RESUMEN

BACKGROUND: A compromised cardiac autonomic function has been found in subjects with insulin resistance related disorders such as obesity, impaired glucose tolerance (IGT) and type 2 diabetes and confers an increased risk of adverse cardiovascular outcomes. Growing evidence indicate that 1 h plasma glucose levels (1hPG) during an oral glucose tolerance test (OGTT) ≥ 155 mg/dl identify amongst subjects with normal glucose tolerance (NGT) a new category of prediabetes (NGT 1 h-high), harboring an increased risk of cardiovascular organ damage. In this study we explored the relationship between 1 h post-load hyperglycemia and cardiac autonomic dysfunction. METHODS: Presence of cardiac autonomic neuropathy (CAN) defined by cardiovascular autonomic reflex tests (CARTs) and heart rate variability (HRV), assessed by 24-h electrocardiography were evaluated in 88 non-diabetic subjects subdivided on the basis of OGTT data in: NGT with 1 h PG < 155 mg/dl (NGT 1 h-low), NGT 1 h-high and IGT. RESULTS: As compared to subjects with NGT 1 h-low, those with NGT 1 h-high and IGT were more likely to have CARTs defined CAN and reduced values of the 24 h time domain HVR parameters including standard deviation of all normal heart cycles (SDNN), standard deviation of the average RR interval for each 5 min segment (SDANN), square root of the differences between adjacent RR intervals (RMSSD), percentage of beats with a consecutive RR interval difference > 50 ms (PNN50) and Triangular index. Univariate analyses showed that 1hPG, but not fasting and 2hPG, was inversely associated with all the explored HVR parameters and positively with CARTs determined presence of CAN. In multivariate regression analysis models including several confounders we found that 1hPG was an independent contributor of HRV and presence of CAN. CONCLUSION: Subjects with 1hPG ≥ 155 mg/dl have an impaired cardiac autonomic function.

Asunto(s)

Sistema Nervioso Autónomo , Glucemia , Prueba de Tolerancia a la Glucosa , Frecuencia Cardíaca , Hiperglucemia , Humanos , Estudios Transversales , Masculino , Femenino , Persona de Mediana Edad , Sistema Nervioso Autónomo/fisiopatología , Glucemia/metabolismo , Hiperglucemia/fisiopatología , Hiperglucemia/sangre , Hiperglucemia/diagnóstico , Adulto , Factores de Tiempo , Biomarcadores/sangre , Enfermedades del Sistema Nervioso Autónomo/fisiopatología , Enfermedades del Sistema Nervioso Autónomo/diagnóstico , Enfermedades del Sistema Nervioso Autónomo/sangre , Corazón/inervación , Corazón/fisiopatología , Electrocardiografía Ambulatoria , Estado Prediabético/fisiopatología , Estado Prediabético/diagnóstico , Estado Prediabético/sangre , Intolerancia a la Glucosa/diagnóstico , Intolerancia a la Glucosa/fisiopatología , Intolerancia a la Glucosa/sangre , Factores de Riesgo

RESUMEN

BACKGROUND: Higher order regulation of autonomic function is maintained by the coordinated activity of specific cortical and subcortical brain regions, collectively referred to as the central autonomic network (CAN). Autonomic changes are frequently observed in Alzheimer's disease (AD) and dementia, but no studies to date have investigated whether plasma AD biomarkers are associated with CAN functional connectivity changes in at risk older adults. METHODS: Independently living older adults (N = 122) without major neurological or psychiatric disorder were recruited from the community. Participants underwent resting-state brain fMRI and a CAN network derived from a voxel-based meta-analysis was applied for overall, sympathetic, and parasympathetic CAN connectivity using the CONN Functional Toolbox. Sensorimotor network connectivity was studied as a negative control. Plasma levels of amyloid (Aß42, Aß40), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were assessed using digital immunoassay. The relationship between plasma AD biomarkers and within-network functional connectivity was studied using multiple linear regression adjusted for demographic covariates and Apolipoprotein E (APOE) genotype. Interactive effects with APOE4 carrier status were also assessed. RESULTS: All autonomic networks were positively associated with Aß42/40 ratio and remained so after adjustment for age, sex, and APOE4 carrier status. Overall and parasympathetic networks were negatively associated with GFAP. The relationship between the parasympathetic CAN and GFAP was moderated by APOE4 carrier status, wherein APOE4 carriers with low parasympathetic CAN connectivity displayed the highest plasma GFAP concentrations (B = 910.00, P = .004). Sensorimotor connectivity was not associated with any plasma AD biomarkers, as expected. CONCLUSION: The present study findings suggest that CAN function is associated with plasma AD biomarker levels. Specifically, lower CAN functional connectivity is associated with decreased plasma Aß42/40, indicative of cerebral amyloidosis, and increased plasma GFAP in APOE4 carriers at risk for AD. These findings could suggest higher order autonomic and parasympathetic dysfunction in very early-stage AD, which may have clinical implications.

Asunto(s)

Enfermedad de Alzheimer , Péptidos beta-Amiloides , Biomarcadores , Imagen por Resonancia Magnética , Humanos , Femenino , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/fisiopatología , Enfermedad de Alzheimer/diagnóstico por imagen , Anciano , Masculino , Biomarcadores/sangre , Péptidos beta-Amiloides/sangre , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Fragmentos de Péptidos/sangre , Sistema Nervioso Autónomo/fisiopatología , Proteína Ácida Fibrilar de la Glía/sangre , Anciano de 80 o más Años , Proteínas de Neurofilamentos/sangre , Enfermedades del Sistema Nervioso Autónomo/sangre , Enfermedades del Sistema Nervioso Autónomo/fisiopatología , Enfermedades del Sistema Nervioso Autónomo/etiología

RESUMEN

OBJECTIVES: To report the association of zinc finger and SCAN domain containing 1 antibodies (ZSCAN1-abs) with rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome in patients without tumor. METHODS: Patients with symptoms compatible with ROHHAD syndrome but without an associated tumor were selected from our database. Serum and CSF samples were examined for the presence of ZSCAN1-abs by an in-house cell-based assay. In addition, samples from 149 patients with several inflammatory and noninflammatory disorders and 50 healthy participants served as controls. RESULTS: Thirteen patients with ROHHAD syndrome were identified. Of these, we had paired serum/CSF samples from 6 patients and only serum from the other 7. Five of 6 patients (83.3%) with paired serum/CSF (4 children, 1 adult) had ZSCAN-abs only in CSF and 1 had antibodies in serum and CSF. ZSCAN1-abs were not detected in the remaining 7 patients with ROHHAD with only serum available or in any of the 199 control samples. DISCUSSION: Patients with ROHHAD syndrome should be investigated for the presence of ZSCAN1-abs in CSF. The antibodies do not necessarily predict the presence of a tumor. The detection of ZSCAN1-abs in an adult patient suggests that this condition also occurs beyond the pediatric age.

