Autonomic Reflex Tests Research Articles

769 EFFECT OF GLUCOSE LOWERING AGENTS ON CARDIAC AUTONOMIC FUNCTION AND STRUCTURE IN TYPE 2 DIABETES MELLITUS

Effects of novel glucose-lowering agents on cardiac autonomic function and structure in type 2 diabetes Ilaria Cavallari, Ernesto Maddaloni, Francesco Veneziano, Carla Indennidate, Maria Valeria Giaccari, Dario Tuccinardi, Silvia Pieralice, Nicola Napoli, Raffaella Buzzetti, Francesco Grigioni Background Novel glucose-lowering agents, such as sodium glucose co-transporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, have the potential to reduce major adverse cardiovascular events among people with type 2 diabetes. However, mechanisms behind their cardiovascular protection and the implications of positive chronotropic effects of GLP-1 receptor agonists are not fully understood. Purpose To elucidate and compare the effects of novel glucose-lowering agents on cardiac autonomic function and structure. Methods This prospective observational study included subjects with type 2 diabetes and either a history of established cardiovascular disease or multiple risk factors and early initiation (within 2 weeks) of a SGLT-2 inhibitor or a GLP-1 receptor agonist on top of standard of care. Patients were followed for a median of 2 months. As per study protocol, background medical therapy should have remained stable for the entire duration of the study. Cardiac autonomic reflex tests (heart rate response to a deep breathing and to standing) and echocardiography were performed in all patients at baseline and at the end of follow-up. Endpoints were changes from baseline of E/I ratio, 30:15 ratio and indices of cardiac structure and function. Results A total of 37 patients completed follow-up, of whom 20 were on SGLT-2 inhibitors and 17 on GLP-1 receptor agonists. Mean age was 69 years, mean disease duration was 14 years and mean HbA1c value was 7.5%. Cardiac autonomic dysfunction, defined as at least an abnormal test, was found in 19% of patients (n=7). At a median follow-up of 2 months, there were no differences from baseline in heart rate response to a deep breathing test (p=0.92) and to standing (p=0.86). No differences were found when patients were stratified according to drug class. Among echocardiographic parameters, significant reductions of left ventricular mass (300.5±73.3 vs 280.4±68.3 g/m2, p=0.048) and left atrial volume (61.3±29.4 vs 54.7±18.0 ml, p=0.034) were found with no interaction by drug class. Left ventricular end-diastolic and systolic volumes, ejection fraction, filling pressures and pulmonary artery pressure did not substantially change. Conclusions In a population of patients with type 2 diabetes, short-term treatment with novel glucose-lowering agents significantly reduced left ventricular mass and left atrial volume but did not affect cardiac autonomic function.

Skin advanced glycation end products as a screening tool of neuropathy in type 2 diabetes mellitus

Aim of the studyTo examine the diagnostic utility of skin advanced glycation end products (AGEs) as screening tool of neuropathy in type 2 diabetes mellitus (T2DM). Patients and methodsWe included 132 participants (88 men) with a mean age of 64.57 years and median T2DM duration of 14.5 years. Skin AGEs were measured with AGE reader mu connect (Diagnoptics) on the dominant arm and were interpreted as normal vs. elevated. Distal sensorimotor polyneuropathy (DSPN) was diagnosed by the Neuropathy Disability Score. Cardiovascular autonomic neuropathy (CAN), sympathetic and parasympathetic nervous system impairment were diagnosed by cardiovascular autonomic reflex tests. ResultsFor DSPN, AGEs yielded high sensitivity (82.8%) and NPV (80.4 %) with moderate specificity (55.4 %). For CAN, they yielded relatively high sensitivity (75.0 %) and NPV (74.5 %) with low specificity (48.7 %). For sympathetic nervous system impairment, AGEs yielded relatively high sensitivity (75.0 %) and high NPV (84.3 %) with low specificity (43.9 %). For parasympathetic nervous system impairment, they yielded high PPV (81.0 %) with moderately high sensitivity (66.7 %) and moderate specificity (55.9 %). ConclusionsIn a simplified approach, skin AGEs may be used as a screening tool of DSPN and CAN (including sympathetic and parasympathetic nervous system impairment) in T2DM.

Dapagliflozin Improves Cardiac Autonomic Function Measures in Type 2 Diabetic Patients with Cardiac Autonomic Neuropathy.

