TEE) and TD (COTD) at the end of expiration during normotension and hypotension (induced by isoflurane).Cardiac output (CO) is an important haemodynamic parameter to monitor in patients during surgery. However, the majority of the techniques for measuring CO have a limited application in veterinary practice due to their invasive approach and associated complexity and risks. Transoesophageal echocardiography (TEE) is a technique used to monitor cardiac function in human patients during surgical procedures and allows CO to be measured non-invasively. This prospective clinical study aimed to compare the transoesophageal echocardiography using a transgastric view of the left ventricular outflow tract (LVOT) and the thermodilution (TD) technique for the assessment of CO during mean arterial pressure of 65–80 mmHg (normotension) and <65 mmHg (hypotension) in dogs undergoing elective surgery. Eight dogs were pre-medicated with acepromazine , tramadol  and atropine , followed by anaesthetic induction with propofol (3–5 mg/kg IV) and maintenance with isoflurane associated with a continuous infusion rate of fentanyl (bolus of 3 μg/kg followed by 0.3 μg/kg/min). The CO was measured by TEE . The bias between COTD and COTEE was 0.14 ± 0.29 L/min . The percentage error of CO measured by the two methods was 12.32%. In addition, a strong positive correlation was found between COTEE and COTD during normotension  and hypotension .There was a strong positive correlation between COThe results of this study indicated that the transgastric view of the LVOT by TEE was a minimally invasive alternative to clinically monitoring CO in dogs during anaesthesia. However, during hypotension, the CO obtained by TEE was less reliable, although still acceptable. Cardiac output (CO) is an important haemodynamic parameter to monitor in patients during surgery. However, the majority of the techniques for measuring CO have a limited application in veterinary practice due to their invasive approach and associated complexity and risks .The thermodilution technique (TD) is the gold standard for monitoring CO in veterinary medicine , 3. It rTransoesophageal echocardiography (TEE) is a technique used to monitor cardiac function in human patients during surgical procedures , 8. The A transgastric approach on TEE proposed for visualisation of the left ventricular outflow tract (LVOT), which has been allowed to quantify the aortic flow and, therefore, to calculate CO in human patients during surgery, has shown a good correlation with TD , 8, 10. Therefore, the aim of this study was to compare the TEE transgastric view of the LVOT and the TD for measuring CO in anaesthetised dogs during surgery. The hypothesis is that CO can be accurately and non-invasively monitored using the TEE technique during clinical anaesthesia in dogs.The study was authorized by written consent of the owners and the protocol (1936/2012) was approved by the university’s ethical committee in the use of animals (CEUA). Eight dogs ASA 1 or 2, weighing 24.5 ± 2.1 kg, and undergoing surgery in the Veterinary Hospital of our institution were included in the study. The sample size for paired data was calculated using power analysis, indicating that a minimum of 8 dogs per group was required to have a 80% chance (with 5% risk) of detecting a difference of 0.78 L/min in the CO between groups and considering a standard deviation of 0.8 L/min.ISO) of 1.3% in 70% oxygen associated with fentanyl .Food was withheld for 12 h and water for 4 h before anaesthesia. All animals were pre-medicated with acepromazine , tramadol , and atropine . After 15 min, the cephalic vein was catheterised, and anaesthesia was induced with propofol to effect , administered through the catheter. After orotracheal intubation, anaesthesia was maintained with an initial end-tidal isoflurane concentration  adjusted to maintain an end-tidal carbon dioxide concentration (ETCO2) of 35–45 mmHg.Neuromuscular blockade was instituted by rocuronium , and the mechanical ventilation  was then started using the pressure-controlled ventilation mode, with a peak inspiratory pressure of 10 cmHA 7F pulmonary artery catheter  was aseptically and percutaneously introduced into the right jugular vein using the Seldinger technique in dogs in dorsal recumbency. The distal sensor of the catheter was located in the pulmonary artery, which was confirmed by waveform analysis  and by transoesophageal echocardiographic imaging. Pressure transducers were connected to a multi-parametric data collection system for continuous monitoring of the pressures and waveforms .2) were monitored using a multiparametric monitor . The end-tidal isoflurane concentration (ETISO) and ETCO2 were assessed by using a gas analyser . The invasive systolic, mean and diastolic pressures  were monitored by catheterisation of the dorsal podal artery. All cardiopulmonary data were monitored continuously and registered at the same time-points as the CO measurement. A continuous infusion of lactated Ringer’s solution was delivered throughout (5 mL/kg/h).Heart rate (HR), RR and pulse oximetry (SpOTD) was measured at the end of expiration by administering 3 mL of 5% glucose at 5°C into the right atrium through the pulmonary artery catheter. The temperature change was detected by the thermosensitive tip of the catheter located into the pulmonary artery, and the CO value was automatically calculated by the multiparametric monitor . The mean value of three measurements within ±10% was registered as COTD.The cardiac output assessed through the thermodilution technique (COTEE) was determined by using a multiplanar 2–5 MHz transoesophageal ultrasound transducer introduced into the mouth and passed into the oesophagus until visualisation of the aortic valve through the transverse caudal view. At this window, the planimetry of the aortic valve was performed to measure the transverse area of the aorta, as previously described by Boon [aortic) was calculated by the outline of the aortic blood flow  and then at an MAP <65 mmHg (hypotension) induced by increasing the ETISO [ISO to baseline values. If necessary, hypotension was treated by further decreasing ETISO and by administering a bolus of crystalloids or colloids, and a bolus of 0.1 mg/kg of ephedrine until normalisation of MAP; these treatments, if any, were registered accordingly.The COhe ETISO . ArteriaThe distribution of all variables was analysed for normality using the Shapiro-Wilk test. The variables with a normal distribution were analysed using the paired Student t-test. The variables with a non-parametric distribution were analysed using the Wilcoxon matched-pairs signed rank test.TEE as the dependent variable and COTD as the independent variable) were calculated to assess the association between COTEE and COTD.The Pearson coefficient, the intraclass correlation coefficient (ICC), and a model of linear regression  and by another independent observer . The VTIaortic and CSA were measured three times in consecutive cardiac cycles in the same frame. The resulting mean values and standard deviations were used to determine the coefficients of variation. The echocardiogram analyses were performed offline.Repeatability CO2, ETISO, and SpO2 had a non-parametric distribution and were analysed using the Wilcoxon test.Animals included in the study are shown in Table ISO was 1.4% (1.00–1.82%) during normotension and 2.0% (1.57–2.47%) during hypotension . The ICC between COTEE and COTD was 0.920 (P < 0.0001) for isolate measurements and 0.958 (P < 0.0001) for the mean of measurements. The linear regression analysis between COTEE and COTD was r2 = 0.855 (P < 0.0001) and resulted in the following equation: COTEE = 0.581+ 0.835 × COTD  and hypotension (P = 0.0761)  and hypotension . The ICC between COTEE and COTD during normal arterial pressure was 0.995 (P < 0.0001) for isolate measurements and 0.998 (P < 0.0001) for the mean of the measurements. During arterial hypotension, the ICC between COTEE and COTD was 0.780 (P < 0.007) for isolate measurements and 0.876 (P < 0.007) for the mean of the measurements.There were no significant differences between CO1) Table ; Fig. 4.TEE and COTD resulted in a r2 = 0.991 (P < 0.0001) and an equation of COTEE = 0.044 + 0.985 × COTD during normal blood pressure, and a r2 = 0.609 (P = 0.022) and COTEE = 0.221 + 0.801 × COTD during hypotension.The linear regression analysis between COThe measurements bias for the condition of normotension and hypotension was 0.001 ± 0.07 L/min (limit of agreement: −0.13 to 0.14 L/min) and 0.27 ± 0.37 L/min (limit of agreement −0.46 to 1.01 L/min), respectively. A 2.55% error was found for the CO measured by both methods during normal arterial pressure and 15.26% during hypotension.TEE measurements ranged from 0.47% to 7.77% and from 0.63% to 8.66%, respectively.The coefficient of variation for the intraobserver and interobserver analysis for the COAll dogs had ventricular arrhythmia during insertion of the pulmonary artery catheter that resolved spontaneously. With regard to the TEE, no complications were recorded.The study showed that the TEE transgastric approach of the LVOT has a clinically acceptable correlation and agreement with the gold standard thermodilution technique, and that it can be used for measuring CO in dogs during surgery.Invasive CO monitoring during surgery is infrequently performed in dogs using the pulmonary artery catheter  due to mPrevious studies in veterinary patients have described the technique and the views obtained by the TEE , 13. HowThe accuracy of the transthoracic echocardiography for measuring CO was demonstrated by other authors , 15, butA strong correlation was found between the techniques TEE and TD to obtain the CO, similar to that described in human patients , 8. AccoCoefficients of variation for intra- and interobserver measurement variability to the COTEE were lower than 10%, similar to that reported by other studies using transthoracic echocardiography , 17.During the study, hypotension was induced in all animals during surgery and then reversed by reducing the isoflurane supply and/or administrating LR bolus. The decrease in arterial pressure was expected since isoflurane is an anaesthetic drug that reduces vascular resistance and that can be used as an inductor of hypotension in dogs undergoing experimental studies . DespiteSome limitations of the study should be discussed. The TD technique can be relatively imprecise when measuring CO due to factors that can influence the accuracy of the measurement, such as dead space of the catheter, velocity of the administration and temperature of the solution . HoweverThe results of the study indicated that the transgastric view of the LVOT acquired by transoesophageal echocardiography is a minimally invasive alternative to TD for monitoring CO in anaesthetised dogs during surgery. However, during hypotension, the CO obtained by TEE was less reliable, although still acceptable.


