Background and Objectives: Kidney transplant recipients represent a unique population with metabolic abnormalities, altered nutritional and immune status, as well as an imbalanced regulation of adipocytokine metabolism. Leptin is a hormonally active protein mainly produced by fat tissue that modulates appetite, satiety, and influences growth, energy, and bone metabolism. There has been great interest in the role of this hormone in chronic kidney disease-related protein energy wasting; thus, a positive leptin correlation with body mass index and fat mass was confirmed. This study was designed to determine the association of pre and post-kidney transplant leptin concentration with nutritional status and body composition. Materials and Methods: We studied 65 kidney transplant recipients. Nutritional status was evaluated before kidney transplantation and 6 months later using three different malnutrition screening tools , Malnutrition Inflammation Score (MIS), and Geriatric Nutritional Risk Index (GNRI)), anthropometric measurements, and body composition ). Demographic profile, serum leptin levels, and other biochemical nutritional markers were collected. Statistical analysis was performed with R software. Results: Median age of the studied patients was 45 years, 42% were females, and 12% had diabetes. Leptin change was associated with body weight (p < 0.001), waist circumference (p < 0.001), fat mass (p < 0.001) and body fat percentage (p < 0.001), decrease in parathyroid hormone (PTH) (p < 0.001) transferrin (p < 0.001), diabetes mellitus (p = 0.010), and residual renal function (p = 0.039), but not dependent on dialysis vintage, estimated glomerular filtration rate (eGFR), or delayed graft function at any time during the study. After adjustment for age and sex, body mass index (BMI) (p < 0.001), fat mass (p < 0.001), and body fat percentage (p < 0.001) were independent variables significantly associated with post-transplant leptin change. Lower leptin values were found both before and after kidney transplantation in the SGA B group. GNRI as a nutritional status tool was strongly positively related to changes in leptin within the 6-month follow-up period. Conclusions: Kidney transplant recipients experience change in leptin concentration mainly due to an increase in fat mass and loss of muscle mass. GNRI score as compared to SGA or MIS score identifies patients in whom leptin concentration is increasing alongside an accumulation of fat and decreasing muscle mass. Leptin concentration evaluation in combination with BIA, handgrip strength measurement, and GNRI assessment are tools of importance in defining nutrition status in the early post-kidney transplant period. Kidney transplantation is a preferred renal replacement therapy for end-stage kidney disease (ESKD), providing a better health-related quality of life  and longLeptin is one of the major adipokines, first described as a biomarker of obesity two decades ago. Expression of leptin in visceral adipose tissue modulates appetite and satiety centers in the hypothalamus, influencing growth, energy, and bone metabolism. Emerging evidence suggests that leptin production is not limited to adipocytes, showing that skeletal muscle together with bone cells are also responsible for that . MoreoveNotably, serum leptin release occurs in the circadian cycle, reaching a peak at night and therefore a disruption of the circadian balance can indirectly affect leptin secretion, thermogenesis, and energy homeostasis ,10. As aPrevious studies highlighted an important role of the kidney as the major site of leptin removal from the circulation. Renal uptake of circulating leptin in normal kidney functions as compared to kidney failure accounts for 12% and 0%, respectively . ConversIn kidney transplant (KT) patients, leptin has been found to be associated with the estimated glomerular filtration rate (eGFR)  and grafA follow-up observational study was conducted in a tertiary care university hospital between January 2018 and December 2019. The primary aim of this study was to evaluate the association of serum leptin level and nutritional status in the relevant KTR population, alongside patient demographics, biochemical markers, and bioelectrical impedance analysis (BIA) parameters. This study was approved by the regional research ethics committee  and the research ethics committee of the hospital, and informed consent was obtained from all patients prior to enrollment in the study. Inclusion criteria were as follows: (1) undergoing hemodialysis (HD) > 3 months before KT; (2) age ≥ 18 years; and the (3) signed informed consent form. Exclusion criteria included patients with pacemakers; who were limbless; and patients who refused to participate in the study. The blood samples were collected into BD Vacutainer SST-II Advance serum separator tubes  by venipuncture after the overnight fast between 7:00 and 9:00 am. The samples for leptin and prealbumin were immediately centrifuged for 10 min at 1800 RCF (ambient temperature) and aliquoted serum was frozen at −20 °C until analysis. Samples for all other biochemical markers were centrifuged at the local clinical chemistry laboratory  and analyzed the same day. Laboratory analysis was performed before KT and 6 months later. The list of performed tests and their analytical methods are summarized in 2). Waist and hip circumferences in centimeters were measured using a measuring tape and the waist-to-hip ratio was calculated.The same nephrologist performed all anthropometric measurements for all participants. Height and post-dialysis weight were measured using an automatic scale with a sensitivity of 0.1 cm and resolution of 0.1 kg. BMI was calculated as the ratio between weight and height in meters squared (kg/mHandgrip strength (HGS) was evaluated using ahydraulic hand dynamometer  with a scale of strength of up to 100 kg. Maximum strength of the non-fistula dialysis arm or, if there was no fistula, on the dominant arm (because the arteriovenous fistula (AVF) is usually located in the non-dominant arm) was measured three times with an interval of 5 s between measurements and the highest recorded value was considered maximal grip strength. 2 and lean mass/height2 (kg/m2).Body composition including intracellular water (ICW), extracellular water (ECW), total body water (TBW), fat free mass (FFM), skeletal lean mass (SLM), skeletal muscle mass (SMM), body cell mass (BCM), bone mineral content (BMC), and phase angle (PhA) were estimated by multiple frequency BIA. Measurements were performed by using the portable body bioimpedance spectroscopy device InBody S10 . Fat mass index (FMI) and lean mass index (LMI) were calculated as the quotient of fat mass/heightAs there is still no specific or validated nutrition screening tool for chronic kidney disease, we have chosen to use the Subjective Global Assessment Scale (SGA) and Malnutrition Inflammation Score (MIS) that were administered through face-to-face interviews and have been previously reported to be applicable tools in this population .The Geriatric Nutritional Risk Index (GNRI) calculated from the serum albumin level and the ratio between ideal and actual body weight. GNRI does not require patient interviewing and therefore it was chosen as an additional nutrition measure. It has been shown to be an appropriate nutrition screening tool and prognostic predictor in the CKD population .t-test for normally distributed data or two–sample Wilcoxon test for non-parametric variables. Correlations of clinical parameters with serum leptin concentrations were evaluated by Pearson’s correlation test.The results were expressed as the mean ± SD and median values. Data were tested for normal distribution by Shapiro–Wilk statistics. Categorical variables were analyzed by a Chi-square test. Comparisons between patients were performed using the Student’s Leptin concentration change ‘∆leptin’ was calculated as: post-transplant leptin (6 months after kidney transplantation) concentration minus pre-transplant leptin concentration. Furthermore, multivariate forward stepwise regression analysis was conducted that evaluated the longitudinal change of ‘∆leptin’ adjusted for pre-transplant leptin concentration, age, sex, and its association with nutrition parameters and outcomes.p-values lower than 0.05 were considered statistically significant. Statistical analysis was performed using 3.3.2 version R commander .Out of 105 eligible recipients for deceased kidney transplantation (KTR), 65 subjects met the inclusion criteria and were enrolled in further analysis. Main pretransplant KTR characteristics are presented in p = 0.922; post-transplant r = 0.083, p = 0.514).Significant leptin level correlations with pre and post-transplant variables are listed in The comparison of pre-transplant and follow-up body composition measurement results, as well as nutritional and biochemical parameters, is presented in p = 0.010) and residual renal function , but not dialysis vintage or delayed graft function, were associated with leptin change after renal transplantation. Interestingly, GNRI as a nutritional status tool was strongly positively related to changes in leptin within the 6 months follow-up period.‘∆Leptin’  was signAfter conducting stepwise model selection using Bayesian information criterion (BIC), we identified independent variables significantly related to post-transplant leptin change .Nutritional issues are highly relevant in all phases of kidney diseases and even in kidney transplantation. Wasting and frailty are related to negative outcomes in kidney transplant recipients; however, post-transplant diabetes, obesity, and accelerated atherosclerosis have a major impact on the overall prognosis . Leptin We observed leptin concentration changes in concordance with a body composition shift, i.e., increase in visceral adiposity and fat mass, and with certain hormonal normalization, a decrease of PTH. These findings are in agreement with the studies of many other authors who clarified that leptin is mainly secreted into circulation from the adipose tissue and its concentration is positively associated with fat mass in both lean and obese individuals . FurtherKidney transplant recipients have usually a better nutritional status compared to dialysis patients not on a transplant waiting list. Based on all of the three used nutrition assessment tools , our patients had normal nutrition status or mild–moderate malnutrition. Only GNRI was related to leptin change largely due to the main constituents of this index, i.e., albumin and body weight, and due to the better performance in detecting sarcopenia . FurtherImmunosuppression regimen that includes the administering of glucocorticoids  could also be a significant factor in our cohort. Glucocorticoids play an important role in metabolic stress, especially in the early post-transplant period when doses are higher. They induce leptin mRNA in adipose tissues and lead to increased plasma levels of insulin, another leptin-inducing agent ,31. SomeLimitations of our study include the small sample size, the absence of a sex disaggregated analysis, and a case-matched control group. The main strengths include the fact that: this is an ongoing follow-up study analyzing the value of leptin concentration as an additional tool in the post-transplant nutrition status evaluation and our study used different nutrition assessment tools including questionnaires and bioelectrical impedance analysis.We confirm that ESKD patients undergoing kidney transplantation obtain early post-transplant changes in leptin concentration (adjusted to age and sex) mainly due to the shift in body composition, i.e., increase in fat mass and loss of muscle mass. The GNRI score as compared to the SGA or MIS score identifies patients in whom the leptin concentration is increasing alongside the accumulation of fat and decreasing muscle mass. Hence, we suggest that leptin concentration evaluation in combination with BIA, HGS measurement, and GNRI assessment are tools of importance in defining nutrition status in the early post-kidney transplant period. Further research elucidating the leptin interplay with muscle mass, hormonal changes, and nutrition after kidney transplantation is warranted.


