Introduction: Prior studies report conflicting evidence regarding exercise pressor and metaboreflex responses in individuals with metabolic syndrome (MetS).Purpose: To test the hypotheses that 1) exercise pressor and metaboreflex responses are exaggerated in MetS and 2) these differences may be explained by elevated resting blood pressure.Methods: Blood pressure and heart rate (HR) were evaluated in 26 participants (13 MetS) during 2 min of handgrip exercise followed by 3 min of post-exercise circulatory occlusion (PECO). Systolic (SBP), diastolic (DBP), and mean arterial pressure (MAP), along with HR and a cumulative blood pressure index (BPI), were compared between groups using independent samples t-tests, and analyses of covariance were used to adjust for differences in resting blood pressure, fasting blood glucose (FBG), and waist circumference (WC).Results: ΔSBP (∼78% and ∼54%), ΔMAP (∼67% and ∼55%), and BPI (∼16% and ∼20%) responses were significantly exaggerated in individuals with MetS during handgrip and PECO, respectively . ΔDBP, ΔMAP, and BPI responses during handgrip remained significantly different between groups after independently covarying for resting blood pressure (p < 0.01), and after simultaneously covarying for resting blood pressure, FBG, and WC (p ≤ 0.03). Likewise, peak SBP, DBP, MAP, and BPI responses during PECO remained significantly different between groups after adjusting for resting blood pressure (p ≤ 0.03), with peak SBP, MAP, and BPI response remaining different between groups after adjusting for all three covariates simultaneously (p ≤ 0.04).Conclusion: These data suggest that exercise pressor and metaboreflex responses are significantly exaggerated in MetS independent of differences in resting blood pressure, FBG, or WC. Metabolic syndrome (MetS) is a clinical condition characterized by the accumulation of specific cardiometabolic risk factors, including abdominal obesity, insulin resistance, hypertension, and dyslipidemia . AccordiOne aspect of MetS that is of particular interest to clinicians is the manifestation of cardiovascular dysfunction. Resting autonomic dysfunction is a hallmark characteristic of both cardiovascular and metabolic disease and is expressed as reductions in heart rate variability , elevatFirst, despite not reaching statistical significance, it is notable that these studies consistently reported net increases in the blood pressure responses to both handgrip exercise  and metaTo that end, the aims of this study were twofold. First, we aimed to directly compare the hemodynamic responses to isometric handgrip and metaboreflex activation between individuals with MetS and control subjects matched for age, biological sex, race, and ethnicity. We expected to observe significantly exaggerated blood pressure and heart rate (HR) responses to handgrip exercise and metaboreflex activation in the MetS group compared to control participants. Secondly, we aimed to determine the potential mediating role of resting blood pressure in explaining these differences. Considering the known association between resting hypertension and exaggerated exercise pressor responses , and conn = 4 in the final analysis) were also counted as expressing that risk factor. Of these eighteen subjects, thirteen were able to be matched to control subjects. Control subjects presented with ≤2 cardiometabolic risk factors, were not taking any medications known to affect cardiometabolic risk factors, and were matched to subjects in the MetS group by age (mean difference between matched pairs = 2 ± 5 years), biological sex assigned at birth, race, and ethnicity. This matching procedure resulted in four matched pairs of non-Hispanic Black/African American (B/AA) males, three matched pairs of non-Hispanic B/AA females, three matched pairs of non-Hispanic White males, one matched pairs of non-Hispanic White females, one matched pair of Hispanic White females, and one matched pair of non-Hispanic Asian females. All other subject demographics are presented in A total of 132 individuals were initially recruited for participation in this study, all of whom were prescreened for MetS. Of these 132 individuals, seventy individuals completed both study visits, eighteen of whom met the criteria for MetS, defined as having any combination of three of the following cardiometabolic risk factors : 1) waisSubjects in this study completed two research visits, the first of which served as a cardiometabolic prescreening. Subjects arrived at the prescreening visit at least 8 hours postprandial, which included abstention from caffeine and prescription or over-the-counter medications/supplements, and having avoided physical exertion  for 24 hours prior. Upon arrival, subjects underwent anthropometric and body composition assessments, followed by the assessment of FBG, fasting blood lipid concentrations, and oral glucose tolerance (OGT). The second visit served as an assessment of resting cBRS and reflex cardiovascular control. Similar to the first visit, subjects arrived at the second visit at least 8 hours postprandial, including caffeine, and having abstained from over-the-counter medications and alcohol for 12 hours and intense physical activity for 24 hours prior. The second visit included assessments of the hemodynamic responses to handgrip exercise and metaboreflex activation.®, Carlsbad, CA, United States). BIS operates by introducing an array of electrical currents through the body and measuring the body’s opposition to these currents, which can be used to estimate total body fat and fat-free mass from estimates of total body water  at the level of the iliac crest as suggested for the assessment of MetS . Body cody water . This asdy water .FBG and lipids were collected using a point-of-care cholesterol analyzer , which has demonstrated accuracy compared to other laboratory methods . After an = 9) did not receive measurements of LDL-C.The cholesterol analyzer was calibrated before each new batch of cassettes (based on Lot #), as recommended by the manufacturer, using two (high/low) multianalyte control solutions. All values produced during calibration were within the expected ranges outlined by the manufacturer. Daily, and prior to testing, the analyzer’s optical scanner was calibrated using a standardized optical control cassette. Notably, this reader would not record TRG values above 650 mg/dL or below 45 mg/dL. Two individuals with MetS returned TRG readings of >650 mg/dL, which were recorded as 650 mg/dL, and four individuals in the control group produced TRG values of <45 mg/dL, which were recorded as 45 mg/dL. Therefore, TRG were likely under- and overestimated in these individuals, respectively. Moreover, this analyzer is unable to produce HDL-C measurements when TRG readings are >650 mg/dL (due to accuracy concerns) and thus, HDL-C was not recorded for the subjects with TRG >650 mg/dL. However, the absence of an HDL-C value did not change the MetS classification for these subjects. In addition, the cholesterol analyzer does not record HDL-C values below 15 mg/dL. One individual in the MetS group returned HDL-C values < 15 mg/dL, which was recorded as 15 mg/dL. Thus, HDL-C was likely overestimated in this subject. Because LDL-C is calculated from TC, TRG, and HDL-C, subjects that had TRG and HDL-C measurements outside of the analyzer’s detectable range (Glycated hemoglobin (HbA1C) was recorded using a second automated HbA1C reader  as a supplement to FBG. This HbA1C analyzer has been shown to be accurate when compared to laboratory-grade reference methods . To meas®, Bloomingdale, IL, Lot #3261408), which was confirmed via third-party testing . Blood glucose was then collected every 30 minutes, in duplicate, for 2 hours following ingestion of the carbohydrate bolus. Duplicate measurements were averaged at each timepoint to produce a final estimate of blood glucose and the final value recorded at the two-hour mark was recorded as the OGT value (mg/dL).In addition to FBG, glucose control was also evaluated using a standard oral glucose tolerance (OGT) test. Subjects were instructed to consume ≥150 g/day of carbohydrates for at least 3 days prior to the collection of data, which was verified using electronic food records. Each OGT test began with a baseline collection of capillary blood glucose , in duplicate, followed by the ingestion of a 250 mL solution of water and 75 g glucose  protocol. This protocol began with 2 minutes of isometric handgrip of the non-dominant arm, assigned at 35% of the subject’s maximal voluntary contraction (MVC), which was determined in triplicate prior to baseline data collection. Just prior to the end of the two-minute contraction period, a pneumatic pressure cuff  was inflated around the upper arm to a suprasystolic pressure and maintained for 3 minutes. This three-minute period of PECO isolates (and exaggerates) the metaboreflex by trapping exercise related metabolic byproducts within the previously active forearm, promoting a sustained hypertensive response .norm; mmHg/kg).Throughout each assessment of cardiovascular function, cardiac rhythm was continuously recorded using a one-lead (lead I) electrocardiogram , and beat-by-beat blood pressure was continuously recorded via finger photoplethysmography . The beat-by-beat blood pressure recorded from the finger was calibrated to brachial blood pressure values collected during the baseline period of each cardiovascular assessment. HR was calculated from each individual R-R interval, and mean arterial pressure (MAP) was calculated as the average of all samples  within a single cardiac cycle. Similarly, SBP and DBP were calculated as the maximum and minimum points recorded within each individual cardiac cycle, respectively. These data were then used to identify the peak responses and relative changes (Δ) in SBP, DBP, MAP, and HR, as well as areas under the curve (for MAP only) observed during handgrip and PECO. The area under the