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  • Essential role of RVL medullary neuronal activity in the lng term maintenance of hypertension in conscious SHR
    Publication . Geraldes, Vera; Gonçalves-Rosa, Nataniel; Liu, Beihui; Paton, Julian F.R.; Rocha, Isabel
    Background: It is well established that sympathetic nervous system is responsible for the onset, development and maintenance of neurogenic hypertension. The rostroventrolateral medulla (RVLM) and medullo-cervical pressor area (MCPA) are important central sympathoexcitatory regions whose role on neurogenic hypertension remains unknown. Objective: To establish RVLM and MCPA roles in the long-term regulation of blood pressure by depressing their neuron activity through the over-expression of hKir2.1-potassium channel in conscious spontaneously hypertensive rats (SHR). Methods: In SHR, a lentiviral vector LVV-hKir2.1 was microinjected into RVLM or MCPA areas. A sham group was injected with LVV-eGFP. Blood pressure (BP) and heart rate (HR) were continuously monitored for 75 days. Baroreflex and chemoreflex functions were evaluated. Baroreflex gain, chemoreflex sensitivity, BP and HR variability were calculated. Results: LVV-hKir2.1 expression in RVLM, but not in MCPA, produced a significant time-dependent decrease in systolic, diastolic, mean-BP and LF of systolic BP at 60-days post-injection. No significant changes were seen in LVV-eGFP RVLM injected SHR. Conclusion: Data show that chronic expression of Kir2.1 in the RVLM of conscious SHR caused a marked and sustained decrease in BP without changes in the baro- and peripheral chemoreceptor reflex evoked responses. This decrease was mostly due to a reduction in sympathetic output revealed indirectly by a decrease in the power density of the SBP-LF band. Our data are amongst the firsts to demonstrate the role of the RVLM in maintaining BP levels in hypertension in conscious SHR. We suggest that a decrease in RVLM neuronal activity is an effective anti-hypertensive treatment strategy.
  • Orthostatic stress and baroreflex sensitivity: a window into autonomic dysfunction in lone paroxysmal atrial fibrillation
    Publication . Ferreira, Mónica; Laranjo, Sergio; Cunha, Pedro; Geraldes, Vera; Oliveira, Mario; Rocha, Isabel
    The abnormal neural control of atria has been considered one of the mechanisms of paroxysmal atrial fibrillation (PAF) pathogenesis. The baroreceptor reflex has an important role in cardiovascular regulation and may serve as an index of autonomic function. This study aimed to analyze the baroreceptor reflex's role in heart rate regulation during upright tilt (HUT) in patients with lone PAF. The study included 68 patients with lone PAF and 34 healthy individuals who underwent baroreflex assessment. Parameters such as baroreflex sensitivity (BRS), number of systolic blood pressure (BP) ramps, and the baroreflex effectiveness index (BEI) were evaluated. The study found that PAF patients had comparable resting BPs and heart rates (HRs) to healthy individuals. However, unlike healthy individuals, PAF patients showed a sustained increase in BP with an upright posture followed by the delayed activation of the baroreceptor function with a blunted HR response and lower BEI values. This indicates a pronounced baroreflex impairment in PAF patients, even at rest. Our data suggest that together with BRS, BEI could be used as a marker of autonomic dysfunction in PAF patients, making it important to further investigate its relationship with AF recurrence after ablation and its involvement in cardiovascular autonomic remodeling.
