Cardiovascular autonomic reflex tests using a handheld device in the diagnosis of cardiovascular autonomic neuropathy in patients with schizophrenia.

Study objective: This study investigated whether schizophrenia and the duration of schizophrenia were associated with cardiovascular autonomic neuropathy (CAN) by using heart rate variability (HRV) as a marker. Design: Cross-sectional study. Setting: The examinations were conducted at the Centre for Psychosis Research and at the Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark. Participants: 240 patients with first-episode and chronic schizophrenia and 180 controls. Interventions: CAN was assessed by the cardiovascular reflex tests (CARTs): HR, RS ratio, E:I ratio, and VM using a handheld device. Main outcome measures: One abnormal CART was interpreted as borderline CAN and ≥2 abnormal CARTs established definitive CAN. Borderline CAN and definitive CAN together was categorized as overall CAN. Analyses were adjusted for age, sex, smoking, overweight, and hypercholesterolemia. Results: A total of 240 patients with schizophrenia (median age 42.5 [28.8, 52.3], 42.9 % women) and 180 controls (median age 45.8 [24.0, 60.1], 47.8 % women) were included, with 50.8 % of patients with schizophrenia having overall CAN compared to 27.2 % among controls. Dividing patients into patients with first-episode and chronic schizophrenia, 32.9 % vs 10 % (p < 0.001) and 59.1 % vs 41 % (p < 0.001) had overall CAN compared with controls, respectively. Schizophrenia was significantly associated with overall CAN (OR, 2.80; 95%CI, 1.75-4.50), with an OR of 2.31 (95%CI, 1.14-4.68) for first-episode schizophrenia and an OR of 2.97 (95%CI, 1.81-4.87) for chronic schizophrenia. Conclusion: It was demonstrated that a diagnosis of schizophrenia was associated with CAN. Patients with chronic schizophrenia had a significantly higher prevalence of CAN compared to patients with first-episode schizophrenia, suggesting an association between the duration of schizophrenia and CAN.

Normative data on cardiovascular autonomic function in Greenlandic Inuit.

INTRODUCTION: Diabetes is increasing among Greenlandic Inuit; however, the prevalence of cardiovascular autonomic neuropathy (CAN) is yet unknown. The assessment of CAN requires an ability to differentiate between normal and abnormal. The aim was to establish normative reference data of cardiovascular autonomic function in Greenlandic Inuit. RESEARCH DESIGN AND METHODS: In this cross-sectional study, cardiovascular autonomic function was evaluated in participants without diabetes during the Greenlandic Population Study 2018 and in the town Qasigiannguit in 2020. Assessment included cardiovascular autonomic reflex tests (CARTs) and power spectral analysis of heart rate variability (HRV). Normative reference limits were estimated by applying piecewise linear quantile regression models at the fifth percentile. Models were adjusted for age and sex. RESULTS: Based on examinations of 472 participants (61.7% females), normative reference data was established for all outcomes. Mean age was 54 years (SD 13.1). Higher age was inversely associated with all outcomes of CARTs and HRV. A linear fall in cardiovascular autonomic function tended to level off beyond age of 60 or 70 years for supine-to-upright position ratio and low frequency power. However, the number of observations in subjects older than 60 or 70 years was limited, which may have caused a flattening of the curve around that age. No other associations were found. CONCLUSIONS: The general level of the CARTs and HRV for all age groups is notably lower than in previous studies from other nationalities. We speculate that sociodemographic and cultural aspects of the Greenlandic Inuit population including body mass index, smoking, physical activity and alcohol consumption may have affected the cardiovascular autonomic function.

Continuous glucose monitoring adds information beyond HbA1c in well-controlled diabetes patients with early cardiovascular autonomic neuropathy.