curve for MAP, termed the blood pressure index , was also normalized to the time-tension index (kg*sec) for the HG period, providing a normalized BPI value (BPIt-tests were used to test the following hypotheses: 1) individuals in the MetS group would demonstrate significantly augmented peak and relative hemodynamic responses to handgrip and PECO compared to the control group and 3) individuals in the MetS group would demonstrate significantly augmented BPI responses to handgrip and PECO compared to the control group. Analyses of covariance (ANCOVA) were then used to determine the influences of resting SBP (in the cases of SBP and HR responses) or resting DBP  in mediating any significant differences between groups. To determine if any potential changes in group differences were unique resting blood pressure, ANCOVA were also used to independently adjust for FBG and WC, and to adjust for all three covariates simultaneously. If resting blood pressure is, in fact, the primary contributor to exaggerated hemodynamic responses, hemodynamic responses should remain significantly different between groups after covarying for FBG and WC separately, but not after adjusting for resting blood pressure. Linear regression analyses were also used to examine the relationships between each dependent variable  and the MetSindex score. All statistical analyses were performed using SPSS statistical analysis software , and all data are presented as the mean ± standard deviation (SD). Of the thirteen individuals with MetS included in the final analysis, all thirteen completed the handgrip trials and twelve completed the PECO trial.Data were first visually inspected for normality and the presence of outliers using histograms and boxplots. Next, independent samples p < 0.01), had a higher percentage of body fat , a higher waist circumference , carried more total fat mass  and fat-free mass , and tended to have a higher HbA1C  compared to controls (p = 0.47). Nevertheless, DBP, BMI, and the MetSindex were all significantly higher in the MetS group compared to controls , and HDL-C was significantly lower (p < 0.01), clearly demonstrating an increased cardiometabolic disease risk in the MetS group. A breakdown of MetS risk factors for each group (MetS vs. control) is also provided in As expected, subjects in the MetS group were significantly heavier , p = 0.38; Results indicated significantly exaggerated peak and relative pressor responses to both HG and PECO in the MetS group compared to controls –3. Specip = 0.01; p = 0.01; p < 0.01; p < 0.01; p = 0.03) and ΔMAP .When the peak pressor responses to PECO were evaluated, results indicated similarly elevated peak pressor responses in the MetS group compared to controls. As in the handgrip trials, SBP was elevated by 18.8% , DBP , and MAP responses , as well as ΔSBP , ΔDBP , ΔMAP , and BPI responses  remained significantly exaggerated in the MetS group. Interestingly, however, these hemodynamic responses to handgrip also remained significantly exaggerated in MetS after independently adjusting for FBG , and all but ΔMAP  remained significantly exaggerated in Mets after independently adjusting for WC . Likewise, peak SBP , DBP , and MAP , as well as ΔMAP , and BPI  responses to PECO remained significantly exaggerated in the MetS group after adjusting for resting blood pressure, and these same responses, with the exception of ΔMAP , remained significantly exaggerated after independently adjusting for FBG . Only peak SBP  and BPI responses  to PECO remained significantly exaggerated in MetS after independently adjusting for WC.Results from the covariate analyses are presented in F = 5.256, p = 0.03), DBP , and MAP , as well as ΔDBP , ΔMAP , and BPI responses  to handgrip exercise remained significantly exaggerated in the MetS group compared to controls. Likewise, peak SBP , peak MAP , and BPI  responses to PECO also remained significantly exaggerated in MetS vs. controls after adjusting for all three covariates.When all three covariates were included in the model, peak SBP , ΔDBP , ΔMAP , and BPI  responses to handgrip and PECO, respectively, in the hypertensive MetS group compared to matched controls , comparisons between the non-hypertensive MetS group and matched controls failed to reach statistical significance, but demonstrated comparable effect sizes (Cohen’s d) for differences in handgrip responses relative to the comparisons in the hypertensive MetS group (n = 7) and non-hyperglycemic (n = 6) MetS groups demonstrated significantly exaggerated ΔSBP , ΔDBP , and ΔMAP  responses to handgrip exercise, and significantly exaggerated BPI responses to PECO , compared to matched controls , but no other significant relationships were observed between the MetSindex and hemodynamic responses.Results from linear regression analyses are presented in This study tested the general hypotheses that 1) cardiovascular reflex responses would be exaggerated in individuals with MetS compared to matched control subjects and 2) these differences would be largely explained by differences in resting blood pressure. Our findings only partially support these hypotheses. Specifically, individuals with MetS demonstrated significantly augmented blood pressure responses to both handgrip exercise and metaboreflex activation, which supports the primary hypothesis. However, these responses remained significantly exaggerated in individuals with MetS even after adjusting for resting blood pressure, FBG, WC, and all three covariates combined. Ultimately, these findings provide strong evidence that 1) exercise pressor responses and metaboreflex responses are significantly exaggerated in MetS, and 2) these changes occur independent of differences in resting blood pressure, FBG, or WC. These findings provide novel insight into MetS related changes in cardiovascular function, as will be discussed in the following sections.As noted previously, the magnitude of exercise pressor responses are known to be significantly exaggerated in some , but notSpecific factors that may have contributed to the observed increase in exercise pressor and metaboreflex responses in the MetS group of the present study may include impaired baroreflex control, augmented afferent receptor function or expression, or increases in central command. For instance, it is known that the baroreflex buffers systemic vascular responses during exercise pressor reflex activation , and prinorm responses during handgrip exercise (p = 0.07), likely explained by differences in fat-free mass  revealed significantly exaggerated blood pressure responses . Of course, this is a complex  perspective, as this would challenge the traditional use of relative handgrip intensities as a method of normalizing sympathetic stimuli. Furthermore, the handgrip exercise performed in the present study largely excluded the influence of body mass, and increases in total body mass may increase the relative intensity of locomotor based physical activity in individuals with MetS. For these reasons, this would be an interesting and valuable area of further investigation.One finding from the present study that would support the argument that the magnitude of cardiovascular reflex responses to exercise  are not exaggerated in MetS is the lack of significant differences in BPIexercise . Upon furee mass . Althougesponses , 2A, butesponses . This raWhile interpreting the results of this study, there are a few experimental considerations that should be taken into account. First, the lack of MSNA recordings in this study does not allow for direct evaluations of sympathetic activity in individuals with MetS. However, it is well documented that both handgrip exercise exceeding 30% MVC and PECO elicit robust increases in MSNA . For thaThere are a series of questions raised by the current study that are worthy of further investigation. First and foremost, it is important to elucidate the casual factors contributing to the development of exaggerated cardiovascular responses to exercise in individuals with MetS. As noted previously, neither resting blood pressure, FBG, nor WC were able to explain these adaptations, and the answer will likely be found by evaluating the neural and cellular adaptations that occur in parallel with disease progression. Understanding this will allow researchers and clinicians to begin working towards uncoupling these adaptations and preventing, or slowing, the development of cardiovascular dysfunction in MetS. Second, it would be valuable to understand the relative differences between contrasting MetS phenotypes (different groupings of cardiometabolic risk factors), and how these phenotypes influence autonomic dysfunction. It may be plausible that MetS, and the resulting impairments in autonomic control, develop differently based on which cardiometabolic risk factors present first, or are most severe. Investigators could examine this using a combination of MetS induced animal models and cross-sectional or longitudinal human studies evaluating different developmental stages of MetS. Likewise, it would also be important to understand how impairments in resting cardiac autonomic modulation, and particularly arterial baroreflex function, influences disease progression.The results from this study indicate that individuals with MetS demonstrate exaggerated exercise pressor and metaboreflex responses compared to control subjects, and that these differences occur independent of resting blood pressure, FBG, and central adiposity. This indicates that other MetS related risk factors likely contribute to the development of cardiovascular dysfunction in MetS, highlighting the complexity of this cardiometabolic condition. Future studies may consider identifying the specific risk factors, or groupings of risk factors, that contribute most heavily to the development of cardiovascular dysfunction in MetS, as this will identify the most appropriate targets for disease mitigation in this population.