Asunto(s)

Autoanticuerpos , Enfermedades Hipotalámicas , Humanos , Masculino , Adulto , Femenino , Niño , Autoanticuerpos/sangre , Autoanticuerpos/líquido cefalorraquídeo , Enfermedades Hipotalámicas/inmunología , Enfermedades Hipotalámicas/sangre , Enfermedades Hipotalámicas/líquido cefalorraquídeo , Adolescente , Factores de Transcripción/inmunología , Hipoventilación/sangre , Hipoventilación/inmunología , Hipoventilación/líquido cefalorraquídeo , Enfermedades del Sistema Nervioso Autónomo/inmunología , Enfermedades del Sistema Nervioso Autónomo/sangre , Obesidad/inmunología , Adulto Joven , Persona de Mediana Edad , Preescolar , Síndrome

RESUMEN

AIMS: To investigate whether higher serum CCL11/Eotaxin-1, a biomarker for aging and neurodegenerative and neuroinflammatory disorders, is associated with diabetic sensorimotor polyneuropathy (DSPN), peripheral nerve dysfunction, and cardiac autonomic neuropathy in people with type 2 diabetes. METHODS: This cross-sectional study included 106 patients with type 2 diabetes and 40 healthy controls, matched for the age and sex distribution of the diabetes group as a whole. The CC chemokines CCL11/Eotaxin-1 and CCL22/MDC were measured in fasting serum samples. DSPN and peripheral nerve function were assessed by neurological examination and nerve conduction studies, and cardiac autonomic function, by heart rate variability (HRV) and corrected QT (QTc) time. The cardio-ankle vascular index (CAVI) was measured as a marker for arterial stiffness. RESULTS: Serum CCL11/Eotaxin-1 levels were significantly higher in diabetic patients than in healthy controls (183 ± 63.5 vs. 113.1 ± 38.5 pg/ml, p < 0.001), but serum CCL22/MDC levels were not significantly different between the two groups. In the diabetes group, the serum CCL11/Eotaxin-1 level was positively correlated with ulnar and sural nerve conduction velocities (p = 0.0009, p = 0.0208, respectively) and sensory nerve action potential (p = 0.0083), and CAVI (p = 0.0005), but not with HRV indices or QTc time, and serum CCL22/MDC was not significantly correlated with any indices of nerve conduction. In a model adjusted for age and duration of diabetes, serum CCL11/Eotaxin-1 was still associated with ulnar nerve conduction velocity (p = 0.02124). Serum CCL11/Eotaxin-1, but not CCL22/MDC, was significantly higher in patients with than in those without DSPN (208.2 ± 71.6 vs. 159.1 ± 45.1 pg/ml, respectively; p < 0.0001). CONCLUSIONS: Serum CCL11/Eotaxin-1 is elevated in patients with DSPN and is associated with peripheral nerve dysfunction, in particular sensory nerve conduction velocity, suggesting that serum CCL11/Eotaxin-1 may be a potential biomarker for DSPN. CLINICAL TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN000040631).

Asunto(s)

Biomarcadores , Quimiocina CCL11 , Diabetes Mellitus Tipo 2 , Neuropatías Diabéticas , Humanos , Masculino , Femenino , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/fisiopatología , Neuropatías Diabéticas/sangre , Neuropatías Diabéticas/fisiopatología , Neuropatías Diabéticas/diagnóstico , Estudios Transversales , Persona de Mediana Edad , Biomarcadores/sangre , Quimiocina CCL11/sangre , Anciano , Conducción Nerviosa/fisiología , Enfermedades del Sistema Nervioso Autónomo/sangre , Enfermedades del Sistema Nervioso Autónomo/fisiopatología , Enfermedades del Sistema Nervioso Autónomo/etiología , Enfermedades del Sistema Nervioso Autónomo/diagnóstico , Frecuencia Cardíaca/fisiología , Estudios de Casos y Controles , Adulto

RESUMEN

AIMS: To assess if advanced characterization of serum glycoprotein and lipoprotein profile, measured by proton nuclear magnetic resonance spectroscopy (1H-NMRS) improves a predictive clinical model of cardioautonomic neuropathy (CAN) in subjects with type 1 diabetes (T1D). METHODS: Cross-sectional study (ClinicalTrials.gov Identifier: NCT04950634). CAN was diagnosed using Ewing's score. Advanced characterization of macromolecular complexes including glycoprotein and lipoprotein profiles in serum samples were measured by 1H-NMRS. We addressed the relationships between these biomarkers and CAN using correlation and regression analyses. Diagnostic performance was assessed by analyzing their areas under the receiver operating characteristic curves (AUCROC). RESULTS: Three hundred and twenty-three patients were included (46% female, mean age and duration of diabetes of 41 ± 13 years and 19 ± 11 years, respectively). The overall prevalence of CAN was 28% [95% confidence interval (95%CI): 23; 33]. Glycoproteins such as N-acetylglucosamine/galactosamine and sialic acid showed strong correlations with inflammatory markers such as high-sensitive C-reactive protein, fibrinogen, IL-10, IL-6, and TNF-α. On the contrary, we did not find any association between the former and CAN. A stepwise binary logistic regression model (R2 = 0.078; P = 0.003) retained intermediate-density lipoprotein-triglycerides (IDL-TG) [ß:0.082 (95%CI: 0.005; 0.160); P = 0.039], high-density lipoprotein-triglycerides (HDL-TGL)/HDL-Cholesterol [ß:3.633 (95%CI: 0.873; 6.394); P = 0.010], and large-HDL particle number [ß: 3.710 (95%CI: 0.677; 6.744); P = 0.001] as statistically significant determinants of CAN. Adding these lipoprotein particles to a clinical prediction model of CAN that included age, duration of diabetes, and A1c enhanced its diagnostic performance, improving AUCROC from 0.546 (95%CI: 0.404; 0.688) to 0.728 (95%CI: 0.616; 0.840). CONCLUSIONS: When added to clinical variables, 1H-NMRS-lipoprotein particle profiles may be helpful to identify those patients with T1D at risk of CAN.