  • Clinical autonomic nervous system laboratories in Europe: a joint survey of the European Academy of Neurology and the European Federation of Autonomic Societies
    Publication . Habek, Mario; Leys, Fabian; Krbot Skorić, Magdalena; Reis Carneiro, Diogo; Calandra‐Buonaura, Giovanna; Camaradou, Jennifer; Chiaro, Giacomo; Cortelli, Pietro; Falup‐Pecurariu, Cristian; Granata, Roberta; Guaraldi, Pietro; Helbok, Raimund; Hilz, Max J.; Iodice, Valeria; Jordan, Jens; Kaal, Evert C. A.; Kamondi, Anita; Pavy Le Traon, Anne; Rocha, Isabel; Sellner, Johann; Senard, Jean Michel; Terkelsen, Astrid; Wenning, Gregor K.; Berger, Thomas; Thijs, Roland D.; Struhal, Walter; Fanciulli, Alessandra; Adamec, Ivan; Aerts, Arnaud; Canta, Leo L.R.; Delamont, Robert Shane; de Lange, Frederik; Del Sorbo, Francesca; Devigili, Grazia; Di Leo, Rita; Dinh, Trang; Fortrat, Jacques‐Olivier; Gierthmühlen, Janne; Hemels, Martin; Köhn, Julia; Krøigård, Thomas; Lipp, Axel; Maier, Andrea; Marinelli, Lucio; Mazzeo, Anna; Milenkovic, Ivan; Motyl, Maciej; Natali Sora, Maria Grazia; Navarro‐Otano, Judith; Nilsen, Kristian Bernhard; Oliveira, Mario; Omland, Petter Moe; Pelliccioni, Giuseppe; Pereon, Yann; Resch, Roland Josef; Rocchi, Camilla; Roche, Frederic; Rutten, Joost; Tijero Merino, Beatriz; Tutaj, Marcin; van der Heijden‐Montfroy, A.M.H.G.; van Hoeve, Bas J.A.; van Orshoven, Narender; Wang, Ruihao; Z’Graggen, Werner J.
    Background and purpose: Disorders of the autonomic nervous system (ANS) are common conditions, but it is unclear whether access to ANS healthcare provision is homogeneous across European countries. The aim of this study was to identify neurology-driven or interdisciplinary clinical ANS laboratories in Europe, describe their characteristics and explore regional differences. Methods: We contacted the European national ANS and neurological societies, as well as members of our professional network, to identify clinical ANS laboratories in each country and invite them to answer a web-based survey. Results: We identified 84 laboratories in 22 countries and 46 (55%) answered the survey. All laboratories perform cardiovascular autonomic function tests, and 83% also perform sweat tests. Testing for catecholamines and autoantibodies are performed in 63% and 56% of laboratories, and epidermal nerve fiber density analysis in 63%. Each laboratory is staffed by a median of two consultants, one resident, one technician and one nurse. The median (interquartile range [IQR]) number of head-up tilt tests/laboratory/year is 105 (49-251). Reflex syncope and neurogenic orthostatic hypotension are the most frequently diagnosed cardiovascular ANS disorders. Thirty-five centers (76%) have an ANS outpatient clinic, with a median (IQR) of 200 (100-360) outpatient visits/year; 42 centers (91%) also offer inpatient care (median 20 [IQR 4-110] inpatient stays/year). Forty-one laboratories (89%) are involved in research activities. We observed a significant difference in the geographical distribution of ANS services among European regions: 11 out of 12 countries from North/West Europe have at least one ANS laboratory versus 11 out of 21 from South/East/Greater Europe (p = 0.021). Conclusions: This survey highlights disparities in the availability of healthcare services for people with ANS disorders across European countries, stressing the need for improved access to specialized care in South, East and Greater Europe.
