Endovascular therapy is the gold standard in patients with hemodynamic relevant renal artery stenosis (RAS) resistant to medical therapy. The severity grading of the stenosis as well as the result assessment after endovascular approach is predominantly based on visible estimations of the anatomic appearance. We aim to investigate the application of color-coded DSA parameters to gain hemodynamic information during endovascular renal artery interventions and for the assessment of the procedures´ technical success.We retrospectively evaluated 32 patients who underwent endovascular renal artery revascularization and applied color-coded summation imaging on selected monochromatic DSA images. The differences in time to peak (dTTP) of contrast enhancement in predefined anatomical measuring points were analyzed. Furthermore, differences in systolic blood pressure values (SBP) and serum creatinine were obtained. The value of underlying diabetes mellitus as a predictor for clinical outcome was assessed. Correlation analysis between the patients´ gender as well as the presence of diabetes mellitus and dTTP was performed.Endovascular revascularization resulted in statistically significant improvement in 4/7 regions of interest. Highly significant improvement of perfusion in terms of shortened TTP values could be found at the segmental artery level and in the intrastenotical segment (p < 0.001), significant improvement prestenotical and in the apical renal parenchyma (p < 0.05). In the other anatomic regions, differences revealed not to be significant. Differences between SBP and serum creatinine levels before and after the procedure were significant (p = 0.004 and 0.0004). Patients´ gender as well as the presence of diabetes mellitus did not reveal to be predictors for the clinical success of the procedure. Furthermore, diabetes and gender did not show relevant correlation with dTTP in the parenchymal measuring points.The supplementary use of color-coding DSA and the data gained from parametric images may provide helpful information in the evaluation of the procedures´ technical success. The segmental artery might be a particularly suitable vascular territory for analyzing differences in blood flow characteristics. Further studies with larger cohorts are needed to further confirm the diagnostic value of this technique. Renal artery stenosis (RAS) describes the pathologic narrowing of the renal artery by at least 50%, leading to a compromised blood supply to the kidney. RAS most commonly is a result of atherosclerotic vessel alterations originating from the aorta. As a consequence, the proximal segment of the renal artery including the ostium is predominantly affected . Less frBeside clinical and laboratory examinations, different diagnostic procedures are used for the work-up of RAS. In the diagnostic work-up, renal duplex ultrasound (US) is a well-established and rapidly performable non-invasive imaging method for both screening as well as follow-up examinations. Nevertheless, duplex US is highly dependent on the examiner skills and can be impeded by patients´ body habitus. Alternatively, cross-sectional imaging like computed tomography angiography (CTA) or magnetic resonance angiography (MRA) revealed high sensitivity and specificity rates in the assessment of RAS –5. PerfoOn the contrary, color-coded DSA enables visualization of hemodynamic flow parameters within a single image. Concerning this post-processing approach, data has only been reported in the setting of neurovascular interventions and peripheral artery disease so far –9. At thA retrospective review of the archives of our interventional radiology division yielded the cases of 59 patients who consecutively underwent endovascular treatment of RAS between February 2009 and April 2019. Due to a lack of available DSA serial imaging and exclusive storage of single elected DSA images, 27 patients were excluded from the study, resulting in a final cohort of 32 patients .All patients were examined and treated as part of routine care. Patients´ characteristics, clinical symptoms, comorbidities as well as diagnostic and therapeutic management strategies were extracted from the medical records. The local institutional review board approved this retrospective study and waived the need for written informed consent (Waiver No. 20200904 01). Written informed consent for the intervention was obtained from all patients prior to the procedure.Underlying condition for RAS was atherosclerosis in the majority of cases . Fibromuscular dysplasia was the underlying disease in two cases and stenosis of anastomosis of renal transplant graft in one further patient. In the last case, time between the renal transplantation and the endovascular procedure was 198 months. Clinical characteristics of the study cohort are summarized in Table Aside from clinical and laboratory assessment, diagnosis of RAS based on non-invasive radiologic investigation including MRA in 24, CTA in two and duplex US in four cases. In two cases documented imaging was not available prior to the intervention, and the indication for the procedure was mainly based on clinical and laboratory findings.All procedures were performed by the same operator in our local angiography suite . Patients were advised not to discontinue antihypertensive medication. With all patients under local anaesthesia, endovascular procedures were carried out via a right retrograde femoral artery approach with a short unbraided or long braided 6-F to 7-F introducer sheath , respectively. Due to the patients’ limited renal function, non-selective abdominal aortographies were not conducted. Instead, selective angiographies of the renal artery stenosis were acquired with manual injection of iodinated contrast  using selective catheters .All renal artery stenoses were passed utilizing a 0.014- or 0.018-inch guidewire . In two patients with FMD, balloon angioplasty was exclusively performed. In all cases of atherosclerotic RAS, pre-dilatation was conducted using a low-profile PTA-balloon  with subsequent implantation of a balloon-expandable cobalt-chrome or bare metal stent . Percutaneous transluminal angioplasty with stent implantation ended with angiographic documentation of an improvement of lumen gain and antegrade flow into the renal artery documented by manual injection of contrast media.After the procedure, acquired DSA series were sent to the local picture archiving and communication system (PACS) .Post-processing of the monochromatic to polychromatic images was performed utilizing the commercially available software Syngo iFlow® , running at a dedicated system software WinNT 5.2, SP 2 at a specialized working station .This tool enables the visualization of blood flow information extracted from a monochromatic DSA series within one single image using color-coding . In thisMeasurement of the DSA series were performed in a standardized manner. In this context, DSA series before and after endovascular treatment of RAS were selected, in which the selective catheter or long introducer sheath was positioned within or near the ostium of the renal artery. Thus, the renal artery was visible in its full length including the renal parenchyma. Only cases with available DSA images fulfilling the criteria described above were included.renal artery proximal to the stenosis or abdominal aorta at the level of the origin of the renal artery (prestenotic),intralesional,renal artery distal to the stenosis (poststenotic),segmental artery of first order at the caudal pole,apical renal parenchyma,renal parenchyma at the level of hilus,renal parenchyma at the caudal pole.After application of the color-coded algorithm, seven standardized measurement points were manually determined as a region of interest (ROI) for each parametric single image Figs. , 2. ThosThe TTP (in seconds) was measured in all the mentioned ROIs in the DSA series before and after angioplasty of the renal artery. The differences of the TTP (dTTP) in the single ROIs pre- and postinterventionally were assessed in order to gain information concerning changes in blood flow characteristics and thus serving as a parameter of technical success. Blood pressure and serum creatinine values were analyzed before and after the intervention. Median follow-up was 24 days and ranged between 1 and 848 days. Blood pressure measurement was performed as non-invasive assessment using an arm-cuff. Correlation between the dTTP and blood pressure as well as creatinine parameters were analyzed in order to estimate the predictive value of color-coded parameters for the clinical outcome of the patients. Being a known risk factor for atherosclerosis and development of RAS, correlation between the presence of diabetes mellitus and the differences in TTP at the parenchymal level was also evaluated. Gained data was collected with Excel .Statistical analysis was performed using a dedicated software . Descriptive data were presented as means ± standard deviation (SD) for normally distributed variables or medians with ranges for non-normally distributed variables, if appropriate; categorical data were expressed as counts and percentages with n (%). With regard to assessment of normality, the Shapiro test was used rejecting the hypothesis of normality when the p-value was less or equal to 0.05.TTP values, blood pressure and creatinine before and after the procedure were compared using Wilcoxon´s signed rank test in cases of non-normally distributed variables and Student´s T test in normally distribution of variables. Differences in TTP values  were compared with differences of creatinine levels utilizing the Spearman-test. The Mann–Whitney-U-test or T-test was used to analyze whether presence of diabetes mellitus and patients´ gender might have influenced the procedures’ outcome. In this