Perioperative management of cases undergoing phaeochromocytoma removal should aim at normalising blood pressure and heart rate, restoring volume depletion, and preventing catecholamine release induced by surgical manipulation. In this case report, a novel pharmacological approach in a dog undergoing surgical tumour excision is described. A 7-year-old 25-kg spayed female Labrador Retriever presented for repeated episodes of generalised weakness, pale mucous membranes, tachycardia, tremor, panting, vomiting, and hypertension over the last month was referred for surgical treatment of a left-sided adrenal tumour with invasion of the caudal vena cava. Severe hypertensive episodes occurred repeatedly, starting early during the anaesthetic period, while clipping and cleaning the abdominal area, and continued intraoperatively when the tumour was handled. Moderate hypotension occurred once the tumour was isolated and worsened during temporary caudal vena cava flow interruption and cavotomy. The patient was treated preoperatively with phenoxybenzamine to prevent hypertensive crises. Intraoperatively, magnesium sulphate and urapidil were used to control blood pressure. This treatment was effective in reducing the magnitude of blood pressure spikes but not sufficient to prevent hypertensive peaks, especially during tumour manipulation. Hypotension was treated with synthetic colloid and crystalloid boli, and noradrenaline continuous infusion. Blood transfusion was performed in response to acute bleeding during cavotomy. The dog recovered successfully from anaesthesia and its quality of life was deemed excellent by the owner at the last follow up, 22 months after surgery. The histopathology confirmed the diagnosis of phaeochromocytoma with an invasion of the phrenicoabdominal vein. In the present case, we obtained a successful outcome but failed to provide haemodynamic stability throughout the procedure. Phaeochromocytomas are catecholamine-producing neoplasia arising from the chromaffin cells of the adrenal medulla –3. In doAccording to Connor et al.  and LendA 7-years-old, spayed female Labrador Retriever weighing 25-kg was referred to the veterinary teaching hospital of the University of Bern, for a second opinion concerning a left-sided adrenal mass.The referring veterinarian described repeated episodes of generalised weakness, pale mucous membranes, tachycardia, tremor, panting, and vomiting during the previous month. Computerised tomography images revealed a left-sided adrenal gland tumour, invading the caudal vena cava (CdVC). According to the results of the endocrinological tests (negative urinary metanephrines and ACTH stimulation) and a lack of recorded hypertensive episodes, an adrenal adenocarcinoma was suspected. However, due to the invasion of the CdVC and the clinical signs, phaeochromocytoma (PCC) could not be ruled out. Surgical removal of the mass was advised. Phenoxybenzamine (PBZ) was started by the referral veterinarian at 0.6 mg/kg twice per day and was maintained at this dose until ~36 h before surgery (14 days). The dose was not titrated based on blood pressure measurement.On the day of surgery, the dog presented a heart rate (HR) of 88 beats per minute (BPM), a respiratory rate of 26 breaths per minute, a rectal temperature of 38.2°C, pink and moist mucous membranes and a capillary refill time of 1.5 s. Oscillometric blood pressure was 124/86 (99) [SAP/DAP(MAP)] mmHg. Lung and heart auscultation were unremarkable. Dog erythrocyte antigen was 1.1+, and blood cross-matching was performed before anaesthesia. Complete blood count, biochemistry, prothrombin, and partial thromboplastin times were within normal values. Baseline magnesium was 0.7 mmol/L. The patient was not treated preoperatively with heparin due to the risk of bleeding.Methadone (0.2 mg/kg IV) was administered in premedication, inducing slight sedation. Preoxygenation was performed using 100% “flow by” oxygen, at 4 L/min, over 5 min. Lidocaine (2 mg/kg IV), fentanyl (0.005 mg/kg IV), and propofol  were used to induce general anaesthesia. The trachea was intubated with an 11-mm internal diameter, low volume, high pressure, silicone endotracheal tube, then connected to an adult anaesthetic circle system. The patient was allowed to breathe spontaneously and a stable depth of anaesthesia  was targeted using isoflurane (Fe 1–1.3%) in oxygen combined with IV lidocaine and fentanyl continuous rate infusions (CRI) . The left cephalic vein was catheterized using an 18-G over the needle catheter to administer emergency drugs and transfusion if needed.The lumbosacral area was clipped and aseptically prepared. Preservative-free morphine (0.1 mg/kg) and methadone (0.1 mg/kg) mixed with 0.2 mL/kg sterile saline solution were administered epidurally in the lumbosacral space, using a spinal needle (no Tuohy needle was available). Correct needle placement was confirmed by a positive hanging drop test and lack of resistance to injection.Overall procedure monitoring consisted of a three-lead ECG, transmittance pulse oximetry, side-stream capnography with agent analyzer and oesophageal temperature, non-invasive oscillometric arterial blood pressure, and invasive arterial blood pressure (IABP). The patient was positioned in dorsal recumbency, and the right dorsal pedal artery was catheterized using a 22-G over-the-needle catheter but not connected to the transducer because during abdominal scrubbing the heart rate dropped from 56 to 34 BPM. Some second-degree atrioventricular blocks were observed; no non-invasive arterial blood pressure value was displayed at that moment. The recumbency was changed to a right lateral and a bolus of glycopyrrolate (0.01 mg/kg) was administered IM. The IABP transducer was placed at the level of the patient's heart and zeroed at atmospheric pressure. The IABP line was connected to the arterial catheter and the fast-flush test showed no under or overdamping. The monitor displayed a systolic/diastolic (mean) arterial pressure [SAP/DAP(MAP)] of 178/77(105) mmHg, respectively. The heart rate increased to 62 BPM and AV blocks disappeared within 10 min from glycopyrrolate administration; at this point, the patient was repositioned in dorsal recumbency. Five minutes later, an ultrasound-guided bilateral subcostal and lateral transversus abdominis plane block was performed, administering 0.1 mL/kg of sterile ropivacaine (0.5%) diluted 1:1 with sterile sodium chloride per each of the 4 injection points .In the surgery room, the dog was placed in dorsal recumbency. Blood pressure (BP) was 133/68(84) mmHg and HR 85 BPM; both remained stable  until the mass was manipulated. Active warming was provided using an electronic warm water pad set to 38°C and warm air set at 40°C, targeting an oesophageal temperature of 37.5–38.5°C. Approximately 40 min before the occlusion of the CdVC, active cooling was started by switching off warming devices and surrounding the patient with ice blocks packed in paper towels. A temperature reduction of around 2 degrees (from 37 to 35.1) was achieved by the end of the occlusion period.2 (EtCO2). Peak inspiratory pressure was maintained between 9 and 13 cmH2O, and no positive end-expiratory pressure was set up. The respiratory rate varied between 18 and 40 breaths per minute and tidal volume between 7 and 13 mL/kg targeting an EtCO2 of 35–45 mmHg.The patient was allowed to breathe spontaneously for the first 115 min; thereafter pressure-controlled ventilation was started due to the increasing end-tidal COAfter median laparotomy associated with left and right paracostal approaches, a 5 cm large left adrenal mass was located, strongly attached to the surrounding structures. Moreover, a 10 cm long and 4 cm large invasion of the CdVC through the left phrenicoabdominal vein was found. Three Rumel tourniquets were placed . Despite careful adrenal mass manipulation, several hypertensive crises occurred. A total of 7 SAP spikes between 150 and 200 mmHg and 14 SAP spikes ≥200 mmHg were recorded, with the highest value being 394 mmHg.4) alone and afterwards combined with urapidil. The haemodynamic evolution thorough the procedure and the pharmacological management of the hypertensive crisis are depicted in more detail in 4 were administered before CRI was started at 15 mg/kg/h. Approximately 1 h later, venous blood was sampled for blood gas analysis and magnesium quantification. The results showed the presence of respiratory acidosis, with a pH of 7.149 and an arterial pressure of CO2 (PaCO2) of 68.5 mmHg. The gap between PaCO2 and EtCO2 was 18.5 mmHg. Magnesium blood concentration was 1.66 mmol/L . Thus, the rate of MgSO4 was reduced and the first bolus of urapidil was administered at 0.35 mg/kg IV, followed by a CRI at 0.05 mg/kg/h, further increased during the procedure up to 0.3 mg/kg/h.The hypertensive crises were treated first with magnesium sulphate  allowed to achieve an average reduction in SAP of 61 ± 5% (from 325.75 ± 48.3 to 124.75 ± 2.6 mm Hg). Similarly, after urapidil boli , the average reduction was 59 ± 6% (from 222 ± 70.2 to 94 ± 4.2 mm Hg). Both MgSOTwo ventricular tachycardia episodes occurred during mass manipulation. Both had a good response to 2 mg/kg lidocaine bolus IV. After the first episode, the lidocaine CRI was increased to 3 mg/kg/h. No further arrhythmias were seen during the whole procedure.4. As the MAP reached values below 60 mmHg, three boli of crystalloids  and two boli of synthetic colloid  were administered. Twenty minutes after tumour isolation, the MAP decreased to <50 mmHg. At this point, lidocaine CRI was reduced to 1.8 mg/kg/h and noradrenaline (NA) started at 0.0005 mg/kg/min.A steady decrease in BP occurred as the tumour was getting surgically isolated. Thus, urapidil infusion was decreased stepwise and finally interrupted, alongside with MgSOThen, Rumel tourniquets were tightened to temporarily interrupt the caval flow. During the tumour removal, the cranial tourniquet broke causing rapid haemorrhage, which was promptly stopped by placing large Satinsky clamps on the venotomy site. One unit of packed red blood cells was administered (no quantification of blood loss was performed), while isoflurane, fentanyl and lidocaine infusions were discontinued due to a sudden marked decrease in blood pressure to 36/22 (27) mmHg. Crystalloids were given at 1,200 mL/h for 20 min while NA CRI was gradually increased reaching 0.005 mg/kg/min, then maintained until the end of the procedure. Total (Rumel tourniquets) and partial (Satinsky clamps) caval