Dexmedetomidine, a central α-2 agonist, is used for procedural sedation and for conscious sedation influences on heart rate and blood pressure. Authors verified whether it is possible to predict bradycardia and hypotension with the use of heart rate variability (HRV) analysis for an autonomic nervous system (ANS) activity assessment. The study included adult patients of both sexes with an ASA score of I or II scheduled for ophthalmic surgery to be performed under sedation. The loading dose of dexmedetomidine was followed by a 15 min infusion of the maintenance dose. The frequency domain heart rate variability parameters from the 5-min Holter electrocardiogram recordings before dexmedetomidine administration were used for the analysis. The statistical analysis also included pre-drug heart rate and blood pressure as well as patient age and sex. The data from 62 patients were analysed. There was no relationship between the decrease in heart rate (42% of cases) and initial HRV parameters, haemodynamic parameters or sex and age of patients. In multivariate analysis, the only risk factor for a decrease in mean arterial pressure (MAP) > 15% from the pre-drug value (39% of cases) was the systolic blood pressure before dexmedetomidine administration as well as for a >15% decrease in MAP sustained at more than one consecutive time point (27% of cases). The initial condition of the ANS did not correlate with the incidence of bradycardia or hypotension; HRV analysis was not helpful in predicting the abovementioned side effects of dexmedetomidine. Initialactivity ,8. Due tactivity . Howeveractivity , it is pThe aim of the study was to determine whether the baseline status of the ANS determines the haemodynamic effect of dexmedetomidine.Although 74 patients were included in this study, there were 12 dropouts .The reasons for the dropouts were as follows: (1) general anaesthesia used instead of sedation because of surgical reasons, (2) withdrawal of consent by the patient, (3) cancellation of the operation, (4) incomplete ECG recording, and (5) no repairable damage to the Holter memory card.Ultimately, the data of 62 patients were analysed and characteristics of the study participants are presented in HRV parameters that were analysed were low frequency (LF) and high frequency (HF) changes and the LF/HF ratio. Haemodynamic parameters that were analysed were heart rate (HR) and systolic arterial pressure (SAP), diastolic arterial pressure (DAP), and mean arterial pressure (MAP). The values of haemodynamic and HRV parameters before dexmedetomidine administration are shown in Haemodynamic values at six time points, including before dexmedetomidine infusion and during loading and maintenance infusions, are presented in The HR decreased by more than 20% from the pre-drug values in 26 cases (42%). There was no relationship between this phenomenon and initial HRV parameters, haemodynamic parameters or sex, and age of patients. A decrease in MAP of more than 15% from the pre-drug value and a decrease in MAP of more than 15% from the pre-drug value, sustained for more than one consecutive time point, were observed in 24 (39%) and 17 cases (27%), respectively .p = 0.016).In the multivariate analysis, the only risk factor for a decrease in MAP > 15% was SAP before dexmedetomidine administration (SAP LI 0) .In the multivariate analysis, the only risk factor for a decrease in MAP > 15% sustained at more than one consecutive time point was SAP LI 0.  over benzodiazepines for sedation in critically ill, mechanically ventilated adults. For delirium treatment in mechanically ventilated adults where agitation precludes weaning from mechanical ventilation or extubation, dexmedetomidine use has been suggested .However, despite its desirable effects on ICU population, the dexmedetomidine sympatholytic effect can even lead to cardiac arrest in ICU patients without cardiovascular comorbidities, just after vagal stimulation, as described in a report by Bahraini et al. .With respect to the above, we searched for the potential relationship between basic autonomic tone and the incidence of bradycardia, and no relationship was found in the present study. Additionally, there was also no relationship between bradycardia and initial HR or arterial blood pressure.According to the literature, HRV is a sensitive method for detecting individuals who may be at risk of BP instability during general anaesthesia . SimilarWith this knowledge, we assessed whether other components of HRV before dexmedetomidine administration can help to predict the occurrence of hypotension caused by dexmedetomidine, and no correlation was found. On the other hand, in the abovementioned Padley study, hypotension was defined as a more severe decrease in SAP or MAP—more than a 30% drop from baseline or a MAP ≤ 60 mm Hg.As mentioned above, the influence of dexmedetomidine on arterial blood pressure has two features. A bolus dose, when the plasma concentration is high, causes an increase in blood pressure , which results from an increase in systemic vascular resistance (vascular α-2 receptor activation). Hypertension may be severe, with systolic blood pressure exceeding 200 mm Hg .2-receptors in the vascular endothelial cells acting together with presynaptic α2-adrenoreceptors, inhibiting the sympathetic release of catecholamines [As the plasma concentration decreases, a hypotensive phase occurs. This is caused by vasodilation resulting from activation of the αolamines ,12,34.The incidence of hypotension in our study was 39%, and hypotension lasting for more than 5 min was found in 27% of cases. We did not observe hypertension during the loading dose.This effect, caused by the activation of the peripheral postjunctional α-1 adrenergic receptors, is seen when intravenous infusion of high doses or when rapid intravenous bolus is administered. This occurs because dexmedetomidine loses its α-2 receptor selectivity when given in a high dose or as a rapid bolus injection. Additionally, transient activation of peripheral α-2B is responsible for hypertensive effects .The loading dose was given within 10 min, according to the product characteristic—this can be the reason for not observing hypertension. Another reason could be the use of non-invasive blood pressure measurement and the measures in 5 min periods. Sudden, transient blood pressure changes are easier to detect when using continuous measurement.In our study, blood pressure  was significantly lower than the pre-administration values at 10 min of loading dose infusion and during 15 min of the maintenance dose. It was found that the only risk factor for hypotension was systolic blood pressure before dexmedetomidine administration.The hypotensive effect may be desirable in some situations; for instance, dexmedetomidine has been used intraoperatively to facilitate controlled hypotension ,36. EvenThe present study included relatively healthy patients scheduled for a planned procedure. This population differs from critically ill patients, in whom dexmedetomidine is used commonly.The clinical characteristics make dexmedetomidine a useful drug in indications other than just sedation; however, these uses, including treatment and prevention of delirium, adjunctive analgesia, therapy for insomnia in the ICU, and treatment of alcohol withdrawal, are off-label ,38,39,40However, dexmedetomidine is used for sedation in this population. The incidence of dexmedetomidine-induced hypotension is similar to that observed in surgical patients.In a study of critically ill patients by Gerlach et al. , hypotenIn our study, the only independent risk factor for hypotension development was systolic blood pressure before dexmedetomidine administration. However, the population studied is totally different from the ICU population.In patients in the cardiovascular ICU, hypotension was also observed in 42% of patients. Bradycardia was found to be an independent predictor of hypotension [It is worth mentioning that on multivariable adjusted analysis, it was found that dexmedetomidine sedation was associated with lower vasopressor requirements to maintain the target MAP in septic shock patients in the first 48 h. The potential bias was deeper sedation in the usual care group, but according to the authors, the findings are exploratory .In a systematic review, it was shown that dexmedetomidine was effective in reducing both the ICU length of stay and time to extubation. The use of dexmedetomidine, however, was associated with an increased risk of bradycardia, but not with overall mortality .Despite haemodynamic side effects, taking into account that dexmedetomidine is safe in terms of the risk of respiratory depression, Weerink et al. , in theiOn the other hand, in new data recently published this year, dexmedetomidine was associated with an increased risk of mortality in the age group ≤ 65 years compared with alternative sedatives . The reason for this is not yet known .In the anaesthesia field, monitoring plays an essential role. Changes in the activity of the ANS measured as heart rate variability changes caused by drugs used for anaesthesia might one day become a part of some algorithms. A pioneering method of monitoring the depth of anaesthesia, using, among other things, physiological parameters and HRV, has been described by Kenwirth et al. . It can The study has some limitations. Since it includes relatively healthy patients, without comorbidities and who are not taking drugs that influence the ANS, the results cannot be extrapolated to more sick patients. At the same time, creating a study with a relatively homogenous population with comorbidities could be extremely difficult and at the same time not feasible for analysis purposes.The next limitation is the sample size . The assumptions that MAP decreases > 15% and HR decreases > 20% and will be clinically significant were made.Another limitation is the use of noninvasive blood pressure monitoring. Direct measurement would be more precise for the detection of sudden, transient blood pressure changes. However, this kind of monitoring is the standard method of intraoperative blood pressure monitoring in patients with an ASA score of I–II and during uncomplicated operations .Bias may also be caused by the fact that during maintenance dose infusion, there was no strictly defined dose volume prescribed for all the patients—the infusion rate was given to maintain a Ramsay score of between 2–3.In conclusion, in the analysed setting, the incidence of bradycardia was relatively high and similar to that reported in the literature. There was no relationship found between the incidence of bradycardia and the analysed haemodynamic and the HRV parameters and demographic characteristics of patients. Hypertension during the loading dose was not observed. Hypotension was common and was recorded at 10 min of loading dose infusion and lasted until the end of the study. The only independent risk factor for hypotension development was systolic blood pressure before dexmedetomidine administration. The initial condition of the ANS did not correlate with the incidence of bradycardia or hypotension; HRV analysis was not helpful in predicting the abovementioned side effects of dexmedetomidine.Ethical approval for this study was provided by the Independent Committee for Scientific Research at the Medical University of Gdansk, Gdansk, Poland (NKEBN/266/2014).This study was registered at ClinicalTrials.gov (Identifier NCT02566863). Written informed consent was obtained from all patients.The study included adult patients of both sexes with an ASA score of I or II scheduled for ophthalmic surgery to be performed under sedation.The exclusion criteria were: a lack of consent to participate in the study, contraindications to the use of dexmedetomidine, history of hypersensitivity to dexmedetomidine, advanced heart block (second or third degree), if cardiac pacing is not used, uncontrolled hypotension, acute cerebrovascular disease, the use of drugs with known effects on the ANS, and coexistence of diseases that modulate autonomic system activity.Data analysed were an incidence of a decrease in heart rate (HR) of more than 20% from the values before dexmedetomidine administration, a decrease in mean arterial pressure (MAP) of more than 15% from the pre-drug value, and a MAP decrease of more than 15% from the pre-drug value that persisted for more than one consecutive time point.The definition of perioperative hypotension differs between studies and varies from a 10 to 60% drop from the baseline values .The relationship of occurrence was assessed for the abovementioned outcomes in relation to heart rate variability, haemodynamic parameters recorded before dexmedetomidine administration, and demographic parameters.In the ophthalmology ward, an ECG Holter monitor with a digital sampling rate of 180/s/s/channel  was connected to the patient approximately 30 min before the planned initiation of anaesthesia, and recording commenced. Once the patient was transferred to the operating suite, standard monitoring of vital functions was initiated . Patients were given oxygen via a face mask and Holter readings were recorded automatically.−1 body weight of dexmedetomidine  was given within 10 min, followed by titrated continuous infusion (range 0.2 to 1 µg kg−1 h−1) with the aim of a Ramsay sedation score of between 2–3. Haemodynamic parameters were noted before dexmedetomidine administration, after 5 and 10 min of loading dose infusion, and after 5, 10, and 15 min of maintenance dose infusion.A loading dose (LI) of 1 µg kgFor the assessment of autonomic tone activity, 5-min recordings before the administration of dexmedetomidine were taken into analysis.During this period of 25 min of drug infusion , no surgical procedures were performed. After the drug infusion, the study was stopped, and the surgical procedure began.Heart rate variability (HRV) in the frequency domain was analysed using a nonparametric model (fast Fourier transformation) over 256 RR intervals. ECG recordings were automatically imported into HRV ver. 1.1 for analysis using H-Scribe .There is no consensus on how to analyze HRV in the frequency domain. Two alternative approaches are nonparametric fast Fourier transformation (FFT) or parametric autoregressive model (AR) . Both meParasympathetic pulsation is thought to be reflected by high frequency (HF) values, while the interpretation of low-frequency (LF) changes is not as clear. Despite the fact that both sympathetic and parasympathetic components are represented by LF changes, the LF component has been deemed responsible for sympathetic changes. As a result of the above argumentation, the LF/HF ratio reflects the balance between sympathetic and parasympathetic activity ,55. An Lp < 0.20 in the univariate analysis. p < 0.05 was considered statistically significant.Statistical analysis was performed using Prism 9 software . The normality of the continuous data distribution was tested with the Shapiro–Wilk test. Continuous variables with a normal probability distribution are presented as the mean with a 95% confidence interval (CI). For the continuous variables with a different probability distribution, the median, the interquartile range (IQR), and the range are given. Risk factors for bradycardia and hypotension were determined using the calculation odds ratio (OR) and 95% CI for the independent predictors using multiple logistic regression. Regression analysis included parameters with The initial condition of the ANS did not correlate with the incidence of bradycardia or hypotension; HRV analysis was not helpful in predicting the abovementioned side effects of dexmedetomidine.