  • Sympathovagal imbalance in early ischemic stroke is linked to impaired cerebral autoregulation and increased infarct volumes
    Publication . Castro, Pedro; Serrador, Jorge; Sorond, Farzaneh; Azevedo, Elsa; Rocha, Isabel
    Background and purpose: Autonomic dysfunction is associated with worse outcome of ischemic stroke patients by mechanisms that are not fully understood. There is evidence of autonomic influence in cerebrovascular control but this has not been studied in acute stroke. Therefore, we examined the relationship between heart rate variability (HRV) and baroreflex sensitivity (BRS) in dynamic cerebral autoregulation in the early hours post ischemia, and its impact in clinical and radiological outcome. Methods: We prospectively enrolled 26 patients with acute ischemic stroke in middle cerebral artery. Arterial blood pressure (Finometer), cerebral blood flow velocity (transcranial Doppler), and electrocardiogram were recorded within 6 h. HRV was assessed by the standard side deviations of normal inter-beat intervals, spectral analysis and non-linear entropy indexes. Spontaneous BRS was assessed by spectral and sequence methods. Dynamic cerebral autoregulation was assessed by transfer function analysis (coherence, phase and gain). Infarct volume was calculated from computed tomography at 24 h. Clinical outcome was assessed by the modified Rankin scale. Results: Increased BRS and HRV high frequencies power, both reflecting increased vagal modulation, were correlated with higher gain values of cerebral autoregulation (p < 0.05). The higher vagal modulation was also associated with later large infarct volumes (p < 0.05) but not with clinical outcome. Conclusions: Increased vagal modulation in early hours of acute ischemic stroke, may interfere with cerebrovascular control and is associated with larger infarcts. Understanding the mechanisms that govern this complex interplay can be useful as novel therapeutic targets to improvement of outcome.
  • Therapeutic effects of IkB kinase inhibitor during systemic inflammation
    Publication . Amaro-Leal, Ângela; Shvachiy, Liana; Pinto, Rui; Geraldes, Vera; Rocha, Isabel; Mota-Filipe, Helder
    Animal models of inflammatory diseases support the idea that nuclear factor κB (NF-κB) activation plays a pathophysiological role and is widely implicated in multiple organ dysfunction (MOD). Indeed, the inhibition of the IκB kinase (IKK) complex, involved in the NF-κB pathway, can represent a promising approach to prevent MOD. The present work employed a rat model of systemic inflammation to investigate the preventive effects of Inhibitor of IKK complex (IKK16). In male Wistar rats, systemic inflammation was induced by a tail vein injection of lipopolysaccharides (LPS challenge; 12 mg/kg). Treatment with IKK16 (1 mg/kg body weight) was administered, by tail vein, 15 min post-LPS. Age- and sex-matched healthy rats and LPS rats without treatment were used as controls. At 24 h post-IKK16 treatment, serum enzyme levels indicative of liver, kidney, pancreas and muscle function were evaluated by biochemical analysis, and RT-PCR technique was used to analyze gene expression of pro-inflammatory cytokines. Hemodynamic parameters were also considered to assess the LPS-induced inflammation. IKK16 treatment yielded a strong therapeutic effect in preventing LPS-induced elevation of serological enzyme levels, attenuating hepatic, renal, pancreatic and muscular dysfunction after LPS challenge. Moreover, as expected, LPS promoted a significantly overexpression of TNF-α, IL-6 and IL-1β in the heart, kidney, and liver; which was diminished by IKK16 treatment. The present study provides convincing evidence that selective inhibition of the IκB kinase complex through the action of IKK16, plays a protective role against LPS-induced multiple organ dysfunction by reducing the acute inflammatory response induced by endotoxin exposure.
  • Study of lead accumulation in bones of Wistar rats by X-ray fluorescence analysis: aging effect
    Publication . Guimarães, Diana; Carvalho, Maria Luisa; Geraldes, Vera; Rocha, Isabel; Santos, José Paulo
    The accumulation of lead in several bones of Wistar rats with time was determined and compared for the different types of bones. Two groups were studied: a control group (n = 20), not exposed to lead and a contaminated group (n = 30), exposed to lead from birth, first indirectly through mother's milk, and then directly through a diet containing lead acetate in drinking water (0.2%). Rats age ranged from 1 to 11 months, with approximately 1 month intervals and each of the collections had 3 contaminated rats and 2 control rats. Iliac, femur, tibia-fibula and skull have been analysed by Energy Dispersive X-ray Fluorescence Technique (EDXRF). Samples of formaldehyde used to preserve the bone tissues were also analysed by Electrothermal Atomic Absorption (ETAAS), showing that there was no significant loss of lead from the tissue to the preservative. The bones mean lead concentration of exposed rats range from 100 to 300 μg g(-1) while control rats never exceeded 10 μg g(-1). Mean bone lead concentrations were compared and the concentrations were higher in iliac, femur and tibia-fibula and after that skull. However, of all the concentrations in the different collections, only those in the skull were statistically significantly different (p < 0.05) from the other types of bones. Analysis of a radar chart also allowed us to say that these differences tend to diminish with age. The Spearman correlation test applied to mean lead concentrations showed strong and very strong positive correlations between all different types of bones. This test also showed that mean lead concentrations in bones are negatively correlated with the age of the animals. This correlation is strong in iliac and femur and very strong in tibia-fibula and skull. It was also shown that the decrease of lead accumulation with age is made by three plateaus of accumulation, which coincide, in all analysed bones, between 2nd-3rd and 9th-10th months.