Ultimately, the newly developed risk score included WHO functional class, 6-min walking distance, N-terminal brain natriuretic peptide concentrations, pericardial effusion, right atrial area, tricuspid annular plane systolic excursion, and fractional area change. Conclusion: Integrating right heart function assessed by echocardiography improves prediction of death or lung transplantation in PAH patients. Independent validation of this finding is warranted.Background: Right ventricular dysfunction is a major determinant of outcome in pulmonary arterial hypertension (PAH). We aimed to identify echocardiographic right heart parameters associated with adverse outcome and to develop a non-invasive, echocardiography-based risk score for PAH patients. Methods and Results: In 254 PAH patients we analyzed functional status, laboratory results, and echocardiographic parameters. We included these parameters to estimate all-cause death or lung transplantation using Cox regression models. The analyses included a conventional model using guideline-recommended variables and an extended echocardiographic model. Based on the final model a 12-point risk score was derived, indicating the association with the primary outcome within five years. During a median follow-up time of 4.2 years 74 patients died or underwent lung transplantation. The conventional model resulted in a C-Index of 0.539, whereas the extended echocardiographic model improved the discrimination (C-index 0.639,  Pulmonary arterial hypertension (PAH) is a rare and severe chronic lung disease, leading to right heart failure and premature death ,2. AlthoComprehensive risk assessment tools have been published in the last years, including a variety of clinical, functional, and hemodynamic variables ,6,7,8,9.Right ventricular (RV) dysfunction is a major determinant of outcome in PAH ,11, but The integration of right ventricular parameters into risk estimation in patients with PAH was identified as an opportunity to improve care by experts ,21. We tIn a retrospective cohort study, we consecutively included 254 patients diagnosed with PAH who presented to the outpatient clinic at the University Medical Center Hamburg-Eppendorf between 2010 and 2018. Diagnosis of PAH was based on current guidelines and resulted from right heart catheterization, requiring mean pulmonary arterial pressure ≥25 mm Hg and pulmonary arterial wedge pressure ≤15 mm Hg . The cohClinical, laboratory, pulmonary function, and echocardiographic data were collected. Clinical assessment comprised demographics, vital parameters, body mass index (BMI), and PAH-specific medication. Laboratory measurements included NT-proBNP, serum creatinine, and estimated glomerular filtration rate (eGFR) values. Functional assessment contained WHO functional class, a standardized 6-min walk test, and pulmonary function testing, including lung diffusion capacity for carbon monoxide (DLCO) and forced vital capacity (FVC).According to the local regulations, written informed consent was not necessary for retrospective data collection , however all data were anonymized and compiled according to the requirements of the local ethics committee and the Declaration of Helsinki. The data underlying this article will be shared on reasonable request to the corresponding author.Transthoracic echocardiograms were performed at baseline by experienced examiners using a Philips echocardiography machine . Image analyses were conducted by dedicated software . A second investigator evaluated the results for accuracy to enhance validity of the results. Echocardiographic variables comprised RA area, RV chamber diameters , peak tricuspid velocity, vena cava inferior (VCI) diameter, and pericardial effusion. RV function was evaluated by measuring fractional area change (FAC), TAPSE, and 2-dimensional RV speckle-tracking strain. To obtain accurate 2-dimensional speckle-tracking analyses, we only used images with a frame rate≥50 frames per second and sufficient demarcation of the RV free wall . For theThe primary endpoint was a composite of all-cause death and lung transplantation in the mid-term follow-up, with censoring after lung transplantation. All patients were regularly assessed in our outpatient department every 3 to 6 months and followed-up for the occurrence of the endpoints via the electronic patients record system of the hospital. Patients were excluded from the analyses if they presented as in need of urgent care with a life expectancy of less than one month.Continuous variables were described as mean ± standard deviation (SD), if normally distributed or median , if non-normally distributed and categorical variables as absolute numbers (percentages). Sex differences were examined using ANOVA, Mann-Whitney U, or χ2 test. We performed complete case analyses .p-value of <0.05). In sensitivity analyses we also adjusted for all other significant clinical variables from the univariable model.Univariable analyses were performed to investigate the association of clinical, laboratory, functional, and echocardiographic parameters with the primary outcome. To explore the predictive value of echocardiographic parameters, we performed multivariable Cox regression analyses, adjusting for established risk predictors from the 2015 ESC/ERS guidelines for PH [Based on this, we derived four different multivariable prediction models: A conventional model (Model 1) only including established predictors used in the 2015 ESC/ERS guidelines for PH, an echocardiographic model (Model 2) adding further echocardiographic parameters, and two clinical models (Models 3 and 4) adding other clinical predictors that were significant in the univariable analyses. Hazard ratios (HR) and confidence intervals (CI) for each predictor were given. To compare each model, C-indices corrected by 5-fold cross validation were calculated.2. Systolic blood pressure had a cutoff of <110 mmHg and DLCO was categorized at <40%. In addition, we compared the performance of these expert recommended cut-off values with the data-driven calculated cut-off values .A 2. In 23.2% patients no PAH-specific treatment was established, 48% received a monotherapy, and 28.7% had a combination therapy with 2 or more different drugs. Among these patients, 45% had arterial hypertension, 16.5% were diagnosed with diabetes, 20.5% had preexisting coronary artery disease, and 3.6% had peripheral artery disease.Demographic features, clinical characteristics, and functional parameters are displayed in Echocardiographic parameters are presented in During a median follow up time of 4.18 years, 63 (24.8%) patients died and 11 (4.3%) underwent lung transplantation, resulting in an incidence rate of the composite endpoint of 25.3 per 1000 person-years. In univariable Cox regression analyses, the following parameters were associated with the composite endpoint: low systolic blood pressure, WHO functional class IV, lower 6MWD, NT-proBNP concentrations, renal impairment, impacted DLCO, reduced TAPSE, and reduced FAC .Based on the above defined criteria TAPSE, FAC, eGFR, systolic blood pressure, and DLCO were selected as additional parameters for inclusion in the multivariable models .p-value 0.017, Model 2). When further adjusting for eGFR <60 mL/min/1.73 m2, systolic blood pressure <110 mmHg, and DLCO < 40%, the C-indices did not improve relevantly, but TAPSE remained an independent predictor for the outcome . When adding TAPSE < 18 mm and FAC < 35% to Model 1, the C-index increased to 0.639  emphasize the prognostic value of TAPSE as an independent predictor for all-cause mortality and lung transplantation, (2) underline the importance of FAC, which is not yet included in current guidelines, and (3) develop an easily applicable non-invasive tool for PAH risk assessment.Our study population was predominantly male, with a median age of 65.5 years and a heterogenous PAH etiology. A shift in clinical characteristics of PAH patients was observed in the past decades. While earlier studies reported mainly young female patients, a decrease of the female predominance with age and an increase of the median age at diagnosis has been reported in recent years ,29. In tThe 2015 ESC/ERS guidelines for PH limit the use of echocardiographic assessment for risk prediction to RA area and pericardial effusion. In several studies, pericardial effusion was reported to be a predictor of adverse outcome ,16. In cPrevious studies showed that RV variables predict risk in patients with PH. TAPSE, being an important RV parameter, showed high reproducibility with small interobserver differences . The 201Data on FAC as a predictor in PAH is sparse, while FAC is mainly investigated in cardiac magnetic resonance imaging . Fine anThe value of RV strain as measure of RV dysfunction and predictor of adverse outcome in PAH has been identified in previous studies ,19,40. TApplication of current risk equations is limited by inclusion of invasive measures, which may not be available in all patients ,7,8,9. IIn terms of the constant improvement of PAH outcome, prediction of mid-term risk is becoming increasingly important . While pA major strength is the well characterized cohort and the recruitment from a specialized PAH-center. Furthermore, the extensive follow-up and the precise echocardiographic assessment, including novel variables precisely mapping RV architecture and function, mark up our cohort. However, the results are limited by the retrospective nature and by representing a single-center design. Therefore, external validation of our model is necessary to confirm our findings. Furthermore, change in therapeutic strategies during the long recruitment period from 2010 to 2018 and including prevalent and newly diagnosed patients might have influenced outcome measures, but concurrently allowed us to report a rather long follow-up and reflects clinical reality. Due to the dependence on image quality for speckle tracking echocardiography the number of missing values for RV, free wall strain might have led to an underestimation of the predictive strength of this variable. Therefore, further prospective studies with detailed echocardiographic assessment are necessary to clarify the impact of specific RV echocardiographic parameters for risk prediction.Our findings highlight the importance of echocardiographic assessment in patients with PAH. An easily applicable point-based score that integrates non-invasive echocardiographic parameters of right heart morphology and function improves the prediction of death or lung transplantation in PAH patients.