Cardiac autonomic neuropathy is a frequent complication of type 2 diabetes mellitus. Cardiac autonomic neuropathy, in which sympathetic tone predominates over parasympathetic activity, increases both cardiovascular morbidity and mortality and unfortunately has no definitive treatment. Sodium-glucose cotransporter-2 inhibitors have been suggested to reduce sympathetic nervous system activity, based on the results from previous studies. In this study, we aimed to investigate the effect of 24-week treatment with dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, on cardiac autonomic function measures in patients with type 2 diabetes mellitus and cardiac autonomic neuropathy. Dapagliflozin 10 mg/day (n=42) or non-sodium-glucose cotransporter-2 inhibitor oral antidiabetic(s) (n=38) was added to the treatment of patients whose glycemic control could not be achieved with existing treatments. The patients with definite or confirmed cardiac autonomic neuropathy diagnosed by cardiovascular autonomic reflex tests underwent 24-hour Holter-electrocardiogram recordings to obtain heart rate variability and heart rate turbulence parameters before starting additional medication and after a 24-week treatment period. In-group analyses showed that dapagliflozin 10 mg/day for 24 weeks improved heart rate variability and heart rate turbulence parameters and decreased the frequency of ventricular premature beats relative to their baseline values. No such findings were observed in the control group despite similar glycemic control. Comparisons between dapagliflozin group and the control group showed that these effects of dapagliflozin were significantly better than non-sodium-glucose cotransporter-2 inhibitor oral antidiabetics. Dapagliflozin improves measures of cardiac autonomic function compared to the control group in type 2 diabetic patients with cardiac autonomic neuropathy. This intergroup benefit, demonstrated for the first time, may be promising for the regression of cardiac autonomic neuropathy with sodium-glucose cotransporter-2 inhibitors.

Advanced glycation end-products are associated with diabetic neuropathy in young adults with type 1 diabetes.

Aims/hypothesisAdvanced glycation end-products (AGEs) may contribute to the development of diabetic neuropathy. In young adults with type 1 diabetes, we aimed to investigate the association between AGEs and cardiovascular autonomic neuropathy (CAN) and distal symmetric polyneuropathy (DSPN).MethodsThis cross-sectional study comprised 151 young adults. CAN was assessed by cardiovascular autonomic reflex tests; lying-to-standing test, deep breathing test (E/I), Valsalva manoeuvre, and heart rate variability indices; and the mean square of the sum of the squares of differences between consecutive R-R intervals and standard deviation of normal-to-normal intervals (SDNN), high- (HF) and low-frequency (LF) power, total frequency power, and the LF/HF ratio. DSPN was assessed by light touch, pain and vibration perception threshold (VPT), neuropathy questionnaires, and objective measures. AGEs were analysed in four groups using z-scores adjusted for relevant confounders and multiple testing: i) “glycolytic dysfunction”, ii) “lipid peroxidation”, iii) “oxidative stress”, and iv) “glucotoxicity”.ResultsA higher z-score of “glycolytic dysfunction” was associated with higher VPT (4.14% (95% CI 1.31; 7.04), p = 0.004) and E/I (0.03% (95% CI 0.01; 0.05), p = 0.005), “lipid peroxidation” was associated with higher LF/HF ratio (37.72% (95% CI 1.12; 87.57), p = 0.044), and “glucotoxicity” was associated with lower SDNN (−4.20% (95% CI −8.1416; −0.0896), p = 0.047). No significance remained after adjustment for multiple testing.Conclusions/interpretationsIn young adults with type 1 diabetes, increased levels of AGEs involving different metabolic pathways were associated with several measures of CAN and DSPN, suggesting that AGEs may play a diverse role in the pathogeneses of diabetic neuropathy.

Effects of meditation on physiological and metabolic parameters in patients with type 2 diabetes mellitus “MindDM”: study protocol for a randomized controlled trial

BackgroundSri Lanka is faced with the challenge of managing a large population with diabetes mellitus by 2030. Psychological stress plays a major role in disease outcome by exerting physiological, psychological and social effects on individuals with chronic disorders.Meditation-based interventions have positive effects on the management of stress and diabetes, which are mediated via modulation of neuro-humoral mechanisms and autonomic functions, among others. Mechanisms of bio-physiological effects of meditation are considered to be through reduction of stress hormones, improvement of insulin resistance and improvement of autonomic dysfunction.MethodsThis study will be conducted as an open-label, randomized controlled clinical trial in the Faculty of Medicine, University of Colombo. The aim is to investigate the effects of meditation on glycaemic control and possible mechanisms of how meditation affects glycaemic control in patients with type 2 diabetes. The study was approved by the Ethics Review Committee of the Faculty of Medicine, University of Colombo (ERC/2019/094). Patients who are attending the professorial unit medical clinic with type 2 diabetes (172 in total) will be recruited based on inclusion-exclusion criteria. Patients who have never meditated or rarely meditated (less than once every three months) will be randomized using block randomization to meditation and waitlisted arms (1:1 allocation ratio). The meditation arm will undergo a mindfulness meditation program (selected after studying several meditation methods) conducted by a qualified instructor weekly for a period of 12 weeks in addition to usual care, while the waitlisted arm will only receive usual care. Daily meditation practices will be recorded in a diary. The primary outcome measure is HbA1c. Secondary outcome measures are fasting blood sugar, fructosamine, insulin resistance (calculated using fasting serum insulin), 24-h urinary cortisol, body mass index, cardiac autonomic reflex testing (Ewing’s battery of tests) and orocecal transit time using hydrogen breath analysis. All these will be done prior to commencement of the intervention and after 3 months in both arms. Data will be analysed using SPSS V-23.DiscussionThis study aims to identify the effect of mindfulness meditation on glycaemic control and the possible mechanisms (neuro humoral and autonomic functions) by which beneficial effects are mediated.Trial registrationRegistered under Sri Lanka Clinical Trial Registry: SLCTR/2021/015The Universal Trial Number (UTN) U1111-1266-8640