  • Intermittent low-level lead exposure causes anxiety and cardiorespiratory impairment
    Publication . Shvachiy, Liana; Geraldes, Vera; Amaro-Leal, Ângela; Rocha, Isabel
    Aim: To characterize behavioural and cardiorespiratory changes in a new, intermittent low-level lead exposure animal model. Introduction: Lead (Pb) is a cumulative toxic metal affecting all body systems that are particularly vulnerable during developmental phase. Permanent lead exposure has been defined as a cause of behavioural changes, cognitive impairment, sympathoexcitation, tachycardia, hypertension and autonomic dysfunction. However, no studies have been performed to describe a new, intermittent low-level lead exposure profile, that has been increased in the past years. Methods: Foetuses were intermittently (PbI) exposed to water containing lead acetate (0.2%, w/v) throughout life until adulthood (28 weeks of age). A control group (without exposure, CTL), matching in age and sex was used. At 26 weeks, behavioural tests were performed for anxiety (Elevated Plus Maze Test) and locomotor activity (Open Field Test) assessment. Blood pressure (BP), electrocardiogram (ECG), heart rate (HR) and respiratory frequency (RF) rates were recorded at 28 weeks of age. Baroreflex gain (BRG) and chemoreflex sensitivity (ChS) were calculated. Student’s T-test was used (significance p < 0.05) for statistical analysis. Results: An intermittent lead exposure causes hypertension (increased diastolic and mean BP), increased RF, decreased baroreflex function and increased ChS, without significant changes in HR, when compared to CTL group. Regarding behavioral changes, the intermittent lead exposure model showed an anxiety-like behaviour without changes in locomotor activity. Conclusion: Intermittent low-level lead exposure induces changes on the cardiorespiratory profile characterized by hypertension, carotid chemosensitivity and baroreflex impairment. According to behavioural tests results, this study also shows that the exposure to lead during developmental phases causes anxiety in adult animals without locomotor activity impairment. In summary, this study brings new insights on the environmental factors that influence nervous and cardiovascular systems during development, which can help creating public policy strategies to prevent and control the adverse effects of Pb toxicity.