Asunto(s)

Biomarcadores , Diabetes Mellitus Tipo 1 , Lipoproteínas , Espectroscopía de Protones por Resonancia Magnética , Humanos , Femenino , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/sangre , Masculino , Adulto , Estudios Transversales , Lipoproteínas/sangre , Biomarcadores/sangre , Espectroscopía de Protones por Resonancia Magnética/métodos , Neuropatías Diabéticas/diagnóstico , Neuropatías Diabéticas/sangre , Neuropatías Diabéticas/etiología , Neuropatías Diabéticas/epidemiología , Persona de Mediana Edad , Pronóstico , Enfermedades del Sistema Nervioso Autónomo/diagnóstico , Enfermedades del Sistema Nervioso Autónomo/etiología , Enfermedades del Sistema Nervioso Autónomo/sangre

RESUMEN

Autoimmune Autonomic Ganglionopathy (AAG) is an uncommon immune-mediated neurological disease that results in failure of autonomic function and is associated with autoantibodies directed against the ganglionic acetylcholine receptor (gnACHR). The antibodies are routinely detected by immunoprecipitation assays, such as radioimmunoassays (RIA), although these assays do not detect all patients with AAG and may yield false positive results. Autoantibodies against the gnACHR exert pathology by receptor modulation. Flow cytometric analysis is able to determine if this has occurred, in contrast to the assays in current use that rely on immunoprecipitation. Here, we describe the first high-throughput, non-radioactive flow cytometric assay to determine autoantibody mediated gnACHR immunomodulation. Previously identified gnACHR antibody seronegative and seropositive sera samples (RIA confirmed) were blinded and obtained from the Oxford Neuroimmunology group along with samples collected locally from patients with or without AAG. All samples were assessed for the ability to cause gnACHR immunomodulation utilizing the prototypical gnACHR expressing cell line, IMR-32. Decision limits were calculated from healthy controls, and Receiver Operating Characteristic (ROC) curves were constructed after unblinding all samples. One hundred and ninety serum samples were analyzed; all 182 expected negative samples (from healthy controls, autonomic disorders not thought to be AAG, other neurological disorders without autonomic dysfunction and patients with Systemic Lupus Erythematosus) were negative for immunomodulation (<18%), as were the RIA negative AAG and unconfirmed AAG samples. All RIA positive samples displayed significant immunomodulation. There were no false positive or negative samples. There was perfect qualitative concordance as compared to RIA, with an Area Under ROC of 1. Detection of Immunomodulation by flow cytometry for the identification of gnACHR autoantibodies offers excellent concordance with the gnACHR antibody RIA, and overcomes many of the shortcomings of immunoprecipitation assays by directly measuring the pathological effects of these autoantibodies at the cellular level. Further work is needed to determine the correlation between the degree of immunomodulation and disease severity.

Asunto(s)

Autoanticuerpos/sangre , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Enfermedades del Sistema Nervioso Autónomo/inmunología , Citometría de Flujo/métodos , Ganglios Autónomos/inmunología , Receptores Colinérgicos/inmunología , Área Bajo la Curva , Autoanticuerpos/inmunología , Enfermedades Autoinmunes del Sistema Nervioso/sangre , Enfermedades del Sistema Nervioso Autónomo/sangre , Línea Celular Tumoral , Humanos , Inmunomodulación , Plasma , Curva ROC , Suero , Método Simple Ciego

RESUMEN

Objectives. Although multiple mechanisms, including autonomic dysfunction, seem to link sleep-disordered breathing (SDB) with dyslipidemia in animal studies, the data in clinical studies are limited. The aim of this study was to explore the association of lipoprotein levels with SDB measures in healthy habitual snorers. We supposed that autonomic dysfunction is the linking mechanism.Methods. We enrolled 110 previously healthy subjects with complaints of habitual snoring. To assess SDB, polysomnography was performed. Blood samples for the analysis of total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein cholesterol (LDL), and triglycerides (TG) were obtained in a fasting condition after the polysomnography. Baroreflex sensitivity (BRS) was used to assess the autonomic dysfunction.Results. In stepwise multiple linear regression analysis, minimal nocturnal blood oxygen saturation (beta=-0.240, p=0.020) and neck circumference (beta=0.224, p=0.03) were the only significant contributors in model predicting TG. SDB measures were not identified as significant contributors in models predicting TC, LDL, and HDL. We failed to find any significant difference in BRS in SDB subjects when compared according to the presence or absence of hypercholesterolemia/ hypertriglyceridemia. In SDB subjects, the area under the curve in a receiver operating curve to predict hypercholesterolemia and hypertriglyceridemia by BRS was 0.468 (95% CI: 0.328-0.608) and 0.425 (95% CI: 0.304-0.546), respectively.Conclusions. Our results suggest that minimal nocturnal blood oxygen saturation is significant contributor in model predicting TG. No significant decrease in BRS was found in SDB subjects with hypercholesterolemia and hypertriglyceridemia. In SDB subjects, the role of autonomic dys-function in the development of dyslipidemia remains controversial.