The morning blood pressure surge (MBPS) is related to an exaggerated risk of cardiovascular diseases and mortality. With increasing attention on circadian change in blood pressure and extensive use of ambulatory blood pressure monitoring (ABPM), chronotherapy that administration of medication according to biological rhythm, is reported to improve cardiovascular outcomes. The aim of this study is to evaluate the influence of chronotherapy of antihypertensive drugs upon MBPS in hypertensive patients.A search strategy was applied in Ovid MEDLINE, EMBASE, Cochrane (Wiley) CENTRAL Register of Controlled Trials, Cochrane Database of Systematic Reviews, and the Chinese Biomedical literature database. No language and date restrictions. Randomized controlled trials (RCT) assessing the efficacy of evening and morning administration of the same medications in adult patients with primary hypertension were included.A total of ten trials, comprising 1724 participants with a mean age of 61 and 51% female, were included in this study. Combined analysis observed significant reduction of MBPS , night-time SBP , night-time DBP  and increase in night blood pressure dipping  in evening dosage compared with traditional morning dosage of blood pressure-lowering drugs. No significant difference was found in the incidence of overall adverse effects  and withdrawal due to adverse effects .Our study suggested that evening administration of antihypertensive medications exerted better blood pressure-lowering effect on MBPS compared with conventional morning dosage. Safety assessment also indicated that the evening regimen did not increase the risk of adverse events. However, endpoint studies need to be carried out to confirm the significance and feasibility of this treatment regimen in clinical practice.The online version contains supplementary material available at 10.1186/s12872-021-02081-8. The circadian rhythm plays a critical role in multiple neurohormonal processes, thus modulating the cardiovascular system , 2. The Chronotherapy is the adaption of medication to biological rhythm, to achieve maximal effectiveness by altering the time of drug administration , which cSome studies documented that bedtime ingestion of blood pressure-lowering agents had a more efficient antihypertensive effect during night-time and at the early morning period –17. MostThe protocol for this systematic review and meta-analysis was registered in PROSPERO (CRD42020180166).The searching databases included: Ovid MEDLINE, EMBASE, Cochrane (Wiley) CENTRAL Register of Controlled Trials and Cochrane Database of Systematic Reviews, the Chinese Biomedical literature database up to April 2020. Besides, we also tracked completed clinical trials that met our inclusion criteria on ClinicalTrials.gov. The major search terms included: “hypertension”, ‘‘morning surge”, “morning blood pressure surge”, “MBPS”, “night* decline”, “Chronotherapy”, “morning OR day OR am OR diurnal OR daytime OR awake”, “evening OR bedtime OR night OR nocturnal OR pm”  by viewing the titles and the abstracts of the search strategies. The disagreements were judged by a third reviewer who was blinded to the first two reviewers’ decisions. The selection process was repeated twice by each reviewer. Studies meeting the inclusion criteria were checked in detail (full text).Only randomized control trials (RCT) were included to assess the effects of chronotherapy. Randomized cross-over trials that only had two treatment periods (two interventions) were also considered. Adults (more than 18) with primary hypertension, which is defined as systolic and/or diastolic blood pressure levels more than 140/90 mmHg were included. Secondary hypertension, alternating shift workers, and severe cardiac insufficiency (NYHA III-IV) were the exclusion criteria. Studies reporting one-drug therapy or combined therapy (two or more drugs) with the antihypertensive drug(s) administered once daily at bedtime when the control group was the same drug(s) at the same dose(s) once a day upon awakening were included. Antihypertensive drugs comprised diuretics, adrenergic beta-antagonists (β-blockers), alpha-antagonists, calcium channel blockers (CCB),vasodilator agents and renin-angiotensin system inhibitors . Administration time in the evening was from 18:00 to 24:00, while in the morning was from 6:00 to 12:00.Included studies must clearly define and measure MBPS. Both continuous and categorical variables were included. Definitions of MBPS must belong to any one of the following: (1) the sleep-trough surge, calculated by the mean value of morning blood pressure within 2 h after waking minus the lowest night-time blood pressure; (2) the prewaking surge, the mean blood pressure within 2 h after waking to subtract the mean blood pressure within 2 h before waking; (3) the rising blood pressure surge, morning blood pressure reading upon rising minus blood pressure reading in the lying position 30 min before rising. The measurement of night dipping is the percentage of reduction in mean nighttime blood pressure relative to mean daytime blood pressure.The primary outcome was the change in MBPS from baseline to the end of treatment  when it was calculated as a continuous variable; or the ratio of patients whose MBPS exceeded the settled threshold after treatment when MBPS was defined as a categorical variable.The secondary outcomes contained night blood pressure dipping, 24-h mean systolic blood pressure (SBP) and diastolic blood pressure (DBP), daytime mean SBP and DBP , night-time SBP and DBP . Safety outcomes include overall adverse effects and withdrawals due to adverse effects during treatment. Adverse effects can be any unplanned and unfavorable symptom, or disease temporally associated with the use of medicine. Withdrawals due to adverse effects are reported as events leading to permanent trial discontinuation.Data were extracted by two independent reviewers (Z.X. and J.Z.) based on a standard form. Necessary information of studies was extracted, such as patients’ demographics , study methods , interventions , outcomes  and safety endpoints . The numeric data  were collected from text and tables. Data in graphs were not extracted due to a possible measurement error. All the studies were double coded by the two reviewers. If there were missing data, we attempted to contact the authors to provide the missing information. Regarding missing data for the standard deviation of the change in MBPS, imputation was conducted based on other similar trials.Evaluation of the risk of bias in all included trials was executed by two independent reviewers (Z.X. and J.Z.) based on the guide of the Cochrane risk of bias tool. Characteristics of assessment included random sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting, and other bias . The assessment was done at the study level.2 ≤ 25% ) and a random-effect model (I2 > 25%).All data analysis and synthesis in the meta-analysis was conducted by RevMan 5.4 . Comparisons of continuous MBPS changes, 24-h, daytime and night-time SBP and DBP between groups were presented as mean ± standard deviation (SD) with corresponding 95% confidence intervals. These data were entered using a generic inverse variance. Categorical MBPS, overall adverse effects, and withdrawals were presented as relative risk ratios (RR). The outcomes were combined using a fixed- effect model , 401 of which were excluded, and the remaining 168 references entered full-text screening for intensive evaluation. Eventually, 10 articles  were considered for analysis and involved in our study. The reasons for excluding 158 references are shown in Fig. Included studies were 8 parallel-designed RCTs and 2 crossover-designed RCT  with 172The overall assessment of the risk of bias in the included studies are shown in Additional 2 = 98%) was detected.The most common definition of MBPS (sleep-trough surge) were compared in included studies Fig. . The ove2 = 0%) was observed in the CCB subgroup, while high heterogeneity (I2 = 97%) was detected in the RASI subgroup. No differences in blood pressure reduction were observed with β-blockers (P = 0.67) and combined CCB and ARB (P = 0.52) in the evening versus morning administration.The