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Background Previous studies have shown that increasing body mass index (BMI) was associated with decreased hypoglycemia in type 2 diabetes, but it remains uncertain whether this finding could be applied to patients with and without cardiac autonomic neuropathy (CAN). Methods The study included 7789 participants with type 2 diabetes from action to control cardiovascular risk in diabetes (ACCORD) trail. CAN was defined as SDNN < 8.2 ms and RMSSD < 8.0 ms. Obesity was defined as BMI ≥ 30 kg/m 2 . Outcomes were identified as severe hypoglycemia requiring any assistance (HAA) or requiring medical assistance (HMA). We assessed the association between obesity and severe hypoglycemia in type 2 diabetes with or without CAN using COX regression models adjusted for baseline characteristics. Results Over a median follow-up of 4.7 years, a total of 893 participants developed HAA and 584 participants developed HMA. Compared with non-obesity, obesity was associated with lower risk of severe hypoglycemia (HAA: hazard ratio [HR] 0.51, 95% confidence interval [CI] 0.38–0.68, P  < 0.001; HMA: HR 0.57, 95% CI 0.40–0.82, P  = 0.002) in CAN present group, but not in CAN absent group (HAA: HR 0.98, 95% CI 0.83–1.16, P  = 0.830; HMA: HR 0.97, 95% CI 0.79–1.19, P  = 0.754). Similarly, increasing BMI was associated with reduced severe hypoglycemic events in participants with CAN, but not in participants without CAN. Conclusions CAN modifies the association between obesity and hypoglycemia in type 2 diabetes. Type 2 diabetic individuals with CAN who are under weight control should pay attention to hypoglycemic events. Trial registry http://www.clinicaltrials.gov . Unique identifier: NCT00000620.

Aims/hypothesis There is limited evidence on how multifactorial treatment improves outcomes of diabetes when initiated in the lead time between detection by screening and diagnosis in routine clinical practice. Cardiac autonomic neuropathy (CAN) in people with diabetes indicates widespread damage to the autonomic nervous system, which may severely affect health and quality of life. We examined effects of early detection and subsequent intensive treatment of type 2 diabetes in primary care on the prevalence of CAN at the 6-year follow-up examination in a pragmatic cluster-randomised parallel group trial. Methods One hundred and ninety general practices were randomised to deliver either intensive multifactorial treatment (IT) or routine care (RC) as recommended by national guidelines to patients with type 2 diabetes, identified through a stepwise screening programme in the primary care setting. 1533 people (IT, n  = 910; RC, n  = 623) were identified and included. At the 6-year follow-up examination, measures of CAN were applied in an unselected subsample of 777 participants using heart rate variability analysis and standard tests of CAN. Results At the 6-year follow-up examination, the prevalence of early CAN was 15.1% in the RC group and 15.5% in the IT group, while manifest CAN was present in 7.1% and 7.3%, respectively. We found no statistically significant effect of intensive treatment on the prevalence of CAN compared with routine care. Conclusions/interpretation In the Danish arm of the ADDITION Study, signs of CAN were highly prevalent 6 years after a screening-based diagnosis of type 2 diabetes. Intensive multifactorial treatment did not significantly affect the prevalence of CAN compared with routine care. However, at follow-up the level of medication was also high in the RC group.

To assess the role of oxidative stress in mediating adverse outcomes in metabolic syndrome (MetS) and resultant cardiovascular autonomic neuropathy (CAN), and to evaluate the effects of lifestyle interventions on measures of oxidative stress and CAN in subjects with MetS. Pilot study in 25 non-diabetic subjects with MetS (age 49±10years, 76% females) participating in a 24-week lifestyle intervention (supervised aerobic exercise/Mediterranean diet), and 25 age-matched healthy controls. CAN was assessed by cardiovascular reflex tests, heart rate variability (HRV) and PET imaging with sympathetic analog [11C] meta-hydroxyephedrine ([11C]HED). Specific oxidative fingerprints were measured by liquid-chromatography/mass-spectrometry (LC/MS). At baseline, MetS subjects had significantly higher oxidative stress markers [3-nitrotyrosine (234±158 vs. 54±47μmol/mol tyrosine), ortho-tyrosine (59±38 vs. 18±10μmol/molphenylalanine, all P<0.0001], and impaired HRV at rest and during deep breathing (P=0.039 and P=0.021 respectively) compared to controls. Twenty-four-week lifestyle intervention significantly reduced all oxidative stress markers (all P<0.01) but did not change any of the CAN measures. Subjects with MetS present with signs of CAN and increased oxidative stress in the absence of diabetes. The 24-week lifestyle intervention was effective in ameliorating oxidative stress, but did not improve measures of CAN. Larger clinical trials with longer duration are required to confirm these findings.