Two-thirds of Americans who are prescribed antihypertensive medications are not at a blood pressure (BP) goal of less than  140/90 mmHg, and low adherence is identified as a primary cause of inadequate control. Improved adherence to antihypertensive medications has been shown to enhance BP control and reduce the risk of cardiovascular complications. This study investigated the effectiveness of a pill box clinic to improve BP in veterans with uncontrolled hypertension taking 3 or more antihypertensive medications.To (a) investigate the reduction of systolic BP by 10 mmHg from pre-intervention to post-intervention (primary outcome) and (b) investigate the percentage of patients meeting goal blood pressure—as defined by The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7)—and percentage of patient adherence to antihypertensive medications (secondary outcomes).Patients with uncontrolled hypertension currently taking at least 3 antihypertensive medications were enrolled in this prospective pre/post study. Under the supervision of a pharmacist, each patient was provided two 7-day pill boxes to organize all antihypertensive medications. In addition, baseline BP and previous history of nonadherence were documented. Following the initial encounter, patients attended 2 follow-up appointments, at 2 and 4 weeks, for refill of pill boxes, BP measurement, and adherence assessment. A chi-square test was used for categorical outcomes and logistic regression for nominal outcomes as well as descriptive statistics, as appropriate.Sixty patients were enrolled, with 50 completing appointments 1 and 2, and 45 completing all 3 appointments. Of those, 24% and 31% achieved at least a 10 mmHg reduction in systolic BP from baseline to appointments 2 and 3, respectively (P = 0.438). Systolic BP readings for appointments 1, 2, and 3 were not statistically significant . Goal BP per JNC7 was achieved by 44% and 51% of patients at appointments 2 and 3, respectively, compared with baseline (P = 0.201). All patients had ≥ 80% adherence to antihypertensive medications, assessed via pill counts at the second and third appointments.Although results were not statistically significant, the pill box clinic resulted in clinically significant reductions in systolic BP by 10 mmHg, as well as an increased number of patients meeting prescribed BP goals.


The assessment of accurate mortality risk is essential for managing pneumonia patients with connective tissue disease (CTD) treated with glucocorticoids or/and immunosuppressants. This study aimed to construct a nomogram for predicting 90-day mortality in pneumonia patients using machine learning.Data were obtained from the DRYAD database. Pneumonia patients with CTD were screened. The samples were randomly divided into a training cohort (70%) and a validation cohort (30%). A univariate Cox regression analysis was used to screen for prognostic variables in the training cohort. Prognostic variables were entered into the least absolute shrinkage and selection operator (Lasso) and a random survival forest (RSF) analysis was used to screen important prognostic variables. The overlapping prognostic variables of the two algorithms were entered into the stepwise Cox regression analysis to screen the main prognostic variables and construct a model. Model predictive power was assessed using the C-index, the calibration curve, and the clinical subgroup analysis . The clinical benefits of the model were assessed using a decision curve analysis (DCA). Similarly, the C-index was calculated and the calibration curve was plotted to verify the model stability in the validation cohort.A total of 368 pneumonia patients with CTD  treated with glucocorticoids or/and immunosuppressants were included. The univariate Cox regression analysis obtained 19 prognostic variables. Lasso and RSF algorithms obtained eight overlapping variables. The overlapping variables were entered into a stepwise Cox regression to obtain five variables , and a prognostic model was constructed based on the five variables. The C-index of the construction nomogram of the training cohort was 0.808. The calibration curve, DCA results, and clinical subgroup analysis showed that the model also had good predictive power. Similarly, the C-index of the model in the validation cohort was 0.762 and the calibration curve had good predictive value.In this study, the nomogram developed performed well in predicting the 90-day risk of death in pneumonia patients with CTD treated with glucocorticoids or/and immunosuppressants. Connective tissue disease (CTD) is a series of autoimmune diseases that often leads to collagen deposition, tissue damage, and eventual target organ failure . GlucocoThe severity assessment of patients with pneumonia is one of the most important predictors of patient prognosis. Several scoring methods exist for the assessment of the severity of community-acquired pneumonia (CAP) , which iMachine learning is a branch of artificial intelligence that uses algorithms to identify relationships in data  and has We constructed a comprehensive predictive nomogram by using machine learning algorithms, clinical features, and laboratory test indicators. In addition, we validated the prognostic performance of the model using an internal validation cohort.The study was based on a previously reported cohort that recruited patients with pneumonia who were hospitalized in six secondary and tertiary academic hospitals in China between January 1, 2013 and December 31, 2017 , 18. Thehttps://datadryad.org/stash). The dataset contained 716 samples and 127 observations. First, patients without CTD were removed; second, clinical observations with missing values greater than 5% were removed  . Prognosn, Expi, and βi indicate the number of hub prognostic variables, variable values, and the stepwise Cox regression coefficient, respectively. In the training cohort, patients were divided into the high- and low-risk groups based on the median risk score, and the difference in prognosis between the two groups was assessed using the Kaplan–Meier analysis.where We constructed prognostic nomogram using the “nomogram” function (default parameters) by package “rms”(v6.2.0) . Calibrat-test was used for the comparison of normally distributed random variables. The Wilcoxon rank test was used to compare non-normally distributed variables. In addition, categorical data were compared using the chi-square test or Fisher’s exact test. Stepwise Cox regression analyses and prognostic model constructions were applied using the R package “survival”. A survival analysis was performed using a Kaplan–Meier analysis and log-rank test.The study was statistically analyzed using R language (version 4.1.3). The mean ± standard deviation was used to represent continuous normally distributed variables, and the interquartile range was used to represent non-normally distributed information. A student’s Data for a total of 712 pneumonia patients treated with glucocorticoids, encompassing 127 variables, were downloaded from DRYAD. A total of 368 patients with CTD pneumonia were selected, and 84 variables had missing values of less than 5%. After multiple interpolations to supplement missing values, 37 variables were selected for analysis. These included age, gender, fever, cough, expectoration, chest pain, dyspnea, heart rate, respiratory rate, systolic pressure, diastolic pressure, cyanosis, CAP, bronchiectasia, interstitial lung disease, coronary heart disease, congestive heart failure, diabetes mellitus, anemia, white blood cells, neutrophils, lymphocyte, hemoglobin, platelets, aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, serum creatinine, K, Na, oxygen inhalation, high-dose glucocorticoid, immunosuppressant, ganciclovir, sulfanilamide, anti-aspergillus, and anti-pseudomonas. Patients were randomized into two parts, with 247 patients in the training cohort and 121 patients in the validation cohort. The groups were comparable at baseline except for the need for sulfanilamide treatment  with a significant impact on mortality . This stWe used two machine learning algorithms to obtain prognostic variables. Shiroshita et al. found low predictive performance when they used a single machine learning algorithm to construct a model for predicting in-hospital mortality in patients with chronic obstructive pulmonary disease pneumonia exacerbations . Ma et aPseudomonas aeruginosa bloodstream infections in children showed that Pseudomonas aeruginosa bloodstream infections occur mainly in immunocompromised patients and are associated with high mortality  are prognostic risk factors for CTD pneumonia patients. Fever is a regulated increase in body temperature caused by the upward shift of the thermoregulatory point due to the action of a thermogenic source. Studies have reported that a longer duration of fever is a risk factor for poorer prognosis in children with severe adenovirus pneumonia . An analortality . Our stuIn this study, a nomogram was created based on these independent risk factors. This study had some advantages over the PSI and the CURB-65. First, the model in this study did not include the age variable, which has stronger applicability than the PSI or the CURB-65. Second, the subjects of this study were patients with pneumonia using glucocorticoids or/and immunosuppressants for CTD. Compared with PSI and CURB-65, this model is suitable for specific populations. However, this study also has some limitations. First, this study was validated using an internal validation cohort and the results have not been further confirmed using an external validation cohort, and caution is needed in clinical use. Furthermore, this study was based on data collected from six hospitals in China, and the applicability of the model to Western cohorts needs further confirmation.This study developed a nomogram based on five variables to predict 90-day mortality in patients with CTD combined with pneumonia treated with glucocorticoids or/and immunosuppressants. The nomogram performed well in predicting 90-day mortality in patients with pneumonia.The original contributions presented in the study are included in the article/Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.Q-GL and JL conceived and designed the study. DL and LD performed the statistical analyses and wrote the manuscript text. Q-GL revised the manuscript. All authors contributed to and review the manuscript. All authors contributed to the article and approved the submitted version.