subgroup analysis observed significant differences in the evening dosage regimen of CCB and RASI compared with morning administration. The evening administration of CCB lowered MBPS by 4.21 mmHg (95% CI − 4.66 to − 3.76), and RASI reduced MBPS by 6.90 mmHg (95% CI − 11.49 to − 2.31). No heterogeneity  and daytime SBP (P = 0.78). However, evening regimen significantly decreased night-time SBP by 2.29 mmHg (95% CI − 4.43 to − 0.15), compared with morning administration. The subgroup analysis , 3.72 mmHg  and by 5.37 mmHg , respectively. There were no significant differences of SBP reduction were detected in RASI and CCB + ARB combined therapy.The data and results of SBP are presented in Fig. P = 0.04) and no significant differences were observed in 24-h DBP (P = 0.31), daytime DBP (P = 0.35). The subgroup analysis  was detected.6 studies with 3674 hypertensive subjects were included and analyzed. The result indicated that bedtime dosing remarkably enhanced nocturnal blood pressure decline by 3.23% (95% CI 5.37 to 1.10), compared with morning dosage regimen  and discontinuations due to adverse effects  had no significant differences between evening and morning regimens .The meta-analysis showed that the incidence of overall adverse effects , and the thresholds are various. The thresholds of MBPS could be defined as top decile, quartiles of MBPS in participants, or determined according to hypertensive guidelines, which have not reached a consensus . Among iOn the other hand, ethnicity is a critical factor affecting morning blood pressure surge. The Ohasama Study  and JMS-This meta-analysis discovered a prominent role of evening CCB in lowering blood pressure. The CCBs in included studies were nifedipine gastrointestinal therapeutic system (GITS) and amlodipine, which both belongs to the dihydropyridine calcium blocker family with long duration of action . AmlodipThis study has some potential limitations. First, the searching results indicated that only ten studies were eligible for combined analysis, and six of them were conducted in China, which reflects the racial differences in the attention to MBPS. The lack of evidence also posed a limitation to the analysis of distinct definitions and thresholds of MBPS and sensitivity analysis according to methodological quality. Besides, the blood pressure-lowering efficacy alone is not adequate to judge the clinical significance of antihypertensive of chronotherapy. Thus long-term, larger scale and multi-racial clinical trials are needed to explore the correlation between MBPS reduction and the incidence of cardiovascular endpoint.MBPS has received considerable attention from clinicians. Our meta-analysis provided the evidence that evening administration of antihypertensive medication improves blood pressure variability by significantly reducing MBPS and increasing nocturnal blood pressure decline without increasing adverse effects.Additional file 1. Search strategy, description of MBPS and supplementary results of meta-analysis.


Objective: To assess the effect of heart rate at baseline on major adverse cardiovascular events (MACEs) among hypertensive patients in China.Methods: A multicenter retrospective study was conducted with a 24 month follow-up period. A total of 10,031 hypertensive patients treated with standard antihypertensive drugs were grouped according to their heart rate before treatment: <65 beats per min (bpm), 65–69 bpm, 70–74 bpm, 75–79 bpm, and ≥80 bpm. The occurrence of any of MACEs was as the endpoint event during the 24 month follow-up period. The effect of heart rate at baseline on MACEs was analyzed using univate and multivariable Cox proportional regression analyses, with hazard ratios (HRs) and 95% confidence intervals (CIs). The restricted cubic spline (RCS) model was used to fit the Cox proportional harzard model with 5 knots at the 5th, 25th, 50th, 75th, and 95th percentiles of heart rate.Results: Totally 9,991 patients were finally enrolled with the mean systolic pressure (SBP)/diastolic pressure (DBP) of 130.59 ± 7.13/77.66 ± 5.99 mmHg at 24 month follow-up. The incidence of MACEs was 4.80% (n = 480). After adjustment for age, gender, baseline blood pressure, alcohol drinking, smoking, hyperlipidemia, diabetes, coronary heart disease, cerebrovascular disease and antihypertensive drug use, patients with heart rate <65 bpm  and ≥80 bpm  showed 0.45 fold and 0.391 fold increases of MACE risks, compared with patients with heart rate of 70–74 bpm. Furthermore, MACE risks were increased by 86.0% and 65.4% in men, and 59.3% and 69.0% in elderly patients aged ≥65 years at heart rate <65 bpm or ≥80 bpm, respectively. We also found a non-liner U-shaped correlation between heart rate and the occurrence of MACEs.Conclusions: Heart rate might be an independent risk factor for MACEs in hypertensive patients. An appropriate range of heart rate control may offer guidance to hypertension treatment. Hypertension is a chronic disease with a highest prevalence in China, which is a serious threat to the life and health of the Chinese population . It is eResting heart rate is an easy-to-measure phenotypic quantitative trait that is routinely used for risk prediction in the field of cardiovascular medicine , 8. SeveHerein, we investigated the association between heart rate at baseline and the risk of major adverse cardiovascular events (MACEs) in hypertensive patients, and further explored an appropriate range of heart rate control which may improve cardiovascular prognoses in hypertensive patients.This was a multicenter, retrospective, and follow-up study. All hypertensive patients treated with levoamlodipine maleate or amlodipine besylate at 110 centers in 21 cities in China, came from a previous study . All theMACEs as the endpoint of this study were defined as any of the following events occurred during the 24 month follow-up period, including death, non-fatal stroke, non-fatal myocardial infarction, unstable angina pectoris, coronary intervention, coronary artery bypass grafting, new onset of atrial fibrillation, heart failure, or aortic dissection aneurysm. An independent Clinical Event Committee whose members were blinded to the grouping of patients during the study made a judgment on of MACEs.Blood pressure was measured by an Omron (model: hem-8102a) medical automatic electronic sphygmomanometer in a face-to-face setting in the consulting room. The patients had been told not to engage in intensive exercise half an hour before blood pressure and heart rate measurement. In addition, smoking and coffee were prohibited on the day of the measurement. The resting setting was achieved by sitting for 5 min, the patient's legs were straight and relaxed, and their right arm was exposed and placed on the level of the heart. The heart rate (bpm), blood pressure (mmHg), systolic blood pressure (SBP), and diastolic blood pressure (DBP) of the patients were detected by an automatic digital blood pressure meter. Each index was measured twice and the average value was recorded as the final reading.Patients demographics and clinical data were collected, including age, gender, height, weight, alcohol drinking history, smoking history, medical history , family history , drug use , etc.The follow-up time of each hypertensive patient was 24 months in the study. Patients were followed up once a month in the first 6 months and once every 3 months thereafter at outpatient department of the hospital. The positive event during 24 month follow-up was MACEs, and the follow-up was terminated when any positive event occurred during the follow-up period. The follow-up sites were located at 110 centers in 21 cities, where the physicians were responsible for the diagnosis and the collection of follow-up information.P-value <0.10 were entered into multivariate analysis during stepwise iteration. The cumulative incidence hazards of MACEs in different heart rate groups were assessed using the Kaplan-Meier method. The restricted cubic spline (RCS) model was used to fit the Cox proportional hazard model with 5 knots at the 5th, 25th, 50th, 75th, and 95th percentiles of heart rate. All statistical analyses were performed using SAS 9.4 . P value <0.05 was considered statistically different.After continuous enrollment, the number of patients who completed the 24 month follow-up was counted and analyzed. All data were tested for normality through the Shapiro test. Comparison between two groups was conducted by the Kruskal-Wallis test. Comparison of means between multiple groups was conducted using one-way ANOVA. The multivariate Cox proportional hazard model was used to identify independent covariates and to estimate the effect of heart rate on the risk of MACEs, with hazard ratios (HRs) and confidence intervals (CIs). Variables achieving 2, the mean SBP of 145.43 ± 17.41 mmHg, and the mean DBP of 84.90 ± 10.67 mmHg. Baseline data on age, sex, blood pressure, and BMI exhibited no statistical differences between the 40 excluded and 9,991 included. We found that there were significant differences between the five groups of heart rate levels in age , gender , BMI , baseline SBP , baseline DBP , alcohol drinking , smoking , medical history , family history , and drug use . The incidences of MACEs in the five groups were found to be significantly different . Demographic data, history of diseases, drug use and outcomes of hypertension cases were