Post-Acute Effect of SARS-CoV-2 Infection on the Cardiac Autonomic Function.

BackgroundRecent studies reported a long-lasting effect of COVID-19 infection that extends beyond the active disease and disrupts various body systems besides the respiratory system. The current study aims to investigate the post-acute effect of SARS-CoV-2 infection on cardiovascular autonomic activity, reactivity and sensitivity in patients who had the infection at least 3 months before.MethodsThis was a comparative cross-sectional observational study. Fifty-nine subjects were allocated into two groups, controls (n=31), who had no history of positive COVID-19 infection, and the post-COVID patients (n=28) who were recruited 3 to 8 months after testing positive for SARS-CoV-2 by reverse transcription polymerase chain reaction (RT-PCR). Baseline cardiovascular autonomic activity was evaluated through recording of baseline heart rate variability (HRV), autonomic reactivity was determined through standard cardiovascular autonomic reflex tests (CART), and cardiac autonomic sensitivity was assessed through cardiac baroreceptor sensitivity (cBRS).ResultsHigher incidence of orthostatic hypotension was observed in post-COVID patients compared to controls (39.3% and 3.2%, respectively, p <0.001). Additionally, significantly reduced handgrip test, and heart rate response to head-up tilt was illustrated in the post-COVID group (p <0.001). About 85.7% of post-COVID participants had at least one abnormal cardiovascular reflex test (CART) compared to the control group (p <0.001). Although HRV parameters (TP, LF, HF, SDRR, RMSSD, pRR50), and the cBRS were numerically lower in the post-COVID-19 group, this did not reach the level of significance.ConclusionThe results of the present study are suggestive of altered cardiovascular reactivity in post-acute COVID patients and demand further investigation and longer term follow up.

Sexual dysfunction among men with diabetes; a cross-sectional study at a specialised diabetes clinic in Sri Lanka

BackgroundMale sexual dysfunction in diabetes is often an unrevealed clinical issue. Though many publications report the prevalence, there is limited data on its associations, impact, and health-seeking behaviour. The objectives were to assess the prevalence of male sexual dysfunction, its associations, impact and treatment-seeking among men with diabetes in a selected tertiary care Diabetes Clinic.MethodsA cross-sectional study was conducted at the Diabetes Clinic, National Hospital of Sri Lanka, from January to September 2020. Men with diabetes aged 18 to 70 years undergoing annual assessment were recruited consecutively. Socio-demographic and clinical information were collected using an interviewer-administered questionnaire. Erectile dysfunction (ED), premature ejaculation, mental health and quality of life were assessed using validated self-administered questionnaires. Cardiovascular autonomic reflex tests and total testosterone levels were performed. Penile colour Doppler ultrasonography was performed on consenting participants with erectile dysfunction. Associations were assessed using the chi-square test or Fisher’s exact for dichotomous variables and independent sample t-test for continuous variables.ResultsTwo hundred and twelve participants were recruited with a mean age of 54.1 (SD = 10.1) years. Erectile dysfunction was present in 168 (79.2%), (mild: 45, mild-moderate: 56, moderate: 26, severe: 41). Premature ejaculation was present in 26 (18.7%). Libido was low among 16%. Sexual dysfunction was not revealed to a health provider by 85.6% despite 60.5% experiencing psychological and/or relationship effects. Out of 18 who sought treatment, only 4 achieved a good response. Mean age (55.4 ± 9.5 vs 48.7 ± 10.6 years, p < 0.001) and duration of diabetes (10.9 ± 7.6 vs 5.8 ± 4.6 years, p < 0.001) were higher while eGFR was lower (73.9 ± 27.7 vs 100.51 ± 28.08 years, p < 0.008) among those with ED compared to those without. Diabetic retinopathy (4% vs 42%, p < 0.001), peripheral neuropathy (17.9% vs 38.4%, p = 0.041) and lower limb arterial disease (0% vs 12.2%, p = 0.04) were associated with ED. Arterial insufficiency was seen among 50% of the participants who underwent penile colour Doppler ultrasonography.ConclusionsMale sexual dysfunction is a pervasive yet underappreciated problem in diabetes care despite its effect on the individual. Patient and disease characteristics would guide the identification of high-risk individuals for targeted screening in clinical practice.