Sodium‐glucose co-transporter 2 (SGLT2) inhibitors have recently emerged as an effective means to protect kidney function in people with type 2 diabetes and chronic kidney disease (CKD). In this review, we explore the role of SGLT2 inhibition in these individuals. SGLT2 inhibitors specifically act to inhibit sodium and glucose reabsorption in the early proximal tubule of the renal nephron. Although originally developed as glucose-lowering agents through their ability to induce glycosuria, it became apparent in cardiovascular outcome trials that the trajectory of kidney function decline was significantly slowed and the incidence of serious falls in kidney function was reduced in participants receiving an SGLT2 inhibitor. These observations have recently led to specific outcome trials in participants with CKD, including DAPA-CKD, CREDENCE and EMPA-KIDNEY, and real-world studies, like CVD-REAL-3, that have confirmed the observation of kidney benefits in this setting. In response, recent KDIGO Guidelines have recommended the use of SGLT2 inhibitors as first-line therapy in patients with CKD, alongside statins, renin–angiotensin–aldosterone system inhibitors and multifactorial risk factor management as indicated. However, SGLT2 inhibitors remain significantly underutilized in the setting of CKD. Indeed, an inertia paradox exists, with patients with more severe disease less likely to receive an SGLT2 inhibitor. Concerns regarding safety appear unfounded, as acute kidney injury, hyperkalaemia, major acute cardiovascular events and cardiac death in patients with CKD appear to be lower following SGLT2 inhibition. The first-in-class indication of dapagliflozin for CKD may begin a new approach to managing kidney disease in type 2 diabetes. At least half of all adults with type 2 diabetes (T2D) have comorbid chronic kidney disease (CKD), with either an elevated urinary albumin excretion rate (uAER) and/or a reduced estimated glomerular filtration rate (eGFR) , 2. T2D Sodium‐glucose co-transporter 2 (SGLT2) inhibitors have recently emerged as an effective means to protect kidney function in patients with T2D. Although SGLT2 inhibitors achieve urinary glucose wasting and were initially developed as glucose-lowering agents for the treatment of T2D, this represents only one of their potential indications. During recent large cardiovascular outcome trials (CVOTs), it was observed that SGLT2 inhibitors may also have additional benefits for preventing the development and progression of CKD in people with T2D beyond what could be expected from glucose lowering alone , 7, 8. SIn this narrative review, we explore the potential role of SGLT2 inhibition in individuals with T2D and CKD or who are at risk of developing CKD. We examine recent clinical trial data and observational evidence following treatment with SGLT2 inhibitors in patients with T2D and CKD, with a focus on their effects on kidney function, cardiovascular (CV) and HF outcomes and safety in this often-challenging setting. As a narrative review, this publication is based on non-systematic searches of PubMed and the authors’ own expertise and knowledge of the relevant literature, without following a specific protocol or set of predetermined inclusion and exclusion criteria.By the time that patients with T2D develop impaired kidney function, there has already been a significant and irreversible loss of nephron mass, which makes a return to normal kidney function impossible, while placing extra functional demands on the remnant kidney that further accelerate kidney function decline, even if the risk factors that established the initial nephron damage are subsequently well controlled. Identifying those individuals at risk of losing kidney structure and function before it is irreversibly gone can be practically achieved by the following:2/year (e.g. their eGFR has gone from 80 mL/min/1.73 m2 to 70 mL/min/1.73 m2 in 3 years) are likely to be at increased risk of developing impaired kidney function.Carrying out serial monitoring of the eGFR: those individuals  who are losing more than 3 mL/min/1.73 mEstimating the urinary albumin to creatinine ratio (uACR): those individuals with a uACR > 30 mg/g, and especially >300 mg/g, are at increased risk of developing impaired kidney function.Identifying individuals experiencing other complications of T2D , erectile dysfunction) who are also at increased risk of developing CKD because of the field nature of end-organ damage in T2D.Noting individuals with poor control of their T2D, blood pressure, lipid levels and/or weight are also at increased risk of developing CKD because each of these factors contributes to kidney function decline.Recognizing that certain ethnic groups  and disadvantaged populations also have an increased risk of developing T2D and CKD.Understanding that individuals with a strong family history of CKD and kidney failure are at increased risk of developing CKD and impaired kidney function, particularly with the development of T2D.In each of these settings, the early initiation of multifactorial interventions to slow the decline in kidney function and reduce the development of impaired kidney function (detailed later) should be strongly considered. Other (low-risk) individuals should continue to be monitored on a regular basis for the development of risks or signs of progressive kidney function decline. Some individuals will also have a personal preference for a more proactive approach to their management, including protection of their kidney function even if it currently appears normal .2)), a diagnosis of CKD should be confirmed by repeat testing   . Intensie (ESKD) . This ste (ESKD)  15). Wh. Wh2/yeae (ESKD) . In addie (ESKD) .Figure Blockers of the renin–angiotensin–aldosterone system (RAAS), such as angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists and mineralocorticoid receptor antagonists also have additional benefits in the kidney beyond simply lowering blood-pressure levels, particularly in patients with severely elevated albuminuria or impaired kidney function , 21, 22.People with CKD are at increased risk of kidney failure, CVD, HF, infections, hospitalization and premature mortality . The mos2, the greater the risk of poor health outcomes. Although the association between eGFR and outcomes is clearly continuous in nature  , 38, theFour large randomized controlled trials, each conducted against a backdrop of the standard of care, have been recently undertaken in participants with established CKD, some or all of whom also had T2D (Supplementary Table 1).P < 0.01). At adjudication, the relative risk of the composite primary outcome  was 30% lower in the participants receiving canagliflozin . The key secondary kidney outcome  was also reduced by 34% , and the relative risk of ESKD was lowered by 32%  with canagliflozin treatment compared with placebo , meaning that all participants were at high risk of developing kidney failure. The DAPA-CKD trial was also stopped early because of clear evidence of benefit at a prespecified interim analysis. The primary composite outcome  was reduced by 39% in participants receiving treatment compared with placebo (The Dapagliflozin and Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD) trial was undertaken in participants with established CKD, who were randomized to receive the SGLT2 inhibitor, dapagliflozin or placebo on top of standard of care. Approximately 68% of participants also had T2D , 45. Mos placebo . Specifi placebo .2/year vs placebo: −3.84 mL/min/1.73 m2/year, equating to a 59% reduction in the rate of eGFR; The secondary kidney-specific composite outcome  was also reduced by 43% in participants with T2D treated with dapagliflozin  and kidney failure was reduced by 30%  . The ratIn participants without T2D (i.e. with non-diabetic kidney disease) enrolled in the DAPA-CKD trial, the primary and secondary composite outcomes were also significantly improved and essentially no different from diabetic individuals . Notably2) (P < 0.001). The MACE outcome  was also reduced , as was the composite outcome of death from CV causes or hospitalization for HF  (2) was reduced by sotagliflozin but failed to reach significance  with a low number of events limiting the power of the trial. The decline in eGFR was also stalled by sotagliflozin, while kidney function declined in the placebo group (sotagliflozin 0.09 mL/min/1.73 m2/year vs placebo −1.31 mL/min/1.73 m2/year)  . Althoug66–0.91) . The comm2/year) .P < 0.001) (P = 0.003) was also reported. Finally, the rate of decline in eGFR was significantly slowed following treatment with empagliflozin, with activity in all subgroups including participants without severely elevated albuminuria  . Reductiuminuria .A recent meta-analysis incorporating all 13 placebo-controlled trials with SGLT2 inhibitors involving over involving 90,000 participants and using a standardized outcome definition for kidney disease progression  concluded that treatment with an SGLT2 inhibitor reduced the risk of kidney disease progression by 37%  (P = 0.0019) in participants receiving an SGLT2 inhibitor  . In particular, recent CVOTs undertaken in patients with T2D and established CVD/high CV risk  included some individuals with established CKD , 53, 54.nhibitor , 56. In nhibitor , 58. Alt system) , 58. AltP < 0.002), 40%  or 50%  to an eGFR < 60 mL/min/1.73 m2 with dapagliflozin compared with placebo. In addition, the rate of decline of eGFR (between day 14 and day 720) was significantly reduced with dapagliflozin treatment compared with placebo, as was the risk of the doubling of serum creatinine, a marker of kidney decline. Importantly, the effect of dapagliflozin on eGFR decline was independent of T2D status.Evidence for the kidney-protective effects of SGLT2 inhibitors is further supported by consistent