shown in The incidence of MACEs was 4.80% among 9,991 hypertensive patients. Compared with patients at heart rate of 70–74 bpm, hypertensive patients at heart rate <65 bpm  and ≥80 bpm  showed higher risks of MACEs. Nevertheless, in contrast to patients with heart rate of 70–74 bpm, those with heart rate of 65–69 and 75–79 bpm showed no differences in MACE risks with HRs of 1.187 (95% CI: 0.901–1.564) and 1.008 (95% CI: 0.781–1.301), respectively. After adjusting for age, gender, baseline blood pressure, alcohol drinking, smoking, hyperlipidemia, diabetes, coronary heart disease, cerebrovascular disease, CCBs, beta-blockers, RASIs, diuretics, and other drugs, there were 0.45 fold and 0.391 fold increases in the risks of MACEs in patients with heart rate <65 bpm  and ≥80 bpm , while no significant differences were found in the other groups . The cumAfter adjustment for age, baseline blood pressure, alcohol drinking, smoking, hyperlipidemia, diabetes, coronary heart disease, cerebrovascular disease, CCBs, beta-blockers, RASIs, diuretics, and other drugs, the results showed that the risks of MACEs were significantly higher in men with heart rate <65 bpm  and ≥80 bpm  than those with heart rate of 70–74 bpm. Moreover, when gender, baseline blood pressure, alcohol drinking, smoking, hyperlipidemia, diabetes, coronary heart disease, cerebrovascular disease, CCBs, beta-blockers, RASIs, diuretics, and other drugs were adjusted, elderly patients (≥65 years old) at heart rate <65 bpm  and ≥80 bpm  had significantly increased MACE risks in comparison with those at heart rate of 70–74 bpm, respectively. There was no difference in women and the group aged <65 years old . The cumIn recent years, heart rate management in patients with hypertension has attracted major attention in clinic. However, the range of beneficial heart rate in hypertensive patients is unclear and still under debate . This stSome studies have revealed that increased heart rate in patients with hypertension was a marker of increased sympathetic excitability , 13. Ther = 0.82, P = 9.3 ×10−5). Therefore, increased heart rate is a sign of increased cardiac sympathetic activity in patients with hypertension  had a higher risk of cardiovascular disease . It was In this current study, we found that the risks of MACEs in male hypertensive patients or hypertensive patients ≥65 years old in the group of heart rate <65 and ≥80 bpm were higher than the risk in the group with heart rate of 70–74 bpm, suggesting the incidence of MACEs was correlated with heart rate of <65 and ≥80 bpm after 24 month follow-up. There were 45.0 and 39.1% increases of MACE risks in the groups of heart rate <65 and ≥80 bpm among all the patients with hypertension, respectively. Moreover, MACE risks were observed to significantly increase to 86.0% (heart rate <65 bpm) and 65.4% (heart rate ≥80 bpm) in the male group, and to 59.3% (heart rate <65 bpm) and 69.0% (heart rate ≥80 bpm) in the elderly group (≥65 years), respectively. It was indicated that managing heart rate at 65–79 bpm may be beneficial in reducing the risk of MACEs in hypertensive cases, particularly in males and the elderly. The gender and age of hypertensive patients have offered prognostic values for cardiovascular diseases , 33. ConInterestingly, a non-liner correlation between heart rate and the occurrence of MACEs in a “U” shape was also discovered in this study. An appropriate range of heart rate was 65–79 bpm, which may contribute to minimize the risk of MACEs. Besides, the lowest risk of MACEs was showed at the heart rate of 72 bpm. Current studies suggested that heart rate control (<80 bpm) was effective in the treatment of fast heart rate disorders, such as atrial fibrillation and congestive heart failure, which was similar to our findings. We provide an optimal value of heart rate that may be helpful to keep a steady circadian rhythm of heart rate, and to decrease the risk of MACEs in hypertensive patients. Tachycardia in hypertension is characterized by increased sympathetic tone and decreased vagal activity, and then antihypertensive drugs that can decrease heart rate via reducing sympathetic outflow should be considered as preferential agents. Several personal digital devices including mobile phones, fitness trackers and eHealth applications can be used for monitoring the heart rate of hypertensive patients to help clinicians as well as the public identify the risk.We conducted a multicenter, retrospective, and follow-up study based on a large Chinese population to assess the association between heart rate and MACE risks in patients with hypertension. The appropriate range and the optimal value of heart rate were mentioned for Chinese hypertensive individuals, which may be useful to guide clinicians in the treatment of hypertension. There are some limitations that should be noted in interpreting our findings. First, this study was based on a previous study “Pragmatic comparative effectiveness trial in a real-world setting,” data about heart rate in the observation period or stable status were not collected, and data on blood glucose and other blood biochemistry indicators could not be monitored. Although most covariables were adjusted, several potential residual confounders may not be controlled –36. A prIn the present study, the relationship between heart rate and MACE risks was investigated among hypertensive patients. The results showed that heart rate of <65 or ≥80 bpm was an independent risk factor for the occurrence of MACEs. The clinical evidence was provided that the heart rate of hypertensive patients was better controlled at 65–79 bpm. Hypertensive patients need to pay attention to the changes in heart rate while strictly controlling their blood pressure. Heart rate can be used as an independent marker of MACEs, which emphasizes the necessity of heart rate management in addition to current treatment regimes in preventing cardiovascular disease.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.The studies involving human participants were reviewed and approved by the Ethics Committees of Peking University First Hospital. The patients/participants provided their written informed consent to participate in this study.The overall study design and scheme, medical advice, and article writing came from NS. Data collection and analysis were done by YC, HW, YX, and LW. All authors have read and approved the final manuscript.This study was supported by the National Science and Technology Major Project (No. 2021ZX09101101).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The aim of this study was to detect the optimal values for Age, Body Mass Index (BMI) and HOMA-IR of obese patients prior to surgery that results in a maximal decrease of visceral fat mass 6 months after bariatric surgery.3 experimental set-ups were designed. This study was approved by Baskent University Medical and Health Sciences Research Board . The study data consisted of 40 obese patients who lost weight through the bariatric surgery between February 2015 and December 2016. The values of BMI, Age and HOMA for the obese patients who lost weight through the bariatric surgery were evaluated in three categories and at three levels; the response variable was determined as the Change in Epicardial Fat Thickness (ΔEFT).In this study, 3As a result of CCD analysis, the optimum ΔEFT = 2.571 was determined when Age = 30.52, BMI = 45.30, and HOMA = 34.62. As a result of the BBD analysis, the optimum ΔEFT = 3.756 was determined, when Age = 38.36, BMI = 63.18, and HOMA = 14.95. The optimum ΔEFT was modeled with Contour and Response Surface plots.Based on the two surface response models used in our study, the maximal decrease of visceral fat mass as assessed by measuring echography images of epicardial fat thickness can be obtained by bariatric surgery of persons who are between 31 and 38 year old, have a BMI between 45 and 63 kg/m2 and have a HOMA-IR 34 between 15 and 35. Central Composite Design and a Box-Behnken Design of suitable patient data predicted 35 optimal settings of independent variables for the maximal clinical response of an intervention. Since biological events are under the influence of multiple factors, it is necessary to evaluate the effects of such factors together in any biological event. For this reason, factorial experiments that can examine different levels of multiple factors in tandem and also address the status of a factor at different levels of other factors widely used in the fields of biology and medicine.Considering the factors that are thought to have an effect on the response variable in the factorial experiments, it is necessary to create an appropriate experimental design and use appropriate statistical analysis methods in order to minimize the experimental error. None of the combinations tried in the a priori experimental design created may be the best. In other words, the combination that provides the highest efficiency can be found among or outside of those tried. Therefore, a large number of factor combinations are needed in the factorial experiments. However, performing experiments like this is both expensive and time-consuming. In addition, as the number of factors increases, it becomes difficult to find the homogeneous experimental materials required to test all combinations. Therefore, statistical methods that do not require performing experiments