  • From molecular to functional effects of different environmental lead exposure paradigms
    Publication . Shvachiy, Liana; Amaro-Leal, Ângela; Outeiro, Tiago; Rocha, Isabel; Geraldes, Vera
    Lead is a heavy metal whose widespread use has resulted in environmental contamination and significant health problems, particularly if the exposure occurs during developmental stages. It is a cumulative toxicant that affects multiple systems of the body, including the cardiovascular and nervous systems. Chronic lead exposure has been defined as a cause of behavioral changes, inflammation, hypertension, and autonomic dysfunction. However, different environmental lead exposure paradigms can occur, and the different effects of these have not been described in a broad comparative study. In the present study, rats of both sexes were exposed to water containing lead acetate (0.2% w/v), from the fetal period until adulthood. Developmental Pb-exposed (DevPb) pups were exposed to lead until 12 weeks of age (n = 13); intermittent Pb exposure (IntPb) pups drank leaded water until 12 weeks of age, tap water until 20 weeks, and leaded water for a second time from 20 to 28 weeks of age (n = 14); and the permanent (PerPb) exposure group were exposed to lead until 28 weeks of age (n = 14). A control group (without exposure, Ctrl), matched in age and sex was used. After exposure protocols, at 28 weeks of age, behavioral tests were performed for assessment of anxiety (elevated plus maze test), locomotor activity (open-field test), and memory (novel object recognition test). Metabolic parameters were evaluated for 24 h, and the acute experiment was carried out. Blood pressure (BP), electrocardiogram, and heart (HR) and respiratory (RF) rates were recorded. Baroreflex gain, chemoreflex sensitivity, and sympathovagal balance were calculated. Immunohistochemistry protocol for NeuN, Syn, Iba-1, and GFAP staining was performed. All Pb-exposed groups showed hypertension, concomitant with a decrease in baroreflex gain and chemoreceptor hypersensitivity, without significant changes in HR and RF. Long-term memory impairment associated with reactive astrogliosis and microgliosis in the dentate gyrus of the hippocampus, indicating the presence of neuroinflammation, was also observed. However, these alterations seemed to reverse after lead abstinence for a certain period (DevPb) and were enhanced when a second exposure occurred (IntPb), along with a synaptic loss. These results suggest that the duration of Pb exposure is more relevant than the timing of exposure, since the PerPb group presented more pronounced effects and a significant increase in the LF and HF bands and anxiety levels. In summary, this is the first study with the characterization and comparison of physiological, autonomic, behavioral, and molecular changes caused by different low-level environmental lead exposures, from the fetal period to adulthood, where the duration of exposure was the main factor for stronger adverse effects. These kinds of studies are of immense importance, showing the importance of the surrounding environment in health from childhood until adulthood, leading to the creation of new policies for toxicant usage control.
  • Prescrição de anti-inflamatórios não esteroides a doentes com Diabetes Mellitus em Portugal
    Publication . Vieira, Miguel Bigotte; Neves, João Sérgio; Baeta Baptista, Rute; Leitão, Lia; Viegas Dias, Catarina; Vicente, Ricardo; Nascimento, Nilton; Costa Leite, Celina; Rocha, Isabel; Magriço, Rita
    Introduction: Portugal presents the highest incidence of stage 5 chronic kidney disease in Europe. It is speculated that a high consumption of non-steroidal anti-inflammatory drugs may contribute to this high incidence. Our aim was to characterize the prescription of non-steroidal anti-inflammatory drugs to patients with diabetes mellitus in Portugal. Material and Methods: We analyzed the national prescription database in triennium 2015 - 2017. In patients with diabetes mellitus, we evaluated the prescription of non-steroidal anti-inflammatory drugs according to age, gender and region of the patient and specialty of the prescribing physician. We evaluated the prescription of non-steroidal anti-inflammatory drugs in all patients with diabetes mellitus, in patients with presumed renal impairment, and in those with concomitant prescription of angiotensin converting enzyme inhibitors or angiotensin receptor antagonists. Results: We analyzed 23 320 620 prescriptions, corresponding to 610 157 adults, including 104 306 patients with diabetes mellitus. The most prescribed non-steroidal anti-inflammatory drugs were ibuprofen (20.1%), metamizole (14.7%), and diclofenac (11.4%). The prescription of non-steroidal anti-inflammatory drugs was higher in females, in patients aged 51 - 70 years and in the Alentejo region. Non-steroidal anti-inflammatory drugs were prescribed to 70.6% of patients with diabetes mellitus, from which 10.6% were prescribed ≥ 10 packages during the three years. Among patients with diabetes mellitus on angiotensin converting enzyme inhibitors/angiotensin receptor antagonists and with presumed reduction in kidney function, 69.3% were prescribed non-steroidal anti-inflammatory drugs and 11.5% were prescribed ≥ 10 packages during the three years. Discussion: The level of prescribing of non-steroidal anti-inflammatory drugs to patients with diabetes mellitus is high. The concern of reducing non-steroidal anti-inflammatory drugs prescription to patients already on angiotensin converting enzyme inhibitors/angiotensin receptor antagonists and/or decreased renal function does not seem to exist. Conclusion: In Portugal, the level of prescribing of non-steroidal anti-inflammatory drugs to patients with diabetes mellitus should be reduced, particularly in the subgroups identified with higher prescription and with higher risk of progression to stage 5 chronic kidney disease.