Research for correlation between heart rate variability parameters and bone mineral density in patients of type 2 diabetes mellitus.

The relationship of CAN and BMD, fracture risk is still unclear in T2DM. The aim of the present study is to investigate the correlation between heart rate variability (HRV) and BMD in T2DM. The study included 276 patients with T2DM aged ≥ 50years, and Cardiovascular Autonomic Reflex Tests (CARTs) were applied to divide patients into two groups: CAN ( ±). 24h Ambulatory ECG was assessed for HRV, BMD was measured by dual-energy X-ray bone densitometry, and FRAX scores were calculated for 10-year hip fracture risk (HF1) and major osteoporotic fracture risk (MOF). Adjusted regression analysis was performed to investigate influence factors for BMD and fracture risk. ROC curve was used to analyze the optimal cut-off point of LF/HF for screening osteoporosis. Baseline data showed significant differences in the duration of T2DM, insulin resistance index (HOMA-IR), 25-hydroxyvitamin D[25(OH)D], femoral neck BMD, hip BMD, lumbar BMD, HF1, and MOF between the CAN ( +) and CAN (-) groups. The proportion of patients with osteoporosis increased as the degree of CAN lesion increased. Correlation analysis showed that LF/HF was significantly correlated with BMD, especially with hip (r = -0.534, p < 0.001). Regression analysis showed that LF/HF was a risk factor for reduced BMD and increased fracture risk. The optimal cut-point value for LF/HF to predict osteoporosis by ROC curve analysis was 3.17. CAN is associated with reduced BMD and increased fracture risk in patients with T2DM, and LF/HF may have the potential to be a predictor of diabetic osteoporosis and have some clinical value in early diagnosis of diabetic osteoporosis and non-traumatic fractures in T2DM.

Autonomic Reflex Testing Confirms Autonomic Disturbances in a Cohort of Patients with Idiopathic Hypersomnia

Autonomic Reflex Testing Confirms Autonomic Disturbances in a Cohort of Patients with Idiopathic Hypersomnia

458-P: Inflammatory Markers and Cardiovascular Autonomic Neuropathy in Type 1 Diabetes

Objective: We aimed to assess the role of chronic inflammation in the pathogenesis of cardiovascular autonomic neuropathy (CAN) , a serious complication of type 1 diabetes (T1D) . Methods: We leveraged an ongoing randomized, placebo-controlled clinical trial targeting inflammation with salsalate in individuals with T1D, to measure a panel of 40 inflammatory markers (Figure) in baseline samples. Measures of CAN included standardized cardiovascular autonomic reflex tests (CARTs) (E/I, Valsalva, 30/15 ratios) and indices of heart rate variability (HRV) . We used Spearman-rank to assess the correlations between inflammatory markers and CAN measures, and linear regression to adjust for age and hemoglobin A1c. Results: The Figure displays the correlation between biomarkers and CAN measures in 58 T1D participants (mean age 51 ± 13 years, and HbA1c 8.4 ± 1.8%) . Amongst all biomarkers, we noted a singular negative correlation between soluble urokinase plasminogen activator receptor (suPAR) and measures of CAN, which remained significant in multivariable analysis (E/I ratio p=0.005, Valsalva p=0.037, RFA p=0.019, LFA p=0.023) . Conclusion: Amongst a large panel of inflammatory markers, we found suPAR to have a notable association with CAN. SuPAR is an immune-mediated signaling glycoprotein which levels are strong predictors of risk in patients with diabetes, thus its role in CAN warrants further exploration. Disclosure L.Ang: None. L.Zhao: None. E.L.Feldman: None. S.Hayek: n/a. R.Pop-busui: Advisory Panel; Averitas Pharma, Inc., Boehringer Ingelheim International GmbH, Nevro Corp., Novo Nordisk, Reata Pharmaceuticals, Inc., Regenacy Pharmaceuticals, Inc. S.V.G.Gunaratnam: None. Y.Huang: None. K.R.Mizokami-stout: None. C.Martin: Advisory Panel; Nevro Corp. J.Reiss: n/a. A.Burant: None. A.Vasbinder: None. C.Launius: None. Funding NIH/NIDDK-1-R01-DK-107956-01