Asunto(s)

Enfermedades del Sistema Nervioso Autónomo/sangre , Lipoproteínas/sangre , Síndromes de la Apnea del Sueño/sangre , Adulto , Barorreflejo , HDL-Colesterol/sangre , Femenino , Humanos , Hipercolesterolemia/fisiopatología , Hipertrigliceridemia/fisiopatología , Masculino , Persona de Mediana Edad , Oxígeno/sangre , Polisomnografía , Ronquido , Triglicéridos/sangre

RESUMEN

AIMS: Cardiac autonomic neuropathy (CAN) is a serious complication of diabetes and is associated with adipokines. The C1q tumor necrosis factor-related protein 9 (CTRP9) is a newly discovered adipokine. This study aimed to evaluate the association of serum CTRP9 levels with the prevalence and severity of CAN in patients with type 2 diabetes mellitus. MATERIALS AND METHODS: We enrolled 262 patients (aged ≥18 years) with type 2 diabetes mellitus into this study. Standard cardiovascular autonomic reflex tests (CARTs) were used to assess CAN and patients were divided into three groups accordingly: a non-CAN group, an early CAN group, and a definite CAN group. Serum CTRP9 levels were measured by enzyme-linked immunosorbent assay, and the tertiles were calculated. RESULTS: Serum CTRP9 levels decreased significantly in the early CAN and definite CAN groups (P < 0.05). The percentage of definite CAN was the highest at the minimum tertile of serum CTRP9 level (T1; P < 0.05). Additionally, serum CTRP9 levels were negatively correlated with age, DM duration, hemoglobin A1c (HbA1c), and fasting plasma glucose (FPG) while positively correlated with high-density lipoprotein cholesterol (HDL; P < 0.05). The level of CTRP9 was also significantly associated with the four indexes of CARTs (P < 0.05). Furthermore, CTRP9 was a protective factor for definite CAN (P < 0.05). Compared with the maximum tertile (T3) of the serum CTRP9 levels, a decreased level of serum CTRP9 in T1 significantly increased the prevalence ratio of definite CAN in patients with type 2 diabetes mellitus (P < 0.05). CONCLUSION: Serum CTRP9 levels were independently associated with definite CAN. CTRP9 represents a reliable biomarker for exploring CAN in patients with type 2 diabetes mellitus.

Asunto(s)

Adiponectina/sangre , Enfermedades del Sistema Nervioso Autónomo/sangre , Diabetes Mellitus Tipo 2/sangre , Neuropatías Diabéticas/sangre , Cardiopatías/sangre , Adulto , Anciano , Envejecimiento , Enfermedades del Sistema Nervioso Autónomo/epidemiología , Biomarcadores , Glucemia/análisis , HDL-Colesterol/sangre , Diabetes Mellitus Tipo 2/epidemiología , Neuropatías Diabéticas/epidemiología , Femenino , Hemoglobina Glucada/análisis , Cardiopatías/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Prevalencia

RESUMEN

Available studies and information on the regulatory effect of the autonomic nervous system (ANS) in pregnancy are insufficient and contradictory due to a variety of research methods of ANS, the lack of a single standardized approach to the assessment of the functional tone of the ANS departments, and interpretation of the results. The aim of the study is investigation and predictive assessment of clinical and laboratory data in pregnant women with suprasegmental autonomic dysfunction with or without hypertension to determine the main directions of effective prevention of the nervous system damage. The material of the study included 206 pregnant women diagnosed with the syndrome of autonomic dysfunction in different variants. Age ranged from 17 to 47 years. All pregnant women had the following laboratory tests: general clinical tests, biochemical blood tests, including prothrombin index, fibrinogen, von Willebrand factor activity. The clinical and laboratory data were analyzed in pregnant women with autonomic dysfunction with or without hypertension. According to the results, it was found that in all groups of pregnant women a sympathetic effect prevails. This study showed that in the group of normotensive pregnant women, the main symptom is venous dysfunction, which poses a risk of an adverse course of cerebrovascular disease.

Asunto(s)

Enfermedades del Sistema Nervioso Autónomo/sangre , Enfermedades del Sistema Nervioso Autónomo/fisiopatología , Complicaciones del Embarazo/sangre , Complicaciones del Embarazo/fisiopatología , Adolescente , Adulto , Enfermedades del Sistema Nervioso Autónomo/diagnóstico , Femenino , Cefalea/sangre , Cefalea/diagnóstico , Cefalea/fisiopatología , Humanos , Hipertensión/sangre , Hipertensión/diagnóstico , Hipertensión/fisiopatología , Persona de Mediana Edad , Embarazo , Complicaciones del Embarazo/diagnóstico , Adulto Joven

RESUMEN

AIMS/HYPOTHESIS: Emerging evidence suggests that in addition to hyperglycaemia, dyslipidaemia could represent a contributing pathogenetic factor to diabetic neuropathy, while obesity and insulin resistance play a role in the development of diabetic cardiac autonomic neuropathy (CAN) characterised by reduced heart rate variability (HRV), particularly in type 2 diabetes. We hypothesised that distinct lipid metabolites are associated with diminished HRV in recent-onset type 2 diabetes rather than type 1 diabetes. METHODS: We analysed 127 plasma lipid metabolites (11 acylcarnitines, 39 NEFA, 12 sphingomyelins (SMs), 56 phosphatidylcholines and nine lysophosphatidylcholines) using MS in participants from the German Diabetes Study baseline cohort recently diagnosed with type 1 (n = 100) and type 2 diabetes (n = 206). Four time-domain HRV indices (number of normal-to-normal (NN) intervals >50 ms divided by the number of all NN intervals [pNN50]; root mean square of successive differences [RMSSD]; SD of NN intervals [SDNN]; and SD of differences between adjacent NN intervals) and three frequency-domain HRV indices (very-low-frequency [VLF], low-frequency [LF] and high-frequency [HF] power spectrum) were computed from NN intervals recorded during a 3 h hyperinsulinaemic-euglycaemic clamp at baseline and in subsets of participants with type 1 (n = 60) and type 2 diabetes (n = 95) after 5 years. RESULTS: In participants with type 2 diabetes, after Bonferroni correction and rigorous adjustment, SDNN was inversely associated with higher levels of diacyl-phosphatidylcholine (PCaa) C32:0, PCaa C34:1, acyl-alkyl-phosphatidylcholine (PCae) C36:0, SM C16:0 and SM C16:1. SD of differences between NN intervals was inversely associated with PCaa C32:0, PCaa C34:1, PCaa C34:2, PCae C36:0 and SM C16:1, and RMSSD with PCae C36:0. For VLF power, inverse associations were found with PCaa C30:0, PCaa C32:0, PCaa C32:1, PCaa C34:2 and SM C16:1, and for LF power inverse associations were found with PCaa C32:0 and SM C16:1 (r = -0.242 to r = -0.349; p ≤ 0.0005 for all correlations). In contrast, no associations of lipid metabolites with measures of cardiac autonomic function were noted in participants recently diagnosed with type 1 diabetes. After 5 years, HRV declined due to ageing rather than diabetes, whereby prediction analyses for lipid metabolites were hampered. CONCLUSIONS/INTERPRETATION: Higher plasma levels of specific lipid metabolites are closely linked to cardiac autonomic dysfunction in recent-onset type 2 diabetes but not type 1 diabetes, suggesting a role for perturbed lipid metabolism in the early development of CAN in type 2 diabetes. Graphical abstract.