context, possible predictors for the procedures´ outcome were aimed to be found.In total, 32 RAS were treated by endovascular revascularization and assessed using color-coding algorithm prior to and after the procedure. All cases demonstrated noticeable improvement of antegrade flow following PTA with or without stent implantation, resulting in a technical success rate of 100%.Mean and median TTP evaluation before and after renal artery revascularization in the seven predetermined measurement points revealed significant reduction of TTP and thus improvement of blood flow in 4/7 assessed regions Fig. . Highly Evaluation of creatinine levels of the treated patients revealed highly significant reductions after endovascular renal artery treatment (p = 0.004). Blood pressure measurements resulted in highly significant reductions after endovascular revascularization . Moreover, correlation between dTTP and improvement of blood pressure values were not statistically significant (p = 0.292).A significant influence of the patients´ gender on the differences in blood pressure (p = 0.836) or on changes of creatinine values (p = 0.316) owing to endovascular procedure was not found. Thus, gender did not reveal to be a predictor for the clinical outcome. Furthermore, existing diabetes mellitus was not a predictor for improvement of blood pressure (p = 1.0) and creatinine values (p = 0.486).The correlation analysis of prevalence of diabetes and patients´ gender, respectively, and the changes of TTP (dTTP) in the measuring points within the renal parenchyma did not show a significant correlation .Due to long-term effects and comorbidities, especially with severe renal impairment, RAS is associated with increased mortality rates . The maiUncertainty about the right therapy regime was exacerbated by large clinical randomized trials like ASTRAL and CORAL, stating no superiority of renal artery revascularization compared with medical therapy with respect to the prevention of clinical adverse events , 15. NevIn the assessment of RAS, non-invasive MRI-based methods to evaluate the hemodynamic significance of RAS in a porcine model revealed a good correlation between the non-invasive transstenotic pressure gradient derived from unenhanced MRI-imaging and endovascular pressure gradient obtained from DSA , 22. HowIn general, the availability of cross-sectional imaging like MRI and CT studies before the intervention is desirable, since it might provide beneficial information, for example regarding the vascular access and the presence of hard- and softplaques in the vascular segments to be treated, and thus may have a positive impact on the development of the endovascular strategy. In the presented study cohort, most patients received CT or MRI examinations prior to the procedure. Nevertheless, in cases of a very high suspicion for RAS based on clinical signs and duplex sonographic findings, further imaging studies had been bypassed and the indication for the procedure without further screening was at the discretion of the referring nephrologist and performing interventional radiologist, as suggested by current guidelines .In contrast, the periprocedural assessment of the interventions´ technical success is mainly based on the visual evaluation of the monochromatic DSA series to date. However, visual assessment of a stenosis severity on the basis of angiography remains subjective and has been shown to correlate poorly with objective measurable parameters like translesional arterial pressure gradients with calculation of renal fractional flow reserve (FFR) . Those fIn a most recently published study, the direct comparison between color-coded single images and conventional monochromatic DSA in the evaluation of superficial femoral artery lesions after percutaneous angioplasty did not reveal any superiority of the parametric imaging mode in an ROC analysis . NeverthSince the final monochromatic angiography showed improvement of the anatomical vessel diameter by visual assessment in our study and the results also revealed a significant improvement of mean and median TTP in four out of seven predefined measurement points, an interrelation between those two effects might be worth considering. Accordingly, the study of Tan et al. showed a statistically significant correlation between the changes of anatomic degree of stenosis and the dTTP of inflow stenosis in haemodialysis accesses, while a correlation analysis with respect to the outflow lesions did not revealed a significant correlation . The autWhile our results demonstrated improved mean and median TTP values in most of the measured anatomic locations as a result of the intervention, the highest effect was documented at the level of the segmental artery. In contrast, TTP parameters at the level of renal parenchyma revealed little influence caused by the treatment. One possible explanation for this observation might be chronic vascular alterations resulting from long-term ischemia in patients with RAS. Those modifications are likely to be permanent and the possible influence by revascularization techniques might be restricted or at least only measurable on a long-term basis. Furthermore, correct assessment of blood flow values at subsegmental artery levels might be limited due to vessel size, also representing a technical obstacle. Even if the intrastenotic and poststenotic dTTP appeared to be significant, these measuring points should be put into question, since the proper measurement in this region might be technically difficult to implement. Major reasons might be a complex stenosis morphology and the small residual vessel lumen, possibly resulting in inaccurate results. Additionally, given by the definition of the TTP, the overall hemodynamic effect of a stenotic lesion might only be shown adequately distal to the stenosis.Based on our results, we hypothesize that the level of the renal segmental artery is the most suitable anatomical vessel region for assessing hemodynamic changes after revascularization. As a possible compatible hemodynamic correlate, the so called “tardus-parvus-pattern” is a known phenomenon in the doppler sonographic assessment of RAS that can be observed in the vessel region distal to the stenosis. This pattern at the downstream circulation of a stenotic lesion is caused by a decreased magnitude of blood flow within the ventricular systole due to the vessel narrowing .Being a potential indicator for the response of therapy, blood pressure measurements and serum creatinine were evaluated before and after the procedure and revealed significant improvements. At the same time, a correlation between patients´ gender and the extent of the effect of clinical therapy was not found. Furthermore, the presence of diabetes mellitus did not correlate with an improvement of the systolic blood pressure or creatinine level. Moreover, a significant influence of the presence of diabetes mellitus and dTTP in the peripheral renal segments could not be found. The hypothesis behind this analysis was the presumption that renal microangiopathy, which is a known long-term sequela in patients with diabetes mellitus, might impact the TTP values by the procedure . Thus, bThere are several limitations of the presented study. First, the heterogeneity of the included patients results in differences in the patients´ risk profile as well as the chosen therapeutic management. Thus, patients with underlying fibromuscular dysplasia were treated with solely balloon PTA of the affected renal artery, while most of the patients with atherosclerotic RAS were treated by a combination of balloon PTA and stent implantation. Furthermore, patients with atherosclerotic alterations leading to RAS are generally characterized by older age and a higher number of comorbidities. Second, follow-up of the patients was not standardized, consecutively the time between the underlying procedure and the assessment of post-interventional parameters varied significantly. Since the impact of RAS on the blood pressure and the renal function is complex and effects of long-term existing RAS might not be completely reversible or at least require a certain amount of time, a uniform and sufficiently long follow-up period might have led to different and more robust results. This might also explain the missing correlation between the clinical therapy responses in blood pressure and serum creatinine with the technical success indicated by TTP. Third, the study design is retrospective, and the number of included patients is limited. Thus, further investigations with a larger patient cohort and a prospective design should be aimed for in order to generate more robust and transferable data. Fourth, parameters of manual contrast agent application before and after angioplasty were not standardized which theoretically may result in deviations that influence the color-coded images. Finally, due to the absence of patients with different procedural outcome in terms of technical failure, the assessment of color-coding DSA usefulness remains limited. As there is no comparison of TTP in patients who did and did not undergo the procedure, including final outcome or prognosis, therefore the added value of this parameter as a diagnostic tool can not be proven by the available data. Therefore, a study design taking those prerequisites into account would be desirable to adequately address the topic of clinical relevance.In conclusion, data and color maps obtained from parametric DSA algorithm provide immediate hemodynamic functional information during endovascular renal artery revascularization and may help to evaluate the procedures’ technical success. The level of the segmental artery seems to be the most suitable anatomic region regarding assessment of blood flow characteristics.