flow occlusion lasted 5 and 10 min, respectively; BP values registered during this period were SAP 54 ± 21, DAP 29 ± 9, and MAP 37 ± 12 mm Hg, and HR value was 125 ± 4 BPM (mean and ±SD). Once the caval flow was restored BP was 59/30 (40) mmHg and it continued increasing until it reached 95/45 (58) mmHg; then, isoflurane, fentanyl and lidocaine were restarted.aCO2-EtCO2 gap (between 12.4 and 25.3 mmHg) persisted. The PaO2/FiO2 ratio was ranging between 250 and 473 mmHg in the arterial samples.A total of 6 blood gas analyses  were performed during surgery . Severe aCO2 from 60 mmHg (last intraoperative measurement) to 40 and 35 mmHg, respectively . After extubation and transferred to the intensive care unit. One and five hours postoperatively, arterial blood gas values showed a decrease in Pectively . DuratioNo evidence of renal damage was detected on postoperative blood work performed on day 1 and 4 after surgery. The patient did not show any visual impairments during hospitalisation although no direct control of the retina was performed. The dog was discharged in good clinical condition 5 days after surgery. The histopathology of the mass revealed a phaeochromocytoma . On a teThe anaesthetic management of dogs undergoing phaeochromocytoma excision raises a true challenge. The rare clinical presentation and the absence of controlled randomised trials, the unpredictable and life-threatening haemodynamic fluctuations and the need for continuous and thorough monitoring to detect them, makes it particularly difficult to deal with these cases.In human medicine, the preoperative administration of alpha-receptor blockers in PCC is suggested  since 2014, even in normotensive patients, in the attempt to prevent perioperative haemodynamic instabilities . In vete4 and urapidil were used.In the veterinary literature, intraoperative hypertension in PCC is treated using drugs such as phentolamine , 15 sodi4 to control catecholamine-induced crises has been already described in human medicine two decades ago . The use of a continuous infusion did not prevent hypertensive peaks even in combination with urapidil. Magnesium should be used with caution, monitoring its plasmatic concentration, ECG activity and BP  to achieve haemodynamic stability during phaeochromocytoma resection  and the fact that the most described arrhythmias due to catecholamine release are tachyarrhythmias , 3 the aIn the present case, we obtained a successful outcome but failed to provide haemodynamic stability throughout the procedure. Further investigations are warranted to find a multimodal approach to effectively avoid blood pressure increase in response to catecholamine release. The combination of magnesium sulphate with urapidil did not provide continuous haemodynamic stability but was effective in treating blood pressure spikes.The anaesthetic approach to phaeochromocytoma excision is based on careful perioperative management. Patients should be handled gently to minimise perioperative catecholamine release. Blood typing must be performed to promptly replace lost volume in case of haemorrhage. A combination of vasoactive drugs pre- and intraoperatively could be helpful in providing haemodynamic stability. Postoperatively, close control of cardiovascular status and respiratory parameters is advocated, especially if V/Q mismatch have been noticed during surgery.In the present case report, the combination of magnesium sulphate with urapidil to treat severe hypertension did not provide continuous haemodynamic stability but was effective in treating blood pressure spikes and finally led to a successful outcome.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Ethical review and approval was not required for the animal study because it is a case report. Written informed consent was obtained from the owners for the participation of their animals in this study.EM was involved in anaesthetic management, data collection, and preparation of the first manuscript. CS was involved in editing and reviewing the draft. SV performed the surgery and was involved in draft reviewing. AM was involved in anaesthetic management, data collection, editing, and reviewing the draft. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The prevalence of comorbidities and their relation to asthma control and treatment is a topic of increasing interest, however comprehensive studies are scarce. We aimed to determine the prevalence of the most common comorbidities in asthma in relation to patient characteristics  and their association with asthma control in a large, specialist-managed representative patient population.A secondary, exploratory analysis of the Asthma Reality (ARL), across-sectional, non-interventional real-life study was conducted. Basic patient characteristics, the prevalence of comorbidities and data on asthma control and risk factors had been collected and their interactions examined. Descriptive statistics and binomial regression were used to assess the distribution of the prevalence of comorbidities and propensity matching was applied to assess their effect on asthma control.Overall, 12,743 patients were enrolled in our study in 187 treatment centres covering all regions of Hungary. Most comorbidities showed significantly different distribution for all basic patient characteristics. Gender, age group, smoking status, BMI and the duration of asthma had a significant impact on asthma control. The frequency of uncontrolled asthma was higher in females (37.1%), in the age group of 46–65 years (39.6%), in severely obese patients (43.2%), in patients who had been diagnosed with asthma for more than 20 years (40.4%), and in active heavy smokers (55%), compared with respective groups in the same category. Based on the binomial regression with propensity score matching, concomitant chronic obstructive pulmonary disease (COPD) , ischaemic heart disease  and cerebrovascular events  had the strongest negative effect on asthma control, with the presence of all of these conditions increasing the risk of uncontrolled asthma.This evaluation of comorbidity data of more than 12,000, adult asthmatic patients has provided a clearer picture of diseases that can frequently co-exist with asthma, and their influence on asthma control, assessed by the prevalence of symptoms. Our study suggests that most asthmatic patients have at least one comorbidity, and the presence of comorbidities may have a high impact on asthma control measures. Asthma is a chronic inflammation of the airways characterized by reversible airflow obstruction and hyperreactivity of airways, which causes bronchospasms triggered by various endogenous and exogenous factors, allergens, or irritants –3. AsthmSince asthma cannot currently be cured (only treated), the emphasis in the treatment is on achieving asthma symptom control  and preventing future asthma attacks. The definition of asthma severity is based on medication required to keep a patient in a well-controlled state, with more complex combination therapy or higher medication need indicating a more severe disease state.We previously reported in a large, real-world evidence study , risk factors for poor asthma outcomes and poor adherence, have a considerable influence on the control level of asthmatic patients . As partIn this secondary, exploratory study, our goal was to determine the prevalence of the most common comorbidities in asthma in relation to patient characteristics—age, gender, and body mass index (BMI)—and their possible relation with asthma control in a large, specialist-managed representative patient population.Details of the ARL study  were preThis was a non-interventional, cross-sectional real-life study. Inclusion of the patients and data recording was performed on a single occasion. For detailed data collection purposes, separate doctor and patient questionnaires were developed. To eliminate seasonal effects, patient recruitment was executed throughout an entire year (from May 2015 to May 2016). To obtain a non-biased patient enrolment, every health institution included a maximum of 15 patients on five predetermined consecutive workdays per month. Enrolment was conducted randomly with the inclusion of consecutive asthmatic patients after they provided informed consent. Dispensaries, outpatient clinics specialising in pulmonology and outpatient departments of hospitals in all regions of Hungary participated in the study. Table A comprehensive data collection form was used to record patient demographic characteristics, major medical history, smoking habits, comorbidities, risk factors, current control state, medications, and all relevant physical assessments. Asthma control, treatment steps, and risk factor assessment were done according to GINA 2014 ; the statistical analysis was conducted by Adatrendező Ltd. . In the data analysis phase, descriptive statistics, graphical outputs, Fisher’s exact test, analysis of variance (ANOVA), and the chi-square test of independence were used. Odds ratios (ORs) were provided with 95% confidence intervals (CIs). In the case of smoking history, patients were grouped according to smoking exposure (measured in pack-years) and smoking status , and the combination of these parameters. Propensity scores were created based on gender, age group, BMI, time since asthma diagnosis and smoking history. Propensity scores are commonly used for stratifying patients into groups with similar characteristics (based on the parameters incorporated in the propensity score). In observational studies, there is no opportunity to randomize patients. However, matching them into groups with similar propensity scores helps to eliminate the confounding effects of differences in baseline parameters. In our case comparing the asthma control of patients with or without a certain comorbidity, in the same propensity score group allows for the comparison of the effect of the comorbidity, free (or at least mostly free) from the confounding effect of baseline characteristics  on asthma control. This method allows for the most accurate analysis of the relation of comorbidities to asthma control in an observational study.https://www.R-project.org/).For statistical analysis, we used the open-source Python 2.7.12 on a MAC operating system  and R for Windows 3.4.2 , similar to the gender distribution of the general adult asthmatic patient population in Hungary [8.1%, simThe distribution of patients into groups according to age was the following: 18–30 years old , 31–45 years old , 46–65 years