Supplemental Digital Content is available in the text. Recent research efforts on bariatric surgery have focused on metabolic and diabetes mellitus resolution. Randomized trials designed to assess the impact of bariatric surgery in patients with obesity and hypertension are needed.2. Patients were randomized to Roux-en-Y gastric bypass plus medical therapy or medical therapy alone. The primary end point was reduction of ≥30% of the total number of antihypertensive medications while maintaining systolic and diastolic blood pressure <140 mm Hg and 90 mm Hg, respectively, at 12 months.In this randomized, single-center, nonblinded trial, we included patients with hypertension (using ≥2 medications at maximum doses or >2 at moderate doses) and a body mass index between 30.0 and 39.9 kg/mP<0.001). Remission of hypertension was present in 25 of 49 (51%) and 22 of 48 (45.8%) patients randomized to gastric bypass, considering office and 24-hour ambulatory blood pressure monitoring, respectively, whereas no patient submitted to medical therapy was free of antihypertensive drugs at 12 months. A post hoc analysis for the primary end point considering the SPRINT  target reached consistent results, with a rate ratio of 3.8 . Eleven patients (22.4%) from the gastric bypass group and none in the control group were able to achieve SPRINT levels without antihypertensives. Waist circumference, body mass index, fasting plasma glucose, glycohemoglobin, low-density lipoprotein cholesterol, triglycerides, high-sensitivity C-reactive protein, and 10-year Framingham risk score were lower in the gastric bypass than in the control group.We included 100 patients , and 96% completed follow-up. Reduction of ≥30% of the total number of antihypertensive medications while maintaining controlled blood pressure occurred in 41 of 49 patients from the gastric bypass group (83.7%) compared with 6 of 47 patients (12.8%) from the control group with a rate ratio of 6.6 (95% confidence interval, 3.1–14.0; Bariatric surgery represents an effective strategy for blood pressure control in a broad population of patients with obesity and hypertension.https://clinicaltrials.gov. Unique identifier: NCT01784848.URL:  The current body of evidence on the improvement of hypertension after bariatric surgery is reported from studies designed for a different primary end point, restricted to patients with diabetes mellitus or from observational studies.In this trial, 100 patients with obesity and hypertension (the majority of whom did not have diabetes mellitus) were randomized to gastric bypass or medical therapy alone.Patients randomized to gastric bypass were 6 times more likely to reduce ≥30% of the total number of antihypertensive medications while maintaining controlled blood pressure levels.In addition, 51% of the patients submitted to gastric bypass showed remission of hypertension.Bariatric surgery represents an effective strategy for reducing antihypertensive drugs in patients with obesity and hypertension.Given the morbidity of surgery, our results do not imply that all patients with obesity and hypertension should be submitted to bariatric surgery.Treatment of hypertensive patients with obesity has multiple barriers, including nonadherence to long-term multiple antihypertensive drugs. Thus, gastric bypass represents 1 extra option to help achieve blood pressure control.Taken together with the improvement of the metabolic and inflammatory profile, such effects have the potential to reduce major cardiovascular events.1 an increasing number of hypertension cases occur in people with excess weight.2 Several patients with hypertension require >2 medications to achieve blood pressure control,3 which creates challenges for long-term adherence to treatment, and it is well documented that hypertension is poorly controlled in patients with obesity.4Given the current high prevalence of obesity,6 Although much recent research efforts have focused on metabolic improvement and diabetes mellitus resolution, previous studies suggest that a significant percentage of patients with coexisting obesity and hypertension are able to reduce or even discontinue their antihypertensive medications after bariatric surgery.10 Because blood pressure control was not the primary focus of these studies and most randomized trials were restricted to patients with diabetes mellitus, the effects of bariatric surgery in a broader population of patients with obesity and hypertension remain uncertain. Thus, we designed the GATEWAY trial (Gastric Bypass to Treat Obese Patients With Steady Hypertension) to assess the impact of bariatric surgery on hypertension improvement in patients with obesity.Bariatric surgery represents the most effective method to treat obesity.11We will share the database containing unidentified individual participant data, data dictionary documentation, statistical analysis plan, and analysis code. Beginning 6 months and ending 24 months after article publication, the trial steering committee will evaluate proposals of studies accompanied by a statistical analysis plan and may grant access to the data for approved proposals. After 24 months, the database and accompanying documents will be publicly available in an institutional data repository.12 Briefly, this is a randomized, nonblinded, single-center, clinical trial. The follow-up period for the primary end point is 12 months, but patients are scheduled for a 5-year extension study. The Research Ethics Board at the Heart Hospital approved the protocol. All patients provided written informed consent.The study design was published previously.The trial was coordinated by the Research Institute at the Heart Hospital. Ethicon Inc provided unrestricted funding for this investigator-initiated trial. All authors had full and independent access to all data and vouch for the integrity and accuracy of the analysis.13 with a body mass index (BMI) ranging from 30.0 to 39.9 kg/m2, and treated with ≥2antihypertensive drugs at maximum doses or >2 drugs at moderate doses (Table I in the online-only Data Supplement).14 Exclusion criteria were systolic blood pressure ≥180 mm Hg or diastolic blood pressure ≥120 mm Hg; cardiovascular disease ; severe psychiatric disorders because of increased risk of low compliance with the study procedures; chronic kidney disease (diabetic nephropathy or glomerular filtration rate <30 mL/min); secondary hypertension, except because of sleep apnea; peripheral arterial disease; atrophic gastritis; type 1diabetes mellitus, latent autoimmune diabetes of adults, or type 2 diabetes mellitus with glycohemoglobin >7.0%; alcoholism or use of illicit drugs; current smoking; previous abdominal surgery; severe hepatic diseases; pregnancy or women of childbearing age not using effective contraceptive methods; cancer in the past 5 years; use of immunosuppressive drugs, chemotherapy, or radiotherapy; or inability to understand or adhere to study procedures (detailed criteria for eligibility are provided in Box I in the online-only Data Supplement).We included patients 18 to 65 years of age with hypertension,Subjects were randomized (1:1) to either gastric bypass combined with medical therapy or medical therapy alone. Randomization was performed through a 24-hour central web-based automated system.Materials in the online-only Data Supplement). Patients were preferably treated with angiotensin converting enzyme inhibitors or angiotensin receptor blockers and a calcium-channel blocker, except if these were contraindicated or if the patients already had controlled blood pressure with their current regimen. If the previously mentioned association was already in use and the systolic and diastolic blood pressure remained >130 mm Hg or 80 mm Hg, respectively, a combination with a thiazide diuretic was preferred. If a thiazide diuretic was contraindicated or if other medications were deemed necessary, then spironolactone or clonidine was used. Medications were reduced or discontinued if patients presented systolic blood pressure <110 mm Hg or diastolic blood pressure <70 mm Hg. For patients with systolic blood pressure between 110 and 130 mm Hg or diastolic blood pressure between 70 and 80 mm Hg associated with symptoms of orthostatic hypotension, dose reduction of antihypertensive medications was attempted. For patients submitted to bariatric surgery, the necessity of reintroducing antihypertensive medications was initially checked on a daily basis in the immediate postoperative period, in the first visit 1 week after the procedure, and in the remaining follow-up visits. Adherence to treatment was based on patient self-report.Medical therapy was standardized for all patients based on office blood pressure. .Besides medical therapy, patients randomized to the gastric bypass group were submitted to Roux-en-Y gastric bypass performed by a single surgeon ,18 echocardiogram, ECG, and laboratory values were measured at baseline and 12 months.At baseline, we collected data on demographic information, comorbidities, anthropometric values, use of medications, and laboratory values. We collected office blood pressure at baseline and months 1, 3, 6, and 12. Twenty-four-hour ambulatory blood pressure monitoring (ABPM) . Secondary end points included number of antihypertensive drugs, systolic and blood pressure (office and 24-hour ABPM), weight and BMI, waist circumference, fasting plasma glucose and glycohemoglobin, homeostasis model assessment of insulin resistance index, lipid profile , uric acid, high-sensitivity C-reactive protein levels, interventricular septum diastolic thickness, a 10-year Framingham risk score, and adverse events.19 at 12 months.We also measured secondary end points defined post hoc: remission of hypertension , remission of hypertension , and reduction of ≥30% of the total number of antihypertensive medications while maintaining an office systolic blood pressure <120 mm Hg The study was initially designed to enroll 60 patients. During trial conduct and while blinded to the study results, the executive committee decided to increase the sample size to 100 patients to improve statistical