On study day 1, microvascular endothelial function was quantified as the increase (Δ from rest) in forearm vascular conductance  during intra‐arterial acetylcholine infusion at 4.0 and 8.0 μg/dl forearm volume/min . [Glucose] and [insulin] were measured in a fasted state as well as following a 75 g OGTT on a second day with an additional fasting blood sample collected to measure HbA1c. FVC increased (Δ) 221 ± 118 and 251 ± 144 ml/min/100 mm Hg during ACh4 and ACh8 trials, respectively (p < 0.05 between doses). [Glucose] and [insulin] increased at the 1‐h time point, relative to fasting levels, and remained elevated 2 h post‐consumption (p < 0.05 for both variables and time points). [Glucose] nor [insulin], fasting or during the OGTT, were associated with ΔFVC during ACh4 or ACh8, respectively (p = 0.11–0.86), although HbA1c was inversely related . Patients whose HbA1c met the ADA’s therapeutic target of ≤7.0% had greater ΔFVC to ACh4 (272 ± 147 vs. 182 ± 74 ml/100 mm Hg/min) and ACh8  compared to those with >7.0%, respectively. Our data show glycemic management is related to acetylcholine‐mediated vasodilation  in skeletal muscle of patients with T2DM.Microvascular endothelial dysfunction precipitates cardiovascular disease mortality in patients with type 2 diabetes mellitus (T2DM). However, the relationship between glycemic management and microvascular endothelial function of these patients remains ill defined. We investigated the association between skeletal muscle microvascular endothelial function with glycemic management (HbA1c) and responses to an oral glucose challenge (OGTT) in 30 patients with T2DM  in patients with type 2 diabetes mellitus (T2DM). Moreover, we found patients who meet the American Diabetes Association's therapeutic target of ≤7.0% HbA1c had greater microvascular endothelial function compared to those >7.0%, yet similar to non‐diabetic controls of similar age, gender, and body mass index. Collectively, we found adequate glycemic management may offset the deleterious effects of diabetes‐induced microvascular dysfunction. Indeed, the approximate 400 million patients with T2DM  or responsiveness to an oral glucose tolerance test (OGTT) in patients with T2DM. Aim 2a was elucidated if patients with T2DM who meets the ADA’s glycemic target (≤7.0% HbA1c)  was to determine if those patients with an HbA1c < 7.0% had similar microvascular endothelial function compared to non‐diabetic subjects of similar age and body mass.While non‐invasive techniques are used to quantify endothelial function 22.1Thirty patients with T2DM and 14 non‐diabetic controls of similar age and body mass index provided written, informed consent prior to enrolment. Exclusion criteria for all subjects included symptomatic coronary artery disease, heart failure, uncontrolled hypertension, renal impairment, and current tobacco use or recent (<6 months) cessation. All but one female subject reported postmenopausal status with no hormone therapy at the time of their experimental visits. The pre‐menopausal female was using a long‐acting implantable contraceptive (Nexplanon) during her visits and had been doing so for 2 years prior to participating in the study. Experiments were performed during two separate visits separated by no more than 7 days, both in the morning after an overnight fast with subjects refraining from prescription medication use the morning of study visits as well as exercise, vitamins, supplements, alcohol, and caffeine 24 h before data collection. Vasodilatory responsiveness to intra‐arterial acetylcholine infusion, measured via Doppler ultrasound, was used to assess skeletal muscle microvascular endothelial function during the first visit. Acetylcholine was infused for 2 min at 4.0 and 8.0 μg/dl forearm volume/min with 10 min separating trials . During their second visit, subjects completed an OGTT, consisting of venous blood sampling and consumption of a 75 g glucose beverage . Study protocols were approved by the Institutional Review Board at the University of Iowa. Data in this manuscript were collected, in part of a clinical trial  with some previously published findings  was inserted into the brachial artery under local anesthesia (1% lidocaine) and attached to a three‐port connector infused with normal saline (3 ml/h). One port was connected to a pressure transducer  positioned at heart level measuring beat‐by‐beat mean arterial pressure (MAP), and another for acetylcholine infusions. For visit 2, a 4.8 cm, 20 g catheter  cannulated a vein, permitting blood samples throughout the study visit.2.3During visit 1, brachial artery diameter and blood velocity were measured using a Doppler probe  with an isonation angle of 60°. End‐diastolic diameters were obtained during the final 30 s of baselines, ACh4, and ACh8. Velocity signals were synchronized to a data acquisition system  via audio transformer  as follows:10,000Glucose0×Insulin0×Glucose120×Insulin120 where subscripts indicate the time of collection. Indices calculated using these time points strongly correlated with the original 5‐point equation . Independent‐samples t‐tests compared vascular responses to acetylcholine between groups (≤7.0% and >7.0% HbA1c) per trial (Aim 2a). If Aim 2a was supported, additional independent samples t‐tests were used to compare patients whose HbA1c was ≤7.0% to non‐diabetic control subjects. Demographic data were compared using independent‐samples t‐tests or chi‐squared test when appropriate. Blood [glucose] and [insulin] during the OGTT were compared across time points and between groups using a two‐way analysis of variance. All analyses were performed using SigmaPlot 11.0 software (Systat Software Inc.) with significance set a priori at p ≤ 0.05.Data are presented as mean ± SD throughout the manuscript. Relationships between vascular responses to intra‐arterial acetylcholine infusions  were compared with biomarkers  using a Pearson correlation  was observed during ACh8. In the composite group of patients with T2DM, blood [glucose] increased at the 1 h (297 ± 65 mg/dl) and remained elevated 2 h (294 ± 84 mg/dl) post‐consumption, relative to fasting concentrations . Likewise, [insulin] was higher 1 h (59.6 ± 48.3 μU/ml) and 2 h post‐consumption (62.7 ± 50.1 μU/ml) relative to baseline . Data shown in Figure p < 0.01 for both); however, no associations were observed for fasting [glucose] (p = 0.73 and 0.46) or [insulin] (p = 0.36 and 0.32). Scatter plots in Figure p = 0.44 and 0.14) nor [insulin] (p = 0.62 and 0.83) responsiveness (A.U.C.) to the OGTT or Matsuda Index (p = 0.65 and 0.56) correlated with microvascular endothelial function .Demographical data for all patients with T2DM are shown in Table 3.23.2.1Aim 2), demographical data are shown in Table p = 0.44), body mass index (p = 0.70), or resting systolic (p = 0.29) or diastolic (p = 0.29) blood pressure between groups (≤7.0% and >7.0% HbA1c). Both HbA1c and fasting blood [glucose] were greater in the T2DM cohort whose HbA1c was >7.0% relative to the ≤7.0% group (p < 0.01 for both) while fasting blood [insulin] tended to be higher in the former (p = 0.07). Groups had similar prevalence of diagnosed hypertension (p = 0.55) and hyperlipidemia (p = 0.58) as well as comparable prescribed medications (p = 0.06–0.23). Patients with an HbA1c > 7.0% had greater blood [glucose] pre‐glucose consumption (136 ± 32 vs. 182 ± 45 mg/dl) as well as 1 h (268 ± 64 vs. 319 ± 58 mg/dl) and 2 h (233 ± 79 vs. 343 ± 49 mg/dl) post‐consumption relative to those with ≤7.0% HbA1c, respectively . However, [insulin] did not differ between subgroups during the OGTT before  or 1 h  or 2 h  post‐consumption. Similarly, there were no between‐group differences in subjects’ Matsuda index . The 14 subjects without T2DM did not differ in age (p = 0.54), body mass index, (p = 0.54) or systolic (p = 0.87) or diastolic (p = 0.43) blood pressure but had lower HbA1c (p < 0.01) compared to patients with T2DM whose HbA1c was ≤7.0%.For the sub‐analyses Aim , demogra3.2.2p = 0.18), MAP , and FVC  were similar between ≤7.0% and >7.0% HbA1c groups, respectively. During steady‐state infusion, FBF , MAP , and FVC  were similar between T2DM subgroups. However, patients whose HbA1c was ≤7.0% tended to have greater ΔFVC during ACh4 than those with an HbA1c > 7.0% , MAP , and FVC  were comparable between ≤7.0% and >7.0% HbA1c groups, respectively. During ACh8, FBF (364 ± 135 vs. 262 ± 139 ml/min) and FVC  were greater in patients whose HbA1c was ≤7.0% compared with those >7.0%, respectively, with similar MAP . Accordingly, patients whose HbA1c was ≤7.0% had greater ΔFVC during ACh8 relative to those >7.0%  or ACh8  trials.Findings from our data, in concert with Kotb et al. , contrasp = 0.11). However, there were no differences between T2DM cohorts (p = 0.52, Table While data in the present study present novel findings, we recognize some limitations in our work. Firstly, the cross‐sectional nature of these experiments may not translate to interventional study designs. Indeed, longitudinal works examining the effects of exercise (Qiu et al., While the deleterious effects of T2DM are observed in nearly all organ systems, microvascular endothelial dysfunction is clinically relevant as it precipitates CVD in many of these patients. Data in the present study link, for the first time, glycemic management to microvascular endothelial function in skeletal muscle of patients with T2DM Figure . MoreoveThe authors have no conflicts of interests to disclose.D. P. C. conceived and designed the project. J. M. B., W. E. H., K. U., A. J. F., S. H., and D. P. C. performed experiments. J. M. B. and D. P. C. analyzed and interpreted data. J. M. B. prepared figures and drafted the manuscript. J. M. B., W. E. H., K. U., A. J. F., S. H., and D. P. C. edited, revised, and approved the final version of the manuscript.