involving all combinations have been developed to find the most appropriate combination of factors. One of these methods is the response surface method. In this method the model is created with the help of regression analysis. The extent to which the main effect or interaction effect of a factor has an important effect on the values of the response variable is decided by the regression coefficients. The first step in the response surface methods is to determine the factors that are thought to have an effect on the response variable and the [effect] levels they have. These two criteria usually determine the experimental designs create the regression model . The maiEpicardial fat [adipose] tissue (EFT) is a part of visceral adiposity. It has endocrine and paracrine effects and is associated with the metabolic syndrome (MetS). EFT is located between the myocardium and the visceral pericardium . There iThe increase in obesity prevalence and the lack of success rates of options other than the surgical treatment have brought this surgical treatment to the fore. Bariatric surgical treatment is very effective in rapid weight loss. There are limited studies in the literature that examine the effect of bariatric surgical treatment on the heart in detail .In this study, small Box-Behnken and Central Composite designs were created to determine the optimum level of the Change in Epicardial Fat Thickness (ΔEFT) of patients who have lost weight through the Bariatric Surgery Method. Both designs were used for the quadratic response surface model. When we determined the group in which we optimized the parameters of Age, Body Mass Index (BMI) and HOMA that were very important in bariatric surgery, we tried to obtain the maximum benefit in the ΔEFT for the patients.There are studies showing that CCD design is superior to BBD design. However, in a clinical experiment, there is no literature in which CCD design was used in this type of study, which has never been thought of before and which we think is a guide in bariatric surgery. Our main motivation is that the findings obtained as a result of two experiments guide the decision-making mechanism of surgeons performing bariatric surgery. For this reason, CCD design cannot be ignored.This study was approved by Baskent University Institutional Review Board and Ethics Committee . In this research article prepared for journal, we: obtained the data, information and documents in the framework of academic and ethical rules; provided all the information, documents, evaluations and results in accordance with scientific ethics and moral codes; referred to all of the articles used in this study with appropriate references; have not made any changes to the data used and the results. The information and findings specified in this study are original. We declare above mentioned issues and accept all rights losses that may arise.The study data consisted of 40 obese patients who lost weight through the bariatric surgery between February 2015 and December 2016. The CCD and BBD experimental designs were determined before the study. Patients were constantly enrolled in the respective designs in the specified experimental set-ups. The values of BMI, Age and HOMA for the obese patients who lost weight through the bariatric surgery were evaluated in 3 categories and at 3 levels; the response variable was determined as the ΔEFT.A experimental design with a first-order model will have a linear structure. However, in experiments, the presence of curvilinearity may occur as a result of the curvature test. In this case, the quadratic [second-order] response surfaces analysis should be used. This model is called the quadratic response surface model and has some features ;(i) Each factor must have at least 3 levels.(ii) The model must have at least 1 + 2k + k (k-1) 2 different parameters. As a result, the experimental design should contain the data obtained from 1 + 2k + k (k-1) 2 different points.In these experiments, the point at which the dependent variable takes the maximum or minimum value is called the “stationary point” . This poThe determination of the components in the quadratic response surface method depends on the size of the coefficients given in the regression equation. The steps to be followed for the calculation of stationary points are as follows.(i) A quadratic response surface model is estimated with the help of the data obtained from the experiment [experimental].(ii) Partial derivatives are taken for each of the factors included in a model and equalized to zero. (iii) It is possible to obtain the stationary points with the help of matrices. If the given model is expressed in matrices; b1 is the model constant, b is estimate of the linear model coefficients, and In In addition; k x k dimensions. Stationary points can be obtained from If we substitute the stationary points in the main equation, ry point .λ1, λ2, …, λk show the eigenvalues to be obtained from the vector W1, W2, …, Wk denote the “canonical variables”. It can be possible to understand the properties of the stationary points obtained with the help of When a quadratic equation is found to be adequate, the canonical analysis is applied to decide about the location and structure of stationary points in a quadratic equation. The signs of the eigenvalues obtained with the help of λ1, λ2, …, λk eigenvalues are all negative, the stationary point represents the maximum point.(i) If λ1, λ2, …, λk eigenvalues are all positive, the stationary point shows the minimum point.(ii) If λ1, λ2, …, λk eigenvalues are mixed, the stationary point indicates the “saddle point” ((iii) If the signs of e point” .Initially, CCD and BBD experimental designs used in patient selection were created with the MINITAB package program  and 2. Tk two-level factorial experiments with 2k number of axis points or star points, where “k” is the number of factors. It also contains nc center points. The factors in the model should be at least two levels. The placement of the axis points in the experimental design [set-up] is given in k experiments, the curvilinearity of the system is tested with the help of the center points and the quadratic terms in the model are estimated with the help of the axis points  is one of the most popular methods for generating a quadratic response level model. The CCD consists of a combination of 2s points .These experimental design, introduced by Box and Behnken in 1980, are an effective method for constructing the quadratic response surfaces model. It is a method built on balanced incomplete block experiments. The factors to be included in the model must be at least three levels. If we try to explain the structure of the experiment with the help of a experimental design with three factors; in the Box-Behnken experimental design, while the value of one of the factors is fixed at the central value, the combinations for all levels of other factors are applied . As can x value that gives the levels of the control variables which minimize the expected squared loss error E2y2.The aim is to reach the minimum response variable. When the aim is to minimize the response variable, the target value for the Taguchi response variable is treated as if it is zero. The squared loss function is defined as : the sum of the values in the outer zone of n response variables. The SNR value will be calculated for each inner zone point.y in Equation 8.2  variables allow the researcher to change the mean without changing the variance. This analysis has two stages. First, the adjustment factors that enable the response variable to reach the target value are selected, and then the levels of other control factors that minimize the SNR value are determined. In this case, the expected squared loss error is obtained as follows \doFor cases where the standard error of the response variable is related to the mean values, a different SNR value is proposed. This is a value that can be best applied in cases where the relationship is linear . (15)\doFrom the results of these experiments, firstly, the point belonging to the factor levels providing the highest efficiency is estimated; then it is tried to determine the point in question (the combination that provides the highest efficiency), with the way to reach where the actual optimum point is or by making the steepest increase from the second-order [quadratic] by using the coefficients of the first-order response surface function of the first experimental results (the steepest ascent method).The study data belong to 40 obese patients who lost weight through the Bariatric Surgery between February 2015 and December 2016. The values of BMI, Age and HOMA for the obese patients who lost weight through the Bariatric Surgery were evaluated in three categories and at three levels. Data from a subset of patients from Altin et al., published in 2016, were used in the current study . “VerbalIn the study, after the CCD and BBD designs were determined, patients were selected for 40 subjects who were admitted to the hospital and met the relevant criteria. The age of 40 subjects is 40.45 ± 11.30 minimum age 18 and maximum 66 years. Also, the BMI is 45.95 ± 7.51 minimum 35.06, maximum 64.47. The pre-experimental HOMA values are 8.09 ± 6.52 minimum 2.72 and maximum 38.40. In the study, weights were measured in kg, 2 digits after the comma, before and after the patients were only