The aim of this study was to investigate whether leisure-time physical activity (LTPA) is associated with the development of severe diabetic retinopathy in individuals with type 1 diabetes.Prospective observational analysis as part of the Finnish diabetic nephropathy (FinnDiane) Study with a mean follow-up time of 10.7 years was performed. A total of 1612 individuals with type 1 diabetes were recruited, and LTPA was assessed at baseline using a validated self-report questionnaire. Severe diabetic retinopathy was defined as the initiation of laser treatment due to severe nonproliferative, proliferative retinopathy or diabetic maculopathy .p = 0.024), a finding that remained significant after adjustment for gender, duration, age at onset of diabetes, kidney function, BMI, triglycerides and systolic blood pressure. However, when HbA1c and smoking were added to the Cox regression model the association was no more significant.A total of 261 patients received laser treatment during the follow-up. Higher frequency of LTPA was associated with a lower incidence of severe diabetic retinopathy  were not associated with severe diabetic retinopathy.The online version of this article (10.1007/s00592-019-01454-y) contains supplementary material, which is available to authorized users. Physical activity has been shown to be beneficial for individuals with type 1 diabetes and is associated with reduced risk of cardiovascular disease (CVD) events and premature mortality . HoweverAmong the studies that have addressed this issue, the Pittsburgh Insulin-Dependent Diabetes Mellitus Morbidity and Mortality Study made the first large attempt, but that study did not find any statistically significant associations between physical activity and diabetic retinopathy , 6. HoweIn our previous study, we showed that a higher intensity of physical activity is associated with a lower risk of progression of diabetic nephropathy during the follow-up . Notablyn = 1), had previously received laser treatment (n = 956) and had end-stage renal disease (n = 14) or unclear renal status at baseline were excluded (n = 79). At baseline, 41 patients had a major CVD event . Type 1 diabetes was defined as a diagnosis of diabetes before the age of 40 years and permanent insulin treatment initiated within 1 year of the diagnosis. The study protocol was approved by the Ethical Committee of the Helsinki and Uusimaa Hospital District as well as by the local ethics committees at the participating centres and conducted according to the Declaration of Helsinki. All patients gave their written informed consent.This prospective observational study is part of the ongoing Finnish Diabetic Nephropathy Study that has previously been described in detail . The FinThe primary study end point was severe diabetic retinopathy, defined as the initiation of laser treatment due to severe nonproliferative retinopathy, proliferative retinopathy or diabetic maculopathy identified from the Care Register for Health Care (HILMO).n = 1396); microalbuminuria, ≥ 20 and < 200 μg/min or ≥ 30 and < 300 mg/24 h (n = 154); or macroalbuminuria, ≥ 200 μg/min or ≥ 300 mg/24 h (n = 62). End-stage renal disease  was defined as ongoing dialysis or having received a previous kidney transplant. Blood pressure was measured after a 10-min rest twice in the sitting position with 2-min intervals, and the average of these two measurements was used in the analysis. Anthropometric data  were recorded by a trained nurse. Fasting blood samples were drawn for the determination of HbA1c, lipid profile and serum creatinine. Smoking was assessed by a standardized questionnaire.Renal function (eGFR) was estimated using the CKD-EPI equation . Renal s2 max [LTPA at baseline was assessed by a validated LTPA questionnaire. The questionnaire is based on the Kuopio Ischemic Heart Disease Risk Factor Study (KIHD) questionnaire that had been converted from the Minnesota LTPA questionnaire to a Finnish setting , 14. The2 max –14. The The statistical analyses were conducted using the SPSS Statistics Software . Comparisons between the groups were made using ANOVA for normally distributed variables and with the Kruskal–Wallis test for non-normally distributed variables. The chi-square test was used for categorical variables. Categorical variables are given as percentages. Normally distributed continuous variables are presented as mean ± SD, and those not normally distributed as median with interquartile range.p value less than 0.05 was considered statistically significant.The cumulative incidence rates of severe diabetic retinopathy were assessed by the Kaplan–Meier method, and the logrank test was used to test the differences between groups. In the Kaplan–Meier analyses, the comparisons between the different levels of LTPA  were assessed by trend test when appropriate. The follow-up started from the baseline visit, and the person-years at risk were calculated until the first severe diabetic retinopathy event, death or the end of year 2015. The association between different LTPA components and severe diabetic retinopathy was analysed using Cox proportional univariable and multivariable hazard regressions. A 1c 66.3 ± 14.9 mmol/mol (8.2 ± 1.4%), median LTPA 17.7 (8.3–33.5) METh/week, and 41.5% of the studied individuals were previous or current smokers.The total number of individuals studied was 1612, and the mean follow-up time was 10.7 ± 4.6 years. Of the whole population, 44.7% were men, mean age was 37.0 ± 11.9 years, mean duration of diabetes 18.9 ± 11.7 years, mean systolic blood pressure (SBP) 131 ± 16 mmHg, mean BMI 25.1 ± 3.6, mean HbA1c, more often a history of smoking and more frequent use of antihypertensive drugs.The baseline clinical characteristics regarding total LTPA are shown in Table During the follow-up, a total of 261 of the patients developed severe diabetic retinopathy. The 10-year cumulative incidence rates for all LTPA components are shown in Table 1c to model 3, and the association between LTPA frequency and severe diabetic retinopathy was no more significant. The final Cox regression model included the previous confounders and history of smoking. There was no association with severe diabetic retinopathy in this model. Notably, HbA1c and history of smoking showed a strong association with the development of severe diabetic retinopathy. Interestingly, after adjustment for the static risk factors (model 2) as well as BMI, triglycerides and systolic blood pressure, the frequency of physical activity was still associated with severe diabetic retinopathy (p = 0.045). However, the association was no more significant after adding either history of smoking or HbA1c to the model. The total amount of LTPA or the other components (intensity and duration) showed no association either in univariable or in multivariable models.The multivariable analyses regarding total LTPA, the LTPA components and the development of severe diabetic retinopathy are shown in Table N = 1396). However, the number of patients with severe diabetic retinopathy in this particular group was small (N = 190), and statistical power rather low. We also performed the same analyses in patients (N = 179) with normal AER, HbA1c < 8%, SBP < 135, BMI < 25 and with no history of smoking. In this subgroup, neither LTPA frequency nor the total amount of LTPA was associated with the development of severe diabetic retinopathy. This might be due to reduced power. Also, when the analyses were conducted in men and women separately, no associations were found.We also performed the same analyses separately for individuals with normal AER. There was no association with LTPA or its components with severe diabetic retinopathy in this subgroup  that theoretically could affect the pathogenesis of diabetic retinopathy. More precise objective physical activity assessment tools are not feasible for such large nationwide cohorts as ours, and they have their own potential bias such as increased activity during surveillance. Some potential confounders such as nutrition and socio-economic status were not either evaluated in our study. Instead, we used smoking as a confounder as smoking has been shown to be strongly correlated with the socio-economic status , 31. TheIn conclusion, frequent LTPA was associated with a lower incidence of severe diabetic retinopathy in type 1 diabetes during the follow-up. The total amount of LTPA or its components (intensity or the duration of a single session) were not associated with severe diabetic retinopathy.Supplementary material 1 (DOCX 32 kb)Below is the link to the electronic supplementary material.


Body mass index (BMI), age, left atrium (LA) dimension and left ventricular ejection fraction (LVEF) have been linked to post-operative atrial fibrillation (POAF) after cardiac surgery. The aim of this study was to better define the role of these risk factors.This retrospective cohort study evaluated 249 patients  undergoing cardiac or aortic surgery. Prior to surgery, the following data were collected: age, BMI, LA diameter, LA area, LVEF, thyroid stimulating hormone (TSH), creatinine and the presence of arterial hypertension (AH) and diabetes. Intraoperative data such as operation time, total clamp time, cardiopulmonary bypass time, and presence of pericardial/pleural effusion were also collected. Only patients without pre- and post-surgery prophylactic anti-arrhythmic therapy were included.N = 127, 51%) and without POAF  were compared. No difference was observed for sex, LA diameter, LA area, LVEF, TSH, diabetes and use of ACE inhibitors or statins prior to intervention. Moreover, no difference was observed in terms of operation time, total clamp time, cardiopulmonary bypass time, and presence of pericardial/pleural effusion. However, patients with POAF were older , had higher BMI , higher baseline creatinine  and a higher frequency of arterial hypertension  and Bentall procedure . Multivariate analysis showed that the only independent predictors of POAF were age  and BMI .Patients with (These findings suggest that advanced age and a higher BMI are strong risk factors for POAF in patients without previous AF even in the presence of comparable LA dimensions and LVEF. Because of persistent high incidence, increased complications, length of hospitalization and costs, post-operative atrial fibrillation (POAF) is still considered a major problem in cardiac surgery –4. It isA close association has been reported between obesity and atrial fibrillation . HoweverThe aim of the present study was to better define the relative role played by these risk factors comparing patients with and without POAF. To eliminate the role of arrhythmia itself as a confounder, only patients without a previous history of AF were included in the present study.This retrospective cohort study undertaken in 2019 included 249 consecutive patients  who underwent cardiac or aortic surgery in a tertiary hospital in Florence, Italy. Patients undergoing emergency surgery, and those with prior atrial dysrhythmia , were excluded. All surgical procedures were performed in extracorporeal circulation and in cardioplegic arrest. In no case was the left auricle closed or removed or surgical ablation of atrial fibrillation performed. The following data were systematically collected 24 h before surgery: age, BMI, left atrium (LA) diameter, LA area, left ventricular ejection fraction (LVEF), thyroid stimulating hormone (TSH), creatinine and the presence/absence of arterial hypertension (AH) and diabetes. To detect the occurrence of incident POAF, cardiac rhythm was continuously recorded over the first seven days postoperatively. The end-point of the study was the occurrence of POAF during the early postoperative period . The prThis study received approval from the institutional review board of the hospital for accessing the electronic medical records of study subjects, and for collecting and processing relevant data from these records. The research plan was submitted to the department of cardiovascular surgery and nursing departments to report the purpose and method of the study and to obtain permission for data collection. This investigation conformed to the principles outlined in the Declaration of Helsinki.p > 0.010 but with potential impact on the pathophysiology of POAF were also entered in the model. All statistical analyses were performed with SPSS V23 package .Continuous variables were reported as mean ± standard deviation (SD) whereas categorical variables were presented as number and percentages. All variables were compared for the presence of POAF (‘no’ vs. ‘yes’). For continuous variables, comparisons were performed using t-test, analysis of variance or nonparametric tests, as appropriate. Categorical variables were compared using the Chi-squared test, or Fisher’s exact test when any expected cell count was less than five. Multivariate logistic regression analysis (method selection: backward deletion) was used to identify independent predictors of incident POAF. In this regard, all variables with p < 0.10 following univariate analysis were included in the model. In addition, potential candidate variables with The main demographic, clinical, laboratory, echocardiographic characteristics, and the surgical procedures of patients without and with incident POAF are presented in Table p = 0.001) and had significantly higher BMI  and baseline creatinine  as well as a greater prevalence of history of arterial hypertension  (Table p = 0.023)  and BMI  were emerged as independent predictors of incident POAF.Multivariate analysis with a binary logistic model included the following covariates as variables associated with POAF that remained significant after univariate analysis: BMI, arterial hypertension, plasmatic creatinine and Bentall procedure in addition to the following variables: use of ACE-I, statins, operation time, total clamp time, cardiopulmonary bypass time, and presence of pericardial/pleural effusion. Considering all these variables, only age (OR = 1.05, 95% CI 1.02–1.07, Using a real-world clinical experience with careful exclusion of patients with a history of atrial tachyarrhythmia, the results of this study provide solid evidence that advanced age and elevated BMI can be considered important POAF risk factors in patients who never had experienced AF prior to surgery. In fact, the association of these two parameters with the probability of incident POAF proved to be independent of left atrial size and ventricular systolic function, as well as the type of surgery performed.Some previous studies have attempted to analyze the behaviour of POAF risk factors in patients without presurgical AF, as in the present study. However, they showed some differences. Sun et al.  analyzedAdvanced age has been defined as one of the most powerful risk factors for incident AF following open heart surgery , 9. ThisA BMI beyond the diagnostic threshold of obesity suggests that a low-grade inflammation might be present in patients with POAF , and excAge and body mass index represent important risk factors for POAF independent of atrial size and ventricular systolic function.


