop early CAN (P adj=0.023 and ORadj=3.43). The rs2910164 SNP in MIR146a showed a protective effect respect to early CAN (P adj=0.052, ORadj=0.32) and to confirmed CAN (P adj=0.041, ORadj=0.13). The same SNP resulted significantly associated with a lower CAN score and a higher E/I (p=0.002 and p=0.003, respectively). In conclusion, we described associations of MIR128a and MIR146a SNPs with DPN susceptibility and of MIR146a and MIR27a SNPs with CAN susceptibility. This is the first study showing that genetic variability in miRNA genes could be involved in diabetic neuropathies susceptibility.

Cardiovascular Autonomic Dysfunction Predicts Severe Hypoglycemia in Patients With Type 2 Diabetes: A 10-Year Follow-up Study

OBJECTIVE The aim of this study was to investigate the development of severe hypoglycemia (SH) in the presence of cardiovascular autonomic neuropathy (CAN) in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS From January 2001 to December 2002, a total of 894 patients with type 2 diabetes were enrolled. A cardiovascular autonomic function test (AFT) was performed using the following heart rate variability parameters: expiration-to-inspiration ratio, response to Valsalva maneuver, and standing. From the results for each of the three tests (0 for normal, 1 for abnormal), a total AFT score of 1 was defined as early CAN, and an AFT score of ≥2 was defined as definite CAN. RESULTS The median follow-up time was 9.5 years. The mean age was 54.5 ± 10.1 years, and the mean duration of diabetes was 8.9 ± 6.3 years. One hundred ninety-six patients (31.4%) showed an abnormal cardiovascular AFT score at baseline. Sixty-two patients (9.9%) experienced 77 episodes of SH (1.33 per 100 patient-years). The number of SH events increased as the CAN score increased (23 patients [5.4%] with normal score; 17 patients [17.2%] with early CAN; and 22 patients [22.7%] with definite CAN; P for trends < 0.001). Cox proportional hazards regression analysis revealed that SH was associated with definite CAN (normal vs. definite CAN: hazard ratio 2.43 [95% CI 1.21-4.84]; P = 0.012). CONCLUSIONS Definite CAN was an independent prognostic factor for the development of SH in patients with type 2 diabetes.

Clinical assessment of the autonomic nervous system in diabetes mellitus and its correlation with glycemic control

Clinical assessment of the autonomic nervous system in Diabetes mellitus (DM) and its correlation with glycemic control. Cross sectional study of 50 adult diabetes patients. Fifty patients with DM who were on regular treatment with either insulin and/or oral hypoglycemic agents were studied. Cardiovascular autonomic neuropathy (CAN) score was calculated using the clinical test variables. Of the 50 patients 30 had no CAN, 10 had early CAN and 10 had severe CAN. The mean of CAN score increased with duration of diabetes. The mean HbA(1C) was 7.73. The mean CAN score was higher in patients who had complication of diabetes as compared to patients without complications. The heart rate variability with respiration was found to be 15.84 ± 7.02/min. The mean valsalva ratio was 1.31 ± 0.23. The mean drop in BP on standing was 7.30 ± 7.24 mmHg. The mean 30:15 ratio was 1.06 ± 0.04. The mean rise in diastolic BP on sustained hand grip was 16.04 ± 4.11 mmHg. The prevalence of autonomic neuropathy in DM as assessed by CAN score was 40%. The CAN score did not correlate with the duration of DM. The HbA(1C) had a significant correlation with the severity of autonomic neuropathy. Occurrence of CAN correlated with the presence of peripheral neuropathy but not with the presence of retinopathy or nephropathy. All individual tests in the battery of CAN score were significantly associated with the presence of autonomic neuropathy, except 30:15 ratio.

Relationship between cardiovascular autonomic neuropathy and coronary artery calcification in patients with type 2 diabetes