EC correlated positively with CI  and male gender , and negatively with age  and presence of heart failure . Beta-blocker dose was not associated with EC. Partial correlation attributable to CI accounted for more than one-third of the variance in EC explained by the model (adjusted R2 = 59.8%). Conclusions: In patients taking beta-blockers, presence of chronotropic incompetence was associated with lower EC, regardless of the beta-blocker dose. CI accounted for more than one-third of EC variance explained by our model.Background: Chronotropic incompetence in patients taking beta-blockers is associated with poor prognosis; however, its impact on exercise capacity (EC) remains unclear. Methods: We analyzed data from consecutive patients taking beta-blockers referred for cardiopulmonary exercise testing to assess EC. Chronotropic incompetence was defined as chronotropic index (CI) ≤ 62%. Results: Among 140 patients all taking beta-blockers , 64% with heart failure, chronotropic incompetence was present in 80.7%. EC assessed as peak oxygen uptake was lower in the group with chronotropic incompetence, 18.3 ± 5.7 vs. 24.0 ± 5.3 mL/kg/min,  Chronotropic incompetence is defined as an inadequate increase in heart rate (HR) during exercise. The presence of chronotropic incompetence is associated with poor prognosis in both symptomatic and asymptomatic patients ,3,4,5,6.p < 0.0001) in a 4.5-year follow-up  × 100%. Resting spirometry parameters, calculated as forced expiratory volume in 1 s., and inspiratory vital capacity were also recorded.t test or the Mann–Whitney test for continuous variables and the χ2 (chi-squared) test for categorical variables. Univariate and multivariate linear regression analyses were performed to establish the association between independent variables and EC. The VO2peak (mL/kg/min) was used as the dependent variable for all models. Logarithmic transformation was used for non-normally distributed variables when analyzed in regression models. Variables for the univariate and multivariate models were selected using the Akaike Information Criterion and stepwise linear regression model. Variables with well-known effects on EC were forced into the model. All statistical tests were two-sided. Statistical significance was established as α = 0.05, and all statistical analyses were performed using R Statistical Software version 3.6.1.Data were presented as mean ± standard deviation for normally distributed or median (25th and 75th percentiles) for non-normally distributed continuous variables. Categorical variables were presented as a number (percentage). Normality for all continuous variables was tested using the Shapiro–Wilk test. Group comparisons were performed using Student’s This study was conducted following the requirements set out in the Declaration of Helsinki. All patients provided written consent to take part in the cardiopulmonary exercise test. The study protocol was approved by the Centre of Postgraduate Medical Education’s Institutional Review Board, and individual consent to participate in retrospective anonymous data analysis was waived.n = 37), patients with implanted pacemakers, n = 27, permanent atrial fibrillation/flutter, n = 20, and patients with severe valvular dysfunction or pulmonary hypertension, n = 8. Secondly, from the stress tests results, we excluded patients with insufficient effort (RER < 1.05), pulmonary or peripheral limitations of exercise, or other symptoms leading to premature stress test termination, such as ischemia, arrhythmia, or abnormal hypertensive response, n = 36. Finally, 140 patients were included into analysis.Among 367 evaluated patients, 268 were treated with beta-blockers. The screening process was as follows: initially, from medical records, we excluded patients with submaximal exercise tests . The percentages of maximum predicted VO2 and VO2 at the anaerobic threshold were also significantly lower in the group with chronotropic incompetence. The VO2peak was 21.3 ± 5.3 mL/kg/min for males, and 14.3 ± 4.9 mL/kg/min for females, p < 0.001.EC assessed as VOr = 0.55), positive linear association between CI and EC.2 = 24.7%) accounted for more than one-third of the variance in EC explained by the model (model adjusted R2 = 59.8%).The regression analysis results are presented in The relationship between beta-blockers, chronotropic response, and EC is currently under investigation, and there are many ambiguities regarding this issue .In our study of consecutive patients taking beta-blockers with a wide spectrum of diseases (including heart failure (64%) and chronic coronary disease (82%)) who were referred for cardiopulmonary exercise testing to assess EC, CI was common (81%) and was related to lower EC.2peak  without differences between groups with and without chronotropic incompetence. Concomitant medication did not significantly differ between groups.It was also shown previously that endurance training during cardiac rehabilitation can improve chronotropic response in patients taking beta-blockers . TherefoIn consecutive non-selected patients taking beta-blockers referred for cardiopulmonary exercise testing, chronotropic incompetence, calculated as CI, was found to be an independent predictor of reduced EC. CI positively and independently correlated with EC with the highest explained variance. Therefore, we recommend that for patients taking beta-blockers, CI is incorporated as an exercise testing parameter also in regular exercise stress tests. Our study revealed that beta-blocker dose was not an independent predictor of EC.Correlations between chronotropic response to exercise and beta-blocker daily doses need to be evaluated in further prospective studies. We are planning a long-term follow-up of this study group to evaluate predictors of mortality.


Background and ObjectivesLiraglutide, an analog of human glucagon-like peptide 1 (GLP-1), has been approved for the treatment of type 2 diabetes mellitus in Pakistan since 2016. It is a GLP-1 receptor agonist that has shown promising results in terms of not only glycemic control but also weight loss. Our study aimed to provide evidence regarding the safety and effectiveness of liraglutide in Pakistan and to look at the adherence rate and treatment satisfaction of patients using liraglutide.MethodsThis is an observational retrospective study that recruited patients who were treated with liraglutide. Data were collected at the first visit and follow-up. Morisky Green Levine Adherence Scale and Treatment Satisfaction Questionnaire for Medication (TSQM-9) were used for the determination of adherence and satisfaction with the treatment.Results2, -1.76%, -12.38 mmHg, and 5.55 mmHg, respectively. Nausea was the main side effect reported. TSQM-9 scores were compared from baseline, and it was found that patients are satisfied with the treatment and its effectiveness.A total of 70 patients were recruited in the study, The mean difference in weight, body mass index, glycated hemoglobin (HbA1C), systolic blood pressure, and diastolic blood pressure from baseline to follow-up was -5.36 kg, -2.14 kg/mConclusionsOur study has demonstrated the effectiveness of liraglutide as a monotherapy or combination therapy in the Pakistani population. Liraglutide led to reduction in HbA1C and weight. This is associated with high treatment satisfaction rate and adherence rate. Thus, liraglutide remains an effective though expensive treatment option in a country like Pakistan. Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder with multiple pathophysiological mechanisms . With inInjectable GLP-1 receptor agonist mimics endogenous GLP-1 by way of stimulating pancreatic insulin secretion as well as suppressing glucagon production . RegardlLiraglutide, an analog of human GLP-1, has been approved for the treatment of T2DM in Pakistan since 2016 . Althoug2 were prescribed liraglutide 0.6 mg subcutaneously once a day irrespective of their meal at the same time initially for the first five days, and from the sixth day they were switched to a dosage of 1.2 mg with further up-titration to 1.8 mg based on tolerance. Other prescribed drugs were advised to be taken accordingly. Patients were excluded if they had type 1 diabetes and a glomerular filtration rate (GFR) < 45 mL / min / 1.73 m2.This is an observational retrospective study that recruited patients from endocrinology clinics of Shifa International Hospital Islamabad and Umar Diabetes and Foot Care Centre, Islamabad, Pakistan, from September 2018 to June 2019. The study was conducted after approval by the respective Ethical Review Committees. All patients with T2DM above 18 years with glycated hemoglobin (HbA1c) ≥ 7% and body mass index (BMI) ≥ 25 kg/mAt first visit, baseline data were collected using a pre-designed data collection form, which included age, weight, BMI, blood pressure, and HbA1c. Morisky Green Levine (MGL) Adherence Scale and Treatment Satisfaction Questionnaire for Medication (TSQM-9) were used for the determination of adherence and satisfaction with the treatment ,8. AnalyStatistical analyses were performed using IBM SPSS Statistics for Windows, Version 20.0 . Categorical variables were recorded as frequencies and percentages for each category and continuous variables were recorded as means and standard deviations. A paired t-test was applied for pre-post changes in clinical outcomes and treatment satisfaction, whereas analysis of variance (ANOVA) was applied to determine the differences between various diabetics groups.A total of 70 patients were recruited in the study, out of which 52.9% were males and 41.1% were females with a mean diabetes duration of 8.53 ± 6.44 years. Baseline characteristics are given in Table 2, -1.76%, -12.38 mmHg, and 5.55 mmHg, respectively. When inquired on follow-up, majority of the patients reported having nausea (48%) as a side effect of liraglutide, and a few reported to experience diarrhea, vomiting, and headache as well.Table TSQM-9 scores were compared from baseline, and it was found that patients are satisfied with the treatment and its effectiveness (p<0.05), whereas in terms of convenience, there was no significant difference Table .Of the patients, 18 were prescribed liraglutide only, 25 liraglutide and oral anti-diabetics , and 27 liraglutide and insulin. These three groups were assessed individually Table , showingThis study shows that liraglutide is beneficial in reducing weight, BMI, HbA1C levels, fasting blood glucose, and blood pressure in Pakistani patients with T2DM. Liraglutide has been shown in LEAD (Liraglutide Effect and Action in Diabetes) trials to improve glycemic control, with HbA1c reduction of up to 0.8-1.6%. We also observed a significant reduction in HbA1C levels similar to the outcome of LEAD trials -13. In IIncretin-based treatments can produce weight loss in contrast to many alternative treatment plans that often lead to weight gain. In our study, liraglutide also showed its efficacy in weight and BMI reduction when used as a monotherapy or in combination with other oral hypoglycemic agents and insulin. The mean weight and BMI reduction at follow-up from baseline in our study were 5.36 kg and 2.14 kg/m2, respectively. As reported in the LEAD-4 trial, a considerable and sustained weight loss with liraglutide monotherapy was stated in contrast with glimepiride. Weight reduction with liraglutide monotherapy happened usually within the first 16 weeks but was then sustained . Weight Liraglutide treatment was associated with reduced systolic and diastolic blood pressure. We observed that the mean systolic and diastolic blood pressure reduction at follow-up from baseline in our study was 12.38 mmHg and 5.55 mmHg, respectively. Similar results were observed in our three different therapy groups. These differences in blood pressure were much higher in our study than reported in LEAD studies that showed a reduction of systolic blood pressure between 2.7 and 2.9 mmHg . AnotherIn addition to glycemic and metabolic benefits, liraglutide is well known for gastrointestinal side effects including nausea, vomiting, and diarrhea . Most (4Strengths and LimitationsThis is one of the few studies that not only evaluate the safety and effectiveness of liraglutide in the Pakistani population but also look at treatment satisfaction and adherence rates. Use of liraglutide has raised the level of treatment satisfaction through better glycemic control and had efficacious treatment adherence. However, the study possesses some limitations being an observational cohort study. Firstly, as data were collected retrospectively, the interval between HbA1c measurements was not constant. Secondly, patient records did not mention whether insulin doses were reduced after initiating liraglutide. Thirdly, as this study analyzed patients treated with liraglutide for a short period, it was not possible to predict therapeutic persistence. Fourthly, although commending BMI and HbA1C levels were reported at follow-up, several confounders such as diet and physical activity could not be monitored in a retrospective study. Lastly, due to the shorter duration of this study, we could not evaluate the cardiovascular and renal benefit of liraglutide in our population. Prospective studies are required to further evaluate the safety, effectiveness, and patient satisfaction of liraglutide, comparing multiple useful consequences of liraglutide in patients with cardiovascular risks and baseline albuminuria and thus evaluating the new cardio defensive and renal protecting role of this drug in South Asian population.Our study has demonstrated the effectiveness of liraglutide as a monotherapy or combination therapy in the Pakistani population. Liraglutide provided HbA1c reductions in addition to rapid and sustained reductions in FPG, weight loss, and systolic blood pressure. This is associated with high treatment satisfaction rate and adherence rate. Thus, liraglutide remains an effective though expensive treatment option in a country like Pakistan.