Identifying patients at high risk of developing kidney disease could lead to early clinical interventions that prevent or slow disease progression. Soluble urokinase plasminogen activator receptor (suPAR) is an inflammatory biomarker thought to be involved in the pathogenesis and development of kidney disease. We aimed to determine whether elevated plasma suPAR measured at hospital admission is associated with incident kidney disease in patients presenting to the emergency department.This was a retrospective registry-based cohort study performed at the Emergency Department of Copenhagen University Hospital Amager and Hvidovre, Hvidovre, Denmark. Patients were included in the study from November 2013 to March 2017 and followed until June 2017. Patients were excluded if they were diagnosed with kidney disease or died prior to index discharge. Plasma suPAR was measured at hospital admission, and the main outcome was time to incident kidney disease, defined by ICD-10 diagnosis codes for both chronic and acute kidney conditions. Association between suPAR and time to incident kidney disease was assessed by Cox proportional hazard regression analysis.P < 0.001) for developing a chronic kidney condition and 2.51  for developing an acute kidney condition.In total, 25,497 patients  were admitted to the emergency department and followed for development of kidney disease. In multivariable Cox regression analysis adjusting for age, sex, eGFR, CRP, cardiovascular disease, hypertension, and diabetes, each doubling in suPAR at hospital admission was associated with a hazard ratio of 1.57 (95% CI: 1.38–1.78, In a large cohort of acutely hospitalized medical patients, elevated suPAR was independently associated with incident chronic and acute kidney conditions. This highlights the potential for using suPAR in risk classification models to identify high-risk patients who could benefit from early clinical interventions. The main limitation of this study is its reliance on accurate reporting of ICD-10 codes for kidney disease. Chronic kidney disease (CKD) is a major health issue affecting 8–16% of people worldwide . PatientSoluble urokinase plasminogen activator receptor (suPAR) is an endogenous signaling molecule and biomarker of chronic inflammation, and elevated suPAR levels have been associated with a range of diseases and mortality . In 2015Patients admitted through the emergency department are characterized by high age and disease burden , and theThis was a retrospective observational cohort study performed at Copenhagen University Hospital Amager and Hvidovre. The initial patient population included all patients admitted to the Acute Medical Unit of the Emergency Department between November 18, 2013 and March 17, 2017 with follow-up data accessible in the Danish National Patient Registry (DNPR). Index admission was defined as the first recorded admission with a suPAR measurement within this study period. Patients were excluded from analysis if they were diagnosed with kidney disease, received dialysis, or died from any cause prior to index discharge. Patients with prior urolithiasis were not excluded. Data on prior kidney disease was obtained from the DNPR dating back to 1977. The study was approved by the Danish Data Protection Agency  and the Danish Health and Medicines Authority (ref. 3-3013-1061/1).® c8000 701/702  with a module instrument using the Roche Creatinine Plus version 2 IDMS-traceable enzymatic assay. CRP was measured on a Roche Cobas® 6000 . suPAR was measured on a Siemens BEP2000 using the suPARnostic® AUTO Flex ELISA  according to the manufacturer’s instructions. Estimated GFR was calculated with the creatinine-based equation from the Chronic Kidney Diseases Epidemiology Collaboration (CKD-EPI) -10 diagnosis codes from the DNPR . Blood sCKD-EPI) .chronic kidney condition  or acute kidney condition . Information on vital status at the end of follow-up was obtained from the Civil Registration System. The primary outcome was time to event during follow-up, which was defined as number of days from index discharge to first kidney disease diagnosis or death (whichever came first).Information about disease status, hospital readmissions, and death was collected during a follow-up period beginning at index discharge and extending to a censor date  90 days after the last patient was included . Patients who left the country during the study period were censored at their last recorded hospitalization. Disease status during the study period was determined by ICD-10 codes obtained from the DNPR, which compiles information from all inpatient and outpatient activity within the Danish secondary healthcare system . The quaPatient characteristics are presented with basic statistics: continuous variables as median with interquartile range, and discrete variables as number with percent of patients. Comparison between included and excluded patients was assessed by Wilcoxon rank sum test. Association between suPAR and incident kidney disease was assessed by Cox proportional hazard regression analysis and graphically represented by cumulative incidence plots. Association between suPAR and all-cause mortality was assessed by Cox proportional hazard regression analysis and graphically represented by a Kaplan-Meier plot.2(suPAR) as the sole explanatory variable and then as a multivariate model adjusted for age, sex, log2(eGFR), log10(CRP), cardiovascular disease, hypertension, and diabetes. In these models, suPAR, eGFR, and CRP were log-transformed for the purpose of interpretation and comparison with previous studies (2(suPAR) and the covariates was assessed by variance inflation factor (VIF), and VIF greater than 5 was considered an indication of collinearity (2(suPAR) and log2(eGFR) was further assessed by linear regression, and normality of residuals was evaluated by QQ-plot. Given the known association between suPAR and eGFR, an additional sensitivity analysis removing patients with eGFR less than 60 mL/min/1.73 m2 was performed for the multivariate models. For a similar reason, sensitivity analysis removing patients with prior diagnosis of cardiovascular disease was also performed for the multivariate models.An initial Cox regression model was generated with suPAR quartile as the explanatory variable and incident chronic kidney condition, acute kidney condition, or death as the endpoint. Start date was set to day of index discharge, censor date was set to June 17, 2017, and all endpoints were modeled as competing events for all other endpoints. Next, the analysis was repeated with suPAR modeled as a continuous variable. This was done first as a univariate model with log studies . Collineinearity . AssociaP < 0.05 was taken to be statistically significant. SAS Enterprise Guide 7.1  was used for statistical analysis and generation of figures.To investigate differences in hazard ratio for specific etiologies of chronic kidney conditions, the continuous Cox regression models were repeated for these endpoints subdivided by disease type . To investigate differences in hazard ratio for specific etiologies of acute kidney conditions, the continuous Cox regression models were repeated for these endpoints subdivided by specific time periods from index discharge to diagnosis . In these time period specific models, patients who were censored or developed an event before each time period were excluded from the model for that time period, and patients who were censored or developed an event after each time period were censored at the end of that time period. Proportional hazard assumption of each regression model was evaluated by Schoenfeld residuals. 2), lower median CRP (4.0 vs. 16.0 mg/L), and lower median suPAR (2.7 vs. 4.5 ng/mL) . Compared with patients excluded for any reason , the study cohort had higher median eGFR (88.7 vs. 57.4 mL/min/1.73 m2), lower median CRP (4.0 vs. 26.0 mg/L), and lower median suPAR (2.7 vs. 4.9 ng/mL) .In total, 29,088 patients with follow-up data had suPAR measured at hospital admission during the study period. Of these, 2,836 patients were excluded due to prior kidney disease and 755 additional patients were excluded due to death from any cause prior to index discharge, resulting in a study cohort of 25,497 acute medical patients . BaselinDuring the follow-up period, 760 patients (3.0%) developed kidney disease, and 3,199 patients (12.5%) died without being diagnosed with kidney disease. Among patients who developed incident kidney disease, 570 patients (75%) developed a chronic kidney condition, and 190 patients (25%) developed an acute kidney condition . Patient2(suPAR) and the covariates, with the largest variance inflation for age (VIF 1.82) and log2(eGFR) (VIF 1.74). However, there was a significant association between log2(suPAR) and log2(eGFR) at index admission, with β = –0.32 . Among patients with eGFR >60 mL/min/1.73 m2, 349 patients (1.7%) developed kidney disease, and 1,908 patients (9.4%) died during follow-up. Among patients with eGFR <60 mL/min/1.73 m2, 379 patients (9.5%) developed kidney disease, and 1,180 patients (29.6%) died during follow-up. For all categories of eGFR, patients who developed kidney disease or died during follow-up had significantly higher suPAR at index admission (There was no indication of collinearity between log = –0.32 . Patientdmission .P = 0.007) for developing an incident chronic kidney condition, patients in the 3rd quartile had a hazard ratio of 2.77 , and patients in the highest suPAR quartile had a hazard ratio of 8.53 .Cumulative incidence of chronic kidney conditions by suPAR quartile is shown in P < 0.001) and an adjusted hazard ratio of 1.57  for developing an incident chronic kidney condition , and sensitivity analysis removing patients with a prior diagnosis of cardiovascular disease resulted in an adjusted hazard ratio of 1.53  for developing an incident chronic kidney condition.Modeling suPAR as a continuous variable, each doubling in suPAR yielded an unadjusted hazard ratio of 2.52  for developing an incident acute kidney condition, patients in the 3rd quartile had a hazard ratio of 10.43 , and patients in the highest suPAR quartile had a hazard ratio of 30.47 .Cumulative incidence of acute kidney conditions by suPAR quartile is shown in P < 0.001) and an adjusted hazard ratio of 2.51  for developing an incident acute kidney condition , and sensitivity analysis removing patients with a prior diagnosis of cardiovascular disease resulted in an adjusted hazard ratio of 2.45  for developing an incident acute kidney condition.Modeling suPAR as a continuous variable, each doubling in suPAR yielded an unadjusted hazard ratio of 2.96  for dying during follow-up, patients in the 3rd quartile had a hazard ratio of 7.99 , and patients in the highest suPAR quartile had a hazard ratio of 23.23 .Survival by suPAR quartile is shown in P < 0.001) and an adjusted hazard ratio of 1.99  for dying during follow-up. Sensitivity analysis removing patients with eGFR <60 mL/min/1.73 m2 resulted in an adjusted hazard ratio of 2.02 , and sensitivity analysis removing patients with a prior diagnosis of cardiovascular disease resulted in an adjusted hazard ratio of 2.01  for dying during follow-up.Modeling suPAR as a continuous variable, each doubling in suPAR yielded an unadjusted hazard ratio of 2.89  to another common assay (Quantikine® Human uPAR-Immunoassay) found that suPARnostic® yielded significantly lower suPAR in healthy controls and higher suPAR in patients with kidney disease (Our study cohort had notably lower median suPAR (2.7 ng/mL) than what has been reported by similar studies in the emergency department, such as the 2016 TRIAGE III trial in Denmark that reported median suPAR of 4.1 ng/mL . This ca disease .While suPAR has previously been associated with kidney disease , this isvβ3-integrin  can alter podocyte shape and disrupt the kidney’s ability to retain large proteins such as albumin  define CKD as eGFR <60 mL/min/1.73 m3 months . The lac picture . For exa picture , hyperte picture , and dia picture  are knowIn conclusion, we found that elevated suPAR in acute medical patients was independently associated with incident chronic and acute kidney conditions, as well as all-cause mortality. We propose suPAR as a candidate biomarker to include in risk classification models for kidney disease. Future studies are needed to evaluate whether early interventions in high risk patients can slow disease progression or avoid complications related to renal dysfunction.The datasets generated for this study are available on request to the corresponding author.Each author was involved in data analysis or contributed important intellectual content during manuscript writing, accepts personal accountability for their contributions, and agreed to ensure that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved.JE-O is a cofounder, shareholder, and Chief Scientific Officer of ViroGates A/S. JE-O and OA are named inventors on patents covering suPAR; the patents are owned by Copenhagen University Hospital Amager and Hvidovre, Hvidovre, Denmark and licensed to ViroGates A/S. LR has received funding for travel from ViroGates A/S. The remaining 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.