old  and > 65 years old . Older patients tended to have more comorbidities than younger ones; however certain diseases showed a different distribution according to age. To aid understanding, we grouped comorbidities into three categories: diseases with age-related increasing prevalence (trend 1), decreasing prevalence (trend 2), and diseases whose age distribution showed a different pattern (trend 3). Figure Cardiovascular diseases were present in 3.5% of all patients in group 1 while 70.4% of patients suffered from them in group 4, with a steep increase in prevalence starting at 50 years of age. A similar trend was observed for IHD , AMI (from 0.2 to 3.0%), atrial fibrillation (from 0.24 to 3.18%), other arrhythmias (from 0.6 to 8.4%), other cardiovascular events (from 0.4 to 3.2%), cerebrovascular events (from 0.1 to 4.7%) and hypertension (from 2.4 to 66.4%). Concomitant COPD showed an increase up to 12.6% in group 4 (vs 0.4% in group 1). Osteoporosis mostly occurred at the age of 40 and increased in prevalence, reaching 17.9% in group 4. Prostate hyperplasia (from 0.0% in group 1 to 6.8% in group 4), IFG (from 0.6 to 13.2%), DM (from 0.8 to 13.9%) and glaucoma (from 0.2 to 3.2%) also showed increased prevalence with age in asthmatic patients.Contrary to the aforementioned diseases, the prevalence of perennial rhinitis (from 82.3% in group 1 to 55.5% in group 4) decreased with age.The occurrence of GERD increased until the age of 55, when it reached 25% and stayed the same after, regardless of increasing age. ‘Other comorbidities’ showed a trend with a similar plateau starting from the age of 50 years. Furthermore, there was a statistically significant difference in the mean age of patients with controlled asthma  and uncontrolled asthma . The proportion of patients with uncontrolled asthma was highest in age group 3 (39.6%).2; 1.8%), normal , overweight , obese  and severely obese .Patients were categorised into five groups according to BMI values: underweight ; glaucoma (p = 0.001); other cardiovascular events (p = 0.001); cerebrovascular disease (p = 0.004); and prostate hyperplasia (p = 0.049). On the other hand, the average BMI was significantly lower in patients with perennial (p < 0.0001) and seasonal (p = 0.019) rhinitis.2.The prevalence of most evaluated comorbidities increased with BMI, with the largest increase observed in the rate of hypertension (present in 8.3% of underweight and 62.1% of severely obese patients). A similar BMI-related increase was seen in the prevalence of IHD, AMI, atrial fibrillation, other arrhythmias, other cardiovascular events, DM, IFG, and ‘other comorbidities’. There was a similarly increasing prevalence for GERD, with a plateau at a BMI of 30 kg/mThere was a reversed trend for perennial and seasonal rhinitis, where the prevalence decreased as the BMI increased. In the case of the much more prevalent perennial rhinitis, 71.9% of underweight and only 61.9% of severely obese patients were affected.There was a trend for an increasing then decreasing prevalence for cerebrovascular events, prostate hyperplasia, and glaucoma.The prevalence of concomitant COPD and osteoporosis were independent of BMI values.2, 95% CI 28.0–28.2) and uncontrolled asthma . The severely obese patients had the highest proportion of uncontrolled asthma (43.2%).Finally, there was a significant difference in the average BMI of the patients with controlled asthma . By contrast, the prevalence of patients with perennial rhinitis, hypertension, other cardiac episodes, osteoporosis, prostate hyperplasia, and other comorbidities correlated with the duration of asthma. On the other hand, the prevalence of AMI and atrial fibrillation was lower in patients who had had their asthma diagnosis for a longer time.There was a statistically significant difference in the duration of asthma of patients with controlled asthma  and uncontrolled asthma . The patients who had been diagnosed for more than 20 years had the highest proportion of uncontrolled asthma (40.4%).Thirteen percent of the patients were active smokers, 20.3% were ex-smokers and 66% of them had never smoked.The data on smoking history and exposure were analysed separately and combined. Overall, 66.2%  of the patients were nonsmokers, while 4.8% (616) smoked < 10 pack-years (‘moderate smoker’) and 8.3% (1053) smoked > 10 pack-years (‘heavy smoker’). Finally, 11.5% (1461) of the patients were ex-smokers, 11.5% (1461) with less than 10 pack-years of exposure and 9.3%  were ex- and heavy smokers.There was a statistically significant difference in the average age of heavy versus moderate and of active smokers versus ex-smokers. Taking into account that the prevalence of comorbidities is affected by age, we incorporated this variable into our calculations when assessing the effect of smoking habits on the prevalence of comorbidities. Thus, we compared the prevalence of certain comorbidities between smokers, ex-smokers and nonsmokers, as well as between heavy and moderate smokers of the same age.There was a statistically significant overall difference between smokers, ex-smokers and nonsmokers in the prevalence of the following comorbidities: COPD, perennial rhinitis, AMI, IFG, DM, prostate hyperplasia, cardiovascular diseases ; other arrhythmias (p = 0.0003); other cardiovascular events (p = 0.001); other comorbidities (p = 0.001); IHD (p = 0.001); osteoporosis (p = 0.002); seasonal rhinitis (p = 0.003); and hypertension (p = 0.007). Based on pairwise comparisons, ex-smokers had the highest disease burden in nine of the 14 aforementioned comorbidities, with a statistically significantly higher prevalence compared with nonsmokers in hypertension, IHD, DM, cardiovascular diseases, other cardiovascular events and other arrhythmias, and a statistically significantly higher prevalence compared with nonsmokers and active smokers in IFG, prostate hyperplasia and AMI. For seasonal rhinitis, osteoporosis, other comorbidities and COPD, active smokers had the highest prevalence compared with ex-smokers and nonsmokers. It is interesting to note that perennial rhinitis was most prevalent in nonsmokers and least prevalent in active smokers .There was a statistically significant overall difference between heavy, moderate and nonsmokers in the prevalence of the following diseases: COPD, perennial rhinitis, AMI, IFG, DM, prostate hyperplasia, seasonal rhinitis ; other arrhythmias (p = 0.0004); cardiovascular diseases (p = 0.0005); IHD (p = 0.003); other cardiovascular events (p = 0.008); GERD (p = 0.027); cerebrovascular diseases (p = 0.033); and hypertension (p = 0.033). Based on the pairwise comparisons of the 15 aforementioned conditions, 14 were significantly more prevalent in the heavy smoker group, 12 were more prevalent compared with nonsmokers and two (GERD and cerebrovascular disease) were more prevalent compared with moderate smokers. The difference was statistically significant compared with nonsmokers and moderate smokers for IFG, DM, seasonal rhinitis, and other comorbidities. Moreover, the prevalence of COPD, AMI, other arrhythmias, and prostate hyperplasia was significantly higher in heavy smokers compared with moderate smokers, and in moderate smokers compared with nonsmokers, suggesting a dose-dependent effect. Interestingly, perennial rhinitis showed a reverse trend, with a significantly higher prevalence in nonsmokers compared with both moderate and heavy smokers.To assess clearly the exact effect of smoking status and exposure on the prevalence of comorbidities in asthma, a combined analysis of the two parameters was performed. For this analysis, patients were assigned to one of the following five groups: NS , ES1 , AS1 , ES2  and AS2 .There was a statistically significant overall difference in the prevalence of the following diseases among the aforementioned groups: other comorbidities, AMI, seasonal rhinitis, perennial rhinitis, concomitant COPD, IFG, DM, prostate hyperplasia ; cardiovascular disease (p = 0.0002); osteoporosis (p = 0.002); other arrhythmias (p = 0.003); other cardiovascular events (p = 0.004); GERD (p = 0.007); hypertension (p = 0.008); IHD (p = 0.014); and cerebrovascular diseases (p = 0.041).Based on the pairwise comparisons, the group most affected by comorbidities was ES2. The prevalence of 11 of the aforementioned comorbidities was significantly higher in this group compared with all other groups , or to nonsmokers . COPD, AMI, other comorbidities, and seasonal rhinitis had a higher prevalence in the active smoker groups, especially in AS2 . Interestingly, the prevalence of GERD was lowest in AS1; this was the only group with a statistically significant difference in prevalence compared with any other groups. While the prevalence of COPD significantly increased with more exposure and active smoking (highest in AS2), similarly to the previous analysis, perennial rhinitis showed a reverse pattern, with nonsmokers having the highest prevalence compared with ES1, ES2, AS1, and AS2. Indeed, AS2 showed the lowest prevalence of all groups.There was no significant difference in the prevalence of atrial fibrillation and glaucoma among nonsmokers and smokers of any definition. Furthermore, the risk of having uncontrolled asthma was highest in active and heavy smokers and lowest in nonsmokers, with a statistically significant difference in prevalence also in the combined analysis. AS2  and ES2 patients had the worst asthma control compared with all other groups.The main goal of our analysis was to assess the possible effects of comorbidities on asthma control and treatment outcomes. We used propensity scores to mitigate the confounding effect of basic patient characteristics for the prevalence of the given comorbidity as well as the treatment outcomes. With this method, patients were classified into five groups within which they only differed in the presence or absence of the evaluated comorbidity (as if they were randomised). The effect of the presence of the given comorbidity and each component of the propensity score on asthma control was evaluated and ORs were calculated.Asthma control was evaluated as controlled  versus uncontrolled n = 4423), and within the whole controlled group as well controlled n = 4588) versus partially controlled (n = 3732) asthmatic patients. For the first comparison  despite the fact that they had underlying asthma for a longer time . UntreatSmoking is not just an important risk factor for developing asthma; it is also one of the leading causes of preventable deaths