wearing surgical gowns. Within the scope of the study per protocol, all patients were followed during the 180-day follow-up period and the final measurements were taken. The study was carried out by providing all the assumptions of CCD and BBD experimental designs. The target is best algorithm was used in our study.The division into three categories for age, BMI and HOMA values in Forty obese patients who lost weight by the bariatric surgery between February 2015 and December 2016 were included in the study. The values of BMI, Age, and HOMA were evaluated in three categories and at three levels, and the ΔEFT was chosen as the response variable. The experimental design [set-up] was planned before the study. The study data were collected in accordance with the experimental design. The informed consent was obtained from the study participants.3  experimental designs [set-ups] were determined by CCD [design] and the contours and response plots were drawn according to the steepest ascent/descent condition.First of all, 3While planning the CCD design; the three factors were set up with α = 1.633, six axial points, four central points, and two axial center points.EFT can be identified as the echo-free space between the free [outer] wall of the myocardium and the visceral layer of the pericardium. It is measured by the standard transthoracic 2D echocardiography  in the parasternal long-axis views of three cardiac cycles at the end of the diastole and perpendicular to the right ventricular free wall as previously described . The samp; 0.041, 0.031 and 0.026, respectively). According to these results, the optimum ΔEFT combinations were determined by drawing the contour and response plots, and the model was expressed as specified in R2 value of the model was found to be 87.75%. As can be seen in When While planning the BBD design, it was established as three factors and three central points.p; 0.043, 0.040 and 0.022, respectively). According to these results, the optimum ΔEFT combinations were determined by drawing the contour and response plots, and the model was expressed as specified in R2 value of the model was found to be 91.27%. When When Today, the obesity surgery is frequently applied in developed countries around the world. Among the surgical procedures, the most preferred method is the sleeve gastrectomy. With weight loss after the bariatric surgery, a significant improvement has been observed in the chronic diseases such as hypertension, hyperlipidemia, atherosclerosis, and diabetes mellitus. This improvement is mainly related to breaking the insulin resistance. However, not all patients benefit equally from these surgical operations. Some patients benefit greatly from them, while others get more limited benefit. If it is known which patient group benefits most, these patients can be directed to the surgery in an earlier time. However, this requires advanced statistical analysis. Epicardial adipose tissue is a visceral adipose tissue, and its measurement is a good marker for these chronic diseases. The reduction in epicardial adipose tissue is a reliable parameter that can be used to determine which patient group benefits most .One of the aims of the response surface studies is to identify an appropriate function (or model) that will determine the relationship between the response variable and the input variables in order to accurately predict the future values of the response variable. Another one is to investigate the maximum or the minimum response value depending on the type of the problem and to determine the values of the input variables that can provide this value. Finally, they contribute to understanding the mechanism underlying a response system. As a result of CCD analysis, the optimum ΔEFT = 2.571 was determined when Age = 30.52, BMI = 45.30, HOMA = 34.62. As a result of the BBD analysis, the optimum ΔEFT = 3.756 was determined when Age = 38.36, BMI = 63.18, HOMA = 14.95. The optimum ΔEFT was modeled with the Contour and Response Surface plots. According to the results of the analysis, it was revealed that BBD analysis generated more positive results for the optimum ΔEFT than CCD, and also the optimum combinations of Age, BMI and HOMA were determined in order to reach the maximum ΔEFT.The body mass index and waist circumference are the widely accepted measurements of generalized adiposity; however, they are poor indicators for the visceral obesity. It is well-known that the visceral adipose tissue accumulation is associated with the subclinical atherosclerosis and increases the cardiovascular risk more strongly than the generalized adiposity . EmerginPatients are generally operated according to the standard bariatric surgical indications in the guidelines . However3). Age and bodyweight are pure variables, but BMI = body weight/ (body lengths) 2 [kg/m2] and HOMA-IR are indexes and in fact are hybrid variables based on the body weight and lengths and fasting blood insulin and glucose concentration, respectively.The response variable was the decrease of epicardial fat thickness as measured by echocardiography. This parameter is a one-dimensional estimate (thickness) of a three-dimensional mass of fat (cmIn our patient population the BBD analysis generated better results for the optimum ΔEFT than CCD for specific values for Age, BMI and HOMA.In conclusion, our study suggests that the weight loss after the bariatric surgery improves the cardiac functions for morbidly obese patients. Our findings showed that there was no negative change in the systolic and diastolic functions of the patients, and the myocardial performance index, which evaluates the systolic and diastolic functions together, improved. At the same time, the positive changes such as decrease in the intracardiac chronic pressure and volume load, significant decrease in the systolic and diastolic blood pressure as well as heart rate and decrease in fasting blood glucose contribute to the current recovery.10.7717/peerj.11831/supp-1Supplemental Information 1Click here for additional data file.


Purpose: Enhanced external counterpulsation is a non-invasive treatment that increases coronary flow in patients with coronary artery disease (CAD). However, the acute responses of vascular and blood flow characteristics in the conduit arteries during and immediately after enhanced external counterpulsation (EECP) need to be verified.Methods: Forty-two patients with CAD and 21 healthy controls were recruited into this study to receive 45 min-EECP. Both common carotid arteries (CCAs), namely, the left carotid (LC) and right carotid (RC), the right brachial (RB), and right femoral (RF) artery were imaged using a Color Doppler ultrasound. The peak systolic velocity (PSV), end-diastolic velocity (EDV), mean inner diameter (ID), resistance index (RI), and mean flow rate (FR) were measured and calculated before, during, and after the 45 min-EECP treatment.Results: During EECP, in the CCAs, the EDV was significantly decreased, while the RI was markedly increased in the two groups (both P < 0.01). However, immediately after EECP, the RI in the RC was significantly lower than that at the baseline in the patients with CAD (P = 0.039). The FR of the LC was markedly increased during EECP only in the CAD patients (P = 0.004). The PSV of the patients with CAD was also significantly reduced during EECP (P = 0.015) and immediately after EECP (P = 0.005) compared with the baseline. Moreover, the ID of the LC, RB, and RF was significantly higher immediately after EECP than that at the baseline  in the patients with CAD. In addition, they were also higher than that in the control groups . Furthermore, by the subgroup analysis, there were significant differences in the FR, PSV, and RI between females and males during and immediately after EECP .Conclusions: Enhanced external counterpulsation creates different responses of vascular and blood flow characteristics in carotid and peripheral arteries, with more significant effects in both the carotid arteries. Additionally, the beneficial effects in ID, blood flow velocity, RI, and FR after 45 min-EECP were shown only in the patients with CAD. More importantly, acute improvement of EECP in the FR of the brachial artery was showed in males, while the FR and RI of the carotid arteries changed in females. Enhanced external counterpulsation is a non-invasive treatment for patients with stable coronary artery disease (CAD), who are not amenable to standard revascularization procedures, such as percutaneous coronary intervention , 2. SeveThese alterations of peripheral vascular and blood flow characteristics play a key role in the modulation of central arterial function, cardiac load, and myocardial perfusion . For insNevertheless, there have been few studies on the effects of EECP on conduit artery vascular and blood flow characteristics, and the controversy remains even in patients with CAD. It has been reported that EECP can increase the peak limb blood flow and improve the endothelium-dependent vasodilation in the resistance arteries . A similGiven the controversial reports of the effects of EECP on systemic circulation, this study aimed to investigate the acute effects of EECP on the vascular and blood flow characteristics in the carotid, brachial, and femoral arteries in patients with CAD. Meanwhile, to further explore the mechanisms of these effects, we also aimed to