Post-operative acute kidney injury is a serious complication and identifying modifiable factors could assist in peri-operative management. This study aimed to identify the pre-operative and intra-operative factors associated with the incidence of post-operative acute kidney injury and acute deterioration of kidney function after total hip arthroplasty.Materials and methods: This single-center, retrospective, observational study included 203 patients who underwent unilateral primary total hip arthroplasty. Acute kidney injury was determined using biochemical markers according to the risk, injury, failure, loss of kidney function, and end-stage kidney disease (RIFLE) criteria. Acute deterioration of kidney function was defined as the reduction of estimated glomerular filtration rate by ≥10ml/min/1.73m2.2 (glomerular filtration rate categories G3a-G5). Incidence rates of acute kidney injury and acute deterioration of kidney function after total hip arthroplasty were 0.49% and 6.9%, respectively. Multivariate regression analysis showed that diabetes mellitus and use of nonsteroidal anti-inflammatory drugs before total hip arthroplasty were significant risk factors for acute deterioration of kidney function. Advanced age, preoperative renal dysfunction, antihypertensive, diuretics, or statin use, operation time, total blood loss, type of anesthetic, and body mass index were not significant risk factors.Prior to total hip arthroplasty, 20% of all patients met the chronic renal dysfunction criterion of glomerular filtration rates <60ml/min/1.73mDiabetes mellitus and use of nonsteroidal anti-inflammatory drugs were controllable risks, and multidisciplinary approaches are a reasonable means of minimising peri-operative acute kidney injury or acute deterioration of kidney function. Therefore, THA is commonly performed for hip osteoarthritis, and the demand for primary and revision arthroplasties is expected to increase exponentially with time2. Although THA is considered a safe elective surgery, it may be associated with serious complications such as aseptic loosening and infections3. Moreover, the surgical stress of total joint arthroplasty may be too great for patients.Total hip arthroplasty (THA) is a successful procedure that improves the quality of life and function of patients with hip osteoarthritis4. AKI is a condition in which the renal function rapidly declines and becomes deficient, resulting in inability to maintain body fluid homeostasis5. AKI after cardiac surgeries has been investigated by many studies8, but AKI after total joint arthroplasty, particularly after THA, has rarely been evaluated16. The incidence of AKI after THA ranges from 0.19 to 8.1%15. A previous systematic review and meta-analysis of acute kidney injury following total hip arthroplasty17 examined seventeen cohort studies that enrolled a total of 24,158 patients undergoing THA. The report determined that the overall estimated incidence rates of AKI and severe AKI requiring dialysis in patients undergoing THA were 6.3% and 0.5%, respectively. Furthermore, this study showed found that the incidence of AKI following THA was 9.2% in Asia, 8.1% in Australia, 7.4% in Europe, and 2.8% in North America. In addition, it was shown that the incidence of AKI following THA in past reports varied, and differences in incidence according to study location were observed. In addition, previous studies used varying criteria for identification of AKI, which ultimately contributes to the unclear incidence of AKI after THA.Post-operative acute kidney injury (AKI) is a serious complication and identifying modifiable factors could assist in peri-operative management17. However, risk factors for AKI in patients undergoing THA differ across reports and are not clearly elucidated. The incidence of AKI after THA in Japanese patients has not been previously reported. Therefore, in this study, we aimed to determine the incidence of post-operative AKI and acute deterioration of kidney function after THA in a Japanese population. We also aimed to identify the pre-operative and intra-operative factors associated with acute deterioration of kidney function after THA. Based on the factors identified, we suggest preventive measures to reduce AKI following THA.Prior studies reported that risk factors for AKI in patients undergoing THA included older age, higher body mass (BMI), reduced baseline estimated glomerular filtration rate (eGFR)/chronic kidney disease (CKD), diabetes mellitus (DM), nonsteroidal anti-inflammatory drugs (NSAIDs) use, and peri-operative blood transfusionsIn this single-center, retrospective, observational study, THA of 230 hips in 219 patients was performed at our institution between January 2015 and June 2015. The indications for the procedure were severe hip pain and/or considerable difficulty in walking and performing daily activities. Patients who underwent bilateral THA within three months, revision THA, and hemodialysis, and those with incomplete data were excluded. Two hundred and three patients who underwent unilateral primary THA were finally included in the study . The patAll patients provided consent for use of their personal examination data in research studies. The study protocol adhered to the ethical guidelines of the 1975 Declaration of Helsinki, and the study was approved by the institutional review board.All THAs were performed by four senior surgeons with the same cementless implants via a posterolateral approach. A suction drain was used and then removed two days after the operation. Patients followed the same clinical pathway, including standard post-operative care and use of prophylactic antithrombotics, analgesics, and prophylactic antibiotics. Cefazolin (1g) was intravenously administered once 30 minutes before THA and thrice after THA.18. Edoxaban is covered by Japan’s National Health Insurance for the prevention of venous thromboembolism after THA. Since the efficacy and safety of edoxaban treatment for 15 days has not been evaluated in Japan, the duration of treatment was set at 7 days in this study. Edoxaban dose was reduced or not used at all depending on age, weight, and renal function; 121 patients received 30mg; 63 patients received 15mg and 19 patients received none.Patients received 15 or 30mg oral edoxaban once per day after THA for one week to prevent deep vein thrombosis. It has been reported that oral edoxaban 30mg once daily significantly reduced asymptomatic deep vein thrombosis after THA without increasing the incidence of bleeding complicationsLaboratory data were obtained before and seven days after THA. Operative data, including operation time and total blood loss, were collected. Intra-operative blood loss was determined based on the contents of the suction bottle and the change in the weight of the surgical sponges used. Post-operative blood loss was determined based on the amount in the suction drain. In this study, we assessed total blood loss as a calculation of blood loss. To exclude the effects of peri-operative infusion, we assessed the total blood loss, which represents a direct measure of bleeding, rather than the change in hemoglobin levels.Data on the medications used before THA, including angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blocker (ARBs), diuretics, statins, antidiabetics, and NSAIDs, were obtained from the medication charts.219. AKI was determined using biochemical markers according to the RIFLE criteria20. The criteria were as follows: (i) risk: eGFR decrease >25% or 1.5 fold increase in serum creatinine or urine production of <0.5ml/kg/h for 6 h; (ii) injury: eGFR decrease >50% or doubling of creatinine or urine production <0.5ml/kg/h for 12 h; (iii) failure: eGFR decrease >75% or tripling of creatinine or creatinine >355μmol/l  or urine output below 0.3ml/kg/h for 24 h or anuria for 12 h; (iv) loss: persistent AKI or complete loss of kidney function for more than four weeks; and (v) end-stage renal disease: need for renal replacement therapy for > three months.CKD before THA was determined according to an eGFR threshold of less than 60ml/min/1.73m2 seven days after THA as “deterioration of renal function”. The number of AKI cases that met the RIFLE criteria after THA were few and would not allow definitive clarification of the associated risk factors. For this reason, we used separate criteria for cases with deterioration of renal function that did not meet the RIFLE criteria and examined the associated risk factors in these cases. We evaluated the incidence and risk factors for CKD and AKI at seven days after THA. Furthermore, we compared the “deterioration of the renal function group” and the “no deterioration of the renal function group”, and evaluated the risk factors for deterioration of renal function.In this study, we defined the reduction of eGFR by ≥10ml/min/1.73mAll statistical analyses were performed using SPSS for Windows software . The mean values of the two groups were compared using Student's t-test. Sex, treatment for DM, and pre-operative medication were compared using the chi-squared test. The correlation coefficient between age and eGFR before THA was analysed with Pearson's correlation analysis. A p-value <0.05 was considered statistically significant. Multivariate logistic regression was performed to determine those factors associated with post-operative acute deterioration of kidney function after THA and their odds ratios (ORs). The model included all variables with a p-value <0.30 in the univariate analysis.2 (standard deviation (SD) ±18.0, range 38.1-142.4). Prior to THA, 20% of all patients met the CKD criterion of eGFR <60ml/min/1.73m2 (eGFR categories G3a-G5). Univariate analysis showed that age at THA and use of pre-operative diuretics were significant risk factors for CKD  . At the same point in time, the overall incidence rate of AKI was 0.49% (n=1). The patient who was diagnosed with AKI was an 84-year-old female. Her BMI was 21.4kg/m2 and she had a history of DM. She had not taken any NSAIDs, but did use ARBs before THA. Fourteen (6.9%) out of the 203 patients were classified into the “deterioration of the renal function group” seven days after THA according to this study’s criteria. The mean pre-operative eGFR in those 14 patients was 74.7ml/min/1.73m2 . On the other hand, the mean pre-operative eGFR in the 189 patients that did not meet these criteria was 79.5ml/min/1.73m2 . In the univariate analysis, pre-operative oral administration of NSAIDs, history of DM, and general anesthesia were determined as significant risk factors for deterioration of renal function  (The mean pre-operative eGFR was 76.5ml//min/1.73mctively) . A signictively) . In the ctively) , Fig. 3.ctively) . In the ctively) , Fig. 4.