Deliberate hypotension is used to provide a bloodless field during functional endoscopic sinus surgery; however, the impact of controlled hypotension during anesthesia on peripheral tissue perfusion has not been extensively evaluated. The aim of this study was to compare the impact of nitroglycerin- versus labetalol-induced hypotension on peripheral perfusion.n = 20) or labetalol (n = 20). Mean arterial pressure was maintained at 55–65 mmHg in both groups. Both study groups were compared according to pulse oximeter-derived peripheral perfusion index (primary outcome), serum lactate level, mean arterial pressure, heart rate, surgical field score, and intraoperative blood loss.The present randomized, double-blinded, controlled trial included adult patients undergoing endoscopic sinus surgery. Patients were allocated to one of two groups according to the drug received for induction of deliberate hypotension: nitroglycerin (p < 0.0001) and lower postoperative serum lactate levels  than the labetalol group. The peripheral perfusion index was higher in the nitroglycerin group than at baseline at most intraoperative readings. The median surgical field score was modestly lower in the labetalol group than in the nitroglycerin group in the first 20 min (2 [interquartile range (IQR) 2–2.5] versus 1.5 [IQR 1–2]; p = 0.001). Both groups demonstrated comparable and acceptable surgical field scores in all subsequent readings.Forty patients were included in the final analysis. The nitroglycerin group exhibited a higher peripheral perfusion index at nearly all records (Nitroglycerin-induced deliberate hypotension was accompanied by higher peripheral perfusion index and lower serum lactate levels than labetalol-induced deliberate hypotension during sinus endoscopic surgery.NCT03809065. Registered at 19 January 2019. This study adheres to CONSORT guidelines.The study was registered at clinicaltrials registry system with trial number:  Controlled hypotension is commonly used during functional endoscopic sinus surgery (FESS) to ensure a bloodless operative field. The main risk in controlled hypotension is impaired peripheral perfusion and subsequent ischemia of vital organs , 2. A taNitroglycerin and labetalol are commonly used drugs for controlled hypotension during anesthesia. Both drugs are also used for acute management of emergent hypertension in emergency departments. Nitroglycerin is a direct vasodilator and its main action is through venodilation. Labetalol combines an α1 blocking effect and beta-adrenergic blocking activity to reduce systemic vascular resistance, with little effect on cardiac output , 6. BothThe aim of this study, therefore, was to compare the impact of nitroglycerin and labetalol on peripheral perfusion when used for induction of deliberate hypotension during FESS. We evaluated peripheral perfusion using PPI and serum lactate levels as markers of peripheral and global tissue perfusion.This randomized, double-blinded, parallel study was conducted at Cairo University Hospital  after receiving approval (N-53-2016) from the Research Ethics Committee, Faculty of Medicine, Cairo University. Written informed consent was obtained from all participants before enrollment.Forty adult patients 18–45 years of age, with American Society of Anesthesiologists physical status I-II and scheduled for FESS, were included. Individuals with uncontrolled hypertension, cerebrovascular disorders, coagulation disorders, cardiovascular diseases, renal impairment, liver impairment, and history of allergic reaction to any of the study medications were excluded from the study.http://www.randomizer.org) was used by a research assistant to generate random sequences. Each code was enclosed in a sealed opaque envelope. Another research assistant, who was not involved in outcome assessment, was responsible for opening the envelope and preparing the study drug. Patients were allocated before induction of anesthesia into either the nitroglycerin (n = 20) or labetalol (n = 20) group. The patient, attending anesthesiologist, and surgeon were blinded to the study group allocation.An online randomization program (2), and temperature probe. PPI was measured using a pulse oximetry probe , which was attached to the patients’ index finger of the non-dominant hand. Invasive blood pressure was monitored using a 20-gauge radial artery catheter connected to a pressure transducer. Arterial blood gases were measured using a specialized, commercially available device .On arrival to the operating room, intravenous midazolam (0.05 mg/kg) and fentanyl (50 μg) were administered as premedication to all participants. Two 18-gauge peripheral intravenous catheters were secured: one for fluid administration; and the other for infusion of the study drug. Monitoring included electrocardiography, non-invasive arterial blood pressure, end-tidal carbon dioxide , propofol (1.5–2 mg/kg), atracurium (0.5 mg/kg) to facilitate insertion of an appropriately sized endotracheal tube, and 1 g paracetamol for analgesia. Anesthesia was maintained using an isoflurane end-tidal concentration of 1.2% and 0.01 mg/kg atracurium every 20 min. Lactated Ringer’s solution was infused at a rate of 5 mL/kg. Mechanical ventilation was adjusted to maintain end-tidal CONitroglycerin  was diluted by adding 3 mL (3 mg) to 47 mL of 0.9% saline in a 50 mL syringe. Labetalol  was diluted by adding 10 mL (50 mg) to 40 mL of 0.9% saline in a 50 mL syringe. Both drugs were infused after endotracheal intubation with a starting dose of 0.5 mL/kg/h to have a starting dose of 0.5 μg/kg/min for nitroglycerin and 0.5 mg/kg/h for labetalol. The infusion was then titrated according to patient response. The rate of nitroglycerin infusion was 0.5–2 μg/kg/min, whereas the labetalol infusion rate was 0.5–2 mg/kg/h.The infusion rate was finely adjusted to maintain invasive MAP at approximately 55–65 mmHg or until achieving the adequate surgical field . Hypotension was defined as a decrease in MAP below the target level, which was managed by decreasing the rate of drug infusion by 50% up to transient holding of infusion. If hypotension persisted after stopping drug infusion, incremental doses of intravenous ephedrine (5 mg) were planned to be administered. Bradycardia was defined as a heart rate < 50 beats/min and was planned to be treated with intravenous atropine 0.5–1.0 mg and discontinuation of the infused drug.The surgical field was evaluated according to SFS  by a surTwenty minutes before the end of the procedure, the infused drugs were gradually weaned off. At the conclusion of surgery, isoflurane was discontinued, and residual neuromuscular blockade was reversed using neostigmine 0.05 mg/kg and atropine 0.02 mg/kg.PPI was measured at the following time points: before induction of anesthesia; 1 min after endotracheal intubation; every 5 min after initiation of study drug infusion until the end of the procedure; and every 10 min in the post-anesthesia care unit for 60 min. During data analysis, measurements were averaged every 15 min until the end of the operation; the postoperative 60 min was averaged in one point.Serum lactate concentration: Two samples were obtained at baseline and 60 min after extubation. Total intraoperative blood loss was measured from the suction device and gauze that was used to dry the surgical field. SFS was measured every 5 min intraoperatively until the end of the procedure. Each two successive measurements were averaged (every 10 min) during analysis.Mean arterial blood pressure and heart rate were assessed at the following time points: pre-induction, 1 min after endotracheal intubation (intubation was performed 2 min after induction of anesthesia); every 5 min after initiation of study drug infusion until the end of the procedure, and every 10 min in the post-anesthesia care unit for 60 min. During data analysis, intraoperative measurements were averaged every 15 min; the postoperative 60 min was averaged in one point.In a pilot study involving 5 patients, an intraoperative, average PPI was reported during the first 1 h of anesthesia after nitroglycerin infusion at a mean ratio of 4.5 ± 0.8 during the same operation. A sample size that could detect 20% difference in PPI  between the two study groups was calculated using MedCalc software version 14.10.2 . A minimum of 34 patients (17 patients per group) was calculated to have a study power of 80% and an alpha error of 0.05. The number was increased to 40 patients (20 patients per group) to compensate for possible/projected dropouts. We chose 20% mean difference in the PPI during sample size calculation because this relative change was previously reported as an accurate index for increased cardiac output after passive leg raising .P < 0.05 were considered to be statistically significant.SPSS version 15  for Windows  was used for data analysis. Categorical data are expressed as frequency (percentage [%]) and analyzed using the chi-squared test. Normality of continuous data was verified using the Shapiro-Wilk test, which are expressed as mean ± standard deviation (SD) or median (interquartile range [IQR]), as appropriate. Continuous data were analyzed using the unpaired t test or the Mann-Whitney test as appropriate. Repeated measures were analyzed using analysis of variance (ANOVA) for repeated measures with post-hoc pairwise comparisons using the Bonferroni test. Differences with Forty-five patients, recruited from January to May 2019, were screened for eligibility in this study. Two patients did not meet the inclusion criteria, three declined to participate, and 40 were randomly assigned to receive one of the two interventions. All patients completed the intervention and data were available for final analysis  until the conclusion of surgery Table .Table 2Results of our study revealed that nitroglycerin-induced deliberate hypotension was associated with more preserved PPI compared with labetalol-induced deliberate hypotension. Both study drugs provided acceptable surgical conditions; however, nitroglycerin infusion appeared to be safer in terms of peripheral tissue perfusion. We also found that using nitroglycerin for induction of controlled hypotension did not impair peripheral tissue perfusion.There are two possible mechanisms that may account for the superiority of peripheral perfusion in nitroglycerin compared to labetalol. 1. Administration of vasodilator drugs improves microcirculatory blood flow by increasing precapillary inflow pressure , 13. 2. We evaluated tissue perfusion using the oximetry-derived PPI. PPI is characterized as a non-invasive, real-time measure that increases during vasodilatation , and decNitroglycerin and labetalol were previously compared in achieving deliberate hypotension –9. HowevThe “art” of hypotensive anesthesia is to achieve proper surgical conditions without suppressing perfusion of vital organs . The risThere were several limitations to our investigation, the first of which was that it was a single-center study. Second, we induced hypotension in only one type of surgery; thus, our findings with regard to surgical field may differ in other procedures. Third, our patients received the available drugs  in our hospital; the impact of study drugs in peripheral perfusion with other agents, such as sevoflurane and remifentanil, may require further research. Fourth, our findings are restricted to patients with no serious comorbidities. Finally, although we demonstrated that deliberate hypotension did not impair peripheral perfusion under the conditions of our study, more studies aimed at evaluating the effect of deliberate hypotension on the perfusion of vital organs are warranted.Nitroglycerin-induced deliberate hypotension was accompanied by higher PPI and lower serum lactate levels compared with labetalol-induced deliberate hypotension during sinus endoscopic surgery.