in Hungary . As a paComorbidities can affect asthma control for two distinct reasons. First, some comorbidities have similar symptoms as asthma. Among others, COPD and IHD could cause coughing, shortness of breath, and decreased physical fitness, all of which could be attributed to asthma and, as such, could result in a patient being classified as ‘uncontrolled’ , 34. ThiAnother way to influence disease control is through the modification or enhancement of the disease pathogenesis, or the decrease of the response to otherwise adequate asthma treatment. Smoking and, consequently, COPD worsens asthma through decrease of lung function and increase of exacerbation risk and modification of the inflammatory reaction. GERD can also increase exacerbation risk and promote bronchoconstriction . AllergiThe most important strength of our study is the large sample size and the diversity of patients enrolled from all regions of Hungary: out of all registered adult asthmatics, 4.3% were enrolled by pulmonologists of 187 treatment centres. Due to the high number of treatment centres, our population can be considered representative of the Hungarian asthmatic population. Another strength of our study is the large number of different comorbidities assessed through a wide spectrum of disease categories.The limitations of our study mainly originate from its cross-sectional nature, which did not allow the follow-up of patients and made it impossible to assess time-dependent relationships between parameters . An important limitation was the lack of further evaluation of the ‘other comorbidities’ disease group. Some important and notable comorbidities were not individually assessed . Assessment of those comorbidities would have been more impactful, and could have provided new insights into understudied, but important comorbid conditions.Our study has shown in a large, real-life patient cohort that most asthmatics have at least one comorbidity, the exact type of which is highly dependent on the patient’s basic characteristics, such as age or gender. Moreover, the presence of the most frequent comorbidities has a considerable impact on asthma control levels. Thus, the appropriate treatment of comorbidities is crucial before escalating asthma treatment.


Moreover, NT-proBNP correlated positively with augmentation index , cIMT , and E/E’ in ECHO . In multivariate analysis, logNT-proBNP was the only significant predictor of cIMT Z-score , p = 0.014) and P2/P1 , p = 0.014). Conclusions: NT-proBNP may serve as a possible marker of thickening of the carotid artery wall in pediatric patients with CKD. The final role of NT-proBNP as a biomarker of arterial damage, left ventricular hypertrophy, or cardiac diastolic dysfunction in CKD children needs confirmation in prospective studies.Assessing cardiovascular disease (CVD) in children with chronic kidney disease (CKD) is difficult. Great expectations have been associated with biomarkers, including the N-terminal pro-brain natriuretic peptide (NT-proBNP). This study aimed to determine the correlation between NT-proBNP and cardiovascular complications in children with CKD. Serum NT-proBNP, arterial stiffness, common carotid artery intima-media thickness (cIMT), echocardiographic (ECHO) parameters (including tissue Doppler imaging), and biochemical and clinical data were analyzed in 38 pediatric patients with CKD . Mean NT-proBNP in CKD patients was 1068.1 ± 4630 pg/mL. NT-proBNP above the norm (125 pg/mL) was found in 16 (42.1%) subjects. NT-proBNP correlated with glomerular filtration rate (GFR) (r = −0.423,  Children with chronic kidney disease (CKD) have been recognized as the pediatric group with the highest risk of cardiovascular disease (CVD) . AssessmNT-proBNP is widely used to diagnose, screen, and stratify patients with heart failure and detect systolic and diastolic left ventricular dysfunction ,7. Its uThis single-center cross-sectional study involved 38 pediatric CKD subjects hospitalized during two years in one tertiary center of pediatric nephrology. The inclusion criteria were: age ≥ five years and CKD stages G2-5 (glomerular filtration rate grade) according to the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines . The folParticipants were included in the study consecutively from among the patients after considering inclusion and exclusion criteria to exclude selection bias. The flowchart of the patients included in the study group is presented in All procedures were in accordance with the ethical standards of the institutional review board  and with the 1964 Helsinki declaration and its later amendments. Informed consent was obtained from all legal representatives and individuals (≥16 years).2), Z-score   , as well2.7] , abnorma2.7] .p < 0.100 in univariate analysis were included in the final model. Parameters that correlated with each other with r > 0.650 were excluded from regression models to avoid collinearity. Logarithmic transformation of non-normally distributed data was performed prior to the analysis. As NT-proBNP and cardiovascular complications of CKD are significantly correlated to GFR, the latter variable was forced into the final model. A p-value < 0.05 was considered statistically significant.Statistica 13.0 PL software  was used for calculations. The normality of the distribution of the analyzed variables was assessed using the Shapiro–Wilk test. Normally distributed data were presented as mean ± standard deviation (SD) and non-normally distributed variables as median and interquartile range (Q1–Q3). Differences between data were tested using the U Mann–Whitney test. The relationship between two variables was analyzed using Pearson’s linear correlation or Spearman’s correlation rank, depending on the distribution. Multivariate analysis was performed using forward stepwise regression analysis. Parameters that correlated with arterial and heart damage markers with 2 did not receive renal replacement therapy yet. Arterial hypertension was present in 26 patients, usually treated with one antihypertensive drug, most commonly calcium channel blockers or angiotensin-converting enzyme inhibitors.Clinical characteristics of children included in the study are summarized in 2.7. NT-proBNP at 5146 (pg/mL) was noted in a 14.5-year-old girl with CKD and steroid-resistant nephrotic syndrome treated with PD, with arterial hypertension treated with three drugs and LVH—her LVMI was 50.0 g/m2.7. The highest NT-proBNP concentration ) was found in a 7.5-year-old female patient with unknown etiology of kidney disease, treated with PD, with arterial hypertension treated with two drugs, and LVH (LVMI—46.5 g/m2.7).The concentration of NT-pro BNP and remaining biochemical parameters are depicted in Relevant biochemical disturbances were found in the following numbers of CKD children—anemia in 13 (34%), hypercholesterolemia in 11 (29%), hypertriglyceridemia in 14 (37%), hypercalcemia in 1 (2.6%), hyperphosphatemia in 2 (5.2%), and elevated iPTH in 8 (21.1%) patients.Blood pressure and markers of arterial and heart damage are shown in Significant correlations of NT-proBNP are depicted in p = 0.034 and r = 0.406, p = 0.04, respectively), LVPWd , LVM , and A’ ; PWV Z-score correlated with heart rate , A , and E/A ; there was also trend towards a positive correlation between PWV Z-score and triglycerides ; AP/PP correlated positively with PTH , cIMT Z-score , and A ; P2/P1 correlated positively with calcium , alkaline phosphatase , PTH , cIMT Z-score , A , and negatively with E/A ; cIMT correlated also positively with triglycerides  and negatively with calcium ; cIMT Z-score correlated positively with triglycerides  and with RWT , negatively with E’  and C’ .PWV correlated significantly with peripheral and central DBP  and uric acid ; RWT with C’ ; E/A with calcium , alkaline phosphatase , and triglycerides ; A’ with number of antihypertensive medications ; E/E’ with calcium ; and C’ correlated positively with hemoglobin , and negatively with AP/PP  and P2/P1 .LVMI correlated positively with triglycerides . Age correlated negatively with serum calcium, inorganic phosphate, alkaline phosphatase, and pH , and positively with both peripheral and central systolic and diastolic blood pressures expressed in (mm Hg) ; no significant associations were found between age and blood pressure Z-scores. Age correlated also positively with PWV (m/s) , but not with PWV Z-score , and negatively with augmentation indices . Moreover, numerous cardiac dimensions  correlated positively with age ; LV mass was positively related to age, too . In addition, age correlated negatively with A and positively with E/A and E’ .The correlations of the analyzed parameters with age are presented in p = 0.014), and P2/P1 , p = 0.014).In the multivariate analysis, logNT-proBNP was the only significant predictor of the cIMT Z-score , Chronic kidney disease and cardiovascular disease are conditions that inter-influence. In CKD patients, a gradual decline in GFR leads to overhydration and accumulation of uremic toxins. Besides fluid overload, CKD patients are exposed to numerous other traditional  and non-traditional, i.e., “uremia-specific” risk factors, such as malnutrition, calcium–phosphorus disturbances, anemia, and hyperhomocysteinemia. Together, they contribute to cardiovascular damage and significant shortening of estimated lifespan ,28. ThusIn our cohort of 38 children, we observed an abnormally elevated value of NT-proBNP in almost half of the individuals. As there is no final consensus on normal pediatric NT-proBNP values, we used the manufacturer’s range. Nir and Lam proposed slightly higher normal values of the marker in the pediatric population, but they used a different kit ,30. NT-pThere are limited data on the usefulness of NT-proBNP as a marker of cardiovascular damage in pediatric CKD patients. A positive correlation between NT-proBNP concentration and E/A, left atrial diameter, and left ventricle hypertrophy (LVH) was reported in small pediatric CKD cohorts ,12. We hArterial damage is the earliest indicator of cardiovascular disease in CKD children. Unique, uremia-related biochemical milieu leads to Mönckeberg’s arteriosclerosis characterized by intramural calcium–phosphorus deposition, the osteoblast-like transformation of fibroblast, and a high risk of stroke or myocardial infarction . We founWe have found positive correlations among NT-proBNP, vascular stiffness indicators , and cIMT. NT-proBNP concentrations  were also significant predictors of cIMT and