AIMS: Hyperglycemia as evaluated by HbA1c is a risk factor for the development of cardiovascular autonomic neuropathy (CAN). The aim of the present study was to investigate whether continuous glucose monitoring (CGM) may add information beyond HbA1c in patients with type 2 diabetes and CAN. METHODS: 81 patients with type 2 diabetes (43 men, mean age 58±11year, HbA1c 6.6±0.5%). Patients were tested for CAN using cardiovascular reflex tests (response to standing, deep breathing and Valsalva maneuver) and underwent CGM for three days. CAN was defined as early (one test abnormal), or manifest (two or three tests abnormal). RESULTS: Twenty patients had early CAN and two patients had manifest CAN. Blood pressure, HbA1c, cholesterol levels and smoking habits were comparable in patients with vs. without CAN. Post-breakfast glycemic peak was significantly higher in patients with CAN (peak 207 vs 176mg/dL, P=0.009). Furthermore, the nocturnal glucose drop and dawn glucose was significantly higher in patients with CAN compared with patients without CAN (mean 134 vs. 118mg/dL, P=0.017 and mean 143 vs. 130mg/dL, P=0.045, respectively). Removing the two patients with manifest CAN from the statistical analysis didn't change the results. CONCLUSIONS: These findings emphasize the importance of monitoring glucose patterns over 24-h and not only rely on HbA1c as therapeutic target in patients with type 2 diabetes and CAN.

Short-term acipimox treatment is associated with decreased cardiac parasympathetic modulation.

AIMS: The nicotinic acid analogue acipimox is an antilipolytic agent, which acutely inhibits lipolysis and suppresses systemic levels of free fatty acids (FFA) and improves insulin sensitivity in obese patients. These effects of acipimox are transient due to a counter-regulatory increase in growth hormone levels that reverse the antilipolytic effect of acipimox. Hypopituitary patients constitute a viable model to study the growth hormone-independent effects of acipimox and the impact of isolated changes in FFA concentrations and insulin sensitivity on parasympathetic nervous activity. The aim of the present study was to investigate if pharmacological antilipolysis with acipimox acutely affects autonomic tone. METHODS: We studied heart rate variability as a measure of autonomic tone in eight hypopituitary men with and without acipimox treatment. The standard deviation of normal-to-normal intervals, root mean square of successive differences and high frequency were measured as heart rate variability parameters. The patients were studied in the basal and insulin-stimulated state with clamped plasma glucose on two occasions in a randomized, double-blind and placebo-controlled crossover study. RESULTS: Plasma glucose (4.7 vs. 4.9 mmol l-1 , P = 0.02) and serum FFA (0.05 vs. 0.41 mmol l-1 , P < 0.001) were significantly decreased during acipimox treatment. Acipimox had an inhibitory effect on standard deviation of normal-to-normal intervals (41.3 vs. 45.3 ms, P = 0.01), root mean square of successive differences (23.2 vs. 11 ms, P = 0.03) and high frequency (3.79 vs 3.60 ln (ms2 ), P = 0.02) and these effects were reversed during clamping. CONCLUSIONS: Short-term inhibition of lipolysis by acipimox treatment lowered circulating FFA levels, improved insulin sensitivity, and was accompanied by reduced parasympathetic tone. The effect of acipimox on the parasympathetic modulation was reversed by hyperinsulinaemia.

Vitamin B12 deficiency is associated with cardiovascular autonomic neuropathy in patients with type 2 diabetes.

AIMS: Vitamin B12 deficiency could be associated with cardiovascular autonomic neuropathy (CAN) in diabetes patients. We aim to investigate the association between serum levels of vitamin B12 and CAN in type 2 diabetes patients. METHODS: 469 ambulatory type 2 diabetes patients (mean diabetes duration 10.0years (IQR 5.0;17.0), mean age 59.0years (SD 11.6), 63% men, mean B12 289.0pmol/l (IQR 217;390)) were screened for CAN using three cardiovascular reflex tests, five minute resting heart rate (5min RHR) and heart rate variability indices. RESULTS: Serum levels of vitamin B12 were significantly lower in patients treated with metformin and/or proton pump inhibitors (PPIs) compared with patients not treated (p<0.001). A 25pmol/l higher level of vitamin B12 was associated with an odds ratio of the CAN diagnosis of 0.94 (95% CI 0.88; 1.00, p=0.034), an increase in E/I-ratio of 0.21% (95% CI 0.01; 0.43, p=0.038), and a decrease in 5min RHR of 0.25 beats per minute (95% CI -0.47; -0.03, p=0.025). CONCLUSION: Vitamin B12 may be inversely associated with CAN in patients with type 2 diabetes. Confirmatory studies investigating a causal role of vitamin B12 for the development of diabetic CAN are warranted.