*CKD, chronic kidney disease; ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin-II receptor blocker*THA, total hip arthroplasty; NSAIDs, nonsteroidal anti-inflammatory drugs; eGFR, estimated glemerular filtration rate.5. Indeed, 12% of patients do not experience normalisation of kidney function21. The occurrence of acute deterioration of kidney function and requirement of renal replacement therapy increase morbidity, mortality, hospital bed use, and costs22. Therefore, determining predictors of acute renal function decline in patients who undergo THA would reduce its frequency and the need for renal replacement therapy. In other words, it would reduce the morbidity associated with renal replacement therapy, mortality, hospital utilisation, and associated costs, and help physicians prepare for this catastrophic complication in advance.Acute deterioration of kidney function is a sudden and sustained decrease in renal function resulting in retention of urea, creatinine, and other waste products24. The lack of consensus on the quantitative definition of acute deterioration of kidney function hinders clinical research in particular, since it confounds comparisons between studies. The RIFLE criteria were presented as the first systematic diagnostic criteria in 2004. In the current study, we used the updated, widely accepted RIFLE definition of AKI and CKD20, which allowed comparison with other patient groups, including both orthopaedic and other patients. For example, post-operative AKI after cardiovascular surgery can be compared with post-operative AKI after orthopaedic surgery.Some definitions of acute deterioration of kidney function, including AKI, employed in clinical studies are extremely complex with graded increments in serum creatinine for different baseline serum creatinine values15. This discrepancy could be attributed to varying predisposition to AKI among different ethnic groups25. Notably, this study is the first to report the incidence of AKI after THA in a Japanese population. Moreover, the difference in rates may also be due to the lower BMI of the Japanese population than that of Western populations. High BMI is associated with increased risk of complications, including AKI. In Japan, a BMI ≥25 is generally used to define obesity. According to a survey conducted in 2001, the rate of adult obesity (BMI ≥25) in Japan was 28.0% among men (2.9% for BMI ≥30) and 21.6% among women (3.4% for BMI≥30), and the proportion of those with BMI≥30 was only approximately 1/10 of that in the United States26.This study showed that the incidence rate of AKI after THA was 0.49%, which is substantially lower than that in previous reports27.In addition, a variety of other factors may be associated with the lower incidence of AKI in Japanese populations, including differences in the incidence of lifestyle diseases such as DM and hypertension, and the amount of analgesics used. For example, in 2015, the number of Japanese people with DM was estimated to be about 7.2 million, the ninth highest in the world. However, the estimates in China, India, and the United States are 109.6 million, 69.2 million, and 29.3 million, with the third largest country, the United States, having rates four times those of Japan29. This difference between Japan and the West may also contribute to the difference in the incidence of AKI after THA.Moreover, the types and doses of analgesics used in each country and institution differ, making direct comparisons difficult. Globally, acetaminophen is listed as the first choice analgesic in several guidelines, but in Japan, NSAIDs are generally the first choice2.Although the incidence rate of AKI after THA was low, acute deterioration of kidney function occurred in some patients. Thus, in the current study, we investigated patients with post-operative eGFR ≥10 ml/min/1.73 m2. Therefore, in this study, we used an eGFR change of 10ml/min/1.73m2 as our own diagnostic criterion. Thus, we have used different criteria to assess deterioration of renal function that does not meet the RIFLE criteria, and examined the risk factors in these cases. The prevalence of CKD generally increases with age30. In the current study, a significant correlation was found between eGFR and CKD. Pre-operative renal dysfunction has been reported as a risk factor for post-operative complications, including AKI and cardiovascular disease, which leads to prolonged morbidity or hospitalisation, and increased mortality14. Pre-operative renal dysfunction was not a risk factor for AKI following THA in this study; however, since a high percentage of patients met the criteria for CKD prior to THA, careful observation of renal function in the peri-operative period is required.The number of post-THA AKI cases that met the RIFLE criteria was small, and we believed that it would be insufficient to appropriately identify risk factors. The SD of the change in eGFR from pre-operative to post-operative values was 8.49ml/min/1.73m31. The degree of increased risk in acute deterioration of kidney function according to our multivariate regression model was 7.1. However, the precise association between DM and AKI after THA is unclear.Insulin resistance results in widespread endothelial dysfunction and impaired renovascular autoregulation, as well as worse kidney injury following ischemia, as shown in murine models. Therefore, DM is a well-known risk factor for deterioration of renal function. In a previous report, patients with DM were 1.3  to 1.7 (for those on insulin therapy) times more likely to develop post-operative AKI13. Although use of NSAIDs is widely known to disrupt renal function, its correlation with post-joint arthroplasty kidney dysfunction is still under debate11. However, pre-operative use of NSAIDs was significantly correlated with AKI in previous reports13, and showed a high odds ratio of 5.0 (p=0.028) of acute deterioration of kidney function in the current study. In surgical patients with normal renal function, a transient decrease in function is observed but is considered to be clinically irrelevant. In the setting of stressed kidneys, continued NSAIDs administration should be avoided. Nevertheless, whether withholding NSAIDs from patients at higher risk of injury would affect the rate or magnitude of AKI is unknown13.NSAIDs affect renal autoregulation through impaired synthesis of renal prostaglandins, which reduces renal plasma flow and GFR32, an association that was not observed in the current study. However, our study group was defined by a reduction in eGFR of ≥10ml/min/1.73m2 seven days following THA, which may have contributed to this significant discrepancy.In this study, renal function was significantly reduced after THA in patients with high eGFR prior to surgery. This indicates that renal function deteriorated renal after THA. CKD was previously identified as a risk factor for AKI in patients undergoing THA33, but not others16. The discrepant findings may be due to differences in ethnicity and prevalence, among others.In the current study, advanced age; use of ACEIs/ARBs, diuretics, or statins; operation time; total blood loss; type of anesthetic ; and BMI were not significantly associated with risk of acute deterioration of kidney function. These factors were reported as risk factors for AKI in some studies12. In patients with acute deterioration of kidney function, advanced age was identified as a significant risk factor for complications after total joint arthroplasty12. In line with previous reports, advanced age and pre-operative kidney dysfunction were also significantly associated with AKI10. In particular, patients older than 85 years were more likely to have severe AKI31. In the current study, advanced age was an independent significant risk factor for preoperative kidney dysfunction. However, no significant relationship was noted between advanced age and acute deterioration of kidney function after THA. This result may be due to the smaller age variation in this study than in other studies14. Age was shown to be a non-modifiable marker in the peri-operative context in many studies; thus, sufficient attention from medical staff is required.Other factors that were reported in previous reports include advanced age, use of antibiotics, revision surgery, and blood transfusion11, revision THA is speculated to pose a higher risk of AKI than primary THA. In addition, blood transfusion rates also increase with revision THA, which further increases the risk of AKI. All patients in this study were undergoing primary THA; nevertheless, paying sufficient attention to AKI and renal function deterioration before revision THA is necessary.None of the patients in this study received blood transfusion; thus, this factor’s influence could not be investigated. Because surgical invasiveness strongly influences AKI34. Patients receiving vancomycin and cefazolin as prophylactic antibiotics were more likely to develop AKI compared with those receiving only cefazolin34. Use of vancomycin with cefazolin also results in a greater severity of kidney injury based on the Acute Kidney Injury Network (AKIN) criteria. However, the mechanism linking vancomycin to development of AKI has not been elucidated.Antibiotics, aminoglycosides, and vancomycin were reported as significant predictors of AKIAlthough important advances have been made in improving our understanding of the pathophysiology and, in particular, recovery from peri-operative renal injury, no effective therapy has been found. No drug has been proven to decrease the incidence of peri-operative renal failure.Collaboration between surgeons and internists to limit NSAIDs use and strictly control blood glucose should be considered as a preventive measure to reduce AKI following THA. For example, oral hypoglycemic agents or insulin can be used prior to surgery while monitoring HbA1c levels, and other drugs such as acetaminophen should be pre-operatively administered in place of NSAIDs. Therefore, DM and the use of NSAIDs can be classified as controllable risks, and a multidisciplinary approach would be reasonable to minimise peri-operative AKI or acute deterioration of kidney function. Thus, a carefully planned approach incorporating interdisciplinary peri-operative care is warranted to reduce both the risk and the consequences of this potentially devastating condition.17; however older age, higher BMI, CKD, and total blood loss were not significantly associated with AKI following THA in this study. This may be due to the small number of patients in this study, and future studies with larger cohorts are necessary. Second, the significance of urine volume could not be evaluated because post-operative urine output was not measured. Third, evaluating the effect of intravenous infusion on renal function is difficult, although it is used after THA to prevent intravascular dehydration. Fourth, the volume of intravenous hydration and the severity of dehydration could not be assessed in this study. Whether kidney function had improved after the first week of THA or not is unknown in patients with permanent deterioration of renal function. In addition, whether exacerbation of renal function was temporary and whether the deterioration of renal function was clinically significant are also unclear. Future double-blind randomised control trials on the pre-operative use of NSAIDs could provide useful information with respect to their effects on renal function. In addition, prospective long-term studies involving a larger number of patients are needed to further substantiate our findings.This study has several limitations, which are inherent to all retrospective studies. First, the study group was relatively small. Previous studies suggested that older age, higher BMI, CKD, and peri-operative blood transfusion were risk factors for AKI following THAWe conducted a retrospective cohort study about the risk factors for AKI or acute deterioration of kidney function after primary THA. This study showed that the incidence rates of AKI and acute deterioration of kidney function, which may occur around the time of primary THA, were 0.49% and 6.9%, respectively. DM and NSAIDs use were controllable risks, and a multidisciplinary approach is reasonable to minimise peri-operative acute kidney injury or acute deterioration of kidney function. While DM and preoperative NSAIDs use cannot be controlled during the peri-operative period, they can be controlled through patient management prior to surgery. Limitation of NSAIDs use and strict control of blood glucose in conjunction with HbA1c level monitoring should be considered preventive measures for reduction of AKI following THA. We confirmed that diligent medical management not only during the peri-operative period but also prior to surgery is necessary for patients undergoing THA.