benefits observed in trials undertaken in patients with established HF. Of course, many of these trials included individuals with CKD because HF is a risk for CKD and vice versa. In addition, in this subgroup with CKD, the greatest absolute benefits were observed. For example, the DAPA-HF trial tested dapagliflozin, on top of the standard of care, in participants with chronic HF with reduced ejection fraction (HFrEF) . In thisP < 0.01) in the EMPEROR-Reduced trial , again including half with diabetes and half with established CKD , 59. In 2, 95% CI 1.34–1.72, P < 0.0001) and that, during follow-up (mean 14.9 months), patients taking SGLT2 inhibitors had a significantly lower rate of the composite kidney outcome (50% eGFR decline or kidney failure). These results were consistent across countries and prespecified subgroups  when starting new medications . This of2 , although these symptoms are often mild and manageable with appropriate patient education and support . DiminisP < 0.0001)  . Consist 0.0001) , and in  0.0001) . Whetheret al., severe complications were rarely reported, with too few cases of Fournier’s gangrene to estimate risk ratios . For example, in the EMPA-REG OUTCOME trials over 30% of women in the placebo group experienced a UTI. However, this was not increased by using an SGLT2 inhibitor. The meta-analysis from Staplin hibitors . Similarhibitors . Even inEuglycaemic ketoacidosis is a rare, but potentially life-threatening, complication of SGLT2 inhibition . In peopet al., there were 159 ketoacidosis events, with the risk of a ketoacidosis event found to be approximately doubled in patients treated with an SGLT2 inhibitor compared with placebo, albeit off a very low baseline risk  . Overalline risk . No episine risk .This risk for ketoacidosis can be simply mitigated by not using SGLT2 inhibitors in individuals with type 1 diabetes and ensuring that insulin doses are not omitted in insulin-treated patients with T2D. In addition, patients receiving SGLT2 inhibitors should be educated to pause therapy if they are not eating and drinking for long periods (e.g. they have gastroenteritis or prior to surgery) or they are unwell (e.g. they have flu COVID-19 or sepsis) , 82, 83.P = 0.014)  . Indeed,= 0.014) .et al. showed that the use of SGLT2 inhibitors actually reduced the relative risk of severe hypoglycaemia by 13% compared with placebo (2), it is seldom necessary to alter background glucose-lowering therapies when adding an SGLT2 inhibitor. Non-diabetic individuals treated with an SGLT2 inhibitor do not experience hypoglycaemia for the same reasons, and similarly, hypoglycaemia is not an issue for people with benign familial glycosuria; a genetic condition due to a mutation in SGLT2.SGLT2 inhibitors lower blood glucose levels by causing urinary wasting of glucose. This mechanism is dependent on blood glucose levels and kidney function such that, if blood glucose levels return to the normal range, glycosuria is minimal. For this reason, these agents do not cause hypoglycaemia as monotherapy. In fact, the meta-analysis by Staplin  placebo . This isFoot disease in people with diabetes increases the risk of ulceration and lower-limb amputation. This risk is highest in people with T2D and CKD because the same processes that damage the kidneys also damage the nerves and vasculature supplying the feet. In the CANVAS Program, it was reported that the risk of lower-limb amputation was increased with canagliflozin treatment compared with placebo, especially in the first few months of treatment . The subBone fractures are a common and serious condition in older adults. Treatment of adults PPAR gamma agonists (e.g. pioglitazone) is associated with a significantly increased risk of major bone fractures. In the CANVAS Program, a potential signal for fracture risk was observed early in the study . However2 (2 (2 (When SGLT2 inhibitors were first developed, their use was contraindicated in patients with impaired kidney function. This was because of the attenuated glucosuria in this setting and limited or no effects on blood glucose levels. Obviously, avoidance of SGLT2 inhibition in this setting has changed with the trial data detailed above demonstrating clear benefits for both kidney and cardiac outcomes in people with CKD, regardless of diabetes status. Currently, most guidelines recommend SGLT2 initiation down to an eGFR of 30 mL/min/1.73 m2 , 26. The2 (2 . Recent 2 (2 (2 , 26. Shode novo admission for HF is reduced in patients using SGLT2 inhibitors. Future research is likely to investigate whether SGLT2 inhibitors can be used to prevent the development of CKD in people with diabetes (SGLT2 inhibitors have rapidly become first-line agents for the management of T2D complicated by CVD, by or CKD. However, for most of these patients, it is too late to restore normal organ function. The next important question is whether the early initiation of SGLT2 inhibitors will be able to prevent or slow the loss of function in the first place. Certainly, diabetes , 90, 91.diabetes . Indeed,diabetes , 92. SucYet, despite these clear data, SGLT2 inhibitors remain seriously underutilized in clinical practice. Less than 10% of those with T2D and CKD are receiving SGLT2 inhibitors and even fewer in those with established CVD , 94. At MCT has received honoraria for educational meetings performed on behalf of Boehringer Ingelheim, Lilly, MSD, Novartis, AstraZeneca, Mylan, Sanofi, & Servier; has received support from Boehringer Ingelheim; and has been an advisory board member for MundiPharma, AstraZeneca and MSD. MCT is a steering committee member for ‘Across Type 2 Diabetes’ and ‘Across CKD’ sponsored by Boehringer Ingelheim & Eli Lilly and Company Alliance. BLN has received fees for advisory boards, scientific presentations, steering committee roles and travel support from AstraZeneca, Bayer, Boehringer Ingelheim and Janssen, with all honoraria paid to his institution. SMT has attended advisory boards and received speaking fees from AstraZeneca, Abbott Diabetes Care and Nevro. MEC has received honoraria for educational symposia conducted on behalf of Boehringer-Ingelheim, Lilly, AstraZeneca, Abbott, Servier, Novartis, Sanofi, Bayer and MSD; has received support to attend and participate in advisory boards for Boehringer Ingelheim, Lilly, Bayer, Intarcia, MundiPharma and AstraZeneca; and has received research funding from Boehringer Ingelheim and Novo Nordisk. SVB has received speaking fees from Bayer, Pfizer and Vifor Pharma; has attended advisory boards for AstraZeneca, Bayer and Vifor Pharma; and has received non-financial research support from Bayer. All honoraria received were paid to SVB’s institution.AstraZenecahttp://dx.doi.org/10.13039/100004325.Editorial support was provided by Emily Manktelow, PhD, of Oxford PharmaGenesis, Melbourne, Australia, and this support was funded by


Despite significant pharmacological advancements, hypertension management remains challenging, with varying quality of primary care. Digital tools and other non-pharmacological interventions hold promise in addressing this challenge. Consequently, a thorough examination of these interventions is recommended. This meta-analysis focuses on clinician-oriented strategies aimed at improving hypertension management, to assess the most effective approaches for improving antihypertensive prescribing and blood pressure control for secondary prevention. This was done through a systematic review of randomized controlled trials published in PubMed and Embase since the beginning of 2010 that aimed to enhance antihypertensive medication prescription in primary care settings for hypertensive patients with secondary complications while reporting changes in blood pressure or target achievement. We screened 6305 records. Four studies met the inclusion criteria, with reported interventions including physician education and the implementation of electronic decision support systems. All studies showed that the control group had a statistically significant lower systolic blood pressure, but the effect on diastolic blood pressure was not statistically significant. The overall mean difference was 2.12 mmHg  for systolic blood pressure in favor of the control group and 1.22 mmHg  for diastolic blood pressure, which was not statistically significant. Despite considerable efforts to control hypertension, it remains a significant obstacle to optimal cardiovascular risk reduction. This review is also limited by a scarcity of studies. Hypertension, often referred to as the "silent killer," continues to loom ominously in the realm of contemporary medical challenges. the high prevalence of hypertension, coupled with its associated comorbidities and mortalities, is a major public health challenge that modern medical science endeavors to combat. In this persistent pursuit, the early identification and proactive intervention for hypertensive individuals, as well as those predisposed to its development, remain one of the cornerstones of public health endeavors . Over thTaking the forefront against this debilitating disease are primary care centers and the dedicated cohort of primary care physicians. As evidenced by studies conducted in developed countries, a staggering 90% of the adult population engages with their primary care physician at least once annually, underscoring the pivotal role these healthcare professionals play in both hypertension prevention and treatment programs . HoweverNon-pharmacological approaches offer a promising path for hypertension management. These methods focus on improving care by primary care physicians and on enhancing patient education and lifestyle choices ,6. CompuHypertension is associated with several serious complications. These include renal disease, which can lead to kidney damage or failure; all-cause