P2/P1 in multivariate analysis. While cIMT is a well-established marker of cardiovascular disease, P2/P1 and its derivative—the augmentation index shows a weaker correlation with hard-end points than the gold standard of arterial stiffness—aortic pulse wave velocity ,37. LittNT-proBNP influences adipocyte function and was found to be negatively related to total and LDL-cholesterol concentrations ,42. ThesNumerous associations between NT-proBNP and calcium–phosphate metabolism parameters were observed in our study group, suggesting cardiovascular damage induced by these metabolic derangements. Similar relations were revealed in research conducted among pediatric CKD G3–G5 patients by Rinat . In bothMoreover, one should remember that, according to literature data, other factors may influence NT-proBNP levels, such as anemia, BMI , and gender ,45,46. NIn our cohort of CKD patients, we revealed numerous significant correlations among biochemical parameters, heart dimensions, arterial stiffness parameters, and age. Of note, there was no significant association between age and NT-proBNP. A negative association between age and parameters of calcium–phosphorus metabolism reflects normal bone metabolism, varying with age, observed in both healthy  and CKD Progressive stiffening of the arteries (measured as aortic PWV) is a well-known phenomenon, responsible, e.g., for isolated systolic hypertension in the elderly . Age-depSome limitations of our study may be identified. We reported only a single-center study with a limited number of CKD patients, and broader research should be carried out, including a comparison of the NT-proBNP level in a control group. In addition, the vast majority of the subjects were in CKD G2 and G3 with minor biochemical and cardiovascular abnormalities, which might have influenced the number of NT-proBNP correlations. Finally, the study’s cross-sectional nature precludes drawing final casual relationships between NT-proBNP and the measured parameters.Our cross-sectional analysis revealed numerous correlations between NT-proBNP and arterial and heart damage indices in children with chronic kidney disease. As NT-proBNP was a significant determinant of cIMT and P2/P1 in the multivariate analysis, we conclude that NT-proBNP may serve as a possible marker of thickening of the carotid artery wall in pediatric patients with kidney function impairment. NT-proBNP could be used in everyday clinical practice to assess cardiovascular risk in these subjects as evaluation of its serum concentration is easy accessible, relatively cheap, and repeatable. Conversely, due to our study’s limitations, the final role of NT-proBNP as a biomarker of arterial damage, left ventricular hypertrophy or diastolic cardiac dysfunction in children with CKD needs confirmation in prospective studies.


Background: There have been previous reports of enhanced sympathoexcitation in autism spectrum disorder (ASD). However, there has been no formal investigation of autonomic dysfunction in ASD. Also, the joint hypermobile form of Ehlers-Danlos syndrome (hE-DS) that maybe overrepresented in ASD and orthostatic related autonomic dysfunction. This study examined the comorbidity of ASD, autonomic dysfunction and hE-DS in two UK autonomic national referral centers. Proven, documented and globally accepted clinical autonomic investigations were used to assess neuro-cardiovascular autonomic function in a cohort of ASD subjects and in age-matched healthy controls.Methods: Clinical data from 28 referrals with a confirmed diagnosis of ASD over a 10-year period were compared with 19 age-matched healthy controls. Autonomic function was determined using methods established in the centers previously described in detail.Results: 20/28 ASD had a diagnosed autonomic condition; 9 had the postural tachycardia syndrome (PoTS), 4 PoTS and vasovagal syncope (VVS), 3 experienced presyncope, 1 essential hyperhidrosis, 1 orthostatic hypotension, 1 VVS alone and 1 a combination of PoTS, VVS and essential hyperhidrosis. 16/20 ASD with autonomic dysfunction had hE-DS. In ASD, basal heart rate and responses to orthostatic tests of autonomic function were elevated, supporting previous findings of increased sympathoexcitation. However, sympathetic vasoconstriction was impaired in ASD.Conclusion: Intermittent neuro-cardiovascular autonomic dysfunction affecting heart rate and blood pressure was over-represented in ASD. There is a strong association with hE-DS. Autonomic dysfunction may further impair quality of life in ASD, particularly in those unable to adequately express their experience of autonomic symptoms. Homeostatic regulation is facilitated by the autonomic nervous system (ANS) and its ability to mediate activity of bodily organs especially the heart and blood vessels via peripheral efferent nerves. The term “autonomic” derives from the fact that its function is largely beyond conscious control. The ANS has sympathetic nervous system (SNS) and the parasympathetic nervous system (PNS) efferent pathways. The SNS increases effector organ activity predominantly via the catecholamines, such as noradrenaline (NA) at the neuro-effector junction. The PNS promotes downregulation of effector organ activity, through neuro-transmitters such as acetylcholine, slowing heart rate and facilitating food digestion by its effects on the gastrointestinal tract.The literature investigating autonomic function in autism spectrum disorder (ASD), particularly during behavioral studies, report a prevalence of enhanced sympathoexcitation (increased cardiovascular and sudomotor activity) . AutonomAutonomic dysfunction can present as a primary or secondary feature, complicating neurological, cardiovascular, endocrine, metabolic and genetic disorders. There are:•“fixed” forms, with autonomic damage and failure that usually is irreversible , and potentially progressive (as in Parkinson’s disease with autonomic failure and multiple system atrophy) , the lat•“intermittent” forms, with no obvious damage to autonomic nerves, but a transient dysregulation of otherwise normal autonomic function due to a specific allostatic stimulus, such as standing upright as in the postural tachycardia syndrome (PoTS) or with temperature change (thermoregulatory dysfunction). Intermittent autonomic disorders can present during adolescence and early adulthood, often with a positive family history .Fixed forms of autonomic disorders with autonomic failure are characteristically due to trauma to the ANS or neurodegeneration , and thus intermittent autonomic dysfunction is more likely to occur in ASD. A common consequence of orthostatic intolerance is fainting (syncope). Autonomic  mediated syncope (AMS) usually occurs due to a transient breakdown of homeostatic autonomic reflex arcs during standing and may be due to:•Situational syncope—attributable to a specific stimulus, such as straining during weightlifting or playing a wind instrument, often increasing intrathoracic pressure;•Vasovagal syncope (VVS)—the most common (80% of cases) form of syncope. In VVS, sympathoexcitation (increased heart rate and sweating) can precede the drop in blood pressure due to vasodilatation  and bradycardia ;•Carotid sinus sensitivity—typically in those aged > 50 years from aberrant baroreceptor overactivation in nerves around the carotid artery.The most common form of orthostatic intolerance probably is PoTS, defined by a heart rate increase of > 30 BPM or heart rate of > 120 BPM with symptoms of orthostatic intolerance , but without orthostatic hypotension  when staEssential hyperhidrosis is the most common form of intermittent autonomic thermodysregulation and is defined by profuse and uncontrollable sweating exceeding that needed to maintain thermostasis, often causing significant functional impairment, and without a definitive cause. Essential hyperhidrosis can present as excessively local, on the palms, soles and axillae, or can be generalized. The prevalence of essential hyperhidrosis has been estimated as 2–3% but the eOrthostatic intolerance is often associated with the joint hypermobility syndrome and Ehlers-Danlos syndrome (E-DS) Type III, now considered as the joint hypermobile form of E-DS (hE-DS). It is a heritable rheumatological condition characterized with variant collagen distribution across connective tissue, but without an identified gene as yet. hE-DS appears overrepresented in ASD  and may National (London—Harrow Research Ethics Committee) and institutional  ethics were acquired for the examination of the medical records of all patients referred over a 10-year period (2007–2017) with a confirmed diagnosis of ASD.n = 19, mean age 29 ± 12.85, 10 female, 9 male). None of the healthy control group had a history of cranial injury, neurological disorder, cognitive impairment or learning disability. The controls were recruited from Imperial College London, University College London and members of the local community. All participants provided written informed consent.We identified 28 autonomic evaluation referrals with a confirmed diagnosis of ASD . ASD data was compared to existing age-matched healthy control data (Medication of relevance to autonomic conditions in those with ASD is detailed in Heart rate and the electrocardiogram (ECG) were continually monitored online (PowerLab 16/30/ECG (Bioamp)  and analyzed offline (Labchart 7). Blood pressure was continually recorded using digital photoplethysmography  and heart rate and blood pressure measures were taken using automated sphygmomanometry . The evaluations were performed during the tests outlined, and performed in the laboratories  in the two autonomic laboratories that were an integral part of the national referral centers.Before autonomic testing, each patient underwent detailed clinical evaluation (history/examination) by a consultant autonomic physician who documented relevant information, to include family history of orthostatic intolerance. This included relevant autonomic symptoms  and factors worsening intolerance . Included was assessment for hE-DS, based on clinical examination and current criteria . Histori•Sympathetic vasoconstriction during mental arithmetic (1 min), isometric exercise (3 min) and cutaneous cold pressor responses (90 s). Pressor maneuvers, including isometric (hand-grip) exercise, cutaneous cold application, deep breathing and mental arithmetic provide an index of sympathetic nerve activity (SNA) and induce autonomic cardiovascular changes, particularly in blood pressure, which