Purpose Bevacizumab is a humanized monoclonal antibody targeting vascular endothelial growth factor. The aim of this study was to gain a better understanding of the overall incidence and risk of significantly raised blood pressure in cancer patients who receive bevacizumab therapy. Methods We performed a meta-analysis of relevant randomized controlled trials (RCTs) identified in PubMed, Cochrane library, Embase, and American Society of Clinical Oncology conferences. Overall incidence rates, relative risks (RRs), and 95% confidence intervals (CIs) were calculated using a random-effects model. The primary clinical endpoint was significantly raised blood pressure (grade 3 or above). Results A total of 12,949 cancer patients with a variety of solid tumors from 19 RCTs were included in our meta-analysis. The overall incidence of significantly raised blood pressure was 8% (95% CI 6-10%) among patients receiving bevacizumab. Bevacizumab treatment was associated with a statistically significant increased risk of developing significantly raised blood pressure (RR 5.38, 95% CI 3.63-7.97). The RRs of significantly raised blood pressure in patients receiving bevacizumab at 5 and 2.5 mg/kg per week were 7.17 (95% CI, 3.91-13.13) and 4.11 (95% CI 2.49-6.78), respectively. Among cancer patients, those with renal cell carcinoma (RR 13.77, 95% CI 2.28-83.15) and breast cancer (RR 18.83, 95% CI 1.23-292.29) who received bevacizumab at 5 mg/kg per week had a higher risk of developing significantly raised blood pressure. Conclusions Among the patients included in the trials analyzed in this meta-analysis, the addition of bevacizumab to cancer therapy treatments significantly increased the risk of significantly raised blood pressure. The risk may be dose-dependent and vary with tumor type.

COVID-19 and its neurological consequences particularly burden marginalized communities, and so can only be effectively treated by advancing health equity.

Sudden death is an important but widely under-recognised consequence of stroke. Acute stroke can disturb central autonomic control, resulting in myocardial injury, electrocardiographic abnormalities, cardiac arrhythmias, and ultimately sudden death. Experimental and clinical evidence suggests that autonomic imbalance is more frequent after infarcts involving the insular cortex, a crucial region for the control of sympathetic and parasympathetic autonomic functions. Cardiovascular comorbidities increase the risk of cardiac morbidity and mortality after stroke. Thus, many sudden deaths and serious non-fatal cardiac events after stroke are probably due to an interaction between cardiovascular and neurological causes. The exact mechanisms leading to sudden death remain incompletely understood. Further research is needed to investigate the autonomic consequences of acute stroke and to identify patients at high risk of sudden death.

Cardiac autonomic dysfunction in diabetic children. M M Massin , B Derkenne , M Tallsund , D Rocour-Brumioul , C Ernould , M C Lebrethon and J P Bourguignon Division of Pediatric Cardiology, University of Liège, Belgium. martial.massin@chrcitadelle.be Abstract OBJECTIVE: Adults with type 1 diabetes may have abnormal alterations in heart rate variability (HRV) due to cardiac autonomic neuropathy. This prospective study was performed to determine whether HRV can be used to detect subclinical autonomic neuropathy in diabetic children. RESEARCH DESIGN AND METHODS: We examined five time domain and three frequency domain HRV indices determined from 24-h Holter recordings in 73 diabetic children and adolescents aged 3-18 years (mean 12.1 years) with a mean duration of diabetes of 55 months. The measures were compared with normal ranges. Z scores were established for each parameter and were compared with classic risk factors of other diabetic complications. RESULTS: Most HRV indices were significantly depressed in children aged > or = 11 years, and the levels of HRV abnormalities were significantly correlated with long-term metabolic control (mean GHb for 4 years) in that age-group. In younger patients, HRV indices were within the normal range and were not correlated with the level of metabolic control. Illness duration and microalbuminuria but not short-term metabolic control (most recent GHb) were also independently predictive of HRV abnormalities. CONCLUSIONS: These results suggest that early puberty is a critical period for the development of diabetic cardiac autonomic dysfunction. Therefore, all type 1 diabetic patients should be screened for this complication by HRV analysis beginning at the first stage of puberty regardless of illness duration, microalbuminuria, and level of metabolic control.