power. This revised sample provides 90% power to detect an increase in the probability of the primary end point from 10% in the medical therapy group to 40% in the gastric bypass group, assuming a 2-sided α of 5%.20 We used the Fisher exact test to analyze the primary end point, and results are reported as rate ratios and 95% confidence intervals (CIs). Continuous end points were analyzed with adjustments for baseline values using repeated measure analysis of variance models. Variables that did not hold a normal distribution assumption were analyzed using generalized estimating equation models with distribution that better fit the data.Continuous variables with a normal distribution are reported as mean and standard deviation. Variables with a non-normal distribution are reported as medians and interquartile ranges. Categorical variables are summarized as frequencies. Main analysis followed the modified intention-to-treat principle, and missing values were imputed with a simple carry-over procedure if the patient had information of 6-month visit.19 We conducted other 5 sensitivity analyses for the primary end point: complete-case analysis, per-protocol analysis, as-treated analysis, worst-case scenario, and multiple imputation analysis. Definitions are provided in Table II in the online-only Data Supplement. We also conducted an adjusted analysis for BMI, number of medications at baseline, 10-year Framingham risk score, basal insulin level at baseline, and duration of hypertension using Poisson regression model with robust variance. In all cases, results are presented as rate ratios and 95% CIs.A post hoc analysis was performed to assess the proportion of patients with a reduction number of the total antihypertensive medications of ≥30% while keeping the SPRINT target.The significance level for the primary end point was 0.05. For all other end points, the significance level was 0.05 without adjustment for multiple comparisons. Because of this, all secondary end points and analyses should be interpreted as exploratory. Analyses were performed using R software, version 3.3.3 .Of the 100 included patients from May 2013 to May 2016, four patients were excluded from the final analysis. One patient withdrew consent after randomization in the medical therapy group, and 2 further patients in the medical therapy group and 1 in the gastric bypass group missed their follow-up visits. Thus, information on the primary end point at 12 months is available for 96 patients   compared with 6 of 47 patients 12.8%) from the control group, with a rate ratio of 6.6  occurred, as well as in most classes of medications for blood pressure control (Table Table III in the online-only Data Supplement).Twenty-five of 49 patients (51%) from the gastric bypass group showed remission of hypertension , whereas no patient submitted to medical therapy was free of antihypertensive drugs at 12 months . The reduction occurred in 16 of 49 patients from the gastric bypass group (32.7%) compared with 4 of 47 (8.5%) from the control group . Eleven patients (22.4%) from the gastric bypass group and none in the control group were able to achieve SPRINT levels without antihypertensives .A post hoc analysis for the primary end point considering the SPRINT target reached consistent results with rate ratio of 3.8 .Exploratory secondary end points are presented in Table ps Table . Blood pFigure III in the online-only Data Supplement). The BMI was 26.8±3.7 kg/m2 in the surgical group and 36.3±3.9 kg/m2 in medical therapy group (P<0.001). Additionally, the waist circumference was lower in the gastric bypass group (86.9±8.5 cm) than in the control group . Whereas weight decreased progressively during the 12-month follow-up in the gastric bypass group, the effect on the primary end point was fully achieved on the first month and was maintained during the 12-month follow-up period , glycohemoglobin (P<0.001), and homeostasis model assessment of insulin resistance (P<0.001) (Table P<0.001 for both comparisons) (Table P=0.05).Patients who underwent gastric bypass had lower levels of fasting plasma glucose (1) Table . The lows) Table . ConversP<0.001). Uric acid was lower in the gastric bypass group than in the control group (P=0.001). Similarly, the interventricular septum diastolic thickness was lower in the gastric bypass group than in the control group (P=0.03), and the 10-year Framingham risk score was lower in the gastric bypass group than in the medical therapy group (P=0.005)  Table .P=0.001) . The glomerular filtration rate at 12 months was 111±16.8 mL/min in the gastric bypass group and 96.6±21.3 mL/min in the medical therapy group (P=0.03). Only 2 of them were hospitalized because of procedure complications. One patient required a reoperation 4 months after surgery because of an abscess near the jejunal anastomosis, and 1 was admitted for vomiting and dehydration. Four patients developed cholelithiasis after the gastric bypass, 3 were symptomatic, and 1 was asymptomatic. All of them were submitted to a laparoscopic cholecystectomy, and all recovered uneventfully. One patient developed an anastomotic ulcer and was successfully treated medically. Anemia was present in 11% and 10% of participants in the gastric bypass group and medical therapy group, respectively (P=1.00).Table P=0.03), and hypovitaminosis B12, 9% to 28%, respectively (P=0.01). No difference for secondary hyperparathyroidism, hypoalbuminemia, iron, and ferritin deficiency occurred (Table VI in the online-only Data Supplement).Nutritional parameters in the gastric bypass group showed significant differences from baseline to 12 months only for anemia, 0% to 11%, respectively  in the medical therapy group showed excessive weight gain .Table II in the online-only Data Supplement. An analysis assessing treatment effect on the primary end point adjusted for BMI, number of medications at baseline, 10-year Framingham risk score, basal insulin level at baseline, and duration of hypertension found similar results with a rate ratio of 6.4 . Accordingly, results for the complete-case, per-protocol, as-treated, worst-case scenario, and multiple imputation analyses were consistent with those observed for the main analysis.Sensitivity analyses are presented in 19 without medications at 12 months. In addition, exploratory end points such as the number of antihypertensive medications, waist circumference, BMI, fasting plasma glucose, insulin resistance, glycohemoglobin, low-density lipoprotein cholesterol, triglycerides, high-sensitivity C-reactive protein, uric acid, and the 10-year Framingham risk score were lower in the surgical than in the medical therapy group. Thus, despite the fact that the groups had similar blood pressure levels at 12 months, patients submitted to gastric bypass were able to achieve these levels with few or any medications and also had their metabolic profile improved.Our results indicated that at 12 months, patients with obesity and hypertension who underwent gastric bypass plus medical therapy were significantly more likely to reduce ≥30% of the number of medications while maintaining controlled blood pressure than patients managed with medical therapy alone. Notably, half of the patients in the surgical group were able to maintain systolic and diastolic blood pressure <140 mm Hg and 90 mm Hg, respectively, without the need for medications (remission of hypertension), whereas no control group patient was free of medications at 12 months. The post hoc analysis indicated that ≈20% of patients in the gastric bypass group achieved SPRINT goals21 Previous randomized trials in patients with diabetes mellitus also assessed the effects of bariatric surgery on hypertension control. In the STAMPEDE trial , the authors observed a significant reduction in the number of antihypertensives after surgery at 12 months, and ≈60% of the patients were able to stop their medications while maintaining hypertension control.8 After 5 years, the number of patients using >3 cardiovascular drugs fell from 61.2% in the baseline to 20.4%.22 In the study by Mingrone et al,10 antihypertensive therapy was reduced or discontinued in 80% of the patients undergoing gastric bypass. Other trials also documented improvement of hypertension after bariatric surgery.24Several observational studies suggested improvement and remission of hypertension after surgery.Our trial confirms the results from the observational studies with better control of residual confounding because of the randomized design. In contrast with the GATEWAY trial, in previous randomized trials, hypertension improvement and remission were measured as secondary end points. In addition, hypertension management and decision to reduce or discontinue antihypertensive medications were not standardized in all studies. Finally, the GATEWAY trial included a broader population of patients with obesity and hypertension, the majority of whom did not have diabetes mellitus. Therefore, our trial provides novel findings and complements the results from the available randomized evidence.26 Insulin resistance is associated with renal sodium reabsorption and increased sympathetic tone.27 Another factor that may influence hypertension control is inflammation, which can modulate arterial stiffness.28 Small mechanistic studies suggest that this modulation is attributable to a reduction in perivascular adipocyte inflammation. In lean healthy subjects, the perivascular adipose tissue exerts an anticontratile effect on adjacent small arteries, which is lost in patients with obesity probably because of inflammation.29 Thus, by reversing inflammation, bariatric surgery can contribute to the restoration of normal anticontratile activity. We demonstrated both a significant reduction in homeostasis model assessment of insulin resistance index and high-sensitivity CRP levels in the gastric bypass group when compared with controls. Reduction of such factors is not immediate after surgery. In our trial, hypertension improvement occurred early after surgery and was maintained for ≤12 months (which is consistent with previous studies) , influencing electrolyte