To test the hypothesis that cardiovascular autonomic neuropathy (CAN) in Type 2 diabetes is a risk factor of coronary artery calcification (CAC), in this cross-sectional study, 118 patients (60 males, 58 females) with type 2 diabetes mellitus were randomly selected from the diabetes clinic of Kyungpook National University Hospital, Daegu, Korea, between January, 2008 and September, 2008. The subjects, whose mean age was 56.9+/-1.1 years, were tested for CAN by Ewing's method which employs five non-invasive tests of autonomic function. The coronary calcium score (CCS) was determined by Multi Detector-row Computed Tomography (MDCT). Statistical analysis was performed by using SPSS 13.0 (SPSS, Inc., Chicago,-Illinois). CAN was found in 31/118 (26.3%) patients. Compared to the patients without CAN, the patients with CAN were significantly older and had significantly higher triglyceride levels, blood pressure, pulse pressure, fasting c-peptide levels, CAN scores, and log-transformed coronary calcium scores [ln(CCS+1)]. The CAN scores correlated positively with ln(CCS+1) values (r = 0.214; P = 0.028). Multiple regression analysis using ln(CCS+1) as a dependent variable showed that CAN score (beta coefficient 0.623, 95% CI 0.059 approximately 1.188, P = 0.031) associated independently with ln(CCS+1). In conclusion, CAN was associated independently with CAC, which suggests that CAN is a risk factor of coronary atherosclerosis in patients with type 2 diabetes. This may help to explain the excess cardiovascular mortality seen in diabetic patients with CAN.

Cardiovascular autonomic dysfunction predicts acute ischaemic stroke in patients with Type 2 diabetes mellitus: a 7‐year follow‐up study

We investigated whether cardiovascular autonomic neuropathy (CAN) is associated with acute ischaemic stroke in patients with Type 2 diabetes. From 1999 to 2000, cardiovascular autonomic function tests were conducted in patients with Type 2 diabetes (n = 1458). Patients were followed up between 2006 and 2007. Standard tests for CAN measured heart rate variability parameters [expiration-to-inspiration (E/I) ratio, responses to the Valsalva manoeuvre and standing]. Using the American Diabetes Association criteria, the CAN scores were determined from the results of each test as follows: 0 = normal, 1 = abnormal (total maximum score 3). We assessed the development of acute ischaemic stroke events. The prevalence of CAN at baseline was 55.7% (E/I 17.1%, Valsalva 39.4%, posture 27.3%) (n = 1126). During follow-up, 131 patients (11.6%) developed acute ischaemic stroke. The vascular events were more frequent in older patients (P < 0.001) and in those with diabetes of longer duration (P = 0.022), hypertension (P < 0.001) or diabetic retinopathy (P = 0.03) than in patients without vascular events. Patients with ischaemic stroke had higher creatinine levels (P = 0.045) and higher urine albumin excretion (P = 0.025) than those of patients without stroke. Cox proportional hazard regression analysis revealed that the CAN score was associated with the development of acute ischaemic stroke (total score 0 vs. 3, adjusted hazard ratio 2.7, 95% CI 1.3-5.5, P = 0.006). Cardiovascular autonomic dysfunction was significantly associated with the development of ischaemic stroke in patients with Type 2 diabetes.

Optimal parameters of short-term heart rate spectrogram for routine evaluation of diabetic cardiovascular autonomic neuropathy

Our aim was to select those parameters of heart rate variability (HRV) within its short-term power spectral analysis (PSA), which have a capability similar to that of the standard Ewing battery of cardiovascular function tests in determining different degrees of cardiovascular autonomic neuropathy (CAN) in diabetes and to compare the usefulness of both methods for diagnostic purposes in the everyday routine. Commonly used standard battery of cardiovascular autonomic function tests evaluated as total Ewing score as well as short-term PSA of HRV were used in 119 diabetic patients (age: 52.7±9.8, diabetes duration: 22.2±12.7 years). From this cohort, patients were selected according to the total Ewing score by matching for age, gender, BMI and diabetes type for 3 groups, each of 17 patients, with no CAN (total Ewing score 0–0.5), with early involvement (score 1.0–2.5) and with definite or severe CAN (score 3.0–5.0). Short-term PSA of HRV performed in three positions (supine1–standing–supine2) included frequency-domain and time-domain parameters of HRV. Cumulative spectral power of total frequency band (0.06–0.50 Hz) and spectral power of low-frequency band (0.06–0.15 Hz) during both supine positions proved to be the most selective and discriminating among all patient groups in inter-group comparison and in analysis of discriminance. The correlation between the total Ewing score and the cumulative spectral power of total frequency band was r=−0.87 ( P<0.001). About 83.2% of cases classified by short-term PSA of HRV using the variables selected by analysis of discriminance was congruent with the classification by the total Ewing score alone. Time expenditure for the performance of each examination was 31±10 min for Ewing test battery vs. 14±2 min for short-term PSA of HRV ( P<0.001). In summary, the latter method showed similar diagnostic value concerning the CAN as the classical Ewing standard battery of cardiovascular function tests, although its application proved to be shorter, less stressful and more independent from patient cooperation. Cumulative spectral power of total frequency band (LFHF cumpower) can be used for overall description of the degree of cardiac denervation in diabetes while using short-term PSA of HRV.