is regulated via the SNS. Isometric and cutaneous cold pressor stimuli raise blood pressure via activation of sympathetic efferent nerve pathways and provide more responsive data in comparison to mental arithmetic or other pressor tests. Peripheral receptors are activated but in both cutaneous cold or isometric exercise tests there is an important central command (isometric) or nociceptive (cold) role, which is more pronounced in isometric exercise leading to a greater increase in SNA compared to the cold pressor test;•Cardiac vagal function during respiratory sinus arrhythmia . In normal subjects there is an increase in heat rate during inspiration and a decrease in HR during expiration, known as “respiratory sinus arrhythmia” (RSA), which is a measure of the functional endpoint of cardioinhibitory vagal fibers emanating from the nucleus ambiguus in the brainstem. In this study cardiovagal function was assessed by subtracting the minimum heart rate response from the maximum heart rate response to deep breathing averaged over a minimum of 5 breathing cycles (HRDB) ;•Baroreflex cardiovagal and adrenergic function using the Valsalva maneuver, measures central and peripheral baroreflex pathways. The Valsalva maneuver involves forced expiratory pressure (40 mmHg) against a blocked airway for 10–15 s (repeated 2/3 times). The increase in intrathoracic pressure causes heart rate and blood pressure changes that can be used to calculate indices of sympathetic and parasympathetic activity;•Orthostatic tolerance, baroreflex and adrenergic function during head-up tilt . HUT is used to diagnose various forms of orthostatic intolerance. In healthy subjects the initial blood pressure fall induced by HUT should recover within 60 s as decreased venous return to the heart causes reduced stroke volume and cardiac output, activating arterial baroreceptors and cardiopulmonary mechanoreceptors that signal autonomic brain centers to increase sympathetic nerve activity, raising HR and causing vasoconstriction in various vascular beds to compensate for gravitational demands. In normal subjects in whom the baroreflex is intact, HUT of 45–90° should not provoke a prolonged fall in BP. HUT is a valuable investigation that can be terminated if syncopal, pre-syncopal or other OI-related symptoms are recorded or reported by the participant.During orthostatic challenge, lower extremities were examined for signs of vascular pooling, such as mottling and cyanotic discoloration, indicative of impaired venous return.t-tests for two groups to compare the results of clinical autonomic testing in patients with ASD and age-matched healthy controls. When appropriate, non-parametric tests were used to compare groups (Mann-Whitney U Test). Statistical significance was specified as a 2-tailed p-value of < 0.05.Statistical analysis was performed using SPSS (version 25). Descriptive statistics are presented as mean (± 1 SD) for normally distributed data. Data were tested (Shapiro-Wilk test) for normality and homogeneity of variance. Quantitative variables were compared at single time points by independent Of the 28 ASD group, 3 were unable to complete the full test protocol due to anxiety, joint pain or apneic episodes but their data was analyzed until the cessation of testing. Group mean values for each autonomic test are shown in t(42) = –4.69, p = 0.001] higher supine resting heart rate (77 bpm ± 14.66) than the control group  = 4.25, p =<0.001) blunted (Δ11 mmHg ± 9.44) systolic blood pressure response to isometric exercise compared to the control group  = 6.12, p = 0.001] blunted diastolic blood pressure response (Δ 7.33 mmHg ± 7.19) to isometric exercise compared to the control group  = 3.20, p = 0.003] blunted diastolic blood pressure response (Δ 4.77 mmHg ± 8.34) to isometric exercise compared to the control group  = 0.333, p = 0.014] blunted diastolic blood pressure response (Δ 2.26 mmHg ± 5.23) to mental arithmetic compared to the control group (In the ASD group there was a significantly  increased cardiac acceleration during inspiration in the ASD group (93 bpm + 13.59) compared to the healthy control group (72 bpm ± 12.27). Vagally-mediated cardiac deceleration during expiration in the ASD group was significantly  attenuated (75 bpm ± 14.31) compared to the healthy control group (55 bpm ± 10.07).Cardiovagal function was assessed by subtracting the minimum heart rate response from the maximum heart rate response to deep breathing averaged over a minimum of 5 breathing cycles. During paced deep breathing, respiratory sinus arrhythmia indicated significantly  attenuated in the ASD group (Δ36 mmHg ± 15.42) compared to the control group  to Valsalva maneuvers. One patient was unable to follow the guidance required to perform the Valsalva maneuver and was therefore excluded from analysis. During phase II early of the Valsalva maneuver, the typical fall in blood pressure due to reduced venous return and stroke volume was significantly [20/28 (71%) ASD subjects had a recognizable autonomic disorder . 9 ASD hThese are listed, with diagnosis and the numbers affected. One had a pre-existing diagnosis of severe cognitive impairment, 1 a pre-existing diagnosis of learning difficulties, 1 a pre-existing diagnosis of anxiety disorder, 1 a pre-existing diagnosis of obsessive-compulsive disorder, self-harm, 1 a pre-existing diagnosis of Tourette’s syndrome, 1 a pre-existing diagnosis of schizophrenia, 1 a pre-existing diagnosis of depression and 2 with a pre-existing diagnosis of anxiety disorder.This is the first study of detailed cardiovascular and thermoregulatory autonomic testing in ASD in two national referral centers for autonomic disorders. The association with hE-DS being over-represented in ASD and orthostatic intolerance also was determined. In ASD, 20/25 (80%) had an autonomic condition; 9 had PoTS, 4 had PoTS and VVS, 3 experienced presyncope  during standing or HUT, 1 had VVS, 1 had generalized essential hyperhidrosis, 1 had orthostatic hypotension and 1 had PoTS, VVS and essential  hyperhidrosis. 80% of ASD with dysautonomia had hE-DS.Resting heart rate was significantly higher in ASD, with a greater increase during HUT, favoring enhanced sympathoexcitation. During phase II early of the Valsalva maneuver, the fall in blood pressure was significantly reduced in ASD compared to controls. This differs from the typical Valsalva profile in PoTS  with a tPressor responses were blunted in ASD, unlike increased cardiac sympathoexcitation during HUT in this group, and this is of relevance to β-adrenergic antagonists that are reported to reduce some of the negative common behaviors, such as aggression and impulsiveness in ASD . The attNeuroimaging studies have offered insights into potential central reasons for perturbed autonomic function in ASD. Both ASD and hE-DS are associated with reductions in right superior temporal volume, an area vital for the sensory processing of social emotional information , and in The psychiatric comorbidities in some with ASD are likely to relate to ASD itself rather than the anxiety symptoms reported in PoTS, VVS and essential hyperhidrosis, which are typically sub-clinical and specific to somatic hypervigilance , 2017. TThis retrospective study was in a relatively small sample of ASD and studies in larger numbers are required to provide further in-depth analyses of ANS function/dysfunction in ASD. The current data also was collected from two national referral centers for autonomic conditions, with subjects referred because of possible autonomic dysfunction. Further studies in a larger cohort with ASD, regardless of autonomic symptoms is needed. There are clear differences between ASD and controls, with 16/20 (80%) of ASD having a confirmed autonomic condition, also with hE-DS suggesting that further examination of the overlapping relationship between ASD, autonomic dysfunction and hE-DS may be informative, particularly in relation to biomarker identification. Additional studies with larger numbers, a broader spectrum of autonomic assessments and detailed autonomic evaluation should provide further in-depth analysis of ANS function and dysfunction in ASD, and the relationship to their key issues. Studies in ASD that are apparently asymptomatic with autonomic dysfunction are likely to provide further information.In this study elevated heart rate while supine and upright was present in ASD in comparison to controls, suggestive of increased sympathoexcitation. Sympathetic vasoconstriction, however, appeared impaired in ASD. Intermittent autonomic dysfunction (cardiovascular and thermoregulatory) was over-represented in ASD, and there was a strong association with hE-DS. Abnormalities in the central autonomic network may be contributory and further compromise autonomic function. Autonomic dysfunction may impair quality of life in ASD, particularly in those unable to express their experience of such symptoms. The interaction of autonomic symptoms with cognitive-affective and socio-emotional symptomatology warrants further investigation in larger groups with ASD, including those initially with no apparent autonomic features.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by London—Harrow Research Ethics Committee. The patients/participants provided their written informed consent to participate in this study.AO, CM, and VI: conception and design of study, analysis, interpretation of data, and drafting and revising manuscript. AO: acquisition of data. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Graves’ disease (GD) is the most common cause of hyperthyroidism and can cause cardiac changes, such as pulmonary hypertension.This is a prospective study in which we obtained demographic, clinical, laboratory data and characteristics of the GD, in addition to investigating cardiorespiratory function, focusing on the detection of pulmonary hypertension. Patients were separated into two groups: thyrotoxicosis and euthyroidism. Ninety patients with GD of both sexes, over 18 years of age, were included. The cardiorespiratory assessment included an echocardiographic evaluation, a questionnaire of specific symptoms, spirometry and a six-minute walk test.The hyperthyroid group included 42 patients (47.73%) and the euthyroid group 46 patients (52.27%); 78 were women (86.67%). The prevalence of pulmonary hypertension between the hyperthyroidism (48.57%) and the euthyroidism (29.41%) groups was not different. Free thyroxine levels (FT4) (OR 1.266), higher left atrium volume (OR 1.113) and right ventricle diameter were associated with pulmonary hypertension. A direct correlation between FT4 with forced vital capacity (FVC) and forced expiratory volume in the first second (FEV1), as also an inverse correlation between initial oxygen saturation (SpO2) with diagnostic time and drop SpO2 with the ratio between the diastolic velocity E of the mitral flow and the diastolic velocity of the mitral ring (E/e’) were observed in the euthyroid group. An inverse correlation between FT4 levels with walked distance as % of predicted value, and a direct correlation between E/e’ ratio and walked distance as % of predicted value were observed in the hyperthyroid group.We emphasize the importance of a cardiorespiratory reassessment in GD, even after a long-term control of the thyrotoxic state, as we demonstrate that about 30% of these patients remain with PH and are subject to specific treatment. Graves’ disease (GD) is the most common cause of hyperthyroidism causing changes in the cardiorespiratory system, such as tachycardia, increased pulse pressure, dyspnea and, not uncommonly, pulmonary hypertension (PH) –5.PH is defined as the mean pulmonary arterial pressure higher than 20 mmHg , 7, requRight heart catheterization is the gold standard for PH diagnosis; however, Doppler echocardiography is usually the method for screening. In most cases, PH is diagnosed by means of the requested echocardiogram due to other suspected cardiac changes, and even so adequate follow-up and management are not always performed .A series of cases , 15 and The main objective of this study was to assess GD patients for the detection of PH, in relation to thyroid hormonal status, both in the presence of thyrotoxicosis or in euthyroidism after controlling the disease. The specific objectives are the thorough cardiorespiratory assessment of both groups.This prospective study which assessed GD attended at the Thyroid Unit of a tertiary Endocrinology Service through a directed interview, demographic, clinical and laboratory data, besides the cardiorespiratory function to detect PH. Patients were separated into 2 groups:a) In Thyrotoxicosis: GD in overt hyperthyroidism, but under treatment with antithyroid drugs during routine medical intervention, aiming at adequate control of thyroid function;b) In Euthyroidism: hyperthyroidism due to Graves’ disease controlled for at least 1 year with the use of thionamides or in remission of the disease or in replacement treatment with levothyroxine due to hypothyroidism after radioiodotherapy or thyroidectomy.The joint investigation with the Pulmonology and Cardiology Services, consisted of a questionnaire to assess respiratory symptoms, spirometry, a pulse oximetry, a six-minute walk test (6MWT) and a transthoracic echocardiogram. Biochemical data were serum TSH , free thyroxine (FT4) (RV 0.9–1.7 ng/dl), free triiodothyronine (FT3) (RV 0.22–0.44 ng/dl), anti-thyroglobulin antibodies (TgAb) (RV <115 mUI/L), anti-thyroidperoxidase antibodies (TPOAb) (RV <35 IU/ml), and thyroid stimulating hormone receptor antibody (TRAb) (RV <1.58 IU/ml), all measured by electrochemiluminescence immunoassay. Hyperthyroidism was confirmed by elevated FT4, suppressed TSH and thyroid autoimmunity by elevated TgAb, TPOAb, and TRAb.Written consent was obtained from the patients and the study was approved by the local Ethics Committee (CAAE 02109412.30000.5404).Ninety GD patients, both sexes, over 18 years old, were included, but 2 of them who did not undergo most assessments, were excluded. Transthoracic echocardiogram was performed in 70 of 88 patients and the respiratory assessment was completed in 79 of 88 patients. Patients with acute sickness or recent previous cardiovascular event, malignant neoplasia or active inflammatory disease, connective tissue diseases, use of amiodarone or iodinated contrast less than 3 months before the study, heart failure (NYHA class III or IV), severe liver disease, advanced kidney disease (stage 4 or 5), under hemodialysis, HIV-positive and hepatitis C infection and other autoimmune diseases were excluded.The cardiorespiratory assessment included an echocardiography, a questionnaire of specific symptoms, spirometry and a six-minute walk test.A) Transthoracic echocardiogram: performed on a Toshiba Xario echocardiograph, with a 3 MHZ sectoral transducer, with two-dimensional evaluation, M mode, pulsed Doppler, continuous Doppler, tissue Doppler and color Doppler, according to the American Society of Echocardiography .The references values were LVEF Simpson >52% in men and >54% in women, SPAP up to 35 mmHg, mPAP up to 20 mmHg, RV diameter up to 27 mm, PCWP of 8–12 mmHg, LA up to 34 ml/mB) Degree of dyspnea: Medical Research Council scale (MRC): Dyspnea on exertion, orthopnea, paroxysmal nocturnal dyspnea, chest pain or oppression, any previous episode of syncope, cough, expectoration, wheezing. The dyspnea on exertion followed the modified MRC  Spirometry: All patients performed spirometry (without and with bronchodilator) and had Oxygen Saturation (SpO2) measurement in room air. Spirometry was performed with the EasyOne Wordspirometer®  in liters (L) and percentage of predicted value (%), the forced vital capacity (FVC) in liters (L) and percentage of predicted value (%), and FEV1/FVC ratio. We consider FVC and FEV1 >80% of the predicted as normal.rometer® , and oxiD) Six-minute walk test: The distance walked and the drop in SpO2 were evaluated. We assessed the distance covered in meters and in percentage of the predicted, initial and final oxygen saturation, final–initial delta SpO2, and initial and final heart rate. We consider the drop in SpO2 ≥4 points as severe.The test was performed inside a hospital corridor on a hard and flat surface, according to international recommendation .Statistical analysis was performed by means of frequency tables of categorical variables with absolute frequency (n) and percentage (%) values, descriptive statistics of numerical variables with mean, standard deviation, minimum and maximum values and median. Chi-square or Fisher’s exact tests were used to compare categorical variables. Mann–Whitney test and ANOVA for repeated measures were used for numerical variables. A logistic regression analysis assessed factors associated to PH. Spearman’s correlation coefficient was used for correlate numerical variables and Mann–Whitney and Kruskal–Wallis tests, to compare categorical and numerical variables, respectively. The level of significance adopted was 5%.The 88 GD patients were divided in 42 hyperthyroid (47.73%) and 46 euthyroid patients (52.27%); 78 were women (86.67%), with a similar frequency of genders between groups. The age and time of diagnosis were lower in the hyperthyroid group than in the euthyroid group. TSH was lower, FT4 and FT3 were higher in the hyperthyroid group compared to the euthyroid group Table 1.Higher FT4 and FT3 were observed in patients with PH Table 2.PH prevalence between the hyperthyroid (48.57%) and the euthyroid (29.41%) groups was not significantly different, as well as SPAP (35 vs 28.5 mmHg). The hyperthyroid group showed lower PCWP than the euthyroid group (10 vs 13 mmHg), similarly to E/e’ ratio (6 vs 8 mmHg) Table 3.LA, PVR, mPAP, and presence of diastolic dysfunction were higher, and LVEF was lower in PH patients Table 4.A univariate analysis for factors associated with PH revealed association with FT4; for each unit of increase in FT4, a 27% greater chance of PH (OR 1.266), with higher left atrium volumes (OR 1.113) and right ventricle diameters (OR 1.103). The presence of diastolic dysfunction increased the chances of PH by 4.8 times (OR 4.875). A multivariate analysis identified increased LA and RV as risk factors for PH  Table 5.The regression analysis model included the variables: age, TSH, FT3, predicted distance, predicted distance (%), FVC (L), FVC (%), FEV1 (L), FEV1 (%), drop SpO2, diagnosis time, and thyroid hormone status. Only the variables that proved to be significant were included in Euthyroid presented a direct correlation between FT4 with FVC and FEV1, an inverse correlation between initial SpO2 with diagnostic time and drop SpO2 with E/e’.Hyperthyroid presented an inverse correlation between FT4 with walked distance as % of predicted value, and a direct correlation between E/e’ ratio and walked distance as % of predicted value in the six-minute walking test. A direct correlation was found between FT4 and FT3 with the final heart rate, as also FT4 and initial heart rate Table 6.We emphasize that smoking, the use of drugs, body surface area, and other variables investigated did not determine an interference in the results.The increase in serum thyroxine and triiodothyronine in GD leads to typical cardiorespiratory changes and can develop PH , 26.In the present study, the prevalence of PH was similarly high both in thyrotoxic 48.57%) and in euthyroid patients (29.41%). This finding suggests persistent vascular injury in GD  proc 302827/2018-8.