To investigate the potential benefits of acarbose therapy on cardiovascular events (CVD) in Type 2 diabetes (T2DM) in an urban community over 10-year follow-up. The study population of Beijing Community Diabetes Study (BCDS) were type 2 diabetes (T2DM) living in 21 communities in Beijing. All patients received comprehensive intervention in accordance with the Chinese guidelines for the prevention and treatment of diabetes. Professors in endocrinology from top tier hospitals regularly visited the communities for consultations, which was a feature of this study. A total of 1797 T2DM in BCDS study had complete screening data, including blood glucose, blood pressure, lipid profiles and acarbose continuous therapy. After 10-year follow-up, the risks of CVD outcomes were assessed according to whether patients had received acarbose therapy or not. All patients were followed-up to assess the long-term effects of the multifactorial interventions. At baseline, compared with the acarbose therapy free in T2DM, there was no significant difference in achieving the joint target control in patients with acarbose therapy. From the beginning of 8th year follow-up, the joint target control rate in patients with acarbose therapy was significantly higher than that of acarbose therapy free. During the 10-year follow-up, a total of 446 endpoint events occurred, including all-cause death, cardiovascular events, cerebrovascular events. The incidences of myocardial infarction (from the 4th year of follow-up) and all-cause death (from the 2nd year of follow-up) in patients who received acarbose therapy were significantly lower than that of acarbose therapy free respectively. In Cox multivariate analyses, there were significant differences in incidences of myocardial infarction and all-cause death between afore two groups during the 10-year follow-up, and the adjusted HRs were 0.50 and 0.52, respectively. After multifactorial interventions, T2DM with acarbose therapy revealed significant reductions of myocardial infarction and all-cause death. The long-term effects of with acarbose therapy on improving joint target control might be one of the main reasons of myocardial infarction and all-cause death reduction.Trial Registration: ChiCTR-TRC-13003978, ChiCTR-OOC-15006090. Since hyperglycemia can cause nephropathy, neuropathy, retinopathy and macrovascular diseases3, the poor control rate of blood glucose should be improved.In 2013, a Chinese nationwide survey by Wang et al. on diabetes epidemiology showed that the prevalence of diabetes in China reached 10.9%. Among them, only 32.2% of the patients received diabetes treatment, and the control rate of blood glucose was only 49.2%4.Collaborative Analysis of Diagnostic Criteria in Europe (DECODE) study showed that the correlation of 2-h postprandial blood glucose with coronary heart disease and total mortality was closer than that of fasting blood glucose5. In a meta-analysis, acabose users in Type 2 diabetes (T2DM) were associated with a 35% reduction in cardiovascular events6. The mechanisms might be putatively attributed to the postprandial hyperglycemia demission, which was benefit for a lowering of reaction of oxidative stress7. However, the above-mentioned studies were investigated in patients with IGT5, short-term studies8, or meta-analysis9.Previous study had shown that there was a 49% risk reduction in cardiovascular events in subjects with impaired glucose tolerance (IGT) after acarbose treatmentThe UK prospective diabetes study (UKPDS), which is a first clinical trial on intensive control of blood glucose in newly diagnosed T2DM for 20 years. After prolonged tracking until 30 years, the results showed that intensive control of blood glucose could significant reduce myocardial infarction. Although there as in small sample of T2DM combined with microalbuminuria, after intensified multifactorial intervention, the results of Steno-2 study showed the reduction in the risk of cardiovascular disease and prolonged life over 21.2 years of follow-up. So far, no large-scale, prospective intervention clinical studies have been found to affect myocardial infarction.10. But there were no population-based long-term investigations about the potential cardiovascular effect of acarbose treatment in patients with T2DM in China.As we all known, the α-glucosidase inhibitors were commonly used as a kind of antidiabetic agents, either for monotherapy in mild diabetes, or for more advanced diabetes in combination with other antidiabetic agents, especially in ChinaTo address this issue, we designed the first 10-year Community Follow-up Study in China. Patients who were diagnosed with T2DM were enrolled from 21 communities of Beijing.11. For the present study (BCDS 23), a total of 21 communities of residents were recruited between August 2008 and July 2009. They were aged between 20 and 80 years, and all had been diagnosed with T2DM. The study was conducted according to the declaration of Helsinki. The study was approved by the Medical Ethics Committee of Beijing Tongren Hospital and all participants provided written informed consent.Details of the BCDS study have been published previously12. Goals of treatment in BCDS are in accordance with 2007 and 2010 China guideline for T2DM. The joint target control was defined as HbA1c < 7.0%, systolic blood pressure (SBP) < 130 mmHg, diastolic blood pressure (DBP) < 80 mmHg, and low-density lipoprotein cholesterol (LDL-C) < 2.6 mmol/L (with coronary heart disease < 1.8 mmol/L).The patients enrolled in BCDS were monitored during the 10-year multi-factorial intervention11; yearly dilated eye examinations; measurements of the lipid profile and ECGs were performed 6-monthly or yearly.Approaches to prevention of diabetic complications in BCDS include the following: patients were seen at clinic visits every 2 months; HbA1c every 3–6 months; Annual micro-albumin checksAll patients were diagnosed with T2DM according to the World Health Organization diagnostic criteria, which combined with or without CVD. The diagnosis of CVD was made by top tier hospitals, including cerebrovascular disease, coronary heart disease, myocardial infarction, angina pectoris, or other CVD clinical indications. Cerebrovascular events in this study included stroke  and transient ischemic attack (TIA). The diagnostic basis for hypertension included self-reported use of antihypertensive drugs and/or systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg.A total of 1796 adults with T2DM were enrolled for analysis who have complete screening data, including blood glucose, blood pressure, lipid profiles and acarbose therapy. Among them, 1461 patients received acarbose therapy while 336 patients did not receive acarbose therapy , and waist circumference (WC) and hip circumference (HC). The neck circumference (NC) at the upper margin of the laryngeal prominence was also measured with the patients’ heads erect and eyes facing forward. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) values in all participants were also obtained.Baseline information on sociodemographic variables were collected11.Laboratory measurements (using established methods) were checked in all T2DM, included fasting plasma glucose (FPG), serum lipid concentrations , blood urea nitrogen, serum creatinine concentrations, low- and high-density lipoprotein [LDL and HDL]-cholesterols, and triglycerides). HbA1c (%) was measured using a Bio-Rad Variant hemoglobin analyzer by a central endocrinology laboratory in Beijing Tongren Hospital. Nonstereoscopic photographs of the central fundus were taken for all eyes All patients underwent a resting 12-lead ECG. Angina pectoris and/or > 0.1 mV ST segment deviation during a treadmill maximal exercise stress test were recorded. Ischemic heart disease was diagnosed based on the results of coronary angiography.On December 31, 2018, participants were informed of the final results and asked to continue with normal medical care every year.2 2-tests for categorical variables and Student’s t-tests for continuous variables.The BCDS database was set up using network database. Statistical analysis was performed using SAS software . The results were expressed as means (± SD) or median . Based on whether the patients were acarbose users or not, age, gender, clinical comorbidities, and concomitant use of other diabetes medications were compared between two groups using χWe used the Cox proportional hazards analysis to estimate hazards ratios (HRs) of cardiovascular risk factors, with 95% confidence interval (CI) for the effects of acarbose on CVD risk. We included the clinically important factor such as age, gender, blood pressure, NC, and lipid profiles, etc. Kaplan–Meier analysis was used to assess the cumulative percent of CVD events between acarbose users and non-users by follow-up time, and then log-rank test was used to assess the difference between two groups. All tests were two-sided, and the level of significance was established as P-values < 0.05.The study was conducted according to the declaration of Helsinki. The Medical Ethics Committee of Beijing Tongren Hospital approved the study protocol, and all participants provided their written informed consent.The baseline clinical characteristics are shown in Table The clinical characteristics, such as age, gender, the frequency of smoking, comorbidities and combination treatment with other oral antidiabetic regimens and use of statins were all similar between the two groups Table . There wResults of micro-vascular complications in diabetes will be published in other articles. Educational attainment was categorized into three levels: low (illiteracy or elementary school), medium (middle school), and high (college or academic degree). According to educational attainment, compared with patients with acarbose therapy free, the acarbose users were well educated, and had more use of insulin therapy P < 0.01) . The postprandial blood glucose was similarly between the two groups. In addition to blood glucose control, compared with the acarbose therapy free, there were no significant differences in clinical control of blood pressure. Although the proportion of hypolipidemic drug used (including Statins) in the two groups was different at the end of the follow-up, dyslipidemia was similar between the two groups Table . After m2 vs. 0.21 kg/m2) at the end of follow-up , while the fasting blood glucose levels increase in two groups. The average levels of SBP and DBP decreased in the two groups  respectively. For some lipid variables, TC and LDL-C levels also reduced  in acarbose therapy free and acarbose treatment. The improvement of body weight showed that BMI reduced in non-users of acabose and acarbose users (0.23 kg/mP < 0.01)  Table , Fig. 2.For glucose metabolism parameters and a number of the hemodynamic values (lipid and serum creatinine concentrations), after 10-year follow-up, there were no significant differences in these variables between the two groups Table .During the 10-year follow-up, a total of 446 endpoint events occurred, including all-cause death, cardiovascular events, cerebrovascular events and tumor. 