Evaluation of Autonomic Neuropathy in Patients with Sleep Apnea Syndrome

Background: Sleep apnea syndrome, which occurs in 1~4 % of the adult population, frequently has different cardiovascular complications such as hypertension, ischemic heart disease, cardiac arrythmia as well as sleep-wake disorder such as excessive daytime hypersomnolence or insomnia. Mortality and vascular morbidity are reported to be significantly higher in sleep apnea syndrome patients than in normal population. According to the recent studies, autonomic dysfunction as well as hypoxemia, hypercapneic acidosis, and increased respiratory effort, may playa role in the high prevalence of cardiovascular complications in patients with sleep apnea syndrome. However the cause and mechanism of autonomic neuropathy in patients with sleep apnea syndrome are not well understood. We studied the existence of autonomic neuropathy in patients with sleep apnea syndrome and factors which influence the pathogenesis of autonomic neuropathy. Method: We used the cardiovascular autonomic neuropathy(CAN) test as a method for evaluation of autonomic neuropathy. The subjects of this study were 20 patients who diagnosed sleep apnea syndrome by polysomnography and 15 persons who were normal by polysomnography. Results: Body mass index and resting systolic blood pressure were higher in sleep apnea group than control group. Apnea index(Al), respiratory disturbance index(RDI) and snoring time percentage were significantly higher in sleep apnea group compared with control group. But there were no significant differences in saturation of oxygen and sleep efficiency in two groups. In the cardiac autonomic neuropathy test, the valsalva ratio was significantly low in sleep apnea group compared with control group but other tests had no differences between two groups. The CAN scores and corrected QT(QTc) interval were calculated significantly higher in sleep apnea group, but there were no significant correlations between CAN scores and QTc interval. There were no significant data of polysomnography to correlate to the CAN score. It meant that the autonomic neuropathy in patients with sleep apnea was affected by other multiple factors. Conclusion: The cardiovascular autonomic neuropathy test was a useful method for the evaluation of autonomic neuropathy in patients with sleep apnea syndrome and abnormalities of cardiovascular autonomic neuropathy were observed in patients with sleep apnea syndrome. However, we failed to define the factors that influence the pathogenesis of autonomic neuropathy of sleep apnea syndrome. This study warrants futher investigations in order to define the pathogenesis of autonomic neuropathy in patients with sleep apnea syndrome.

13C]0ctanoic acid breath test for non-invasive assessment of gastric emptying in diabetic patients: Validation and relationship to gastric symptoms and cardiovascular autonomic function

Since there is a need for a widely applicable non-invasive test to assess gastric emptying in diabetic patients, we evaluated the sensitivity, specificity, and reproducibility of the [13C]octanoic acid breath test as compared with scintigraphy. Moreover, we examined the relationship between the breath test indices and gastric symptoms, cardiovascular autonomic function, and metabolic parameters. Forty healthy control subjects and 34 diabetic patients were studied. Three indices of gastric emptying, assessed by the breath test, were computed: half-emptying time (t1/2breath), gastric emptying coefficient (GEC), and lag phase. Furthermore, the half-emptying time, measured by scintigraphy (t1/2scint), was calculated and gastric symptoms and cardiovascular autonomic neuropathy (CAN) were scored. The coefficients of variation of day-to-day reproducibility in 10 healthy subjects were 29.6% for t1/2breath, 7.4% for GEC, and 46.5% for lag phase. An abnormal delay for t1/2scint (> 100 min) or t1/2breath (> 200 min) was noted in 12 patients. Based on the results for t1/2scint, the sensitivity of t1/2breath and GEC was 75% and the specificity was 86%. Both t1/2breath (rs = 0.523; p < 0.05) and GEC (r2 = -0.594; p < 0.05) were significantly associated with the gastric symptom score. A significant relationship to the CAN score was demonstrated for t1/2breath (rs = 0.448; p < 0.05), GEC (rs = -0.467; p < 0.05), and t1/2scint (rs = 0.602; p < 0.05). There were no significant associations of the breath test indices with the blood glucose levels during the test, HbA1c, age, and duration of diabetes. In patients with abnormal t1/2scint (n = 12) not only was t1/2breath significantly prolonged and GEC reduced, but also the scores of CAN and gastric symptoms were significantly increased as compared with those who had a normal t1/2scint (n = 22). We conclude that the [13C]octanoic acid breath test represents a suitable measure of delayed gastric emptying in diabetic patients which is associated with the severity of gastric symptoms and CAN but not affected by the blood glucose level.