mortality, indicating an increased risk of death from various causes; stroke, a sudden disruption of blood flow to the brain; combined cerebrovascular disease (CVD), encompassing conditions like angina and myocardial infarctions; combined coronary heart disease (CHD), indicating a broad range of heart and blood vessel-related issues ,6. ManagA systematic review by Fahey et al. has meticulously investigated the potency of educational and organizational interventions in hypertension control. Their findings resonate in highlighting that systematically designed platforms for continuous assessment of antihypertensive regimens have resulted in noteworthy reductions in blood pressure levels . ConversMaterials and methodsA systematic review and meta-analysis were conducted as per the Preferred Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines .Eligibility CriteriaWe included randomized controlled trials published from 2010 onwards that compared new interventions to routine care for optimizing blood pressure (BP) control in primary care settings for hypertensive patients with secondary complications. We excluded studies where interventions solely focused on patients’ education or involved community health workers. Additionally, we excluded studies that focused on telemedicine, collaboration with specialists, pay-for-performance, or home blood pressure monitoring. Studies that involved pregnant patients, active controls, or did not report blood pressure change or control were also excluded. Healthcare delivery and feasibility studies were not eligible for this study.Primary OutcomeThe primary outcome is to identify interventions that can optimize blood pressure control for hypertensive patients with secondary complications in primary care settings, compared to usual care.Literature Search StrategyThe databases used in this systematic review are MEDLINE and Embase through the OVID platform. Citation tracking from the 2010 Cochrane review that evaluated the interventions to improve antihypertensive medication prescribing was conducted [Selection of StudiesThe title and abstract of articles identified from the literature searches and citation tracking were assessed independently by four authors. The full texts of relevant articles reports were retrieved and those articles that met the eligibility criteria were selected. A fifth author adjudicated where authors who screened the articles disagreed on a report’s eligibility.Data Extraction and ManagementThe data extraction form was based on the Cochrane data collection form for intervention reviews. The data extraction spreadsheet followed Cochrane’s data collection form for intervention reviews. The data extraction form was tested against randomly selected articles and adjusted accordingly. The two authors independently assessed the risk of bias in randomly selected articles using Cochrane's risk of bias tool for randomized controlled trials. A third author resolved any disagreements. The data extraction form included study-related data, baseline characteristics, the outcome of interest data as well as our assessment of their risk of bias. The study-related data included first author, year of publication, the country where the study was conducted, journal in which the study was published, study design, study size, the clinical condition of the study participants, type of intervention and comparison. Baseline characteristics included participants' age, gender, ethnicity, systolic blood pressure (SBP) and diastolic blood pressure (DBP), and the percentage of controlled blood pressure at the beginning of the study. The outcome of interest data included SBP and DBP post-intervention, mean change in their respective mean as well as the percentage of controlled blood pressure at the end of the study.Data SynthesisReview Manager 5.4.1 software and Robvis, a web-based application for visualizing risk of bias assessment, were used for data synthesis. We used a random effects model to analyze the data. We reported the results as mean SBP and DBP post-intervention using a Forest plot for the four meta-analyzable studies.Assessment of Heterogeneity2). The I2 statistic was calculated to quantify the inconsistency between the studies. The I2 statistic is a measure of the proportion of the total variability in the effect estimates that is due to heterogeneity rather than sampling error. Cochrane’s guide was used for (I2) interpretations. The guide suggests that heterogeneity values between 0% and 40% might not be of importance and considers (I2) values between 75% and 100% as a considerable heterogeneity range. However, the guide states that (I2) is reliant on the magnitude and direction of effects as well as the strength of heterogeneity evidence and hence (I2) should be interpreted while considering these factors [Heterogeneity was assessed using the Cochrane Q test :This is a cluster randomized controlled trial conducted in Belgian primary care practices between 2017 and 2018. The study investigated the effectiveness of an evidence-based medicine electronic decision support system in controlling hemoglobin A1C (HbA1C), low-density lipoprotein (LDL) cholesterol, and blood pressure compared to usual care. At the end of the study, the data of 3815 of the participants was analyzed .Jafar et al. (2015):This is a multi-center randomized controlled trial conducted in Pakistan. The study investigated the effect of GP education on blood pressure control in patients with hypertension, using the British Hypertension Society guidelines for the Indo-Asian population and the Joint National Committee's seventh report. The intervention continued for two years, and the sustainability of the effect was assessed five years after the study. At the end of the seven years, the data of 632 patients was analyzed. The other two intervention groups were excluded from the review because they met the exclusion criteria .Johnson et al. (2011):This is a randomized controlled trial conducted in the USA and compared physician education, patient education, and combined physician and patient education to usual care in African Americans with hypertension. The patients were followed up for six months. The data of 235 patients from the physician education and usual care arms was analyzed. The data from the other two arms was excluded because they met the exclusion criteria .Pouchain et al. (2013):This is a multi-center randomized controlled trial conducted in France. The trial recruited patients with hypertension and followed them up for 24 months. The study compared the effect of usual care and GP education on the ability of patients to reach the therapeutic targets recommended by the French guidelines. Patients who did not reach the target were followed up for an additional six months. The general practitioners were also provided with a six-page leaflet summary of therapeutic targets and patient encouragement strategies which is to be kept by the general practitioners on their office desks. The outcome of 1832 patients were reported at the end of the study .Changes in BP Control2=0%, P-value= 0.49) in terms of SBP. Figure 2=45%, P-value= 0.14) in terms of DBP.We assessed how different interventions can help optimize both systolic and diastolic blood pressure control. Figure Following the use of the Cochrane risk assessment tool for randomized controlled trials, half of the studies had a low risk of bias overall. The other half had an unclear risk of bias. Furthermore, the studies included had a common feature of either having unclear or high risk of bias in terms of allocation concealment. However, they all had low risk of bias in terms of incomplete data reporting and selective reporting, as shown in Figure DiscussionThe four studies included in this review showed an unexpected result of lowering SBP in the control groups. This might be explained by the differences in recommendations specifying the choice of anti-hypertensive medications, which primarily target improving comorbidity-specific parameters rather than blood pressure numerical targets . For exaThere is also the proposition of the need to implement both interventions to control blood pressure and the accompanying secondary complications, such as chronic kidney disease and heart failure, in order to achieve numerical blood pressure targets. This is supported by the fact that diabetes and hypertension pathophysiology and metabolic pathways intertwine at insulin resistance where the glucose deposition in small blood vessel walls at the collagenous layers can reduce the elasticity of the blood vessels and smooth muscle cell proliferation and thus increase blood pressure . FurtherThe evidence presented here suggests that we need to research interventions that target hypertension and its secondary complications in order to reach lower blood pressure targets and thus lower all-cause mortality and major adverse cardiovascular events (MACE). This study has a limitation in that it only looked at blood pressure control in patients who already had secondary complications, rather than preventing them from developing in the first place.In our systematic review and meta-analysis, the interventions aimed at optimizing blood pressure control for secondary prevention in primary care settings were less effective than traditional care. We found that traditional care was better at lowering systolic blood pressure than the interventions, while the difference in diastolic blood pressure was not statistically significant. Our study was limited by the small number of studies that targeted secondary prevention and hence the inability to generalize whether a particular physician-focused intervention is superior to routine care or not. More research is needed to determine the effectiveness of interventions for secondary prevention of hypertension.