Asunto(s)

Enfermedades del Sistema Nervioso Autónomo/sangre , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 2/sangre , Neuropatías Diabéticas/sangre , Lipidómica , Adulto , Enfermedades del Sistema Nervioso Autónomo/etiología , Enfermedades del Sistema Nervioso Autónomo/fisiopatología , Carnitina/análogos & derivados , Carnitina/sangre , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 2/complicaciones , Neuropatías Diabéticas/etiología , Neuropatías Diabéticas/fisiopatología , Dislipidemias/sangre , Ácidos Grasos no Esterificados/sangre , Femenino , Técnica de Clampeo de la Glucosa , Frecuencia Cardíaca , Humanos , Resistencia a la Insulina , Metabolismo de los Lípidos , Lisofosfatidilcolinas/sangre , Masculino , Persona de Mediana Edad , Obesidad/sangre , Fosfatidilcolinas/sangre , Esfingomielinas/sangre , Adulto Joven

RESUMEN

BACKGROUND: Recurrent hypoglycemia blunts counter-regulatory responses to subsequent hypoglycemic episodes, a syndrome known as hypoglycemia-associated autonomic failure (HAAF). Since adrenergic receptor blockade has been reported to prevent HAAF, we investigated whether the hypoglycemia-associated rise in plasma epinephrine contributes to pathophysiology and reported interindividual differences in susceptibility to HAAF. METHODS: To assess the role of hypoglycemia-associated epinephrine responses in the susceptibility to HAAF, 24 adult nondiabetic subjects underwent two 2-hour hyperinsulinemic hypoglycemic clamp studies (nadir 54 mg/dL; 0-2 hours and 4-6 hours) on Day 1, followed by a third identical clamp on Day 2. We challenged an additional 7 subjects with two 2-hour infusions of epinephrine (0.03 µg/kg/min; 0-2 hours and 4-6 hours) vs saline on Day 1 followed by a 200-minute stepped hypoglycemic clamp (90, 80, 70, and 60 mg/dL) on Day 2. RESULTS: Thirteen out of 24 subjects developed HAAF, defined by ≥20% reduction in average epinephrine levels during the final 30 minutes of the third compared with the first hypoglycemic episode (P < 0.001). Average epinephrine levels during the final 30 minutes of the first hypoglycemic episode were 2.3 times higher in subjects who developed HAAF compared with those who did not (P = 0.006).Compared to saline, epinephrine infusion on Day 1 reduced the epinephrine responses by 27% at the 70 and 60 mg/dL glucose steps combined (P = 0.04), with a parallel reduction in hypoglycemic symptoms (P = 0.03) on Day 2. CONCLUSIONS: Increases in plasma epinephrine reproduce key features of HAAF in nondiabetic subjects. Marked interindividual variability in epinephrine responses to hypoglycemia may explain an individual's susceptibility to developing HAAF.

Asunto(s)

Enfermedades del Sistema Nervioso Autónomo/etiología , Epinefrina/sangre , Hipoglucemia/complicaciones , Adulto , Sistema Nervioso Autónomo/fisiopatología , Enfermedades del Sistema Nervioso Autónomo/sangre , Enfermedades del Sistema Nervioso Autónomo/fisiopatología , Glucemia , Femenino , Técnica de Clampeo de la Glucosa , Humanos , Hipoglucemia/sangre , Hipoglucemia/fisiopatología , Insulina/sangre , Masculino , Persona de Mediana Edad

RESUMEN

OBJECTIVE: In type 1 diabetes, autonomic dysfunction may occur early as a decrease in heart rate variability (HRV). In populations without diabetes, the positive effects of exercise training on HRV are well-documented. However, exercise in individuals with type 1 diabetes, particularly if strenuous and prolonged, can lead to sharp glycemic variations, which can negatively impact HRV. This study explores the impact of a 9-day cycling tour on HRV in this population, with a focus on exercise-induced glycemic excursions. RESEARCH DESIGN AND METHODS: Twenty amateur athletes with uncomplicated type 1 diabetes cycled 1,500 km. HRV and glycemic variability were measured by heart rate and continuous glucose monitoring. Linear mixed models were used to test the effects of exercise on HRV, with concomitant glycemic excursions and subject characteristics considered as covariates. RESULTS: Nighttime HRV tended to decrease with the daily distance traveled. The more time the subjects spent in hyperglycemia, the lower the parasympathetic tone was. This result is striking given that hyperglycemic excursions progressively increased throughout the 9 days of the tour, and to a greater degree on the days a longer distance was traveled, while time spent in hypoglycemia surprisingly decreased. This phenomenon occurred despite no changes in insulin administration and a decrease in carbohydrate intake from snacks. CONCLUSIONS: In sports enthusiasts with type 1 diabetes, multiday prolonged exercise at moderate-to-vigorous intensity worsened hyperglycemia, with hyperglycemia negatively associated with parasympathetic cardiac tone. Considering the putative deleterious consequences on cardiac risks, future work should focus on understanding and managing exercise-induced hyperglycemia.