Background: A new method using blood pressure-to-height ratio for diagnosing elevated blood pressure/hypertension in children has been introduced recently. We aimed to compare blood pressure-to-height ratio (BPHR) and Body Mass Index (BMI) in predicting incidence of hypertension (HTN). Methods: The sample consisted of 1133 boys and 1154 girls aged 7–15. We used the following equations for BPHR: systolic BPHR (SBPHR) = SBP (mm Hg)/height (cm) and diastolic BPHR (DBPHR) = DBP (mm Hg)/height (cm). In order to determine the accuracy of SBPHR, DBPHR and BMI as diagnostic tests for elevated blood pressure (elevated BP), we used the receiveroperating characteristic curve analyses. Results: The area under the curve (AUC) values for BMI ranged from 0.625 to 0.723 with quite low sensitivity rates from 62% to 72.5% and specificities from 58.2% to 67.3% showing a modest ability to identify children with elevated BP and HTN. On the contrary, BPHR showed a great predictive ability to identify elevated BP and HTN with AUC values of 0.836 to 0.949 for SBP and from 0.777 to 0.904 for DBP. Furthermore, the sensitivity ranged from 78.5% to 95.7%, and the specificity from 73.9% to 87.6%. Conclusion: the current study showed that BPHR is an accurate index for detecting elevated BP and HTN in children aged 7 to 15 years and can be used for early screening. Hypertension/high blood pressure (HTN/HBP) can be defined as systolic BP (SBP) and/or diastolic BP (DBP) above the 95th percentile, and blood pressure (BP) between the 90th and 95th percentile can be considered as “elevated blood pressure” . Due to A recent survey in Serbia , which iThis study aimed to compare BMI-for-age (Z score) and blood pressure-to-height ratio (BPHR) in predicting incidence of hypertension, and for the first time to evaluate the diagnostic value of BPHR for diagnosing hypertension in children and adolescents from the north part of Serbia.The cross-sectional study was performed in the period between 2017 and 2019 and included 2287 children (<13 years) and adolescents (≥13 years). In total, 1133 male and 1154 female subjects aged 7–15 years were investigated. The data used in this study were gathered in a large-scale survey of children and adolescents, covering most of the geographical areas of the North Bačka region of Vojvodina (Republic of Serbia).Age was calculated as the difference between the date of birth and date of data collection. Each age group was categorized according to the midpoint of an age range. For example, the group of participants aged 7 years included all participants between 6.50 and 7.49 years. The subjects were grouped into nine age categories (6.50–15.49). Informed consent was obtained from participants and their parents before data collection, and the inclusion of subjects was on a voluntary basis. The written consent for conducting the surveys was also obtained from the Academic Council of Faculty of Sciences and Department of Biology and Ecology in Novi Sad, the Provincial Secretariat for Higher Education and Scientific Research and primary and secondary school principals. The surveyed traits included height and weight. Height was measured with an anthropometer  with the head positioned in the Frankfurt plane, and a portable electronic digital scale was used to measure weight with accuracy of ±0.1 kg. Blood pressure (BP) was measured three times, with digital sphygmomanometer OMRON M6 Comfort from the bare right arm of participants, at the level of the heart, while participants remained seated with back support, after at least 5 min of rest.2). The subjects were classified into four groups: underweight, normal, overweight and obese, according to the International Obesity Task Force—IOTF [Body mass index (BMI) was calculated as weight (kg) divided by height squared , we used the receiveroperating characteristic curve analyses. The discriminating power of the BMI and the BPHR was expressed as area under the curve (AUC) and 95% confidence intervals (CI). An AUC value of ≥0.90 was considered an excellent accuracy; 0.80–0.89 good; 0.70–0.79 satisfactory and <0.70 bad accuracy. The sensitivity and specificity of BPHR and BMI as indicators of HTN were determined with cutoff values. The Youden index was used to determine optimal cutoff values BMI and BPHR for identification of elevated BP/HTN ) .This study was approved by the Institutional Review Committee of the University of Novi Sad, Provincial Secretariat for Higher Education and Scientific Research (Ref. No. 128-611-68/2019-01), and was conducted under the Declaration of Helsinki.p < 0.01), weight and SBP (p < 0.001) were higher in boys, while DBP was higher in girls (p < 0.05).The general characteristics of the participants are shown in p = 0.049), while underweight is more prevalent in girls (p = 0.000). The prevalence of elevated BP and HTN shows no statistically significant differences between boys and girls. Elevated SBP and DBP in general resulted in a prevalence of 6.6%, and for the HTN the prevalence is 5.05%. The correlation between BMI-for-age (Z score) and blood pressure was significant and positive for SBP , while there was no correlation for DBP . Based on the IOTF categorization , it can The areas under the ROC curve of BMI-for-age (Z score), SBPHR and DBPHR as predictors of elevated BP and HTN in boys and girls, and their confidence intervals (95% CI), as well as the cutoff points and their relevant sensitivity and specificity, can be seen in It is noted that both BMI-for-age (Z score) and BPHR take over larger areas, but BMI-for-age Z-score has a modest ability and, on the contrary, BPHR shows very good ability to identify children with elevated BP and HTN. The optimal thresholds of SBPHR/DBPHR for defining elevated BP were 0.79/0.55 for boys and 0.80/0.54 for girls, and for defining HTN were 0.83/0.57 for boys and 0.82/0.54 for girls. The sensitivity ranged from 78.5% to 95.7%, and the specificity from 73.9% to 87.6%.This study aimed to identify the predictive power and to propose cutoff points of BMI-for-age (Z score) and blood pressure-to-height ratio (BPHR) for prediction of high blood pressure in school children of Vojvodina (North Serbia). It is difficult to compare the prevalence of HTN in children and adolescents due to methodological differences and different reference criteria which can cause high variability in the prevalence of high blood pressure. In this study, the prevalence of elevated BP was 6.6% and for the HTN the prevalence was 5.05%. These results are similar with recent investigations in Serbia  which esHypertension in childhood may remain undiagnosed, and the reasons are mostly related to the measurement and interpretation of BP, as well as complicated diagnostic criteria. In this study, we have shown that BMI-for-age (Z-score) has a modest ability to identify children with elevated BP/HTN with AUC values ranging from 0.625 to 0.723 with low percentages of sensitivity (62% to 72.5%) and specificity (58.2% to 67.3%). On the contrary, BPHR had excellent predictive ability to identify elevated BP/HTN with AUC values of 0.882 to 0.949 for SBP and 0.777 to 0.904 for DBP. Sensitivity ranged from 78.5% to 95.7% and specificity from 73.9% to 87.6%. This study showed that BPHR ratios are a simple and accurate method of diagnosing high values of blood pressure. The findings are in agreement with the previous studies on this matter ,14,15,28The results of our study are in line with other investigations as they show that BPHR is a reliable tool for diagnosing and screening for high blood pressure, and can be easily used to screen children at high risk of elevated BP/HTN in large epidemiologic surveys or by children and their parents. However, the limitations of this research lie in that the subcategories of hypertension, i.e., stage 1 and stage 2, were not separately considered. Also, data on the existence of possible target organ damage were not taken into account, which would be helpful to reinforce the use of the indexation of BP over height. However, the contribution of this study is that it is based on a large number of participants, and the results are in line with other investigations, both in Serbia and other regions of the World. It shows that BPHR is a reliable tool for diagnosing and screening for high blood pressure, and can be easily used to screen children at high risk of elevated BP/HTN in large epidemiologic surveys or by children and their parents. Nevertheless, these methods can only be used as screening tools for the identification of children and adolescents who need further evaluation of their BP. They should not be used to diagnose elevated BP or HTN by itself. The screened children with potential hypertension should be assessed by medical professionals.BPHR is a simple, screening and diagnostic tool with high sensitivity and specificity to detect elevated BP. To the best of our knowledge, this study is the first in the North part of Serbia to report the predictive ability of BPHR for elevated BP/HTN, which can be used as a reliable tool for diagnosing and also screening for high BP in ambulatory care setting in children.