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Coronary microvascular dysfunction (CMD) is common in end-stage renal disease (ESRD) and is an adverse prognostic marker. Coronary flow velocity reserve (CFVR) is a measure of coronary microvascular function and can be assessed using Doppler echocardiography. Reduced CFVR in ESRD has been attributed to factors such as diabetes, hypertension and left ventricular hypertrophy. The contributory role of other mediators important in the development of cardiovascular disease in ESRD has not been studied. The aim of this study was to examine the prevalence of CMD in a cohort of kidney transplant candidates and to look for associations of CMD with markers of anaemia, bone mineral metabolism and chronic inflammation.Twenty-two kidney transplant candidates with ESRD were studied with myocardial contrast echocardiography, Doppler CFVR assessment and serum multiplex immunoassay analysis. Individuals with diabetes, uncontrolled hypertension or ischaemic heart disease were excluded.7/22 subjects had CMD (defined as CFVR < 2). Demographic, laboratory and echocardiographic parameters and serum biomarkers were similar between subjects with and without CMD. Subjects with CMD had significantly lower haemoglobin than subjects without CMD . There was a positive correlation between haemoglobin and CFVR . Similar results were seen for haematocrit. In regression analyses, haemoglobin was an independent predictor of CFVR  and of CFVR < 2 .Among kidney transplant candidates with ESRD, there is a high prevalence of CMD, despite the absence of traditional risk factors. Anaemia may be a potential driver of microvascular dysfunction in this population and requires further investigation. Coronary microvascular dysfunction (CMD) is common among patients with chronic kidney disease (CKD) . With eaThe syndrome of uraemic cardiomyopathy, characterised by left ventricular hypertrophy (LVH), diffuse interstitial fibrosis, systolic and diastolic dysfunction and an increased risk of sudden cardiac death, represents advanced cardiac disease in ESRD, and is associated with significantly worse cardiovascular outcomes , 8. FactTwenty-two kidney transplant candidates with ESRD who successfully underwent CFVR assessment at the Queen Elizabeth Hospital, Birmingham (QEHB), United Kingdom between March 2019 and March 2020 were included in this analysis. These individuals were research participants in the Chronic Renal Impairment in Birmingham Coronary Flow Reserve (CRIB-FLOW) study or the Prospective Study of the Effects of Renal Transplantation on Uraemic Cardiomyopathy using Magnetic Resonance Imaging (RETRACT) echocardiogram sub-study, both of which examined CFVR in patients with ESRD.2 and were pre-dialysis or on peritoneal dialysis (PD). Exclusion criteria were: pregnancy, haemodialysis (HD), diabetes mellitus, uncontrolled hypertension, known ischaemic heart disease, moderate/severe valvular heart disease and contraindication to adenosine or sulphur hexafluoride contrast agent .Participants were > 18 years old, considered suitable for kidney transplantation by the renal transplant team at QEHB, had estimated glomerular filtration rate (eGFR) < 15 ml/min/1.73 mOffice blood pressure (BP) was measured using an automated BP monitor , which takes 6 BP readings over 6 min. After exclusion of the first reading, an average of the remaining 5 readings was used to represent office BP.All subjects underwent comprehensive two-dimensional echocardiography by a British Society of Echocardiography accredited physician (AR). Studies were performed on a Philips iE33 machine  using a S5-1 transducer for TTE and myocardial contrast echocardiogram (MCE) studies and a S8-3 transducer for CFVR measurements. Echocardiograms were stored under an anonymous code and analysed offline by a single investigator (AR) using commercially available software .Left ventricular mass was estimated using the Cube formula and indexed for body surface area . The SimDoppler CFVR assessment was performed as previously described . The lefMyocardial contrast echocardiography was performed as previously described . Images N-terminal pro-brain natriuretic peptide (NTpro-BNP) was assayed using the Alere point of care assay . High sensitivity C-reactive peptide was assayed using the Architect MULTIGENT CRP Vario assay . The remaining laboratory parameters were assayed using standardised automated methods. The fluorescence responses of 16-analytes of inflammation, atrial stretch, cardiac fibrosis, kidney injury and LVH were obtained using Human Magnetic Luminex® Asssays  and the Bio-RAD Bio-Plex™ 200 system for analysis. Concentrations were calculated using the Bio-Plex Software Manager™ (version 6.1) generated standard curves and a 5PL logistic curve fitting technique as per the manufacturer’s instructions.Statistical analysis was performed using SPSS version 26 . The Shapiro–Wilk test was used to assess data normality. Continuous variables are expressed as mean ± standard deviation for parametric data or median (interquartile range—IQR) for non-parametric data. Unpaired group comparisons for continuous data were made using the unpaired t-test or the Mann-Whitney U test. Unpaired categorical data were compared using Fisher’s exact test. Correlation was assessed using the Pearson correlation coefficient. Univariable and multivariable linear regression models were performed with CFVR as the dependent variable. Factors known to influence CFVR  as well as markers of anaemia , bone mineral disease  and inflammation  were included as independent variables in regression models. Binary logistic regression was also performed, with CFVR < 2 as the dependent variable, and the parameters listed above as independent variables. Parameters that were significant in univariable analysis were entered into multivariable regression models. A variance inflation factor > 5 was taken to represent collinearity. Statistical tests were 2-tailed, and a p value < 0.05 was considered statistically significant.Twenty-two kidney transplant candidates with ESRD  were included. The aetiology of ESRD was: glomerulonephritis (45%), polycystic kidney disease (23%), hypertension (9%), obstructive uropathy (9%), pyelonephritis (9%) and idiopathic (5%). No participants had symptoms of ischaemic heart disease or heart failure at study enrolment. 14/22 (64%) had undergone prior cardiovascular assessment for CAD as part of the transplant recipient cardiac work-up protocol at the Queen Elizabeth Hospital, Birmingham using myocardial perfusion scintigraphy (n = 11), exercise stress echocardiography (n = 2) or invasive coronary angiography (n = 1). Median time from cardiovascular assessment to study enrolment for these individuals was 18 months (IQR 3–33 months). The remaining 8 participants did not require cardiovascular assessment as per our institutional protocol.Using CFVR < 2 to signify CMD, 7/22 (32%) of our cohort with ESRD had CMD. Mean CFVR for subjects with CMD was 1.6 ± 0.2. Mean CFVR for subjects without CMD was 3.2 ± 0.9. Previously published data by our group demonstrated a reference value of CFVR in healthy controls of 3.8 ± 0.6 . BaselinAnaemia   was presMarkers of CKD bone mineral disease were similar between the two groups. Calcium, phosphate and PTH were all numerically higher in patients with CMD, but this was not statistically significant.One subject with CMD did not provide stored blood for serum multiplex immunoassay. Inflammatory markers were similar among subjects with CMD and those with normal coronary microvascular function—Table Echocardiographic data are reported in Table In univariable linear regression analysis, haemoglobin and iron were independent predictors of CFVR—haemoglobin  and iron . However, in multivariable analysis, only haemoglobin was an independent predictor of CFVR . In univariable binary logistic regression, haemoglobin was a negative predictor of CFVR < 2 . No other parameters showed a significant association with CFVR < 2.This study has confirmed a high prevalence of CMD in subjects with ESRD. To our knowledge, it is also the first study to suggest an association between CMD and anaemia in this population. It is recognised that patients on the kidney transplant waiting list are often younger, have fewer comorbidities, and a reduced risk of death compared to ESRD patients not suitable for kidney transplantation . HoweverThe presence of anaemia in patients with CKD is associated with a significantly increased risk of cardiovascular and all-cause mortality . Thus, oThese findings are of potential importance. While we cannot assume causation in either direction, it seems unlikely that anaemia could be caused by CMD. Our findings are also unlikely to be related to the methodology of our imaging technique since measurement of CFVR by Doppler TTE is not conventionally adjusted for haemoglobin as the pulse wave Doppler velocity signal is independent of haemoglobin concentration . There aAlternatively, a common causative factor may result in both anaemia and CMD. Possibilities include systemic inflammation and malnutrition, which are both commonly found in chronic disease states. We found no strong evidence that patients with CMD had higher levels of inflammatory markers. Markers of nutritional status such as body mass index, albumin and cholesterol were numerically lower among subjects in our cohort with CMD, but this was not statistically significant. It is possible that the small sample size means that we were unable to detect subtle differences in these variables.To date there are no other studies examining the effect of anaemia on CFVR in CKD. However, there is some evidence from other conditions of an association between anaemia and CMD. In patients with beta thalassemia minor, Doppler CFVR was significantly lower compared to control subjects matched for age, gender and BMI . SimilarThe clinical significance of our findings requires further investigation. Current guidelines recommend aiming for a haemoglobin concentration > 90 g/L in patients on dialysis and > 100 g/L in non-dialysis CKD patients . We haveThe main limitation of our study is the small sample size, which was limited by the outbreak of the global COVID-19 pandemic. Despite the small sample size, we found a high prevalence of CMD among this cohort. Furthermore, the size of the difference in haemoglobin and the strength of the relationship between haemoglobin and CFVR in multivariable analysis suggests that this is a true finding. Our study was underpowered to find small differences in the other variables tested.Similar to other non-invasive studies of CFVR, we could not fully exclude occult CAD among our population. However, the majority of subjects in our study had undergone prior screening for CAD. Furthermore, all subjects were asymptomatic, had normal electrocardiograms and no coronary distribution perfusion defect or regional wall motion abnormality on vasodilator MCE—a highly sensitive and specific technique for the diagnosis of CAD . This prWe included only patients eligible for kidney transplantation in this study. We also excluded patients on HD, as echocardiographic measurements in this population are more volume dependent . These tFinally, our study was cross-sectional in design, meaning that causation cannot be definitively demonstrated. Future longitudinal work examining the role of anaemia and its correction on CFVR is needed.Among patients suitable for kidney transplantation, there is a high prevalence of CMD, even in the absence of traditional risk factors such as diabetes, uncontrolled hypertension or significant LVH. In this population, we have shown that CMD is associated with low haemoglobin and an increased cardiac output—findings that require further investigation and independent confirmation. Together, they suggest that anaemia is a possible driver of CMD in ESRD. If this association is confirmed in larger studies, then correction of anaemia may represent a potential therapeutic target to improve microvascular function in ESRD.