transport in the renal tubular cells as well as causing diuresis.32Although hypertension improvement after bariatric surgery could be attributable to hemodynamic changes and decreased intra-abdominal pressure associated with weight loss, it is likely that several factors play an important role.) Figure .30 Thus,Our study has limitations that merit consideration. These limitations include the relatively short duration of follow-up (12 months), being a single-center trial, and the open-label nature of the study . We attempted to minimize the potential systematic errors associated with the lack of masking of investigators by training all the personnel involved in the study and guaranteeing that they strictly follow the trial protocol. A single surgeon with long-term expertise in bariatric surgery performed all the surgeries. Thus, one may question the external validity of our findings, especially to sites with less experience in these procedures. Because of the study’s academic nature (investigator-initiated) and the consequent limited funding, in our trial, compliance with study medications was based on patient self-report. Therefore, the risk of verification bias in our primary end point represents a major limitation of our trial. At 12 months, information on the primary end point was not available for 4 out of 100 patients. Nevertheless, our findings for the primary end point were robust to all sensitivity analyses assumptions. We excluded patients with systolic blood pressure ≥180 mm Hg and diastolic blood pressure ≥120  Hg as well as elderly patients. Whether our results can be extrapolated to these populations remains to be determined. Finally, we are not able to generalize from a study cohort containing patients with class I obesity (BMI 30–34.9) to the overwhelming number of individuals who undergo bariatric surgery, those with class II and III obesity (BMI >35).In conclusion, bariatric surgery represents an effective strategy for reducing antihypertensive drugs at 12 months in patients with obesity and hypertension while maintaining controlled blood pressure levels. The durability of our findings remains uncertain, but further 4-year follow-up of patients should allow assessment of the long-term effects of bariatric surgery in the studied population. Given the morbidity of surgery, our results do not imply that all patients with obesity and hypertension with similar characteristics to those included in our trial should be submitted to bariatric surgery. However, multiple barriers exist to managing hypertension in obesity, including nonadherence to long-term multiple antihypertensive drugs. Thus, gastric bypass represents 1 extra option to help achieve blood pressure control with the added benefit of improving metabolic and inflammatory profile. Taken together, such effects have the potential to reduce major cardiovascular events, although further trials are needed to confirm these benefits.The authors thank the Surgical Center and Ward staff and the Surgical Team and Research Institute-Heart Hospital for assistance with the GATEWAY trial.Dr Schiavon received a significant research grant from, participated in a Speakers Bureau for, and received honoraria from Johnson & Johnson Brazil. Dr Cohen received a significant research grant from Johnson & Johnson Brazil; participated in a Speakers Bureau for Johnson & Johnson Brazil; and served as a significant consultant on the advisory board of GI Dynamics. Dr Gonçalves de Souza participated in a Speakers Bureau for Daiichi-Sankyo Brasil Farmacêutica and served as a modest consultant on the advisory board of Aché Laboratório Farmacêutico. Dr Drager received a research grant from Philips Respironics and participated in a Speakers Bureau for Johnson & Johnson Brazil. Dr Berwanger received a significant research grant from AstraZeneca, Boheringer Ingelheim, Sanofi, Amgen, Pfizer, Roche, and Bayer. The other authors have nothing to disclose.


Radial pressure pulse wave (RPPW) examination has been a key diagnostic component of traditional Chinese medicine. The objective of this study was to investigate the changes in RPPW along with various hemodynamic variables after acupuncture stimulation and to examine the validity of pulse diagnosis as a modern diagnostic tool.We conducted acupuncture stimulation at both ST36 acupuncture points in 25 healthy volunteers. We simultaneously assessed the RPPW by pulse tonometry; heart rate variability (HRV) by electrocardiogram; photoplethysmogram (PPG) signals, respiration rate, peripheral blood flow velocity and arterial depth by ultrasonography; and cardiac output by impedance cardiography, before, during and after a session of acupuncture stimulation.We observed consistent patterns of increased spectral energy at low frequency (<10 Hz) and pulse power using RPPW examination and in the amplitude and systolic area of the PPG signal during the entire acupuncture session. The low- and high-frequency domains of HRV increased and decreased, respectively, during the acupuncture session. The peripheral blood velocity rose shortly after needle insertion, reached a maximum in the middle of the session and decreased afterwards. The augmentation index (AIX) and pulse transit time (PTT) obtained from RPPW did not change significantly.Acupuncture stimulation at ST36 in healthy subjects increased the peripheral pulse amplitudes (pressure pulse wave (PPW) and PPG), blood flow velocity (ultrasonography) and sympathetic nerve activity (HRV). The lack of changes in the AIX and PTT suggests that the increased pulse amplitudes and blood flow velocity may result from increased cardiac output.KCT0001663).Clinical Research Information Service (The online version of this article (doi:10.1186/s12906-017-1787-z) contains supplementary material, which is available to authorized users. Pulse diagnosis is a specific diagnostic and prognostic method used in traditional East Asian medicine (TEAM), including traditional Chinese medicine, traditional Korean medicine, and traditional Kampo medicine. Examining the pressure pulse wave (PPW) along arteries, especially along the radial artery, using the index, middle and ring fingers is a common practice in TEAM clinics . Pulse dFrom the viewpoint of modern medicine and biological science, the pulse is understood as a quantity that primarily reflects cardiac and hemodynamic activities . The PPWRevealing the connection between the behavior of the PPW and various body conditions is a way to modernize and revitalize the pulse diagnosis of TEAM. Investigating the relationship between PPW and other cardiac and hemodynamic bio-signals may elucidate the underlying mechanism of pulse diagnosis and will help promote it as a modern scientific diagnostic method. In this sense, studying the continuous and simultaneous assessments of various hemodynamic factors associated with PPW changes is an important research agenda for understanding and modernizing the pulse diagnosis of TEAM.A popular treatment modality that affects the characteristics of the PPW is acupuncture. According to the emperor’s inner canon (Huangdi Neijing), “The key to acupuncture treatment is Qizhi, which brings about the therapeutic effect of acupuncture,” where Qizhi may refer to the changes in the pulse wave . TherefoThis study was a prospective, single-arm, exploratory clinical study to observe the effect of acupuncture stimulation on various hemodynamic variables, such as RPPW, in healthy young participants. This study was conducted at the Korean Medicine Clinical Trial Center, Kyung Hee University Korean Medicine Hospital, Seoul, South Korea, from October 2015 to December 2015. The study protocol was approved by the Institutional Review Board of Kyung Hee University Korean Medicine Hospital, Seoul, Korea (KOMCIRB-150818-HR-030) and was registered with the Clinical Research Information Service (registration number: KCT0001663) before the first participant was included. Written informed consent was obtained from each participant prior to study participation. Twenty-five healthy adults were recruited through advertisements on bulletin boards at the local hospital and university. Through history taking and assessment of vital signs including blood pressure, respiratory rate, pulse rate and body temperature, we evaluated general health status of the potential participants. The detailed protocol for the study is described in Shin et al. .The following inclusion criteria were applied as follows: healthy participants aged between 20 and 30 years old who had provided signed written informed consent.Use of medications within 1 month before participation, including antihypertensives, hypoglycemic agents, narcotics, tranquilizers, antithrombotic or antiplatelet agents, anticoagulants, or hormone drugsPregnancy or lactationKorean Medicine College students or Korean medical doctorsAcupuncture treatment within the last 4 monthsInability to undergo evaluation with the pulse tonometric device or ultrasonographyA history of heart disease or transplanted devices such as pacemakersParticipation in other clinical trials within the last 3 monthsCommunication disorderDrug addiction or alcohol abuseConditions where acupuncture might not be safe, such as metal allergyRefusal to participate in the trial or provide informed consentExclusion at the investigator’s discretionParticipants who met the following criteria were excluded from this study:10-30Hz), spectral energy from 0 to 10 Hz (SE0-10Hz), pulse power index (PPI), pulse depth index (PDI), and pulse volume index (PVI) were measured on the left wrist of each subject with an appropriate pulse tonometric device  and on sedentary behavior using 16 questions (P1-P16). The domains are “activity at work,” “travel to and from places,” and “recreational activities” . CEQ was10-30Hz (the primary outcome of this study), SE0-10Hz, PPI, PDI, PVI, systolic area, diastolic area, subendocardial viability ratio (SEVR) and radial augmentation index (AIX) were extracted from the KIOM-PAS for every measurement.Details of RPPW and other bio-signal parameters are presented in Table Bio-signal variables, including