199 patients 13.62%) who had received acarbose treatment developed CVD as compared to 49 patients (14.58%) who never took acarbose therapy. Furthermore, 81 patients (5.54%) with acarbose treatment developed cerebrovascular disease as compared to 18 patients (5.36%) without acarbose therapy. Compared with acarbose therapy free, acarbose users had a lower incidence of myocardial infarction events  and all-cause death  (Table .62% who P < 0.001)  Fig. . No firsThere were no significant differences in the survival ratio of patients with previous CVD between acarbose therapy group and acarbose therapy free group Table .Table 5SFactors analysis was performed to explore the variables contributing to the incidence of 10-year all-cause endpoint events. After adjusting for age, gender, smoking, educational attainment, application of hypolipidemic drugs use (including Statins) and concomitant use of other antidiabetic regimens, by using those without exposure to acarbose as reference value, during the 10-year follow-up, the crude (95% CI) hazard ratio (HR) of acarbose users in all-cause death was 0.53  Table . Further14. Especially in Asian diabetic subjects, postprandial hyperglycemia contributes more prominently to the level of HbA1c15.Most evidence-based studies implied that compared with fasting blood glucose level, postprandial blood glucose level might be related to chronic complications in T2DM more closely. Previous studies have indicated that postprandial hyperglycemia seems to play an important role in cardiovascular complications development in T2DM7. A lot of experience in the application of acarbose has been obtained in clinical research, which can be used alone or in combination with other oral hypoglycemic drugs and insulin, especially in the Chinese T2DM guidelines17.Although treatment strategies in T2DM are increasingly updated, but the optimum strategy for glycemic control remains controversial. Chinese population is dominated by the traditional high-carbohydrate dietary pattern. Acarbose, an oral antidiabetic agent, could competitively inhibit α-glucosidases absorption in small intestine. Since carbohydrate absorption and digestion occur throughout the small intestine, acarbose is used to delay sugar absorption to reduce postprandial blood glucose18.Although recent study once focused on the potential benefits of acarbose treatment of cardiovascular disease (CVD) in patients with T2DM by using the Taiwanese National Health Insurance Research Database (NHIRD), there were no retrieve clinical data like lipids and glycemic, blood pressure control from this claim datasetSince little information exists about the potential cardiovascular effect of α-glucosidase inhibitor use in Asian populations; we aimed to ascertain the effectiveness of the acarbose on the risk of cardiovascular events in T2DM, extensively adopted in China. This is the only 10-year study in oral antidiabetic drugs that reduces myocardial infarction events.The main findings from the present study indicated that acarbose therapy, either as monotherapy or in combination with other antidiabetic regimens in T2DM, provided an important impact on the subsequent development of CVD. Specifically, during the 10 years follow-up, the relative risk of myocardial infarction reduction was similar at 50% in patients with acarbose therapy. Acarbose therapy has the potential to prevent deaths from complications related to diabetes as cardiovascular and cerebrovascular disease account for 52% of all mortality. Even after adjusting for major risk factors, the reduction in the risk of cardiovascular events associated with acarbose treatment was still statistically significant. From the 2nd year of follow-up, the incidences of all-cause death in patients who received acarbose therapy were significantly lower than that of acarbose therapy free; while from the 4th year of follow-up, the patients received acarbose therapy had lower incidences of myocardial infarction than that of non-users Fig. .19.Analysis of the clinical characteristics, such as age, gender, the frequency of smoking, comorbidities and combination treatment showed similar patterns between the two groups at the baseline. Indeed, compared with patients with acarbose therapy free, the acarbose users had higher educational attainment and more use of insulin therapy. To our knowledge, previous study explored acarbose were associated with significant insulin-sparing effects in both the fasting state and after standard meal test20. In the present study, at the end of follow-up, compared with the baseline, the mean levels of 2-h postprandial blood glucose and HbA1c decreased, while the fasting blood glucose levels increase. These results showed a light that the improvement of HbA1c was mainly due to the control of postprandial blood glucose in our study. Therefore, acarbose might be involved in preventing the onset and progression of diabetic chronic complications by reducing postprandial blood glucose. This needs to be further confirmed by prospective studies.The changes in postprandial glucose with acarbose treatment were in agreement with previous studies21. With respect to the reduction of SBP by acarbose, although many previous studies have provided evidence for an effect22, it is still unclear.In addition, the present study showed that many metabolic indicators  were significantly improved in both acarbose therapy and acarbose therapy free after 10 years multi-factorial invention when compared with baseline. These findings are in agreement with results from the previous studies9. Acarbose’s effects on body weight reduction in this study are in line with those of previous studies in Chinese23 and other populations24. Overweight/obesity is recognized as one of the most common risk factors for CVD. Neck circumference was shown in many studies to be an indicator for evaluating overweight/obesity25, and was associated with the occurrence of cardiovascular events in type 2 diabetes in Chinese communities, and may increase the risk of cardiovascular events by about 2.3-fold26. In the present study, the neck circumference was significant higher in patients with acarbose therapy free than that of acarbose therapy, while after 10 year-follow-up, there were no significant difference between the two groups. We speculated that individuals with overweight/obesity might be most likely to benefit from reduction of weight as they are particularly at risk from the myocardial infarction risk of T2DM. However, the underlying mechanisms of weight reduction by acarbose and its clinical relevance need to be examined further.A meta-analysis to assess if treatment with the α-glucosidase inhibitor acarbose can reduce cardiovascular events in T2DM showed that body weight improved significantly during acarbose treatment28. What's important is this article differs from other research is the 10 years’ observation, which explained the relationship between acarbose therapy and myocardial infarction. At baseline, compared with the acarbose therapy free in T2DM, there was no significant difference in achieving the joint target control in patients with acarbose therapy. However, from the beginning of 8th year follow-up (2016), the joint target control rate in patients with acarbose therapy (30.66%) was significantly higher than that of acarbose therapy free (20.24%). This trend was maintained in the following years  of blood pressure, HbA1c and acarbose therapy were independent predictive factors for CVD events in T2DM. Acarbose therapy was negatively correlated with CVD disease. Intervention with acarbose can prevent myocardial infarction and cardiovascular disease in T2DM while most of them are already on intensive concomitant.To our knowledge, this is the first study to evaluate the effect of acarbose therapy on the risk of cardiovascular events in T2DM during 10-year multifactorial interventions. Otherwise, this study was a well-documented clinical trial, which increase the reliability of our findings.Our study suggests that treatment with acarbose in T2DM revealed a relatively pattern of benefits on developing CVD. After the 10 years’ multifactorial interventions, in patients with acarbose therapy, the relative risk of myocardial infarction reduction was similar at 50% and all-cause death reduction was about 52%. The effects of acarbose on improving joint target control might be one of the main reasons of CVD events reduction. This study was only studied in Chinese population and not in non-Chinese population. So the data was only as a suggestion to the Chinese population.Because the population in this study requires a follow-up of 10 years, unfortunately, patients with less than 10 years of follow-up were not included in this study population. At the same time, patients without medication information were also excluded in the statistics of this article. Due to afore reasons, the samples of patients in this study were limited. Since the food of Chinese is mainly carbohydrates, Chinese people are more suitable for acarbose treatment. Acarbose therapy is safe and the incidence of hypoglycemia is low. This study is not a double-blind controlled study, based on the actual data of patients, the number of patients receiving and not receiving acarbose might be significantly different.