  • EFAS/EAN survey on the influence of the COVID-19 pandemic on European clinical autonomic education and research
    Publication . Fanciulli, Alessandra; Skorić, Magdalena Krbot; Leys, Fabian; Carneiro, Diogo Reis; Campese, Nicole; Calandra-Buonaura, Giovanna; Camaradou, Jennifer; Chiaro, Giacomo; Cortelli, Pietro; Falup-Pecurariu, Cristian; Granata, Roberta; Guaraldi, Pietro; Helbok, Raimund; Hilz, Max J.; Iodice, Valeria; Jordan, Jens; Kaal, Evert C. A.; Kamondi, Anita; Le Traon, Anne Pavy; Rocha, Isabel; Sellner, Johann; Senard, Jean Michel; Terkelsen, Astrid; Wenning, Gregor K.; Moro, Elena; Berger, Thomas; Thijs, Roland D.; Struhal, Walter; Habek, Mario; Adamec, Ivan; Aerts, Arnaud; Canta, Leo L. R.; Delamont, Robert Shane; de Lange, Frederik; Del Sorbo, Francesca; Devigili, Grazia; Di Leo, Rita; Dinh, Trang; Fortrat, Jacques-Olivier; Gierthmühlen, Janne; Hemels, Martin; Köhn, Julia; Krøigård, Thomas; Lipp, Axel; Maier, Andrea; Marinelli, Lucio; Mazzeo, Anna; Milenkovic, Ivan; Motyl, Maciej; Sora, Maria Grazia Natali; Navarro-Otano, Judith; Nilsen, Kristian Bernhard; Oliveira, Mario; Omland, Petter Moe; Pelliccioni, Giuseppe; Pereon, Yann; Resch, Roland Josef; Rocchi, Camilla; Roche, Frederic; Rutten, Joost; Tijero-Merino, Beatriz; Tutaj, Marcin; van der Heijden-Montfroy, A. M. H. G.; van Hoeve, Bas J. A.; van Orshoven, Narender; Wang, Ruihao; Z’Graggen, Werner J.
    Purpose: To understand the influence of the coronavirus disease 2019 (COVID-19) pandemic on clinical autonomic education and research in Europe. Methods: We invited 84 European autonomic centers to complete an online survey, recorded the pre-pandemic-to-pandemic percentage of junior participants in the annual congresses of the European Federation of Autonomic Societies (EFAS) and European Academy of Neurology (EAN) and the pre-pandemic-to-pandemic number of PubMed publications on neurological disorders. Results: Forty-six centers answered the survey (55%). Twenty-nine centers were involved in clinical autonomic education and experienced pandemic-related didactic interruptions for 9 (5; 9) months. Ninety percent (n = 26/29) of autonomic educational centers reported a negative impact of the COVID-19 pandemic on education quality, and 93% (n = 27/29) established e-learning models. Both the 2020 joint EAN-EFAS virtual congress and the 2021 (virtual) and 2022 (hybrid) EFAS and EAN congresses marked higher percentages of junior participants than in 2019. Forty-one respondents (89%) were autonomic researchers, and 29 of them reported pandemic-related trial interruptions for 5 (2; 9) months. Since the pandemic begin, almost half of the respondents had less time for scientific writing. Likewise, the number of PubMed publications on autonomic topics showed the smallest increase compared with other neurological fields in 2020-2021 and the highest drop in 2022. Autonomic research centers that amended their trial protocols for telemedicine (38%, n = 16/41) maintained higher clinical caseloads during the first pandemic year. Conclusions: The COVID-19 pandemic had a substantial negative impact on European clinical autonomic education and research. At the same time, it promoted digitalization, favoring more equitable access to autonomic education and improved trial design.