Aims/hypothesisCardiac autonomic neuropathy (CAN) is independently associated with silent myocardial ischaemia, major cardiovascular events, myocardial dysfunction and cardiovascular mortality. Several studies have highlighted the increased prevalence of CAN in prediabetes (impaired glucose tolerance and/or impaired fasting glucose). Considering the exponential rise of prediabetes, we aimed to determine the prevalence of CAN through a systematic literature review.MethodsThis systematic review was registered with PROSPERO (CRD42019125447). An electronic literature search was performed using MEDLINE, EMBASE, PubMed, Web of Science, Scopus and Cochrane databases. Published full text, English language articles that provide CAN prevalence data of studies in individuals with prediabetes and aged over 18 years were included. Prevalence data for normal glucose tolerance and diabetes were also extracted from the selected articles, if present. All articles were screened by two independent reviewers using a priori criteria. Methodological quality and risk of bias were evaluated using a critical appraisal tool.ResultsDatabase searches found 4500 articles; subsequently, 199 full text articles were screened, 11 of which fulfilled the inclusion criteria (4431 total participants, 1730 people with prediabetes, 1999 people with normal glucose tolerance [NGT] and 702 people with predominantly type 2 diabetes). Six of the selected studies reported definite CAN prevalence data (9–39%). Only a single large population-based study by Ziegler et al (KORA S4 study, 1332 participants) determined definite CAN based on two or more positive autonomic function tests (AFTs), with a mean prevalence of 9% in all prediabetes groups (isolated impaired glucose tolerance 5.9%; isolated impaired fasting glucose 8.1%; impaired fasting glucose plus impaired glucose tolerance 11.4%), which was higher than NGT (4.5%). This study is most likely to provide a reliable population-specific estimate of CAN in prediabetes. There was a higher than expected prevalence of CAN in prediabetes (9–38%) when compared with normal glucose tolerance (0–18%) within the same studies (n = 8). There was a wide prevalence of possible CAN based on one positive AFT (n = 5). There was heterogeneity between the studies with variations in the definition of CAN, methodology and characteristics of the populations, which likely contributed to the diversity of prevalence estimates. The overall risk of bias was low.Conclusions/interpretationThere is a higher than expected prevalence of CAN in prediabetes. Early detection of CAN in prediabetes through population screening needs careful consideration in view of the excess morbidity and mortality risk associated with this condition.

This systematic review aimed to explore the relationship between diabetic peripheral neuropathy (DPN) and cardiac autonomic neuropathy (CAN) in individuals with type 1 and 2 diabetes mellitus (DM). Methods: The systematic review follow the protocol registered in Prospero (CRD42020182899). Two authors independently searched the PubMed, Scopus, Embase, Cochrane, and Web of Science databases. Discrepancies were resolved by a third author. The review included observational studies investigating the relationship between CAN and DPN in individuals with DM. Results: Initially, out of 1165 studies, only 16 were selected, with 42.8 % involving volunteers with one type of diabetes, 14.3 % with both types of diabetes and 14.3 % not specify the type. The total number of volunteers was 2582, mostly with type 2 DM. It was analyzed that there is a relationship between CAN and DPN. It was observed that more severe levels of DPN are associated with worse outcomes in autonomic tests. Some studies suggested that the techniques for evaluating DPN might serve as risk factors for CAN. Conclusion: The review presents a possible relationship between DPN and CAN, such as in their severity. •There is no systematic review in the literature that analyzes studies on this possible relationship between neuropathies;•The analysis revealed a correlation between the two neuropathies;•The analysis of a possible association between the two neuropathies (diabetic peripheral neuropathy and cardiac autonomic neuropathy) may facilitate an early diagnosis of future complications.

Purpose Cardiovascular autonomic neuropathy (CAN) is a common diabetic complication associated with excess morbidity and mortality. CAN is also seen in conditions such as Parkinson’s disease. Normative reference data for cardiovascular autonomic function are used to stratify individuals into those with and without CAN. However, reference thresholds for both cardiovascular autonomic reflex tests (CARTs) and heart rate variability (HRV) are scarce and based on small sample sizes. The aim of the study was to establish contemporary normative reference thresholds based on a large non-diabetic population free of cardiovascular disease (CVD). Methods Cardiovascular autonomic function, CARTs and 5-min HRV indices were assessed in individuals without diabetes and CVD from the Lolland-Falster Health Study (2018–2020) by applying the point-of-care device Vagus™. Age-specific normative reference thresholds were estimated by using log-transformed quantile regression models at the 5th and 10th percentile, with adjustments made for sex. Models assessing the association between age and HRV indices were further adjusted for heart rate. Results We present age-specific normative reference thresholds for cardiovascular autonomic function, including CARTs and HRV, for 875 individuals (48% females) aged 15–85 years. The reference thresholds are presented for both the 5th and 10th lower percentile. Higher age was inversely associated with all outcomes. Females tended to have a higher parasympathetic drive compared to males. Pre-test conditions did not affect CARTs significantly. Conclusions The presented age-related normative reference thresholds for both CARTs and HRV indices based on a large Danish cohort may facilitate improved quality of research and treatment.