Patients with insulin-dependent diabetes mellitus type 1 (IDDM1) and end-stage kidney disease (ESKD) undergoing simultaneous pancreas kidney transplantation (SPKT) are a population with diffuse atherosclerosis and elevated risk of cardio- and cerebrovascular morbidity and mortality. We aimed to investigate the feasibility of preoperative screening for peripheral arterial disease (PAD), specifically ankle-brachial index (ABI) testing, to predict peri- and postoperative outcomes in SPKT recipients.Medical data (2000–2016) from all patients with IDDM and ESKD undergoing SPKT at our transplant center were retrospectively analyzed. The correlation between PAD  were diagnosed with PAD before transplantation. PAD, as defined by a low ABI index, was an independent and significant predictor of death , p = 0.049) and pancreas graft failure , p = 0.022). No significant differences were observed for kidney graft failure (HR 1.85 (95% CI 0.76–4.50), p = 0.178). In terms of the secondary outcomes, patients with PAD were more likely to have myocardial infarction, stroke, limb ischemia, gangrene or amputation , p = 0.019).Pre-transplant screening for PAD and cardiovascular risk factors with non-invasive ABI testing may help to reduce perioperative complications in high-risk patients. Future research on long-term outcomes might provide more in depth insights in optimal treatment strategies for PAD among SPKT recipients. Simultaneous pancreas kidney transplantation (SPKT) represents the “state of the art” treatment modality for patients with insulin-dependent diabetes mellitus type 1 (IDDM1) and end-stage kidney disease (ESKD) . All methods in the study were carried out in accordance with the Helsinki guidelines and declaration or any other relevant guidelines.From a prospectively collected electronic database, we retrospectively analyzed medical data on all patients undergoing SPKT at the University Hospital of Leipzig between 2000 and 2016. We focused on the identification of patients with PAD who had undergone non-invasive vascular diagnostics, specifically ABI testing, in the pre-transplantation evaluation examination. Patients younger than 18 years, those receiving kidney transplantation alone and those receiving pancreatic re-transplantation were excluded.Standard demographic and clinicopathological characteristics were collected and analyzed before, at the time of and after transplantation (in the follow-up period) for each patient: the pre-transplantation data included recipient and donor characteristics such as age, sex, body mass index (BMI) and additional data including the duration of diabetes mellitus, smoking habits, time on the wait list, the duration of pre-transplantation dialysis, metabolic endocrine and lipid metabolism, information on the cardiovascular system such as the presence of coronary heart disease (coronary artery bypass grafts or stents), CVA, the type and level of PAD , blood pressure parameters and the number of antihypertensive agents.All patients with IDDM1 who were potential transplantation candidates underwent structured cardiovascular examinations including echocardiography and coronary angiography as a routine part of the cardiac work-up at our center before enrollment on the wait list.For the detection of PAD, a structured vascular screening protocol including extensive physical examination (for detection of ulceration/gangrene) and symptom-oriented medical history , Doppler ultrasonography such as Doppler-derived ABI testing and carotid artery duplex imaging were performed. The vessels of patients with suspected PAD were further evaluated with computed tomography/magnetic resonance angiography and/or conventional angiography, as indicated, to better define the location and extent of disease.As a part of the pre-transplantation PAD screening, physiologic arterial vascular studies including Doppler-derived ABI measurements were performed by a well-trained vascular nurse in each patient in a quiet environment after at least 5 min of supine rest.ABI measurement was performed with a standard hand-held continuous wave 8 MHz Doppler pencil probe and a sphygmomanometer with a 12 × 35 cm blood pressure cuff.For ABIs, systolic blood pressures were measured and recorded in the supine position on both arms , on the basis of the appearance of the pulse sound registered by the Doppler at the brachial artery as the cuff was deflated , 12. DopThe ABI was calculated by division of the systolic pressure measured in each lower limb through the systolic blood pressure of the arm with the higher pressure .According to previously published consensus guidelines, participants were considered to have PAD in our analysis if they had an ABI below 0.9 and clinical symptoms (claudication/signs of limb ischemia) .The ABI measurements were divided into five subcategories: normal (0.9–1.39), mild disease (0.70–0.89), moderate disease (0.40–0.69), severe disease (0–0.39) and non-compressible arteries (> 1.40) .In accordance with the recent consensus guidelines, in cases of a high ABI (>1.4) or non-compressible arteries associated with medial calcification, as was evident in five of our patients with diabetes, we performed toe−brachial index (TBI) measurement and/or further noninvasive or invasive vascular diagnostic procedures for safe detection of PAD –29.TBI measurement was performed as previously described in detail and was calculated by dividing the systolic pressure of the great toe by that of the brachial artery .Cut-off values < 0.7 in TBI testing were defined as the diagnostic criterion for PAD .The procurement and transplantation of pancreatic and kidney allografts were performed according to international standard and guidelines, as previously described –37. The χ2, analysis of variance, Kruskal–Wallis and Wilcoxon–Mann–Whitney test.Continuous variables are reported as mean/median values with standard deviation, whereas categorical variables are presented as whole numbers and percentages (%). For analysis of baseline data, we used the appropriate statistical significance tests, including Student’s t-test, The primary end point of this study was graft (pancreas/kidney) failure and/or death after transplantation. In this context, pancreatic graft failure was defined as insulin substitution or return to transplant, and kidney graft failure was defined as the need for dialysis or return to transplant. The secondary end points included occurrence of CVA, MI and/or peripheral vascular complications, defined as limb ischemia, gangrene, amputation or revascularization treatments (bypass surgery or angioplasty).For the estimation of patient and graft (pancreas/kidney) survival, such as event-free survival for the secondary events after transplantation, the Kaplan–Meier method and log-rank test were used. Cox proportional hazard regression models were used to calculate hazard ratios (HR) for the primary and secondary end points in relation to PAD.The association between PAD and the primary and secondary end points was then assessed after adjustment for known cardiovascular risk factors including recipient age, sex, recipient BMI, duration of diabetes mellitus, smoking habits, duration of dialysis, aspirin and statin use and known cardiovascular comorbidity .If patients who had multiple ABI measurements available, we used the ABI value closest to the date of transplantation for analysis.All data were analyzed in SPSS software . A p value < 0.05 was considered statistically significant.Note: Data from our prospectively maintained database have been previously published , 37. HowBetween January 2000 and July 2016, a total of 101 patients undergoing SPKT at the University Hospital of Leipzig received structured evaluation for PAD, specifically ABI testing before transplantation. One patient had to be excluded from further analysis due to missing data. The mean follow-up period of the study was 101 ± 34.4 months.Demographic and clinico-pathologic baseline characteristics between the patients with and without PAD are shown in Table In the patients in the PAD group, compared with patients without PAD, the following cardiovascular and arteriosclerotic risk factors were higher: diastolic blood pressure (p = 0.04) and the presence of known CAD (p = 0.02), such as a history of micro- and macrovascular events  (p = 0.03).During the pre-transplantation evaluation, 17 of the 101 patients (17%) were diagnosed with PAD. Among them, 12 (12%) had a low ABI, and 5 (5%) had a high ABI. The low ABI group included mild , moderate  and severe  categories. A TBI < 0.7 and positive findings in imaging confirmed the diagnosis of PAD in the five patients with high ABI in the pre-transplantation evaluation.Post-transplantation outcomes were measured from the time of transplantation until January 2019. Until that time point, 27 patients (27%) had secondary events including new events of cardiac disease  in 23 (23%) patients, events of cerebrovascular disease (TIA/stroke) in 19 (19%) patients, and further 21 patients (21%) developed peripheral vascular complications . Pancreas and kidney graft failure was observed in 24 (24%) and 21 (21%) patients, respectively. Eighteen patients (18%) died after transplantation during the follow-up period.Kaplan–Meier plots for patient and pancreatic graft survival according to the presence of PAD are shown in Figs. The 5-year patient survival  and pancreatic graft survival  were significantly lower in patients with PAD.Tables We found that PAD, defined by a low ABI, was an independent and significant predictor and risk factor of death , p = 0.049) and pancreatic allograft failure , p = 0.022). However, no significant differences were observed for kidney allograft failure (HR 1.85 (95% CI 0.76–4.50), p = 0.178). A normal ABI was associated with better patient survival  in our patient cohort.Patients with PAD were at greater risk of pancreatic graft failure, secondary outcomes and death Figs. , 2 and 3With regard to secondary outcomes, a low ABI was an independent and significant predictor of early MI, stroke, limb ischemia, gangrene and amputation , p = 0.019) Table . In addiIt’s a scientific fact that the presence of IDDM1 and ESKD are strongly related to accelerated development of atherosclerosis, and further development of PAD , 8, 17. The detection of arteriosclerosis at early stages through adequate and non-invasive preoperative screening and the consequent initiation of optimal preventive medical treatment may help decrease perioperative cardiovascular mortality before transplantation . In thisThe ABI is also an indicator of atherosclerosis at other vascular sites, and it can serve as a prognostic marker of cardiovascular events and functional impairment even in the absence of PAD symptoms , 9, 13.However, the conditions and comorbidities associated with media calcification and vessel stiffness, such as IDDM, ESKD and advanced age, can lead to falsely elevated or normal pressures , 28, 40.In our pre-transplantation screening algorithms, the vascular PAD diagnostic consisted of structured arterial physiologic testing, including Doppler-derived ABI or alternatively TBI testing, ultrasonography, patient history and clinical examination.TBI testing is performed for diagnostic assurance in patients with elevated ABIs and expected vessel stiffness due to relevant comorbidities .In cases of functional symptoms, further noninvasive and invasive physiologic examinations were performed, including pulse wave, Doppler wave and computed/magnetic resonance angiography and walking tests on a treadmill. In this current study, we sought to address the value of ABI testing in a large population of SPKT recipients.In the pre-transplantation evaluation examinations of SPKT recipients, we found that PAD was identified by a structured lower arterial extremity physiologic evaluation in almost one-fifth of our patients over a study period of approximately 20 years. This finding is consistent with the few previous studies that have found an increased prevalence of PAD in patients with diabetes with ERSD waiting for kidney and/or pancreas transplantation, as compared with patients without these risk factors , 42, 43.Furthermore, we observed that PAD defined by a low ABI was an independent and significant predictor of postoperative patient death, pancreatic graft failure and postoperative cardio- and cerebrovascular events  in SPKT recipients. This result was independent of other cardiovascular comorbidities and the number of years of dialysis. Our findings support the use of ABI or accurate preoperative PAD testing for predicting