Asunto(s)

Enfermedades del Sistema Nervioso Autónomo , Ciclismo/fisiología , Diabetes Mellitus Tipo 1 , Frecuencia Cardíaca/fisiología , Hiperglucemia/sangre , Adulto , Atletas , Enfermedades del Sistema Nervioso Autónomo/sangre , Enfermedades del Sistema Nervioso Autónomo/etiología , Glucemia/análisis , Glucemia/metabolismo , Automonitorización de la Glucosa Sanguínea , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/fisiopatología , Angiopatías Diabéticas/sangre , Angiopatías Diabéticas/fisiopatología , Ejercicio Físico/fisiología , Femenino , Corazón/fisiopatología , Humanos , Hiperglucemia/etiología , Hiperglucemia/fisiopatología , Masculino , Persona de Mediana Edad , Adulto Joven

RESUMEN

BACKGROUND AND AIMS: The prognostic value of uric acid in ischemic stroke remains controversial, and it is unclear whether renal function status modifies the prognostic value of uric acid in ischemic stroke patients. METHODS: A total of 3284 acute ischemic stroke patients from the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS) with creatinine and uric acid measurements were included in this analysis. The primary outcome was a composite of death and major disability (modified Rankin Scale score ≥3) at 1 year after stroke. RESULTS: The prognostic value of uric acid in ischemic stroke was appreciably modified by patients' renal function status (p for interaction <0.05). After multivariate adjustment, higher uric acid level was significantly associated with a better prognosis in patients with normal renal function (odds ratio, 0.61; 95% confidence interval, 0.45-0.83), but not in those with abnormal renal function (odds ratio, 0.87; 95% confidence interval, 0.48-1.55), when two extreme quartiles were compared. Linear association between uric acid and primary outcome was observed among patients with normal renal function (p for linearity = 0.023). CONCLUSION: The present study suggests that high serum uric acid concentration is associated with better prognosis in ischemic stroke patients with normal renal function, but not in those with abnormal renal function. The establishment of causality between increased uric acid levels and better stroke prognosis needs more suitably designed randomized clinical trials.

Asunto(s)

Presión Sanguínea/fisiología , Isquemia Encefálica/diagnóstico , Accidente Cerebrovascular Isquémico/diagnóstico , Ácido Úrico/sangre , Anciano , Anciano de 80 o más Años , Enfermedades del Sistema Nervioso Autónomo/sangre , Enfermedades del Sistema Nervioso Autónomo/diagnóstico , Biomarcadores/análisis , Biomarcadores/sangre , Determinación de la Presión Sanguínea/métodos , Isquemia Encefálica/sangre , Isquemia Encefálica/tratamiento farmacológico , Femenino , Humanos , Accidente Cerebrovascular Isquémico/sangre , Masculino , Persona de Mediana Edad , Pronóstico , Factores de Riesgo

RESUMEN

BACKGROUND: Sclerostin inhibits bone formation and its expression is upregulated in the vasculature during the arterial calcification process as a counterregulatory mechanism preventing further calcification. Lower extremity arterial calcification (LEAC) is common in neuropathic patients with type 2 diabetes (T2DM). Herein, we investigated for associations between plasma sclerostin levels and diabetic neuropathy as well as LEAC in subjects with T2DM. METHODS: A total of 74 individuals with and 76 without T2DMwere recruited. Plasma sclerostin levels were measured by ELISA. Diagnosis of cardiac autonomic neuropathy (CAN) was based on the battery of the four autonomic tests, while of somatosensory peripheral neuropathy (DPN) on neuropathy symptom score and neuropathy disability score. LEAC was assessed with conventional ankle and foot x-rays. RESULTS: Plasma sclerostin levels were higher in participants with LEAC vs. those without LEAC in both diabetes and non-diabetes cohorts (p = 0.035 and p = 0.003, respectively). In the diabetes cohort, patients with CAN, but not with DPN, had higher sclerostin levels when compared with those without CAN (p < 0.001). Multivariate analysis in the diabetes cohort demonstrated that sclerostin levels were associated positively with CAN and LEAC, while in the non-diabetes cohort there was a trend for a positive association with male gender and presence of LEAC. CONCLUSION: Plasma sclerostin levels are increased in individuals with LEAC irrespectively of diabetes status. In addition, plasma sclerostin concentrations are associated independently with LEAC and CAN in people with T2DM.

Asunto(s)

Proteínas Adaptadoras Transductoras de Señales/sangre , Enfermedades del Sistema Nervioso Autónomo/sangre , Diabetes Mellitus Tipo 2/sangre , Neuropatías Diabéticas/sangre , Enfermedad Arterial Periférica/sangre , Calcificación Vascular/sangre , Anciano , Enfermedades del Sistema Nervioso Autónomo/complicaciones , Estudios de Cohortes , Diabetes Mellitus Tipo 2/complicaciones , Neuropatías Diabéticas/complicaciones , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad Arterial Periférica/etiología , Factores de Riesgo , Calcificación Vascular/etiología

RESUMEN

BACKGROUND: Treatment induced neuropathy of diabetes (TIND) is an iatrogenic painful sensory and autonomic neuropathy. Although the prevalence is not known, it is seen in up to 10% of tertiary cases referred for evaluation of diabetic neuropathy. EVIDENCE: TIND is associated with a decrease in the glycosylated hemoglobin A1C in individuals with longstanding hyperglycemia. TIND is more common in individuals with type 1 diabetes, but can occur in anyone with diabetes through the use of insulin, oral hypoglycemic medications or diet control. There is an acute or subacute onset of neuropathy that is linked to the change in glucose control. Although the primary clinical manifestation is neuropathic pain there is a concurrent development of autonomic dysfunction, retinopathy and nephropathy. CONCLUSION: TIND is more common than previously suspected. The number of cases reported over the past 10 years is much greater than historical literature predicted. Increased attention to target glucose control as a physician metric could suggest a possible explanation for the increased in TIND cases reported in recent years. At present, supportive care is the only recommended treatment. Future research is necessary to define the underlying mechanism, prevent development and to guide treatment recommendations.