Kidney transplant immunosuppressive medications are known to impair glucose metabolism, causing worsened glycemic control in patients with pre-transplant diabetes mellitus (PrTDM) and new onset of diabetes after transplant (NODAT).To determine the incidence, risk factors, and outcomes of both PrTDM and NODAT patients.This is a single-center retrospective observational cohort study.The Ottawa Hospital, Ontario, Canada.A total of 132 adult (>18 years) kidney transplant patients from 2013 to 2015 were retrospectively followed 3 years post-transplant.Patient characteristics, transplant information, pre- and post-transplant HbA1C and random glucose, follow-up appointments, complications, and readmissions.t-test was used to compare means, chi-squared test was used to compare percentages, and univariate analysis to determine risk factors was performed by logistical regression.We looked at the prevalence of poor glycemic control (HbA1c >8.5%) in the PrTDM group before and after transplant and compared the prevalence, follow-up appointments, and rate of complications and readmission rates in both the PrTDM and NODAT groups. We determined the risk factors of developing poor glycemic control in PrTDM patients and NODAT. Student P < .01). PrTDM patients were more likely to receive follow-up with an endocrinologist (P < .01) and diabetes nurse (P < .01) compared to those with NODAT. There were no differences in the complication and readmission rates for PrTDM and NODAT patients. Receiving a transplant from a deceased donor was associated with having poor glycemic control, odds ratio (OR) = 3.34, confidence interval , P = .04. Both patient age, OR = 1.07, CI , P < .01, and peritoneal dialysis prior to transplant, OR = 4.57, CI , P = .02, were associated with NODAT.A total of 42 patients (31.8%) had PrTDM and 12 patients (13.3%) developed NODAT. Poor glycemic control (HbA1c >8.5%) was more prevalent in the PrTDM (76.4%) patients compared to those with NODAT (16.7%; Our study was limited by our small sample size. We also could not account for any diabetes screening performed outside of our center or follow-up appointments with family physicians or community endocrinologists.Poor glycemic control is common in the kidney transplant population. Glycemic targets for patients with PrTDM are not being met in our center and our study highlights the gap in the literature focusing on the prevalence and outcomes of poor glycemic control in these patients. Closer follow-up and attention may be needed for those who are at risk for worse glycemic control, which include older patients, those who received a deceased donor kidney, and/or prior peritoneal dialysis. New onset of diabetes after kidney transplantation (NODAT) is a common complication, and its incidence, associated risk factors, and adverse outcomes have been well studied in the literature. However, there exist very few Canadian studies on this topic and even fewer studies that have looked at the impact of kidney transplant immunosuppressive medications on the glycemic control of patients with pre-existing diabetes (PrTDM).Our study adds to the limited Canadian research on the incidence, risk factors, and adverse outcomes of both NODAT and PrTDM population.13 In the kidney transplant population, diabetes mellitus is an extremely common disease.4 Immunosuppressive medications taken post-transplant  are known to impair glucose metabolism,5 leading to both worsened glycemic control in patients with pre-transplant diabetes mellitus (PrTDM) and new onset of diabetes after kidney transplant (NODAT). Diabetes in the kidney transplant population, whether pre-existing or newly acquired, is associated with increased risk for complications, including increased risk for infection, graft failure, cardiovascular complications, and increased mortality.611Kidney transplantation is the preferred treatment for patients with end-stage renal disease (ESRD), due to its cost effectiveness and ability to provide a better quality of life and prognosis than maintenance dialysis.12 Risk factors that are associated with NODAT include age, body mass index (BMI), African-American race, pre-diabetes prior to transplant, prednisone dose, tacrolimus use, receiving a deceased donor kidney, and cytomegalovirus (CMV) and hepatitis C virus infections.12New onset of diabetes after kidney transplant has been well studied in the literature. The reported incidence of NODAT is broad ranging from 10% to 74% depending on varying diagnostic criteria, screening protocols, and follow-up duration.In Canada, the data on the incidence and risk factors of NODAT are limited. The few studies that exist have primarily investigated the incidence and risk factors associated with poor glycemic control in kidney transplant patients with PrTDM. The aim of this single-center study is to determine the incidence, risk factors, and outcomes of both poor glycemic control post-transplant and NODAT in this population, as well as identify any gaps in their care.This is a retrospective analysis of kidney transplant patients treated at a single Canadian tertiary center  between January 9, 2013 and January 9, 2015. Data were collected until 3 years post-transplant for each subject and were collected via electronic medical record and paper charts. There were no exclusion criteria as part of this review.The data collected were divided into 3 categories: (1) baseline/pre-transplant (2) during hospital stay post-transplant, and (3) 3 years post-transplant. Baseline data included age, sex, race, BMI, blood pressure at transplant, etiology of ESRD, type of renal replacements therapy prior to transplant, comorbidities, donor status , and medications prior to transplant. In hospital data included days in hospital, type of immunosuppressive agents used, total dose of prednisone, days on intravenous insulin, and number of in-hospital complications. Follow-up data included follow-up appointments with members of the diabetes health care team and number of complications and rehospitalizations during the 3-years post-transplant. Random blood glucose, HbA1c, creatinine, albumin-to-creatinine ratio (ACR), and serum concentrations of immunosuppressive agents were collected quarterly from routine blood tests during the 3 years following transplant.This study was approved by the Ottawa Health Science Network Research Ethics Board.13Poor glycemic control was defined as having at least one HbA1c >8.5% based off less stringent cut offs from the American Diabetes Association,14 with adequate glycemic control defined as HbA1c <8.5%. Very poor glycemic control was defined as having at least HbA1c >10% as this has been associated with random glucose levels >12 mmol/L.15Pre-transplant diabetes mellitus was defined as the presence of a confirmed diagnosis of diabetes prior to transplantation as documented in the pre-transplant evaluation note or transplant surgery admission note. New onset of diabetes after kidney transplant was defined by at least one of the following criteria: (1) a random glucose >11.1 mmol/L, (2) a HbA1c >6.5%, or (3) the prescription of a new diabetes medication in patients without a previous diagnosis of diabetes. These criteria were based on the guidelines from the 2013 International Consensus Meeting on Post-transplantation Diabetes Mellitus.Complications in hospital included wound issues, urinary tract infections (UTI), pneumonia, cardiac events, rejection, anemia requiring transfusion, and delayed graft function. Cardiac events included coronary artery disease, stroke, and severe peripheral arterial occlusive disease. Delayed graft function was defined as a requirement of hemodialysis post-transplant during hospital admission.Post-transplant complications included UTI, rejection, and CMV infection that were determined by urine cultures, renal biopsy, and CMV DNA titers respectively.Elevated serum levels of tacrolimus were considered >8 ng/mL at 3 months and >6 ng/mL after 6 months post transplant. Elevated serum cyclosporine was defined as >800 ng/mL at 3 months and >600 ng/mL after 6 months post-transplant. Elevated blood glucose levels in hospital were defined as having a point of care glucose level of >11 mmol/L.t-test was used to compare means, and chi-squared test was used to compare percentages. To determine whether both poor glycemic control was associated with adverse outcomes, and risk factors for poor glycemic control and NODAT, a univariate analysis was performed by logistical regression. We used one-way analysis of variance (ANOVA) to assess relationship between HbA1C and time post transplantation. For all tests, a P value, less or equal to .05, was considered to indicate statistical significance. All statistical analyses were computed with MedCalc for Windows .Continuous variables were expressed as means with standard deviations. Categorical variables were expressed as numbers and percentages. Student There were a total of 170 kidney transplants from 2013 to 2015. Based on the availability of their paper charts, of these patients, 132 adult kidney transplant patients were included in our study, with 42 (31.8%) patients having PrTDM. The baseline data are displayed in P = .01) and systolic blood pressure  at kidney transplant were significantly higher in patients with PrTDM. The most common comorbid conditions for both groups were hypertension, dyslipidemia, and coronary artery disease as determined by their physician. Hypertension (P = .02), dyslipidemia (P = .01), and congestive heart failure (P = .01) were more prevalent in the PrTDM group compared to those without diabetes. Hemodialysis was the most common form of renal replacement pre-transplant for both groups. Most of the kidney transplants were from donors who were younger than 60 years of age in both groups. A total of 17 PrTDM patients (40.5%) received a transplant from a deceased donor, which was comparable to the 47 recipients without diabetes (52.2%). Tacrolimus was the most common maintenance immunosuppression administered in both groups, but was significantly more commonly used in the nondiabetes group (P = .02), while cyclosporine was used most often in patients with PrTDM , and in those without diabetes was glomerulonephritis (40%). Of the 42 patients with PrTDM, 27 (64.3%) had type 2 diabetes, while the rest had type 1 diabetes. Body mass index  had very poor glycemic control. HbA1c was measured consistently during the post-transplant period for each patient. Of the 42 patients with PrTDM, 30 (71.4%) had poor glycemic control and 13 (31%) had very poor glycemic control post-transplant. There was no significant difference between the proportion of poor glycemic control within 6 months before transplant vs within 3 years after transplant, although there was a trend toward an increase in proportion of patients with elevated HbA1c  had ed HbA1c .ANOVA analysis revealed that that there was no statistically significant difference in HbA1c in the post-transplant period .The proportion of random glucose concentrations >11 mmol/L were 45% at 6 months pre-transplant, 41% within the first 3 months post-transplant, and 46% from 3 months to 3 years post-transplant .P < .01; The incidence of NODAT was 13.3% . Poor glycemic control was more prevalent in the PrTDM patients compared to those with NODAT 3 months to 3 years post-transplant P < .01; .P < .01). Similarly, 88% of PrTDM were seen by a diabetes nurse, compared to the 33.3% of NODAT patients (P < .01). All patients with NODAT and PrTDM received follow-up with a dietician, and more than 90% of patients from both groups were seen by a pharmacist , P = .02, were associated with NODAT , P = .04 . Both path NODAT .9 reported that 51.9% of the PrTDM had poor glycemic control, defined as an average HbA1C >7% or fasting glucose of ≥8.3 mmol/L. In terms of outcomes, Tabet et al9 study showed that there was no difference in mortality and graft loss between transplant patients with uncontrolled diabetes compared to those with controlled diabetes, although it is possible that a difference would have been observed had the authors used a higher HbA1c cut-off in their definition for poor glycemic control.The analysis of this single-center retrospective cohort study has generated several important findings, with the most relevant being the inadequate glycemic control seen in the PrTDM patients pre- and post-transplant. Almost 3 quarters of the patients with PrTDM had poor glycemic control, with half of these patients having an HbA1c reading >10% post-transplant. The literature primarily focuses on NODAT, and few studies have looked at the prevalence and outcomes of poor glycemic control in the kidney transplant population. One study, by Taber et al,16 cardiovascular events,17 and increased risk for mortality.9 Graft dysfunction1820 is also more likely in the PrTDM population, which is supported by the findings in our study. While it is reasonable to assume that PrTDM patients with poorer glycemic control are more likely to have more complications and poorer outcomes, our study did not support this hypothesis. There is currently a paucity of observational data looking at longer term outcomes in this patient population, representing an important area to focus for future research.Patients with diabetes often have multiple comorbidities. The presence of diabetes in patients undergoing kidney transplant increases the likelihood to develop complications such as infections,2125 As per standard of care, our study found that patients with PrTDM were less likely to receive tacrolimus and more likely to receive cyclosporine. However, despite being treated with a more glycemic-friendly immunosuppressant, a large proportion of patients still had poor glycemic control.Different immunosuppressants are known to affect glycemic control in patients, with tacrolimus being shown to be associated with greater prevalence of post-transplant hyperglycemia and greater incidence of NODAT when compared to cyclosporine.26 Although both studies indicated a fairly high incidence, many recent studies have reported even higher incidences 3 years post-transplant, such as those reported in the United States (16%-24%),27 Europe (17%-30%),2830 and Asia (31%-34%).31 Differences between studies may be due to variability in NODAT diagnostic criteria and patient demographics such as BMI and ethnicity, as well as post-transplant surveillance.26In the current study, the overall incidence of NODAT 3 years post-transplant was slightly higher than that of another single-center Canadian study with similar diagnostic criteria.We found that patients with PrTDM were also more likely to be seen by both an endocrinologist and diabetes nurses compared to those with NODAT. This is possibly due to the fact that PrTDM patients are able to readily schedule follow-up appointments with an already established diabetes health care team. Nonetheless, there were a large number of PrTDM patients that were not followed at our center by the diabetes team. In addition, despite having more follow-up compared to those with NODAT, PrTDM patients still showed a higher prevalence of poor glycemic control after transplant. These findings highlight that follow-up appointments with the PrTDM patients remain an important area needing more attention and an opportunity to improve outcomes in this patient population.33 however, PrTDM has been well supported by the literature as a risk factor for hospital readmission with most studies showing high rates of rehospitalization within the first year after transplant.35 With post-transplant rehospitalization representing a main contributor to health care expenses after kidney transplant,3337 future studies are needing in clarifying whether poor glycemic control predisposes them to adverse outcomes, which may support the need for preventative strategies, as potential means for resource optimization.The current study demonstrated that patients with PrTDM and NODAT were not more likely to have rehospitalization or complications compared to patients without diabetes. There are currently conflicting studies associating NODAT as a risk factor for rehospitalization;39 However, to our knowledge, no other study has reported a deceased donor kidney to be a significant risk for poor glycemic control in patients with PrTDM, although the mechanism is likely the same. Deceased donor kidney allografts have more ischemia and are more likely to come from older and more comorbid donors. They are known to express higher levels of proinflammatory cytokines in comparison to living kidney donor grafts, whether related or unrelated, demonstrating that graft injury is more likely with a deceased donor kidney.4042 The resulting increased risk of rejection potentially requires more aggressive immunosuppression, thus further impairing glycemic control. In addition, higher levels of systemic inflammation are known to play a major role in the pathogenesis of type 2 diabetes,43 which would be expected to be seen from deceased donor recipients. To note, however, our study did not find donor age, graft rejection, in-hospital prednisone dose, and high serum level of tacrolimus or cyclosporine post-transplant to be independent risk factors for poor glycemic control in patients with PrTDM.Receiving a kidney from a deceased donor is a well-known risk factor for NODAT.45 Insulin resistance that develops with aging is mainly attributed to factors that include diminished physical activity, poor diet, obesity, and loss of lean body mass. There is also the development of a functional decline of pancreatic B-cells as well as impaired B-cell adaptation to insulin resistance, resulting in glucose intolerance.46Risk factors for NODAT were age and prior peritoneal dialysis. Just as with type 2 diabetes, NODAT is more likely to occur in older patients.47 However, a study by Courivaud and colleagues found no impact of pre-transplant dialysis modality on incidence of NODAT.48 Peritoneal dialysis commonly involves infusing a dextrose dialysate into the peritoneal cavity to create an osmotic gradient for blood filtration and fluid exchange. This poses a risk for hyperglycemia due to the high glucose load from the dialysate; this has been shown to contribute to impaired fasting glucose and metabolic syndrome,49 predisposing patients for NODAT. Our study did not find that BMI had a significant effect on the development of NODAT, despite most studies demonstrating it as an independent risk factor for NODAT.50Our study demonstrated peritoneal dialysis as a risk factor for NODAT. Our results are similar to a cohort study by Madziarska and colleagues of 377 patients, who were the first to report a significantly greater incidence of NODAT in peritoneal dialysis patients (35.4%), when compared to those who received hemodialysis (21.2%).5153 Therefore, the diagnosis for poor glycemic control and NODAT using HbA1c is likely underestimated, particularly as the estimated glomerular filtration rate (eGFR) was not normalized. However, the unreliability of HbA1c is typically only significant in moderate to severe renal impairment (eGFR <45 mL/min/1.73 m2).54 As the patients in our study had good renal function post-transplant with eGFR ≥ 60 mL/min/1.73 m2  of them having absent readings. We also did not perform standard oral glucose testing and had to rely on random glucose and HbA1c measurement alone to classify NODAT and poor glycemic control. This approach primarily reflects the practice of most centers, given that oral glucose testing is a cumbersome test. In addition, our study did not do multivariable analysis and there could be collinearity between our identified risk factors . This study was also performed primarily on Caucasians (71.2%), and the results may not be applicable to other ethnicities. Finally, another potential limitation to consider is the use of HbA1c as a measure of glycemic control in this patient population. Poor renal function has been shown to be associated with a skewed HbA1c as a result of the alteration in the hemoglobin lifespan and the administration of erythropoietin./1.73 m2 , we expeIn conclusion, poor glycemic control is a common and important issue in the kidney transplant population. The findings of this study indicate that glycemic targets for patients with PrTDM are not being met and highlights the gap in the literature focusing on the prevalence and outcomes of poor glycemic control in these patients. Significant risk factors for NODAT were age and previous peritoneal dialysis, and a risk factor for poor glycemic control was type of donor. Our study adds to the body of knowledge for these risk factors, and their recognition in this patient population may be useful to prevent a deterioration in glycemic control. Overall, early identification of impaired glycemic control in the post kidney transplant population will allow implementation of lifestyle modifications, adjustments of immunosuppressive, and initiation of glucose-lowering therapies as indicated, thereby preventing progression of diabetes or NODAT and associated complications.