HRV, CO, PPG and respiration rate, were assessed using a Biopac MP150 . Specifically, the electrocardiogram (ECG) signal was recorded using an ECG100C module with lead II to analyze HRV, and the impedance cardiography signal was recorded using a NICO100C module to calculate the stroke volume (SV) and CO. The PPG signal was acquired using a PPG100C module to determine the average amplitude and average systolic area, and the RSP signal was acquired using an SKT100C module to calculate the respiration rate. Finally, the pulse transit time (PTT) was calculated by analyzing the time delay between the ECG and the RPPW.For ultrasonography, a medical ultrasound scanner  was used with a 12 L probe. The diameter of the artery was measured in the B mode, and the maximum and average of the blood flow velocity were measured in color Doppler mode. The angle of incidence for the ultrasound was maintained at 60° in the color Doppler mode and 20° in the B mode.All unexpected responses related to the acupuncture treatment and measurements (adverse events) were reported to the investigators by the participants or were examined by an investigator. Adverse events were evaluated by investigators as mild, moderate, or severe according to the World Health Organization Draft Guidelines for Adverse Event Reporting  and Spil13-50Hz) showed a significant mean change between pre- and post-acupuncture stimulation. Based on this result, we derived a mean change of 3.38 and a common standard deviation of 5.23 using the sample size and p-value presented in this paper. We planned to recruit 25 participants to detect differences with a 5% type I error, 80% power and 5% dropout rate. The significance level for all tests was set to 0.05 (two-sided). The baseline characteristics of the participants were described with the available data. Categorical outcomes were represented as the numbers of participants and percentages, and continuous variables were summarized as the means and standard deviation for normal data and the medians and interquartile range (25th and 75th quartiles) for skewed data. The Shapiro-Wilk test was used to verify the normality of the quantitative measures. Analyses of the primary and secondary outcomes were conducted on a full analysis set on the basis of the intention-to-treat principle and on per-protocol subsamples for the purpose of sensitivity analyses. The last observation carried forward (LOCF) method was used to impute missing data.All statistical analyses were performed using the current version of R statistical software . The sam13-50Hz, it had almost the same properties as those obtained from SE10-30Hz [10-30Hz between pre- and post-acupuncture stimulation measured at the baseline and at the end, respectively.Although the sample size in this study was obtained from SEE10-30Hz . Thus, tp-values. The changes in SE10-30Hz at six time points  were investigated using a linear mixed-effect model (LMM) as a secondary analysis. The LMM included covariates  and interaction terms between sex and time effects. The model was modified by excluding the interaction term if it was not significant. The ANOVA table for the model was provided, and the least square mean, standard error, and 95% CI were provided for each time point. Differences in a value between a given time point and baseline (before acupuncture) were examined using Dunnett’s test.A paired two-sample t-test was used to determine the significance of the change induced by the acupuncture stimulation. The results of the analysis were presented as the means, standard deviation, 95% confidence intervals (CI), t-values and From October to December 2015, 25 healthy volunteers participated in this study, including 13 female and 12 male young adults  2.4 years). No participants dropped out due to compliance problems related to acupuncture stimulation or repeated assessments , but the differences increased continuously after 7 min  and 14 min , immediately after needle removal  and 7 min after needle removal . SE10-30Hz, however, did not show any differences between before and after acupuncture needling, except at the final assessment .Significant increases in SEPPI also showed an increasing pattern in the difference between the baseline and after needling values. No significant differences were observed immediately after needling  or 7 min after needling , but the differences increased gradually after 14 min , at needle removal  and 7 min after needle removal . The PDI values did not show significant differences for any measurement. The PVI values showed significant increases in the measurements 7 min after  and 14 min after needle insertion .The systolic area and diastolic area also showed an increasing pattern during the procedure. Significant differences were observed 14 min after needle insertion , at needle removal , and at the final assessment  for the systolic area and at needle removal  and at the final assessment  for the diastolic area. SEVR showed an opposite decreasing tendency after needle insertion, and significant differences were observed 14 min after needle insertion  and immediately after  and 7 min after needle removal . AIX and PTT did not show significant differences between baseline and any assessment (Table .51), at For HRV, the variables showed significant differences from the baseline value only at the last measurement session. The variables were NN , HF , nLF , nHF  and LF/HF . Similarly, PPG systolic area showed a significant increase from the baseline only at the last measurement session .CO and SV, which were estimated with the impedance cardiography device, did not present any significant change between baseline and any measurement throughout the entire procedure. Lastly, respiratory rate also did not show any significant changes during the study Table .Table 4RThe diameter of the radial artery did not show significant changes throughout the entire procedure. However, the maximum blood velocity increased immediately after needle insertion , reached the maximum value 7 min after needling , and subsequently decreased significantly until 14 min after needling ; subsequently, no differences were observed immediately after needle removal or 7 min after needle removal . The average blood flow velocity showed a similar pattern as the maximum velocity. Significant increases were observed immediately after needling  and during needle retention , but there were no differences immediately after needle removal  or 7 min after needle removal  of HRV and a decrease in the high-frequency domain (0.15–0.4 Hz) during the acupuncture session, although these changes did not reach statistical significance. These responses imply that the acupuncture treatment induced an increase in sympathetic activity and a decrease in parasympathetic activity. Typical physiological changes associated with increases in sympathetic tone are an increase in cardiac output (CO) and/or vascular constriction .We assume that these hemodynamic changes are consequences of either increased CO and/or decreased arterial compliance. We calculated AIX and PTT from the RPPW and estimated the CO using an impedance cardiography module . PreviouThe most valuable feature of this study is that we simultaneously analyzed various hemodynamic variables during the acupuncture session. Previous studies assessed only one or two variables and could not draw comprehensive conclusions regarding the hemodynamic changes with acupuncture stimulation –10. In tOur study has several limitations. Changes in the hemodynamic variables were observed for only a limited time around the acupuncture session. There is controversy over the effective duration related to acupuncture practice. Generally, studies on acupuncture treatment consider both short-term and long-term effects . In thisFrom the analysis of this study, several future research directions can be suggested. Several variables showed consistent trends but lacked statistically significant differences, probably due to the low power of this study. Therefore, a clinical study with a sufficiently large sample size is desired. Second, reflecting actual clinical practice, studies adopting acupuncture stimulations at multiple points are also necessary, and point-specific effects need to be investigated. Third, studies on actual patients need to be conducted. Compared to treatments of healthy subjects, appropriate acupuncture treatments on patients will improve body conditions that should be reflected more dramatically in pulse diagnosis and, thus, in PPW and other hemodynamic variables. In addition, studies with patients would allow disease-specific characteristics of pulse diagnosis to be more clearly identified, which will help elucidate the underlying mechanism of pulse diagnosis in diverse cases.In conclusion, in an attempt to find scientific evidence and the mechanism underlying pulse diagnosis, we investigated the changes in RPPW and related bio-signals from PPG, ECG, and ultrasonography with a conventional acupuncture treatment in healthy subjects. The results indicated that ST36 acupuncture stimulations at both legs induced increases in the blood flow velocity in the radial artery and peripheral arterioles and induced a relaxation effect; the treatment increased the radial pulse pressure – especially the systolic pulse pressure and the power spectral density in the low-frequency domain (<10 Hz) – and increased the PPG systolic area and blood flow velocity at the radial artery. In addition, the treatment increased the high-frequency HRV and decreased the low-frequency HRV. Through further analysis, we showed that these increased blood flow velocity indicators were possibly the consequence of increased CO, especially during the systolic period. Using this integrative approach, the analysis of radial pulse pressure can be a predictive tool for the changes in hemodynamic variables during an acupuncture session. Studies with patients and diverse acupuncture point stimulations and more direct measurements of CO are needed to confirm our results and generate a deeper understanding of the mechanism of pulse diagnosis in various health conditions.