mortality and graft failure in individuals with PAD, independently of other known cardiovascular risk factors.Recent reports have demonstrated that a successful SPKT that leads to euglycemia can slow the progress of macrovesicular disease, as described in PAD –44.In contrast, according to previous studies from renal transplant recipients, the presence of PAD is associated with an increased risk of allograft failure, as was also seen in our study , 26. HowHowever, despite recent excellent advances in treatment, patients with SPKT, IDDM and ESKD-related conditions tend to have high rates of cardio- and cerebrovascular complications, and CVD remains the leading cause of mortality in SPKT recipients with functioning grafts, as also seen in the current study , 24, 45.Despite of the immanent perioperative cardiovascular risk, successful SPKT offers the best known protection against the progression of CVD and future cardiovascular events , 46–48. Nevertheless, coronary angiography, an invasive and cost-intensive technique, should be applied only in high-risk patients with a long history of diabetes, severe peripheral or coronary vascular disease or a history of acute myocardial infarction , 53.Therefore, the preoperative assessment of all patients undergoing SPKT by coronary angiography does not appear to be feasible; however, because transplantation in cardiovascular high-risk patients is increasing, a non-invasive but sufficiently sensitive stratification strategy is needed to assess perioperative cardiovascular risk as well as transplant outcomes.However, a consensus is lacking regarding the best assessment and optimization strategy for cardiovascular risk and transplant outcomes.In the current study, we therefore aimed to verify the value of screening for PAD through pre-transplantation ABI testing to identify cardiovascular high-risk patients who were eligible for further invasive assessment, as well as specifically modified preoperative risk factors and perioperative protective strategies.We found that ABI testing is an inexpensive and easily applicable assessment tool during preoperative screening of patients eligible for SPKT.First, this study was limited by its retrospective nature and small sample size, particularly in the ABI subcategories (‘low-ABI’ and ‘high-ABI’ patients) in both the pre-transplantation and post-transplantation ABI results; the sample size was too small for further analysis or drawing conclusions.Second, in few SPKT recipients , vascular exams were performed quite some time before the transplantation , and these patients were subsequently categorized as normal controls. However, if peripheral vascular disease and arteriosclerosis might have progressed while the patient was on the waiting list without additional documentation this might have created a small bias. In other words, this bias may have led to an underestimation of PAD at the time of transplant and consecutive outcome analyses. Ideally, all patients should have their vascular diagnostics performed within a year after transplantation.Third, the results of ABI testing in our patient cohort with IDDM and ESKD must be interpreted carefully, because both comorbidities could lead to increased vascular calcification, thus resulting in vessel stiffness and/or non-compressible vessels , 28. TheFourth, the natural history of PAD involves a decrease in ABI over time. However, why the ABI would increase in some patients and decrease in others after transplantation is not well understood. The reason for these findings remains unclear, and the principal patterns of causation should be further evaluated in future prospective studies.In conclusion, we demonstrated that ABI evaluation combined with TBI testing in unclear cases is a valuable, inexpensive and feasible assessment tool for accurate examination of perioperative cardiovascular risk in patients undergoing SPKT. We showed that PAD associated with low and high ABIs predicted higher mortality, pancreatic graft failure and poorer cardiovascular outcomes. With the information gained from preoperative ABI testing, patients at high-risk for perioperative cardiovascular complications and simultaneous graft failure can be identified so that further invasive examination and, if possible, reduction of preexisting risk factors can be initiated.Further research, ideally in large randomized and controlled multicenter trials, are needed to evaluate the use of ABI testing in pre-operative PAD screening in high-risk patient populations. Moreover, future research should focus on the evaluation of functional capacity or walking distance as a comparative tool for ABI testing, to establish the role of ABI in further perioperative risk assessment in high-risk cardiovascular patients and to identify different ABI subcategories for optimized risk stratification.


Bisoprolol reduced heart rate and left cardiac work, and increased subendocardial viability index in supine and upright positions . Bisoprolol increased stroke volume in the supine  but not in the upright position, while only upright  but not supine cardiac output was reduced. Upright elevation in systemic vascular resistance was increased 2.7-fold (p = 0.002), while upright pulse pressure amplification was decreased by ~20% (p = 0.002) after bisoprolol. Aortic augmentation index, augmentation pressure, and pulse pressure were not changed in the supine position but were increased in the upright position . In conclusion, although bisoprolol treatment reduced peripheral blood pressure, central systolic blood pressure in the upright position was not decreased. Importantly, the harmful influences of bisoprolol on central pulse pressure and pressure wave reflection were manifested in the upright position.Treatment with beta-blockers is characterized by inferior reduction of central versus peripheral blood pressure. We examined changes in blood pressure, cardiac function, and vascular resistance after 3 weeks of bisoprolol treatment (5 mg/day) during passive head-up tilt in 16 never-treated Caucasian males with grade I–II primary hypertension. A double-blind, randomized, placebo-controlled cross-over design was applied, and hemodynamics were recorded using continuous tonometric pulse wave analysis and whole-body impedance cardiography. Bisoprolol decreased blood pressure in the aorta (~8/10 mmHg,  The use of beta-adrenoceptor blockers (beta-blockers) as first line treatment for hypertension has declined in recent years due to inferior efficacy in the prevention of cardiovascular events when compared with vasodilatory antihypertensive agents –3. One oAugmentation index (AIx) is delineated as the proportion of the reflected pressure wave  to pulse pressure (PP). It has been applied as a surrogate measure of arterial stiffness, but it is mainly a measure of wave reflections  that is Amplification of PP is defined as the ratio of peripheral PP to central PP, and due to this phenomenon PP in peripheral arteries is higher than in central arteries . Beta-blDuring orthostatic challenge, SVR and heart rate increase while cardiac output (CO) decreases . In addin = 14) and from occupational health care clinics (n = 2) , 1413, 1A tonometric sensor with automatic adjustment  was applied to record radial BP and pulse wave form continuously, and the BP signal was calibrated at ~2.5 min intervals by use of the brachial cuff in the contralateral arm , 14. Ther = 0.781, bias 4.1 ml, 95% CI −2.2 to 10.4)  and diastolic BP 9 mmHg  lower, and aortic systolic BP 8 mmHg  and diastolic BP 9 mmHg  lower during bisoprolol than during placebo. In the upright position bisoprolol treatment reduced radial systolic BP by 10 mmHg , diastolic BP by 10 mmHg , and aortic diastolic by 10 mmHg  Fig. , but conp < 0.001). Ejection duration was prolonged in supine  and upright  positions with bisoprolol  and upright  positions with bisoprolol when compared with placebo  and upright  positions Fig. , while tlol Fig. . SEVR inebo Fig. .Fig. 3He5*m2, p = 0.003)  but not during the head-up tilt Fig. , whereas03) Fig. .Fig. 4Stp = 0.368) or upright (p = 0.418) (not shown). No difference in forward wave amplitude between the bisoprolol and placebo treatments was found  and upright (p = 0.8) (not shown).While there were no changes in aortic PP or AP in supine measurements, upright aortic PP was increased+4 mmHg  and aortic AP +3 mmHg  with bisoprolol Fig. . AIx remund Fig. . Radial In this randomized, placebo-controlled double-blind cross-over study, non-invasive evaluation of hemodynamics was carried out in men with mild to moderate primary hypertension during non-vasodilating beta-blocker therapy. The results show that bisoprolol did not lower central systolic BP in the upright position although it was efficient in reducing peripheral BP. Moreover, the harmful influences of bisoprolol on central PP and wave reflection were uncovered in the upright position. This emphasizes the influence of body posture on the hemodynamic changes induced by beta-blocker therapy. The supine hemodynamics and home BP measurements of the present study subjects were previously reported , and theAlthough the position of beta-blockers in the treatment of essential hypertension has changed, they remain a mainstay of pharmacotherapy after myocardial infarction. We observed a decrease in LCWI, indicating reduced workload of the left ventricle during bisoprolol therapy, and an increase in SEVR that reflects an improved ratio between myocardial oxygen supply and demand. These hemodynamic changes can explain the antianginal effect of beta-blockers.During orthostatic challenge, blood pools in the lower extremities resulting in a decrease in venous return to the heart. As compensatory mechanisms SVR and heart rate increase to maintain the level of BP. Despite this adaptation, CO usually decreases, but there is significant inter-individual variation in the magnitude of these changes . Of noteAIx was clearly increased during bisoprolol in the upright position. The level of AIx is inversely related with heart rate  and direPrevious studies evaluating the effect of upright posture on wave reflection have suggested that the associated increase in heart rate may not fully explain the observed reduction in AIx in non-medicated healthy subjects , 29, andPulse wave velocity (PWV) is an important determinant of AIx since the kinetics of the reflected wave depend on the traveling speed of the pressure wave in the arterial tree . In our The mechanism behind the beta-blockers’ inferior reduction of cardiovascular events when compared with vasodilatory antihypertensive drugs is still not completely understood –3. The CThere are some limitations in this study. The number of subjects does not allow multivariate analyses to be carried out. However, the findings were very clear in this population. The investigations were done in men only so the results might not be directly applicable to women. Mathematical transfer functions were required to derive central BP and other hemodynamic variables but good correlation with direct measurements using these methods has been shown .Bisoprolol decreased peripheral and central BP in men with grade I to grade II hypertension. However, central systolic BP was not reduced during head-up tilt. In addition, the non-beneficial effects on central BP and wave reflection with bisoprolol were especially manifested in the upright position. These findings show that central BP regulation is substantially affected by posture during treatment with beta-blockers. Altogether, the influence of posture should be taken into account when evaluating the effects of antihypertensive agents on hemodynamics.Beta-blockers do not prevent cardiovascular events to same extent as other antihypertensive drugs.Beta-blockers do not reduce central blood pressure as well as vasodilatory antihypertensive drugs despite similar reduction of peripheral blood pressure.In supine measurements bisoprolol reduced peripheral and central blood pressure in never-treated grade I to grade II hypertensive men with no effect on central wave reflection or central pulse pressure.During passive upright tilt, the effect of bisoprolol on central pulse pressure and wave reflection was clearly detrimental and there was no reduction in central systolic pressure compared to placebo.Hemodynamic measurements performed at rest seem to underestimate the effect of beta-blocker therapy on the regulation of hemodynamics as harmful influences of bisoprolol on central blood pressure and wave reflection were manifested only during upright tilt.Letter from JHH editorial office