0397 Autonomic Reflex Testing Confirms Autonomic Disturbances in a Cohort of Patients with Idiopathic Hypersomnia

Abstract Introduction Symptoms suggestive of autonomic nervous system (ANS) dysfunction have been previously described in patients with idiopathic hypersomnia (IH), however, objective ANS reflex testing data has not been reported. We aimed to better quantify symptoms of ANS dysfunction in a cohort of patients with IH through the use of standardized ANS reflex testing. Methods Patients diagnosed with IH based on ICSD-3 criteria using overnight video polysomnography and multiple sleep latency testing (MSLT) were consecutively enrolled in our study, regardless of ANS symptoms. All patients underwent ANS reflex testing, including measures of parasympathetic (heart rate variability with deep breathing and Valsalva ratio) and sympathetic adrenergic function (Valsalva blood pressure response and 10-minute head-up tilt at an angle of 70 degrees) with continuous blood pressure and heart rate monitoring. Eleven patients also underwent measures of sympathetic cholinergic function (quantitative sudomotor axon reflex testing). All medications that affect ANS function were held prior to ANS testing, including wake-promoting medications and sodium oxybate. Results Twenty patients with IH were enrolled. Fifty percent (10/20) were long sleepers (&amp;gt;11hrs). Mean sleep onset latency and number of sleep onset REM periods (SOREMs) on MSLT were 6.9 (± 3.1) mins and 0.2 (± 0.4), respectively. Mean duration of IH symptoms prior to the date of ANS testing was 6.3 (± 8.1) yrs. Eighty-five percent (17/20) of patients had abnormal ANS testing. Of these, 75% (15/20) had sympathetic adrenergic impairment, 64% (7/11) had sympathetic cholinergic impairment, and 5% (1/20) had parasympathetic impairment. Fifty-five percent (11/20) of patients were diagnosed with postural tachycardia syndrome (POTS), 45% (5/11) with small fiber neuropathy, 5% (1/20) with inappropriate sinus tachycardia and 15% (3/20) with neurally-mediated syncope. Seventy percent (14/20) of patients reported orthostatic intolerance regardless of autonomic diagnosis. Conclusion ANS dysfunction was common and severe in our cohort of IH patients, affecting all domains of ANS reflex testing, with more prominent impairment in sympathetic domains. POTS was the most common comorbid diagnosis, and most patients reported orthostatic intolerance. There was no association with IH disease duration, though our sample size was limited. Future studies will focus on ANS testing in larger cohorts of IH patients, specifically on shared pathophysiological mechanisms of hypersomnia and ANS dysfunction. Support (If Any)

Effect of the Glucagon-Like Peptide-1 Receptor Agonists on Autonomic Function in Subjects with Diabetes: A Systematic Review and Meta-Analysis.

In addition to the metabolic effects in diabetes, glucagon-like peptide 1 receptor (GLP-1R) agonists lead to a small but substantial increase in heart rate (HR). However, the GLP-1R actions on the autonomic nervous system (ANS) in diabetes remain debated. Therefore, this meta-analysis evaluates the effect of GLP-1R agonist on measures of ANS function in diabetes. According to the Cochrane Collaboration and Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement, we conducted a meta-analysis considering clinical trials in which the autonomic function was evaluated in diabetic subjects chronically treated with GLP-1R agonists. The outcomes were the change of ANS function measured by heart rate variability (HRV) and cardiac autonomic reflex tests (CARTs). In the studies enrolled, HR significantly increased after treatment (P<0.001), whereas low frequency/high frequency ratio did not differ (P=0.410); no changes in other measures of HRV were detected. Considering CARTs, only the 30:15 value derived from lying-to-standing test was significantly lower after treatment (P=0.002), but only two studies reported this measurement. No differences in other CARTs outcome were observed. The meta-analysis confirms the HR increase but seems to exclude an alteration of the sympatho-vagal balance due to chronic treatment with GLP-1R agonists in diabetes, considering the available measures of ANS function.

Thermal quantitative sensory testing as a screening tool for cardiac autonomic neuropathy in patients with diabetes mellitus.