Clinical guidelines recommend monitoring of blood pressure at home using an automatic blood pressure device for the management of hypertension. Devices are not often calibrated against direct blood pressure measures, leaving health care providers and patients with less reliable information than is possible with current technology. Rigorous assessments of medical devices are necessary for establishing clinical utility.The purpose of our study was 2-fold: (1) to assess the validity and perform iterative calibration of indirect blood pressure measurements by a noninvasive wrist cuff blood pressure device in direct comparison with simultaneously recorded peripheral and central intra-arterial blood pressure measurements and (2) to assess the validity of the measurements thereafter of the noninvasive wrist cuff blood pressure device in comparison with measurements by a noninvasive upper arm blood pressure device to the Canadian hypertension guidelines.The cloud-based blood pressure algorithms for an oscillometric wrist cuff device were iteratively calibrated to direct pressure measures in 20 consented patient participants. We then assessed measurement validity of the device, using Bland-Altman analysis during routine cardiovascular catheterization.The precalibrated absolute mean difference between direct intra-arterial to wrist cuff pressure measurements were 10.8 (SD 9.7) for systolic and 16.1 (SD 6.3) for diastolic. The postcalibrated absolute mean difference was 7.2 (SD 5.1) for systolic and 4.3 (SD 3.3) for diastolic pressures. This is an improvement in accuracy of 33% systolic and 73% diastolic with a 48% reduction in the variability for both measures. Furthermore, the wrist cuff device demonstrated similar sensitivity in measuring high blood pressure compared with the direct intra-arterial method. The device, when calibrated to direct aortic pressures, demonstrated the potential to reduce a treatment gap in high blood pressure measurements.The systolic pressure measurements of the wrist cuff have been iteratively calibrated using gold standard central (ascending aortic) pressure. This improves the accuracy of the indirect measures and potentially reduces the treatment gap. Devices that undergo auscultatory (indirect) calibration for licensing can be greatly improved by additional iterative calibration via intra-arterial (direct) measures of blood pressure. Further clinical trials with repeated use of the device over time are needed to assess the reliability of the device in accordance with current and evolving guidelines for informed decision making in the management of hypertension.ClinicalTrials.gov NCT03015363; https://clinicaltrials.gov/ct2/show/NCT03015363 (Archived by WebCite at http://www.webcitation.org/6xPZgseYS) Hypertension is a global health problem affecting over a billion people . If uncotreatment gap refers to hypertensive patients who are left untreated because of underestimated noninvasive blood pressure readings, which could be a health risk for the patient.Manual auscultatory and automated oscillometry  are common means for diagnosing hypertension and guiding appropriate medical management. Current guidelines  recommend confirmation of hypertension  with ambulatory or home blood pressure monitoring -6 . In rAutomated clinical oscillometric or consumer-level devices have been generally compared with manual auscultatory measurements -12, whilIncreasingly, automated devices are being assessed against direct intra-arterial standards for clinical certainty, yet, most still do not report the uncertainty of the single blood pressure measurement. Comparing direct and indirect blood pressure measures simultaneously ensures that intraphysiological variability can be accounted for in the measures. The difference between 2 methods can then be validated with multiple measures within a patient population. There is a growing need for more accurate devices to measure blood pressure  to betteThe clinical protocol was approved by the Horizon Health Network Research Ethics Board, and the study is registered with the National Institute of Health Clinical Trials Registry database (NCT 03015363). The patient participant inclusion/exclusion criteria were: (1) a referral from the patient’s attending cardiologist to undergo a first-time nonemergent diagnostic cardiac catheterization procedure for clinically valid indications; (2) participants aged ≥19 years; (3) wrist circumference should be in the range of 13.5 to 23 cm; (3) participant should be willing to voluntarily sign the study-specific informed consent form; and (4) participant should have no previous percutaneous coronary intervention, coronary artery bypass graft, abdominal aortic aneurysm, peripheral vascular disease, aortic stenosis, arrhythmia, tremors (before or during procedure), or carotid bruits. In accordance with the Association for the Advancement of Medical Instrumentation (AAMI) standards for clinical investigation using reference-based invasive blood pressure monitoring [Logistically, the wrist cuff cannot be applied to the same arm that is being cannulated for radial pressure. Thus, patients were screened for bilateral upper arm auscultatory blood pressure equality , patients were given 1mg of midazolam and 50 µg of fentanyl for presedation ; blood pressure readings were taken as indicated in Intra-arterial pressure was measured with a fluid-filled 5 or 6 French gauge catheter (Cordis AVANTI+) attached to a pressure transducer , which is consistent with the recent recommendation by the ARTERY Society task force . The preCalculated device values of systolic and diastolic pressures were initially derived from the Cloud Diagnostics Inc application reports . The intra-arterial dataset was split into a training set and a testing set using the jackknife technique, as originally described . The jacData analysis was performed via Bland-Altman (Tukey mean difference) plot analysis ,23 to asHere, we used intra-arterial blood pressure measurements in comparison with the noninvasive wrist cuff method .A total of 74 potentially eligible patients were screened, of which 37 consented, 3 withdrew, and 14 failed to meet the criteria during the (day 2) procedure. A summary of the patients’ characteristics that completed all aspects of this study is presented in P<.001, as a result of pressure augmentation [P=.23).The mean direct right radial arterial systolic pressure was 145.7 (SD 20.2) mm Hg, and the mean direct ascending aorta systolic pressure was 133.4 (SD 22.0) mm Hg. This illustrates the real physiological difference of 14.4 (SD 10.3), with entation . There wP<.001, while the absolute mean difference of the diastolic measures was 16.1 (SD 6.3), with P<.001 (See P=.87 and 4.3 (SD 3.3), with P>.99, respectively (P=.97 and 4.3 (SD 3.3), with P=.98, respectively , with .001 See . Next, wectively . Howeverectively , with a To further assess the value of the central algorithm independently of our calibration dataset, we sourced an arms-length dataset of double-observer auscultatory blood pressure measures from Cloud Diagnostics Inc . The average absolute mean difference of the initial algorithm markedly improved with the central pressure calibrated algorithm in both the systolic and diastolic pressures  or with physical limitations to upper arm cuff use . To achieve broad clinical reliability, additional use and monitoring of the device, such as in clinical trials, is warranted.This wrist cuff device offers several advantages in comparison with many upper arm devices for the measurement and medical management of hypertension. A common complaint among patients and front-line health care providers, especially when performing repetitive blood pressure monitoring, is that they experience pain with upper arm compression . Frail pIndividual blood pressure measures from this wrist cuff device report the degree of uncertainty in each measure. While several mean blood pressure measurements were below the threshold for hypertension based on the CHEP guidelines  or the SThe variability between radial and aortic pressures is a function of differences in compliance, vasoactivity, and pressure augmentation, which become more variable with aging and disease ,28,32. TBlood pressure devices are almost exclusively calibrated to manual auscultatory measurements -12,17. IFurther calibration studies using this device should include special populations such as pediatric, obese, or frail patients, or those with an underlying arrhythmia or peripheral vascular disease. Also, patients with peripheral movement artifacts  represent an incremental challenge to wrist cuff devices that would be less pronounced for upper arm cuff devices. Finally, more work is required to determine whether diastolic pressure and diagnoses using indirect diastolic pressure measures are required to be accurate to direct central pressures.To diagnose hypertension according to guidelines, we must be confident with device measures ,46. It iThe wrist cuff calibrated here to the gold standard—the central (ascending aortic) pressure—is an accurate device that can be used in accordance with guidelines for informed decision making in the management of systolic hypertension.


The combination of budesonide + formoterol (BFC) offers the advantages of dose adjustment in a single inhaler according to asthma symptoms. We analyzed the relationship between asthma symptoms in terms of peak expiratory flow (PEF) and dose adjustment by the patient.Twenty-eight patients with asthma who used BFC for alleviation of their symptoms  were instructed that the inhaled BFC dose could be increased to a maximum of 8 inhalations per day according to symptom severity. Patients measured and recorded PEF every morning and evening in their asthma diary along with their symptoms and the dose of drugs taken.p < 0.05) and when they had only one symptom compared with two or three symptoms . The relationship between PEF  when the dose was increased (Y) and the days for the increased dose to achieve a PEF greater than PEF in the symptom-free state (X) was determined to be Y = − 0.591X + 89.2 .Sixteen of the 28 patients increased their dose for asthma symptoms. The time to recovery from the asthma symptoms was significantly shorter when cough was the only symptom present compared with dyspnea or wheeze . One of the advantages of using the combination of budesonide + formoterol  is that the dose can be adjusted in a single inhaler according to the severity of asthma symptoms –3. The dAs stated above, many studies support the finding that SMART reduces exacerbations of asthma and prevents overuse and/or single-use of SABA and/or long-acting beta-agonists, although some do not. A key aspect of the advantages and disadvantages of SMART is the timing of BFC dose adjustment, because most previous studies on SMART have no detailed description of the timing of increasing the BFC dose, simply referring to the timing as “as needed”. We anticipate that the key to explaining these conflicting results is to determine the conditions under which the BFC dose should be increased. In this study, we analyzed the relationship between various parameters, including peak expiratory flow (PEF) and symptoms, and the time point at which the BFC dose was adjusted by the patient to determine the optimal management of