Obstructive sleep apnoea is frequent in patients with type 1 diabetes.

AIM: Obstructive Sleep Apnoea (OSA) is frequent in patients with type 2 diabetes. The aim of this study is to evaluate prevalence of OSA in patients with type 1 diabetes. METHODS: In a cross-sectional design, all patients with type 1 diabetes attending the outpatient clinic were offered screening for OSA for one night with the ApneaLink+ home-monitoring device. OSA was classified by the Apnoea-Hypopnea index (AHI; apnoeas/hypopneas per hour sleep). Symptoms of OSA were scored using the Epworth Sleepiness Score. Presence of autonomic neuropathy was evaluated by the Vagus® device. RESULTS: A total of 200 of 518 eligible patients with type 1 diabetes (39%) participated (68% men; age 52±15years (mean±SD), diabetes duration 24±14years and BMI 25.3±3.3kg/m2). OSA was diagnosed in 92 patients (46% (95% CI: 40-53)). Five patients had known OSA, and OSA was newly diagnosed in 87 patients, predominantly mild OSA (60 patients (69%)). OSA was present in 32% of the patients with normal BMI, in 60% of overweight patients, and in 61% of obese patients. Patients with type 1 diabetes and OSA were largely asymptomatic and did not report more sleepiness than patients without OSA. At multivariate analysis, age, BMI and presence of nephropathy were positively associated with risk of OSA. CONCLUSIONS: The prevalence of asymptomatic OSA is high in a cohort of patients with type 1 diabetes. Older age, overweight, and presence of nephropathy are associated with OSA.

Reduced Subendocardial Viability Ratio Is Associated With Unfavorable Cardiovascular Risk Profile in Women With Short Duration of Type 2 Diabetes.

BACKGROUND: The pathophysiological perturbations underlying the unfavorable cardiovascular prognosis in women with type 2 diabetes (T2DM) remain elusive. Low subendocardial viability ratio (SEVR), an index of myocardial oxygen supply and demand, has been associated with intermediate cardiovascular risk markers and cardiovascular mortality in various populations. However, whether SEVR is associated with sex and cardiovascular risk markers in patients with T2DM remains to be clarified. METHODS: We examined 86 T2DM patients (mean age 59±10 years, 47% women, median diabetes duration 1.9 (range 0.2-5.0) years) and 86 sex- and age-matched control subjects in a cross-sectional study. SEVR was noninvasively assessed by tonometry and markers of cardiovascular risk by carotid-femoral pulse wave velocity (PWV), homeostasis model assessment of insulin resistance (HOMA2-IR), C-reactive protein, urinary albumin/creatinine ratio, and heart rate variability. RESULTS: Women with diabetes had significantly lower SEVR compared to both men with diabetes (161% ± 26% vs. 178% ± 32%, P < 0.01), women without diabetes (185% ± 24%, P < 0.001), and men without diabetes (188% ± 28%, P < 0.001). The differences remained significant after adjustment for age, systolic blood pressure, heart rate, diabetes, and smoking. SEVR was associated with PWV, HOMA2-IR, C-reactive protein, and reduced heart rate variability in patients and control subjects, but the associations became nonsignificant after adjustment for heart rate. CONCLUSIONS: SEVR is reduced in women with short duration of T2DM and associated with cardiovascular risk markers. The latter association seems to be at least partly mediated via heart rate. We hypothesize that reduced SEVR may contribute to the unfavorable cardiovascular prognosis in women with diabetes.

The degree of autonomic modulation is associated with the severity of microvascular complications in patients with type 1 diabetes.

OBJECTIVE: The objective of this study was to elucidate whether the degree of autonomic modulation is associated with the degree of microvascular complications in patients with type 1 diabetes. METHODS: A total of 290 type 1 individuals with diabetes were randomly recruited during normal visits to outpatient clinics at 4 Danish hospitals. The degree of autonomic modulations was quantified by measuring heart rate variability (HRV) during passive spectral analysis and active tests (valsalva ratio [VT], response to standing [RT], and deep breathing [E:I]). To describe possible associations between severity of microvascular complications and measures of autonomic modulation, multivariate analysis was performed. RESULTS: After adjusting for diabetes duration, sex, age, pulse pressure, heart rate, and smoking, autonomic dysfunction remained significantly correlated with severity of retinopathy, nephropathy, and peripheral neuropathy in individuals with type 1 diabetes patients. CONCLUSIONS: Autonomic dysfunction is present in early stages of retinopathy, nephropathy, and peripheral neuropathy in patients with type 1 diabetes.