IntroductionElectrophysiological diagnosis of cardiac autonomic neuropathy (CAN) is based on the evaluation of cardiovascular autonomic reflex tests (CARTs). CARTs are relatively time consuming and must be performed under standardized conditions. This study aimed to determine whether thermal quantitative sensory testing (TQST) can be used as a screening tool to identify patients with diabetes at a higher risk of CAN.MethodsEighty‐five patients with diabetes and 49 healthy controls were included in the study. Neurological examination, CARTs, TQST, biochemical analyses, and neuropathy symptom questionnaires were performed.ResultsCAN was diagnosed in 46 patients with diabetes (54%). CAN‐positive patients with diabetes had significantly higher warm detection thresholds (WDT) and significantly lower cold detection thresholds (CDT) in all tested regions (thenar, tibia, and the dorsum of the foot). CDT on the dorsum < 21.8°C in combination with CDT on the tibia < 23.15°C showed the best diagnostic ability in CAN prediction, with 97.4 % specificity, 60.9% sensitivity, 96.6% positive predictive value, and 67.3% negative predictive value.ConclusionTQST can be used as a screening tool for CAN before CART.

Elevated levels of interleukin-12/23p40 may serve as a potential indicator of dysfunctional heart rate variability in type 2 diabetes

BackgroundSystemic inflammatory processes plausibly contribute to the development of cardiovascular complications, causing increased morbidity and mortality in type 2 diabetes. Circulating inflammatory markers, i.e., interleukin (IL)-6 and tumour necrosis factor-α, are associated with neurocardiac measures. We examined a broad panel of various inflammatory and inflammation-related serum markers to obtain more detailed insight into the possible neuro-immune interaction between cardiovascular regulation and systemic level of inflammation.MethodsSerum samples from 100 participants with type 2 diabetes were analysed. Heart rate variability, cardiovascular autonomic reflex tests, and cardiac vagal tone tests were performed based on electrocardiographic readings. Data regarding covariates (demographic-, diabetes-, and cardiovascular risk factors) were registered.ResultsIncreased serum levels of IL-12/IL-23p40 (p < 0.01) and intercellular adhesion molecule (ICAM)-1 (p < 0.007) were associated with diminished heart rate variability measures. After all adjustments, the associations between IL-12/23p40, SDANN and VLF persisted (p = 0.001). Additionally, serum levels of vascular endothelial growth factor (VEGF)-C were associated with response to standing (p = 0.005).DiscussionThe few but robust associations between neurocardiac regulation and serum markers found in this study suggest systemic changes in proinflammatory, endothelial, and lymphatic function, which collectively impacts the systemic cardiovascular function. Our results warrant further exploration of IL-12/IL-23p40, ICAM-1, and VEGF-C as possible cardiovascular biomarkers in T2D that may support future decisions regarding treatment strategies for improved patient care.

A Study of Cardiovascular Autonomic Neuropathy in Adult Patients with Diabetes Mellitus at Levy Mwanawasa University Teaching Hospital

Cardiac autonomic neuropathy (CAN) is the diminished capacity of autonomic regulation of the cardiovascular system occurring in the presence of diabetes mellitus (DM) and in the absence of other aetiologies. Diabetes mellitus is a well- known cause of peripheral neuropathy. However, in comparison to somatic neuropathy, autonomic neuropathy is an under-diagnosed and under-treated chronic complication of diabetes mellitus despite its serious and significant contribution to morbidity and mortality in the diabetes mellitus population. A variety of tests, based on evaluation of the cardiovascular reflexes triggered by performing specific provocative manoeuvres, have been proposed to measure autonomic function. This study used four cardiovascular reflex tests to estimate appropriate autonomic function by examining heart rate, heart rate variation and the baroreceptor reflex. The aim of this study was to determine the presence of cardiovascular autonomic neuropathy in adult patients with diabetes mellitus at Levy Mwanawasa University Teaching Hospital in Lusaka, Zambia. Adult patients with diabetes mellitus, aged between 21 and 70 years, participated in this cross-sectional study. Four, non-invasive, cardiac autonomic reflex tests to assess for cardiac autonomic neuropathy were employed according to Ewing’s method. The parasympathetic function was analysed based on the heart rate response to paced deep breathing and to Valsalva manoeuvring. The sympathetic function was assessed by measuring heart rate and blood pressure response to postural change. Ewing`s criteria was used for the categorisation of cardiac autonomic neuropathy. Data were analysed using SPSS version 20. Continuous data were presented as means and standard deviation. Categorical data were analysed using a Fishers’ Exact Test (χ2) and a logistic regression was performed to verify the effects of diabetes mellitus’ duration, sex and age on the probability that the participants have cardiac autonomic neuropathy. A total of 52 patients participated in the study. The prevalence of Cardiac autonomic neuropathy was 48.1%. Out of 52 patients, 42.3% had definite cardiac autonomic neuropathy and 5.8% had severe cardiac autonomic neuropathy. Early cardiac autonomic neuropathy was observed in 34.6% of patients while 17.3% had no signs of cardiac autonomic neuropathy. The mean age of patients with cardiac autonomic neuropathy was 54.44 ± 10.90 years and the mean duration of diabetes mellitus from diagnosis was 5.36 ± 6.78 years. The probability of developing cardiac autonomic neuropathy increased with increasing age and hypertensive participants were more likely develop cardiac autonomic neuropathy (ѵ = 5.82, p = .001). In conclusion, cardiac autonomic neuropathy was present in a significant proportion of adult patients with diabetes mellitus at Levy Mwanawasa University Teaching Hospital, reflecting the increased morbidity encountered by this population. In order to improve patient quality of life and reduce disease burden, screening for cardiac autonomic neuropathy should be implemented using cardiovascular autonomic reflex tests which are relatively simple, safe and affordable.