Assessment of central blood pressure (BP) has grown substantially over recent years because evidence has shown that central BP is more relevant to cardiovascular outcomes than peripheral BP. Thus, different classes of antihypertensive drugs have different effects on central BP despite similar reductions in brachial BP. The aim of this study was to investigate the effect of nebivolol, a β-blocker with vasodilator properties, on the biochemical and hemodynamic parameters of hypertensive patients.  Experimental single cohort study conducted in the outpatient clinic of a university hospital.  Twenty-six patients were recruited. All of them underwent biochemical and hemodynamic evaluation , central BP and augmentation index) before and after 3 months of using nebivolol. 2) with large abdominal waist (102.1 ± 7.2 cm). There were significant decreases in peripheral systolic BP (P = 0.0020), diastolic BP (P = 0.0049), HR (P < 0.0001) and central BP  after treatment, in comparison with the baseline values. There was no statistical difference in the augmentation index or in the biochemical parameters, from before to after the treatment.  88.5% of the patients were male; their mean age was 49.7 ± 9.3 years and most of them were overweight (29.6 ± 3.1 kg/m Nebivolol use seems to be associated with significant reduction of central BP in stage I hypertensive patients, in addition to reductions in brachial systolic and diastolic BP.  In recent studies, nebivolol was shown to improve artery stiffness to a greater extent than older β-blockers. It has been shown to have vasodilation properties in humans and animals.The aim of this study was to analyze the 12-week effect of nebivolol treatment on hemodynamic , central BP and augmentation index) and biochemical parameters in stage I hypertensive patients without previous treatment.A total of 33 patients from our outpatient hypertension clinic who were interested in entering the study were initially screened for eligibility; among these, seven did not satisfy the inclusion/exclusion criteria. Thus, the sample for participation in this single-group prospective cohort study was composed of 26 stage I hypertensive patients. Stage I hypertension was defined as systolic BP ≥ 140 and < 160 mmHg and/or diastolic BP ≥ 90 and < 100 mmHg. Subjects presenting age < 18 years, hypertensive patients treated previously, obesity, alcohol abuse, current corticosteroid treatment, history of asthma, peripheral vascular disease, chronic kidney disease, secondary hypertension, unstable angina or previous myocardial infarction, previous stroke, heart failure, atrioventricular block, bradycardia < 50 bpm, pregnancy, uncontrolled diabetes mellitus or insulin therapy, neoplasia, history of drug abuse or any other clinical conditions associated with poor prognosis were excluded.Eligible participants visited our clinical research laboratory at 7:00 am after a 12-hour fast, to undertake the protocol procedures. Anthropometric variables were measured and blood was sampled for the lipid profile and routine laboratory parameters . LDL-cholesterol was calculated using the Friedewald formula.Treatment with nebivolol started after confirmation of the inclusion criteria. The patients received nebivolol at a dose of 5 mg/day. Follow-up visits for BP measurements, physical examination and study medication dispensation were made every month. The study participants' adherence to the therapy administered was assessed at the follow-up visits by means of tablet counts. At the end of the study (three months), the baseline measurements were repeated for all of the 26 patients evaluated initially. Peripheral BP at the level of the brachial artery was measured in the seated position after a ten-minute rest, using a mercury sphygmomanometer and cuffs with bladder size encircling at least 80% of the upper-arm circumference and covering two-thirds of the upper-arm length.18 Brachial BP was measured in both arms, and if there was a difference in BP levels between the two arms, the measurements in the arm with the higher BP were taken into account. Three BP measurements with at least a one-minute interval between them were obtained, and the mean of the three measurements was recorded. Phase I and V Korotkoff sounds were recorded for systolic BP (SBP) and diastolic BP (DBP), respectively.Central blood pressure and augmentation index ,Arterial pulse waveforms from the left radial artery were measured noninvasively by means of an automated tonometry system , after the participants had rested in a seated position for 10 minutes. Pulsewave analyses were performed at least three times and the mean of the measurements was calculated. The radial arterial waveforms from this device were used to calculate the augmentation index (AIx). The first systolic peak (SBP1) and the late (second) systolic peak (SBP2) were automatically identified using the fourth-derivative wave as the second and third zero crossing points, respectively. The augmentation index (AIx) was defined as the ratio of the height of SBP2 to that of SBP1. The brachial BP and heart rate (HR) were measured simultaneously in the right brachial artery using an oscillometric device incorporated in the HEM-9000 AI device. Late systolic BP in the radial artery, as an index of central BP, was calculated using the following equation: rSBP2 = r-AIx.  + brachial diastolic BP. The HR-adjusted augmentation index (AIx(75)) was calculated by adjusting AIx at an inverse rate of 4.8% for each ten-beats-perminute increment in heart rate. All measurements were performed by a single examiner, after the subject had fasted for at least eight hours, both before and after three months of nebivolol use.A power analysis calculation was conducted using the site http://www.lee.dante.br/pesquisa/amostragem/calculo_ amostra.html. Assuming an error of 0.01 and a study power of 80%, the calculated size of the sample required in order to reject the hypothesis of nullity was 23.Descriptive analysis was performed for qualitative variables, and quantitative results are presented as means ± standard deviations. The Wilcoxon test was used to compare quantitative variables before and after treatment with nebivolol, among these stage I hypertensive patients without previous treatment. All statistical analyses were performed using the Minitab 15.0 statistics software. For all tests, a P-value < 0.05 was considered significant.This study was approved by the Research Ethics Committee of the Medical School and was registered under no. 312/2008. The study protocol was approved by the National Ethics Committee (CONEP-372/2007). Informed consent was obtained from all participants, in relation to both the treatment and the biochemical and hemodynamic evaluation.2) and had large abdominal waist circumference (102.1 ± 7.2 cm). Significant decreases in systolic BP  and diastolic BP  were observed during the treatment with nebivolol, and these were associated with decreases in heart rate  and central BP   with a mean age of 49.7 ± 9.3 years, who were predominantly overweight (29.6 ± 3.1 kg/m 0.0083) . There wIn the present study, we examined the 12-week effect of nebivolol on biochemical and tonometry parameters among stage I hypertensive patients without previous treatment. To our knowledge, this is the first study on Brazilian individuals to evaluate the beneficial effects of nebivolol on the hemodynamic profile, and it showed worthwhile reductions in peripheral and central blood pressure.This study investigated in detail the potential effects of nebivolol, a beta-1 selective beta-blocker, on aortic stiffness, wave reflections and central hemodynamic parameters in patients with mild hypertension that had never been treated. In this study, nebivolol significantly reduced brachial and central BP, even though the AIx remained unchanged. ,,,Brachial BP measurement is considered to be the best method for screening for and diagnosing clinical hypertension. However, over recent years, assessment of CV risk in subjects with hypertension has led to development of more sophisticated methods of BP measurement, such as central BP.,,Regarding CV complications, when large-conduit arteries are healthy and compliant , the reflected wave merges with the incident wave in the proximal aorta mostly during diastole, thereby augmenting aortic DBP and supporting coronary perfusion. In contrast, when the arteries are stiff , wave travel is faster and the reflected wave merges earlier with the incident wave, thus augmenting aortic systolic rather than diastolic pressure. As a result, left ventricular afterload is increased and coronary filling is compromised. This pathophysiological mechanism supports the idea that central BP is superior to peripheral BP for predicting CV risk and that it acts on CV risk independently of atherosclerosis and other traditional CV risk factors.The choice of drug treatment for hypertension is also influenced by wave reflections: both by their amplitude (i.e. the proportion of the incident wave which is reflected) and by their timing. Acutely, vasodilator drugs reduce the amplitude of wave reflections and hence SBP.-,,,,It is well accepted that calcium channel blockers and drugs acting on the RAS improve endothelial function and arterial stiffness.Our results, along with other recent findings, support the conclusion that nebivolol has vascular effects that are more favorable than those of first and second-generation β-blockers. In a double-blind randomized study comparing nebivolol and metoprolol, Kampus et al.Studies on Caucasian and African-American subjects have suggested that the less effective central blood pressure control and consequently lower cardiovascular protection with older β-blockers may be due to an adverse effect from heart rate lowering on arterial wave reflection.The present study had several limitations. These included the duration of follow-up, lack of a control group and the study design. If the patients had been followed for a longer time, perhaps we would have observed changes in the AIx. The lack of a comparison group, in our viewpoint, was the main limitation of this study. The randomised, placebo-controlled, and double blind trial represents the gold standard in evidence based medicine. However, this does not invalidate the significant results of central BP reduction after 12 weeks of treatment with nebivolol. Although brachial BP remains the principal tool used for the clinical diagnosis and monitoring of hypertension, there is an increasing body of evidence demonstrating that central BP measurement may be a better prognostic marker for hypertension. Moreover, recent evidence suggests that some antihypertensive drugs can influence central BP more consistently than peripheral BP. This is especially true for agents acting on the RAS or calcium channel blockade, as well as newer β-blockers. Nevertheless, large prospective studies aiming to compare the predictive value of peripheral and central BP in the general population, as well as studies comparing the effectiveness of hypertension management based on peripheral BP measurements, compared with central BP measurements, are needed before algorithms based on central BP can be recommended for clinical practice.In summary, nebivolol presents a favorable effect as an antihypertensive drug with possible additional capacity to improve arterial stiffness by reducing central BP, a characteristic not exhibited by other β-blockers.