asthma symptoms with BFC. Evidence supporting the use of SMART may be further strengthened if the timing of increasing the BFC dose is explained to patients in detail, based on our results.We enrolled patients with asthma who used BFC for alleviation of their asthma symptoms over a period of 4 weeks, as defined in the Global Strategy for Asthma Management and Prevention, in whom daytime symptoms, limitation of activities, and nocturnal symptoms/awaking were all absent, indicating that the asthma control test (ACT) scores were 25 points , 19. We The prospective study was approved by the ethics committee of Dokkyo Medical University Hospital (No. 22072) and the ethics committee of Dokkyo Medical University Koshigaya Hospital (No. 1409). This study was registered at the University Hospital Medical Information Network Center, Clinical Trials Registry (UMIN-CTR: No. UMIN000009599). Written informed consent for participation in the study was obtained from all patients.p < 0.05). No significant differences were observed in other baseline characteristics. Patients using both AMD and SMART regimens were 4 women (mean age: 60.8 years), and 12 patients increased their dose of BFC by AMD. Additional number of inhalations was 2.0 ± 0.5 inhalations per day and mean time to decrease the BFC dose was 2.6 ± 5.3 days per event when patients increased the BFC dose.Thirty-three patients were enrolled in this study, but 5 patients were later excluded , leaving data from the remaining 28 patients for analysis. The baseline characteristics of the patients are shown in Table p < 0.05 were considered significant. The results are expressed as mean ± standard deviation (SD).The personal best PEFR in the observation period was set as 100%. All statistical analysis was performed using Microsoft Excel® 2007 SP3 MSO  and JMP® Pro version 11.2.0  statistical software. Differences between two independent samples were examined by the chi-square test, Mann-Whitney U test. Differences between two related samples were examined by Wilcoxon signed-rank test. Relationships between two parameters were examined by correlation coefficients and regression line analysis. Differences at PEF changes are shown in Table p < 0.05, p < 0.05, and p < 0.01, respectively); PEF in December was significantly lower than that in February, April, and November .We calculated the mean PEF for each month Table . There wp < 0.01, p < 0.05, p < 0.05, p < 0.05, and p < 0.01, respectively). In the relationship by month for all patients, ACT score was significantly lower in May than in July, August, September, October, November, and December ; ACT score was significantly lower in January than in November (p < 0.05) and in April than in July (p < 0.05).We calculated the mean ACT score for each month Table . ACT scop < 0.01). However, no significant differences were observed between backgrounds, such as sex, age, atopy/non-atopy, and the initial number of eosinophils. The mean times to recovery from asthma exacerbation were 8.1 ± 6.0 days in Step 1, 3.9 ± 7.5 days in Step 2, and 3.5 ± 4.9 days in Step 3. The time to recovery from asthma exacerbation in Step 1 was significantly longer than that in Step 2 (p < 0.05). However, no significant differences were shown between backgrounds, such as sex, age, and atopy/non-atopy, except the initial number of eosinophils. That in patients with under 300/mm3 of eosinophils was significantly shorter than in those with over 300/mm3 of eosinophils . Although patients in Step 1 presented with few exacerbations, recovery took a long time once they had exacerbation of asthma. However, PEF at BFC increase was not significantly different between Steps (Step 1:Step 2:Step3 = 84.4 ± 7.7%:89.2 ± 6.8%:84.7 ± 6.1%).Sixteen patients adjusted their BFC dose according to symptom severity. Their data were used for this analysis. In the severity of asthma based on medication, the frequencies of exacerbation of asthma were 0.20 ± 0.60 times per month in Step 1, 0.71 ± 0.69 times per month in Step 2, and 1.32 ± 0.34 times per month in Step 3, and a significant difference was observed between those in Step 1 and Step 3 (p < 0.05) or wheeze  or three  symptoms  compared with when they increased it in the presence of dyspnea . Because patients assessed their asthmatic status in the morning and evening, the shortest time to recover from asthmatic symptoms is half a day; for example, a patient presented with asthmatic symptoms in the morning and inhaled the adjusted dose of BFC, and the symptoms resolved by evening of the same day. The half-day value of “X = 0.5 days” represents the best timing for increasing the dose of BFC. When X is 0.5 days, PEF is 88.9% according to linear regression. To achieve this best timing, BFC should be increased before PEF is decreased to 88.9% of personal best PEF for all data. When BFC was decreased to 80% of personal best PEF, 15.6 days were required to recover from the asthma symptoms, as shown by the regression line.We analyzed PEF when patients increased BFC dose, because patients sometime feel inexpressible asthma symptoms or asthma symptoms other than cough, dyspnea, or wheezing. We determined the events when BFC dose was increased because of asthma symptoms. Then, we calculated the time from the day when BFC was increased to the day when PEF at symptom-free status was achieved. Eighty-four events with 16 patients who adjusted their BFC dose were included in this analysis. PEF when patients increased BFC dose was 86.8 ± 6.9% of personal best PEF. Mean time to improve asthmatic symptoms, when the dose was increased to achieve a PEF greater than the PEF in the symptom-free state, was 2.0 ± 3.2 days. Fig. Based on our results, to minimize the duration of asthma symptoms, BFC should be increased when the symptoms are mild. Our subjects showed high treatment adherence 94.9%) for over 8 months and therefore were good subjects for our study, even though the number of patients with mild asthma was small, because most of the patients in our university hospital have severe asthma. Furthermore, to include cases of clear asthma symptoms, we also enrolled patients with controlled asthma. When taking mean personal best PEF as 100%, 18/28 patients had PEF of > 90% and 26/28 patients had > 80%. Morning dipping was a decrease of only 1.03%. These subjects were therefore suitable to evaluate the relationship between BFC dose and PEF fluctuation, although some of them did not have asthma symptoms. In the study design, it is ideal to randomly separate adjusted and non-adjusted dose groups at the start. However, the ethics committee of our institution does not approve studies that prohibit adjustment of BFC because of patient rights. However, no significant difference was observed in background factors between these groups, except for sex, and these groups were suitable subjects for this study. Also, many previous publications analyzed the relationship between two different groups, such as SMART and non-SMART groups .9% for o. Yet, noIn the PEF for each asthma symptom, the differences were very small, 87.1% in cough and 83.6% in wheeze, and the decrease from personal best PEF was small. In the Global Strategy for Asthma Management and Prevention, the dose of inhaled corticosteroid should be increased, if PEF has fallen by > 20% for more than 2 days . However2 = 0.431, p < 0.05). Therefore, there is no essential difference between ACT scores and PEF in each month. Good control of asthma was achieved by adjustment of BFC, and these regimens are very effective for long-term management of asthma.Asthma symptoms tend to fluctuate seasonally, and thunderstorms and pollen are risk factors for exacerbation of asthma . GeneralThe number of patients in the adjusted group was smaller than expected. Significant sex differences were found between the fixed-dose and adjusted-dose groups. Twelve patients did not adjust their BFC dose during the study period, although we had explained to them that they could adjust the dose for asthma symptoms. We asked patients in the fixed-dose group their reasons for not adjusting BFC doses, and they gave two main reasons: either it was not necessary to increase BFC because they did not have any asthma symptoms, which implies that their asthma was under control, or they could not determine when BFC should be increased, because they were not given detailed suggestions for increasing the dose by their physician. Also, the mean time to recovery was longer in patients with Step 1. The reason for this was that they could not determine the optimal timing for increasing the BFC dose, because they had less experience of exacerbations of asthma. Our results will be useful for those patients to help them determine when BFC should be increased, and these patients should be instructed in great detail.With regard to SMART, we also asked the patients who did not use SMART about why they did not use BFC for symptom relief. Again, the reasons were twofold. The first was that BFC could not be used when at work. This is a very important problem in Japan to address. These patients may need sufficient regular doses of BFC more than SMART. We have previously reported that young adults without a primary care physician frequently visited our emergency department with asthma symptoms even though they probably needed only regular asthma treatment . The secRegarding differences in sex, 75% (12/16) of patients were female in the dose-adjusted group, and 100% (4/4) of patients treated with both AMD and SMART were female; there were more male than female subjects in the fixed-dose group. However, no significant differences were found in baseline characteristics and mean PEF between male and female subjects. Women with asthma are reported to be at low risk of poor adherence to inhaled corticosteroids . SimilarIn relation to concomitant drugs, 50% of patients were treated by BFC alone in the adjusted-dose group, compared with only 33% of patients in the fixed-dose group. We could not find any previous publications with similar findings. We could not identify the reason from the questionnaire responses in our study. One possibility may be that although our subjects had good adherence, adjusting the BFC dose may have been complicated for patients taking multiple medications. For such patients, full regular treatment is needed without the use of additional inhalers.We think that PEF would be a more useful reference marker than symptoms for increasing BFC because PEF allows for objective evaluation of dyspnea and involves less error. Relying on symptom severity might not be an accurate enough method because patients with severe asthma show poor awareness of dyspnea , 21.To improve asthmatic symptoms in a shortest time for patients with mild or stable asthma, the BFC dose should be increased when PEF is decreased to 88.9% of the patient’s personal best PEF. When BFC dose is increased in the presence of cough as the only symptom, the asthma symptoms recover just 1.4 days after the dose increase. However, if the BFC dose is increased when PEF is decreased to 80% of the patient’s personal best PEF, it requires 15.6 days for the symptoms to completely subside. These criteria could help patients with mild or stable asthma to increase their BFC dose to achieve a quicker symptom-free status after asthma symptoms.