Imbalance in Cardiac Autonomic Nervous System Mediates Fatigue

Aims To explore the impact of the autonomic nervous system function in “disease-free” people for testing and appropriate therapies in different age-groups. Methods Seventy-five disease-free volunteers who participated in a previous study were randomly selected from five age-groups (30-79 years) for a cross/sectional study to assess the impact of fatigue on cardiac/autonomic function by analysis of heart rate variability (HRV) and measures of cognitive and physical fatigue on quality-of-life-fatigue (QOLF) scores. Written informed consent was obtained and protocol approved. To induce fatigue, three 5-minute walking trials were performed on an instrumental treadmill, increasing the incline in increments of 2°/min to measure perceived exertion (RPE) at the beginning and end of each trial. Polar monitors measured heart rate (HR); a modified Borg 10-point scale measured RPE. Cardiac autonomic reflex tests (CART) with time/frequency domains analyzed HRV. QOLF scores were measured and analyzed for correlation with sympathetic/parasympathetic function on the Norfolk QOL-F fatigue scale. Results QOL-F scores were not significantly different among 5 age groups, likely due to wide standard deviations and small subject numbers. Significant correlations between overall fatigue severity and several indices of HRV were found, independent of age, gender, and body mass index (p&lt;0.05). Self-rated physical fatigue and compromised activities of daily living (ADLs) were related to sympathetic hyperactivity and autonomic imbalance (p=0.04). Participants in the (70–79-year-olds) category had impaired scores. Conclusions The study identifies a relationship between autonomic nervous system function and cognitive and physical fatigue even in “disease-free” people in different age- groups and suggests that fatigue is impacted by somatic and autonomic nerve function. Higher self-ratings of perceived fatigue were associated with sympathovagal hyperactivity. Impaired HR response to exercise in older people corresponding with vagal over-activity, and paradoxically, best self-rated QOL-F, mandates clinical autonomic dysfunction testing and lifestyle therapies to prevent catastrophic events

Cardiovascular autonomic neuropathy and incident diabetic kidney disease in patients with type 2 diabetes

AimsWe investigated the association between cardiovascular autonomic neuropathy (CAN) and incident diabetic kidney disease (DKD). MethodsThis retrospective longitudinal study included 2,033 patients with type 2 diabetes (mean age 57.2 years, 57.4% male, and median diabetes duration 8.0 years), free of renal dysfunction or cardiovascular disease at initiation. Cardiovascular autonomic reflex tests were performed once at baseline, and CAN was defined as ≥ 2 abnormal parasympathetic test results. Urine ACR and eGFR were concurrently measured at baseline and every 3–6 months thereafter. Incident DKD was defined as the development of ACR ≥ 30 mg/g at two or more follow-up examinations or eGFR < 60 ml/min/1.73 m2 with ≥ 25% decrease from baseline. ResultsDuring a median follow-up of 2.9 years (1.1 – 4.8), 290 (14.3%) patients developed DKD, comprising 79.7% (N = 231) cases of new-onset albuminuria alone, 14.5% (N = 42) cases of eGFR decline alone, and 5.8% (N = 17) cases of both. Compared to those without CAN, patients with CAN had a significantly higher risk of incident DKD in a multivariable Cox regression model (HR 1.56, 95% CI 1.15 – 2.12; P = 0.005). ConclusionCAN is may be a useful marker for long-term complications including DKD in patients with type 2 diabetes. Monitoring of CAN helps to identify high risk patients of future renal impairment.

The Association Between Cardiovascular Autonomic Function and Changes in Kidney and Myocardial Function in Type 2 Diabetes and Healthy Controls.