Cardiovascular autonomic neuropathy is associated with macrovascular risk factors in type 2 diabetes: new technology used for routine large-scale screening adds new insight.

The objective was to identify the presence of cardiovascular autonomic neuropathy (CAN) in a cohort of individuals with diabetes in outpatient clinics from 4 different parts of Denmark and to explore the difference between type 1 and type 2 diabetes in relation to CAN. The DAN-Study is a Danish multicenter study focusing on diabetic autonomic neuropathy. Over a period of 12 months, 382 type 1 and 271 type 2 individuals with diabetes were tested for CAN. Patients were randomly recruited and tested during normal visits to outpatient clinics at 4 Danish hospitals. The presence of CAN was quantified by performing 3 cardiovascular reflex tests (response to standing, deep breathing, and valsalva). To describe possible associations, multivariate analysis with CAN as the dependent variable was performed. The prevalence of CAN was higher among patients with type 2 diabetes (35%) compared to patients with type 1 diabetes (25%). Multivariate analysis revealed significant associations between CAN and different risk markers in the 2 populations. In type 1 diabetes patients CAN was associated with microalbuminuria (P < .001), macroalbuminuria (P = .011), simplex retinopathy (P < .001), proliferative retinopathy (P < .001), and peripheral neuropathy (P = .041). Among type 2 diabetes patients CAN was independently associated with high pulse pressure (P < .01), BMI (P = .006), and smoking (P = .025). In this cross-sectional observational study CAN was independently associated with microvascular complication in type 1, whereas in type 2 CAN was associated with macrovascular risk factors.

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.

Paper electrocardiograph strips may contain overlooked clinical information in screen-detected type 2 diabetes patients.

BACKGROUND: A large number of nondigitized electrocardiograph (ECG) strips are routinely collected in larger cohort studies such as the ADDITION study (Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen-Detected Diabetes in Primary Care). These ECG strips are routinely read manually but may contain overlooked information revealing cardiac autonomic dysfunction. The aim of this study was to investigate whether clinical information may be lost using manual R wave to R wave (RR) interval measurements in the calculation of heart rate variability (HRV) in patients with type 2 diabetes mellitus (T2DM). METHOD: From the Danish part of the ADDITION study, we randomly selected 120 T2DM patients at baseline of the ADDITION study. Analysis of the ECG strips was performed using two different methods: (1) by experienced technicians using rulers and (2) by experienced technicians using a high-resolution computer-assisted method. Calculation of heart rate and time domain HRV [standard deviation of normal-to-normal RR intervals (SDNN) and root mean square of successive differences (RMSSD)] were performed with the same software. RESULTS: When comparing results from the two methods, the following values of Pearson's r are obtained: 0.98 for heart rate, 0.76 for SDNN, and 0.68 for RMSSD. These results indicate that heart rate and HRV measurements by the computer-assisted and manually based methods correlate. However, Bland-Altman plots and Pitman's test of difference in variance revealed poor agreements (p < .01) for both HRV measurements (SDNN and RMSSD); only heart rate showed substantiated agreement (p = .54) between the two methods. Low HRV was statistically significantly associated to high heart rate, systolic blood pressure, and diastolic blood pressure in these screen-detected T2DM patients. CONCLUSIONS: Paper ECG strips may contain overlooked clinical information on the status of autonomic function in patients with T2DM. In our study, manual measurements of RR intervals were inferior to the computer-assisted method. Based on this study, we recommend cautiousness in the clinical use and interpretation of HRV based on manual or low resolution measurements of RR intervals from ECG strips. High resolution measurements of RR intervals reveal significant associations between low HRV and high heart rate, systolic blood pressure, and diastolic blood pressure among patients with screen-detected T2DM. It is feasible to use a computer-assisted method to determine RR intervals in patients with T2DM.