Reduced ankle–brachial index (ABI) is a predictor of cardiovascular events. However, the significance of high ABI remains poorly understood. This study aimed to assess the characteristics and outcomes of patients with high ABI.The IMPACT-ABI study was a retrospective cohort study that enrolled and examined ABI in 3,131 patients hospitalized for cardiovascular disease between January 2005 and December 2012. From this cohort, 2,419 patients were identified and stratified into two groups: high ABI  and normal ABI . The primary endpoint was the cumulative incidence of major adverse cardiovascular events (MACE), including cardiovascular-associated death, myocardial infarction, and stroke.Compared with the normal ABI group, patients in the high ABI group showed significantly lower body mass index (BMI) and hemoglobin level, but had higher incidence of chronic kidney disease and hemodialysis. Multivariate logistic regression analysis revealed that hemodialysis was the strongest predictor of high ABI , 3.05–12.52; P < 0.001). During the follow-up , 172 cases of MACE occurred. Cumulative MACE incidence in patients with high ABI was significantly increased compared to that in those with normal ABI . In traditional cardiovascular risk factors-adjusted multivariate Cox proportional hazard analysis, high ABI was an independent predictor of MACE .Lower BMI, chronic kidney disease, and hemodialysis are more frequent in patients with high ABI. Hemodialysis is the strongest predictor of high ABI. High ABI is a parameter that independently predicts MACE. Peripheral artery disease (PAD) is a well-established predictor of all-cause and cardiovascular mortality and morbidity , 2. The While the majority of previous studies have focused on patients with low ABI and excluded patients with high ABI, a few studies have evaluated the baseline characteristics and outcomes in patients with high ABI. Aboyans et al. reported a strong association between diabetes mellitus and high ABI . On the Previous studies have reported the association of high ABI and cardiovascular mortality and morbidity. In the Strong Heart Study (SHS), which was a large-scale prospective study, high ABI was strongly associated with total and cardiovascular mortality . HoweverTherefore, the purpose of this study was to evaluate (1) the characteristics of patients with high ABI and (2) the association between a high ABI value and future cardiovascular events and mortality.The current study was performed using integrated data from the impressive predictive value of ABI for clinical long-term outcomes in patients with cardiovascular disease examined by ABI (IMPACT-ABI) study. The IMPACT-ABI study was a retrospective cohort study that enrolled 3,131 consecutive patients who were admitted to Shinshu University for cardiovascular disease and examined by ABI between January 2005 and December 2012. Clinical, demographic, laboratory, and follow-up data were collated from hospital records or by contacting patients and their family. The present study was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR), as accepted by the International Committee of Medical Journal Editors . The study protocol was performed in accordance with the ethical guidelines of the Declaration of Helsinki and was approved by the Ethics Committee of Shinshu University School of Medicine. Because of the retrospective nature of the current study, informed written consent for participation was not obtained from patients and data were analyzed anonymously.Among the potential subjects, 712 patients were excluded due to ABI values < 1.0 in at least one leg, and 2,419 patients were subsequently enrolled. The study cohort was divided into two groups based on ABI: normal ABI group and high ABI group. Based on the latest ACCF/AHA guidelines [For ABI measurement, systolic blood pressure in the upper extremities  and lower extremities  were measured using the Form PWV/ABI  with the patient in the supine position for at least 10 minutes of bed rest. This instrument is an automated device that can simultaneously measure blood pressure in the bilateral upper and lower extremities via the oscillometric method. ABI was calculated by dividing the systolic blood pressure in the lower extremity by the highest of the bilateral systolic blood pressure values in the upper extremity.All-cause death was defined as any death recorded during the follow-up period. Cardiovascular-associated death was defined as mortality due to acute myocardial infarction, significant cardiac arrhythmia, congestive heart failure, stroke, or other cardiovascular causes . Myocard2) = 194×serum creatinine−1.094×age−0.287 for male patients, and the same formula multiplied by 0.739 was used for female patients [2 [Diabetes mellitus was defined as fasting blood glucose levels ≥ 7 mmol/l and/or a casual plasma glucose levels ≥ 11.1 mmol/l, HbA1c ≥ 6.5%, or by clinical use of insulin or hypoglycemic agents. Hypertension was defined as systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg, or current treatment with antihypertensive agents. Dyslipidemia was defined as total cholesterol ≥ 5.7 mmol/l; or alternatively, low-density lipoprotein cholesterol levels ≥ 3.6 mmol/l, high-density lipoprotein cholesterol levels ≤ 1.0 mmol/l, triglyceride levels ≥ 1.7 mmol/l, or current treatment with cholesterol-lowering agents. Coronary artery disease was defined as a history of angina and/or previous myocardial infarction. Previous heart failure was defined as a prior heart failure diagnosis according to the Framingham criteria  or currepatients . ChronicThe primary endpoint of this study was composite of major adverse cardiovascular events (MACE), including cardiovascular-associated death, myocardial infarction, and stroke. The secondary end-point was all-cause death, and cardiovascular-associated death.th–75th percentile) for variables that were not normally distributed. Categorical variables were reported as numbers and percentages. Patient characteristics among each group were compared by the Chi-squared test for categorical variables and the Mann-Whitney U test for continuous variables. Overall occurrences of MACE, all-cause death, and cardiovascular-associated death were calculated using the Kaplan-Meier method, and differences between the groups were compared by the log-rank test. Associations of variables, including traditional cardiovascular risk factors [All statistical analyses were performed using SPSS version 22 software . Normal data distribution was assessed via the Shapiro-Wilk test. Continuous variables were reported as median and interquartile range . During the follow-up period were registered 172 MACE cases, including 115 cardiovascular-associated deaths, 58 strokes, and 27 myocardial infarctions. A total of 302 deaths  occurred.In patients with high ABI, a total of 9 MACE  and 12 all-cause deaths occurred. In patients with normal ABI, a total of 163 MACE  and 290 all-cause deaths occurred. Kaplan-Meier analysis demonstrated that MACE incidence was significantly higher in patients with high ABI values than in those with normal ABI values  . SimilarCox proportional hazard analyses were performed to evaluate the prognostic value of ABI for MACE . After aIn addition, we performed univariate and multivariate Cox proportional analysis for all-cause and cardiovascular-associated death  Tables. In a separate analysis, we excluded patients on hemodialysis (n = 81) and included eGFR as a variable into the multivariable analysis model in order to assess the prognostic value of high ABI in patients without hemodialysis. A total of 5 MACE occurred in patients with high ABI (n = 52). In patients with normal ABI (n = 2286), a total of 153 MACE occurred. As shown in In the present study, patients with high ABI exhibited significantly reduced BMI, hemoglobin and decreased eGFR, and more frequent chronic kidney disease  than those with normal ABI. In the multivariate logistic regression analysis, hemodialysis and lower BMI were independently associated with high ABI. Furthermore, the outcomes of patients with high ABI were evaluated, which demonstrated that the incidence of MACE, all-cause death, and cardiovascular-associated death were significantly higher in patients with high ABI values compared to those with normal ABI values. Moreover, multivariate Cox proportional hazard analysis adjusted for traditional cardiovascular risk factors, including hemodialysis, showed that a high ABI value was an independent predictor of MACE.Few studies have evaluated the association of high ABI with prevalent diseases. Aboyans et al. reported a strong association between diabetes mellitus and high ABI . AllisonWhen the ankle artery is incompressible or the systolic pressure of the ankle artery is much higher than that of the brachial artery, the ABI value is abnormally high. This phenomenon is thought to occur in patients with diabetes mellitus and end-stage renal disease due to their non-compressible vessels caused by medial artery calcification , 6. One In addition, regarding the prognosis of patients with high ABI, previous studies have reported inconsistent results. The SHS is a large-scale and long epidemiologic study in Native Americans, which consisted of 4,549 participants aged 45 to 74 years. In this study, 404 participants (9.2%) had high ABI (> 1.4) or incompressible arteries and this group had a higher risk of all-cause and cardiovascular associated death than the group with ABI between 0.9 to 1.4 . The invIn the present study, a high ABI was a parameter that independently predicted MACE. In addition to a high ABI value, increased age, previous myocardial infarction, heart failure and cerebral infarction, diabetes, hemodialysis, and smoking were independent predictors of MACE, which was consistent with previous studies , 24.The pathophysiologic mechanism underlying the association between high ABI and poor prognosis has not been clearly elucidated. However, it is generally well accepted that a high ABI reflects increased arterial stiffness caused by medial artery calcification –8, and tIn our unadjusted analysis, high ABI was associated with all-cause and cardiovascular-associated death. However, high ABI was not associated with all-cause death after adjustment for cardiovascular risk factors . High ABI tended to be a risk factor for cardiovascular-associated death, although the HR did not reach statistical significance in the multivariate Cox proportional hazard analysis . In this study, we concluded that high ABI independently predicts MACE (primary endpoint), including cardiovascular-associated death, myocardial infarction, and stroke. As stated above, vascular stiffness is reported to contribute to cardiovascular and cerebrovascular events , and theOur findings did not only indicate that patients receiving hemodialysis had poor outcomes, as multivariate Cox proportional hazard analysis adjusted for confounding variables  showed that high ABI was an independent predictor for MACE. These findings suggest that patients with high ABI values should be monitored, as the increased ABI values may be an indicator of increased risk for poor outcomes, even if ABI values are 1.0–1.4 in the other leg.The current study included a large data set and was able to detect a sufficient number of cardiovascular events. However, this study has several potential limitations. First, the current study was a single center, retrospective analysis that consisted of patients who were hospitalized for cardiovascular disease. Therefore, our sample study group differed from the general population. Second, ABI was measured by an oscillometric method. When measuring ABI, the Doppler method is recommended, because of its increased reproducibility compared to the oscillometric method, which may have led to an overestimation of pressure . Third, The current study showed that hemodialysis was the strongest independent predictor of high ABI. Patients with high ABI values exhibited a higher incidence of MACE, cardiovascular-associated death, and all-cause death as compared with those with normal ABI values. High ABI was an independent predictor of MACE. Notably, patients with ABI values > 1.4 exhibited a higher incidence of future cardiovascular events.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.