BackgroundThe mechanisms linking cardiovascular autonomic neuropathy, diabetic kidney disease and cardiovascular mortality in type 2 diabetes are widely unknown. We investigated the relationship between baseline cardiovascular autonomic function and changes in kidney and myocardial function over six years in patients with type 2 diabetes and healthy controls.Methods Post-hoc analysis of a cohort study in 24 patients with type 2 diabetes and 18 healthy controls. Baseline determinants were cardiovascular autonomic reflex tests (heart rate response to: standing (30:15); deep breathing (E:I); and the Valsalva test) and time- and frequency-domain heart rate variability indices. Outcomes were changes in estimated glomerular filtration rate (eGFR), albuminuria, myocardial flow reserve (MFR) measured by cardiac 82Rb Positron emission tomography computed tomography (PET/CT), and coronary artery calcium score (CACS).ResultsMean age at inclusion was 61 ± 10 years and 36% were female. Mean follow up time was 6 ± 0 years. A lower response in heart rate to the Valsalva test (corresponding to weaker autonomic function) was associated with a larger decline in eGFR (p=0.04), but not significantly after adjustment for sex, baseline age, smoking status, systolic blood pressure, heart rate, HbA1c, body mass index and baseline eGFR (p=0.12). A higher baseline response in heart rate to standing (30:15) was associated with a larger decline in myocardial flow reserve in the unadjusted analysis (p=0.02) and after adjustment (p=0.02). A higher response in heart rate to the Valsalva maneuver was associated with a larger increase in CACS (p = 0.02), but the association became insignificant after adjustment (p = 0.16).ConclusionA lower response in heart rate to the Valsalva test was associated with a larger decline in kidney function, indicating that autonomic dysfunction may predict future loss of kidney function. However, we did not find any association between lower values in cardiovascular autonomic function at baseline and a worsening in albuminuria, myocardial function, or atherosclerotic burden.

Diagnosis, staging, and associated conditions of cardiovascular autonomic neuropathy in Libyan patients with diabetes

Background: Cardiovascular autonomic neuropathy (CAN) can affect daily activities and patients' quality of life and evoke potentially life-threatening outcomes in diabetes mellitus (DM). Objectives: We aimed to identify and characterize CAN and associated disorders in Libyan patients with DM at National Diabetes Hospital. Patients and Methods: Ninety-nine patients with DM seen in the outpatient clinics from October 2017 to April 2018 at National Diabetes Hospital were prospectively evaluated. Assessments for CAN were made by clinical symptoms and signs, cardiovascular autonomic reflex tests, and echocardiogram. Patients with potentially confounding concomitant medical conditions were excluded. CAN is defined as possible (one abnormal cardiovagal test), confirmed (two abnormal such tests), and severe (with concomitant orthostatic hypotension and heart rate abnormality). Results: Sixty-two percent of the studied patients (mean age: 52 ± 1.5 years, 53% – female) with DM had CAN. CAN diagnosis was possible in 18% of these patients, confirmed in 6%, and severe in 38%. The presence of severe CAN was associated with hypoglycemic unawareness (P = 0.01), dyslipidemia (P = 0.012), and microvascular diabetic complications (P = 0.04). Conclusions: In this cohort of relatively old and high-risk cardiovascular disease, patients with diabetes, uncontrolled blood pressure, associated dyslipidemia, presence of microvascular complication of diabetes, and history of hypoglycemic unawareness were strongly associated with a severe form of cardiac autonomic neuropathy with potentially serious clinical consequences. Larger and more detailed studies are needed to elucidate further the complex association between hypoglycemia and cardiac autonomic dysfunction.

Leisure-Time Physical Activity and Glycemic Control Independently Predicts Cardiac Autonomic Neuropathy in Type 2 Diabetes Mellitus.

Though cardiac autonomic neuropathy (CAN) is a common complication of type 2 diabetes mellitus (T2DM); still, there is lack of clarity on pathophysiological correlates for its onset and progression. Therefore, the purpose of this study was to investigate the predictive ability of lifestyle and cardiometabolic risk factors for CAN in T2DM patients. A total of 105 Indian T2DM patients were recruited in the present study. Cardiometabolic risk factors, such as glycemic control, lipids, resting heart rate, systolic and diastolic blood pressure, and lifestyle risk parameters, such as physical activity levels and sleep quality were assessed. Standard cardiovascular autonomic reflex tests were performed for diagnosing CAN by Ewing's criteria. Leisure-time physical activity and glycosylated hemoglobin were significant independent predictors of CAN in T2DM. Leisure-time physical activity and glycosylated hemoglobin predicted the occurrence of CAN at cutoff values ≤4.68 metabolic equivalent-hours per week (P = .007) and >7.5% (P = .002), respectively. The T2DM patients should be encouraged to engage in leisure-time physical activity of at least 4.68 metabolic equivalent-hours per week (equivalent to 1.2h of walk or 0.6h of jog per week) and therapeutic strategies for controlling hyperglycemia in T2DM should aim to reduce glycosylated hemoglobin below 7.5% to reduce CAN occurrence.