Asunto(s)

Enfermedades del Sistema Nervioso Autónomo/inducido químicamente , Diabetes Mellitus/tratamiento farmacológico , Neuropatías Diabéticas/inducido químicamente , Hemoglobina Glucada , Hipoglucemiantes/efectos adversos , Enfermedad Iatrogénica , Neuralgia/inducido químicamente , Enfermedades del Sistema Nervioso Autónomo/sangre , Neuropatías Diabéticas/sangre , Humanos , Neuralgia/sangre

RESUMEN

Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common type of hereditary neuropathy worldwide and diabetes mellitus (DM) is the most frequent cause of peripheral neuropathy in the Western world. CMT1A typically manifest as a predominant motor neuropathy, while, DM-related neuropathy often manifests as a predominant sensory disorder. There are some evidences that CMT1A patients that also had DM had a more severe neuropathy. Although the real frequency and the underlying mechanisms related to this association has not yet been addressed in the literature. We sought to characterize the phenotypic variability of CMT1A patients with persistent high glucose levels (DM or impaired glucose tolerance [IGT]). Nineteen patients with CMT1A and DM (CMTdiab), seven with CMT1A and IGT (CMTintol) and 27 with CMT1A without comorbidities were analyzed. They were evaluated through clinical assessment, application of the following scales: visual analogue scale, McGill, CMTNS, SF-36 and COMPASS 31 and electrophysiological studies. Patients CMTdiab had a more severe motor and sensory neuropathy, more intense autonomic symptoms and worse quality of life. Surprisingly, proximal weakness and temporal dispersion on nerve conduction studies are frequently observed in this group. Patients CMTintol also had a more severe neuropathy. Curiously, we observed that the association of CMT1A and glucose metabolism disorders (CMTglic) clustered in some families. Patients CMTglic develop a more severe neuropathy. As there is yet no cure to CMT1A, a strict blood sugar control may be a useful measure.

Asunto(s)

Enfermedades del Sistema Nervioso Autónomo , Enfermedad de Charcot-Marie-Tooth , Diabetes Mellitus , Neuropatías Diabéticas , Intolerancia a la Glucosa , Adulto , Enfermedades del Sistema Nervioso Autónomo/sangre , Enfermedades del Sistema Nervioso Autónomo/epidemiología , Enfermedades del Sistema Nervioso Autónomo/etiología , Enfermedades del Sistema Nervioso Autónomo/fisiopatología , Enfermedad de Charcot-Marie-Tooth/sangre , Enfermedad de Charcot-Marie-Tooth/complicaciones , Enfermedad de Charcot-Marie-Tooth/epidemiología , Enfermedad de Charcot-Marie-Tooth/fisiopatología , Comorbilidad , Diabetes Mellitus/sangre , Diabetes Mellitus/epidemiología , Diabetes Mellitus/fisiopatología , Neuropatías Diabéticas/sangre , Neuropatías Diabéticas/epidemiología , Neuropatías Diabéticas/etiología , Neuropatías Diabéticas/fisiopatología , Femenino , Intolerancia a la Glucosa/sangre , Intolerancia a la Glucosa/complicaciones , Intolerancia a la Glucosa/epidemiología , Intolerancia a la Glucosa/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Conducción Nerviosa/fisiología , Examen Neurológico , Calidad de Vida

RESUMEN

The clinical importance of autoantibodies against the ganglionic acetylcholine receptor (gAChR) remains to be fully elucidated. We aimed to identify the clinical characteristics of autoimmune autonomic ganglionopathy (AAG) in patients with gAChR autoantibodies. For this cohort investigation, serum samples were obtained from patients with AAG between 2012 and 2018 in Japan. We measured the levels of autoantibodies against gAChRα3 and gAChRß4 and evaluated clinical features, as well as assessing the laboratory investigation results among the included patients. A total of 179 patients tested positive for antibodies, including 116 gAChRα3-positive, 13 gAChRß4-positive, and 50 double antibody-positive patients. Seropositive AAG patients exhibited widespread autonomic dysfunction. Extra-autonomic manifestations including sensory disturbance, central nervous system involvement, endocrine disorders, autoimmune diseases, and tumours were present in 118 patients (83%). We observed significant differences in the frequencies of several autonomic and extra-autonomic symptoms among the three groups. Our 123I-metaiodobenzylguanidine myocardial scintigraphy analysis of the entire cohort revealed that the heart-to-mediastinum ratio had decreased by 80%. The present study is the first to demonstrate that patients with AAG who are seropositive for anti-gAChRß4 autoantibodies exhibit unique autonomic and extra-autonomic signs. Decreased cardiac uptake occurred in most cases, indicating that 123I- metaiodobenzylguanidine myocardial scintigraphy may be useful for monitoring AAG. Therefore, our findings indicate that gAChRα3 and gAChRß4 autoantibodies cause functional changes in postganglionic fibres in the autonomic nervous system and extra-autonomic manifestations in seropositive patients with AAG.

Asunto(s)

Enfermedades Autoinmunes/diagnóstico , Enfermedades Autoinmunes/inmunología , Autoinmunidad , Enfermedades del Sistema Nervioso Autónomo/diagnóstico , Enfermedades del Sistema Nervioso Autónomo/inmunología , Ganglios Autónomos/inmunología , Receptores Colinérgicos/inmunología , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Autoantígenos/inmunología , Enfermedades Autoinmunes/sangre , Enfermedades del Sistema Nervioso Autónomo/sangre , Biomarcadores , Humanos , Japón , Imagen de Perfusión Miocárdica , Fenotipo

RESUMEN

OBJECTIVE: To investigate the association between serum C-peptide level and cardiovascular autonomic neuropathy (CAN) in individuals with type 2 diabetes mellitus (DM) according to estimated glomerular filtration rate (eGFR) METHODS: In a cross-sectional study, we examined 939 individuals with type 2 DM. We measured fasting C-peptide, 2-hour postprandial C-peptide, and ΔC-peptide (postprandial C-peptide minus fasting C-peptide) levels. The individuals were classified into 2 groups based on eGFR: individuals without impaired renal function (eGFR ≥60 ml∙min-1 1.73m-2) and those with impaired renal function (eGFR <60 ml∙min-1 1.73m-2). RESULTS: Individuals with CAN had lower fasting C-peptide, postprandial C-peptide, and ΔC-peptide levels in patients both with and without impaired renal function. Multivariate logistic regression analyses adjusted for gender, age, and other confounders, including eGFR, showed that serum C-peptide level was significantly associated with CAN (odds ratio [OR] per standard deviation increase in the log-transformed value, 0.67; 95% confidence interval [CI], 0.52-0.87 for fasting C-peptide, P < 0.01; OR, 0.62; 95% CI, 0.47-0.83 for postprandial C-peptide, P < 0.01; OR, 0.71; 95% CI, 0.54-0.93 for ΔC-peptide, P < 0.05). CONCLUSIONS: Serum C-peptide level was negatively associated with CAN in individuals with type 2 DM independent of eGFR.

Asunto(s)

Péptido C/sangre , Diabetes Mellitus Tipo 2/complicaciones , Neuropatías Diabéticas/sangre , Adulto , Anciano , Sistema Nervioso Autónomo/fisiopatología , Enfermedades del Sistema Nervioso Autónomo/sangre , Enfermedades del Sistema Nervioso Autónomo/etiología , Enfermedades del Sistema Nervioso Autónomo/fisiopatología , Estudios Transversales , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/fisiopatología , Angiopatías Diabéticas/sangre , Angiopatías Diabéticas/etiología , Angiopatías Diabéticas/fisiopatología , Nefropatías Diabéticas/sangre , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/fisiopatología , Neuropatías Diabéticas/etiología , Neuropatías Diabéticas/fisiopatología , Femenino , Tasa de Filtración Glomerular/fisiología , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo

RESUMEN

Systemic inflammation is associated with arteriosclerotic disease progression and worse stroke outcome in patients with carotid arteriosclerotic disease. We hypothesize that systemic inflammation is mediated by impaired carotid baroreceptor and chemoreceptor function induced by carotid arteriosclerosis rather than by the generalized inflammatory arteriosclerotic process.Heart rate variability (HRV), serum levels of inflammatory markers, demographic and life style factors, and concomitant diseases with potential impact on systemic inflammation were determined in 105 patients with asymptomatic carotid stenosis of varying degree. Multivariate linear regression analyses were performed to ascertain independent determinants of carotid stenosis severity, autonomic function, and inflammation.Systemic inflammation (C-reactive protein, beta = .255; P = .014), age (beta = .232; P < .008), and arterial hypertension (beta = .206; P = .032) were associated with carotid stenosis severity. Only carotid stenosis severity and not generalized arteriosclerotic disease, concomitant diseases (arterial hypertension, diabetes mellitus, dyslipidemia, hypothyroidism), life style factors (smoking, obesity), or age was associated with a reduction in vagal tone (HRV HF band power beta = - .193; P < 0.049). Systemic inflammation was related to a reduction in vagal tone (HRV HF band power, beta = - .214; P = .031), and not to generalized arteriosclerotic disease, concomitant diseases (arterial hypertension, diabetes mellitus, dyslipidemia), life style factors (smoking, obesity), and age.In conclusion, systemic inflammation is associated with carotid rather than with generalized arteriosclerotic disease. The association between systemic inflammation and carotid arteriosclerosis is mediated by a reduction in vagal tone which indicates a major role of carotid arteriosclerosis-mediated autonomic dysfunction in the pathogenesis of systemic inflammation in arteriosclerotic disease.

Asunto(s)

Arteriosclerosis/complicaciones , Enfermedades del Sistema Nervioso Autónomo/complicaciones , Estenosis Carotídea/complicaciones , Inflamación/complicaciones , Adulto , Anciano , Anciano de 80 o más Años , Arteriosclerosis/sangre , Enfermedades del Sistema Nervioso Autónomo/sangre , Estenosis Carotídea/sangre , Femenino , Frecuencia Cardíaca , Humanos , Inflamación/sangre , Estilo de Vida , Masculino , Persona de Mediana Edad

RESUMEN

The aim of the study is to investigate differences in non-standard adrenergic baroreflex sensitivity (BRS) indices in patients with different phenotypes of multiple sclerosis (pwMS) and healthy controls (HC). Retrospective analysis of types of systolic blood pressure (BP) curves during Valsalva maneuver (VM) [balanced (BAR), augmented (AAR) and suppressed (SAR) autonomic responses] and adrenergic baroreflex sensitivity (BRSa) measured with BRSa1, α-BRSa and ß-BRSa in patients with clinically isolated syndrome (CIS), relapsing remitting multiple sclerosis (RRMS), progressive multiple sclerosis (PMS) and HC. We also investigated correlations between BRSa1, α-BRSa, ß-BRSa and resting catecholamine levels. pwMS had higher α-BRSa compared to HC (p = 0.02). There was no difference in BRSa1, s and ß-BRSa between patients with CIS, RRMS and PMS. There was no association between pwMS and HC, and the type of sBP curve [χ2 = 4.332, p = 0.114]. pwMS and BAR or AAR had higher supine systolic and diastolic BP compared to pwMS and SAR. There was a significant correlation between α-BRSa and upright systolic BP (rp =0.194, p = 0.017), α-BRSa and norepinephrine (rs =0.228, p = 0.021), and BRSa1 and epinephrine (rs = 0.226, p = 0.040). pwMS and HC exhibit different alpha-adrenergic response to Valsalva maneuver. These results may explain the connection between MS and increased cardiovascular risk.

Asunto(s)

Barorreflejo/fisiología , Enfermedades Cardiovasculares/fisiopatología , Esclerosis Múltiple/fisiopatología , Adulto , Enfermedades del Sistema Nervioso Autónomo/sangre , Enfermedades del Sistema Nervioso Autónomo/fisiopatología , Enfermedades Cardiovasculares/sangre , Comorbilidad , Epinefrina/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/sangre , Norepinefrina/sangre , Estudios Retrospectivos