compare the responses to those of the controls at the baseline, during, and immediately after 45 min-EECP.We enrolled patients with CAD to EECP treatment, diagnosed by angiographically proven stenosis ≥50% in at least one major coronary artery. They were admitted to the Department of Cardiovascular Medicine of the Eighth Affiliated Hospital of Sun Yat-sen University. The exclusion criteria were contraindications for EECP, including uncontrolled hypertension (SBP ≥ 180 mmHg and/or DBP ≥ 100 mmHg), carotid dissection, and deep vein thrombosis at lower extremities. In addition, we recruited healthy people as the control through the Health Examination Center of the Eighth Affiliated Hospital of Sun Yat-sen University. After explaining the purpose of this study and the potential risks, all the participants provided written informed consent. This study was conducted in accordance with the Declaration of Helsinki and was approved by the medical ethics committee of the Eighth Affiliated Hospital of Sun Yat-sen University.All participants received a single, 45-min session of EECP treatment. They lay supine on the EECP treatment bed with their legs and buttocks wrapped in cuffs, which were sequentially inflated from the lower to the upper thigh and buttocks at the beginning of the diastolic phase, followed by a quick, simultaneous deflation of all the cuffs just before the onset of systole. The EECP was conducted using an Oxygen Saturation Monitoring Enhanced External Counterpulsation Instrument . The pressure generated by the device was 0.028–0.033 MPa (212.8–250.8 mmHg).A Color Doppler Ultrasound (GE logic E) examination was performed 10 min before the start of the EECP at 15–25 min after its start and 30 s−1 min immediately after the end of the session. The measurement time for each part was about 2 min and the measurements were performed in the order: RC, LC, right brachial (RB), and right femoral (RF) arteries , 22. TheThe variables, PSV, RI, peak diastolic velocity (VD), PSV/VD (VS/VD), and velocity-time integral (VTI) in the CCAs were continuously recorded for 10 s and then were tracked and calculated.The mean inner diameters (ID) of all the arteries were calculated asIDsys and IDdia are the systolic and diastolic diameters, respectively.where RI was analyzed only in the carotid arteries because, as a measure of cerebral resistance, it is closely associated with cardiovascular risk. It was calculated asThe peak is the PSV and Vend−dia is the EDV.where VThe mean flow rate (FR) was calculated from the vessel diameter, cardiac period, and velocity-time integral ast is the averaged cardiac cycle time.where VTI is the averaged velocity-time integral, and t-test. A Chi-square test was also used for the analysis of the gender and risk factors in the two groups. The dependent variables before, during, and after the 45-min EECP, and between the patients with CAD and controls were analyzed by two repeated measures-ANOVA. Gender was regarded as a covariate in the two-way ANOVA of the inter and intra groups. In addition, the hemodynamic variables in each artery were also performed by subgroup analysis of gender. The post hoc analysis was conducted using Fisher's least significant difference. The software SPSS version 20.0  was used for all the statistical tests, and P < 0.05 was taken as a measure of statistical significance.The results are expressed as means ± SE. The normal distribution for all the vascular and blood flow characteristic variables was evaluated by a Kolmogorov–Smirnov test. The basic characteristics of the two groups were compared by an independent p > 0.05), while significant differences appeared in gender and risk factors in this study (P < 0.05).The basic information of the two groups is listed are 7. In addition, the significant differences in the hemodynamic parameters in females and males of both groups were analyzed by subgroup analysis. These results are shown in The ultrasound picture and Doppler spectrum of carotid and brachial arteries during EECP are presented in P = 0.013, P < 0.05) in the patients with CAD. In addition, the ID of the patients with CAD in the carotid, brachial and femoral arteries was also higher than that in the control groups .During EECP, the ID of the LC was significantly increased compared with the baseline in the patients with CAD (P = 0.015) and after EECP (P = 0.005) compared with the baseline in the patients with CAD. However, in the control group, the PSV in the RC and RB was significantly decreased after and during EECP, respectively. These results are illustrated in P < 0.05, The PSV of the LC was significantly reduced during  and immediately after EECP . The FR in the RC was significantly reduced immediately after EECP compared with during EECP only in the controls. Contralaterally, the FR in the RB was markedly higher immediately after EECP than that during EECP in both groups . By contrast, the FR of the RB was significantly increased in the healthy males and those with CAD during and immediately after EECP  and the National Key Research and Development Program of China (No. 2020YFC2004400).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Background and objectivesPulmonary hypertension (PH) is an independent risk factor for increased mortality, especially in patients undergoing hemodialysis (HD), but the mechanism of its development is unknown. This study aimed at evaluating volume overload and inflammation as potential variables to cause its development in patients undergoing maintenance hemodialysis.Materials and methodsThis was an observational cross-sectional study conducted on patients undergoing hemodialysis at a tertiary hospital in northern India. Patients of end-stage renal disease, aged 18 years or more, on maintenance hemodialysis for over two months were included in the study. The patients were divided into two groups based on the presence or absence of PH, determined by measuring systolic pulmonary arterial pressure (SPAP). The severity of PH was defined as: mild (SPAP 35-45 mmHg), moderate (SPAP 46-55 mmHg), and severe (SPAP> 55mmHg). The two groups were evaluated for demographic variables, type of vascular access, biochemical parameters, and markers of inflammation and fluid overload. Data between the two groups were compared statistically.ResultsThis study included a total of 82 patients showing the prevalence of PH to be 25.6% with a men-to-women ratio of 2:1. Out of 21 cases of PH, mild PH was found in seven (33.3%) cases, moderate in 14 (66.7%), and cases with severe PH were none. The two groups differed significantly in ejection fraction and markers of inflammation and volume status. Laboratory data associated with PH were alpha-1-acid glycoprotein (p<0.05) and pro-b-type natriuretic peptide (p <0.05).ConclusionThe present study showed higher levels of inflammatory markers alpha-1-acid glycoprotein and pro-b-type natriuretic peptide and lower levels of ejection fraction in patients undergoing HD, indicating a significant association with PH. Despite, advances in the field of medicine, morbidity and mortality remain very high in patients with chronic kidney disease (CKD)/end-stage renal disease (ESRD). Cardiovascular complications are the leading contributing factors for high morbidity and mortality in this group of patients. Evidence suggests that even mild to moderate renal impairment increases the risk of cardiovascular disorders . Among cHowever, these observations are based mostly on retrospective studies, and inflammatory markers have been evaluated in very few studies. Therefore, the present study is aimed to evaluate the role of inflammation in the development of PH and its interrelationships with fluid overload in patients with ESRD on maintenance HD.This was an observational cross-sectional study conducted in the dialysis unit of the department of medicine at a tertiary care center in northern India. A sample size of 81 patients was calculated from the following equation:Where,z = standard normal variate (at 5% type I error [p<0.05] it is 1.96)p = expected prevalence depending upon previous studiesd = margin of errortaking, p=30% and d=10%, sample size (SS) comes out to be 81.Patients of ESRD, age greater than 18 years, on maintenance HD for over two months and who gave written informed consent were included in the study. Patients with the presence of ventricular dyskinesia or hemodynamically significant valvular disease, alcohol dependence, psychiatric disorders, chronic liver disease, malignant neoplasm, acute infectious diseases, other chronic inflammatory diseases, chronic pulmonary diseases and patients having a positive human immunodeficiency virus serology were excluded. The study was approved by the Institutional Ethics Committee. The procedure was carried out in accordance with the Declaration of Helsinki and the International Council for Harmonization-Good Clinical Practice (ICH-GCP).The participants were divided into two groups on the basis of the absence or presence of pulmonary arterial hypertension. The clinical and laboratory findings were compared between these two groups. Demographic and clinical data  were recorded. Blood samples were collected for testing complete blood count, sodium (Na+) / potassium (K+), urea /creatinine, liver function test, total protein, albumin, C-reactive protein (CRP), pro-b-type natriuretic peptide (Pro-BNP), alpha-1-acid glycoprotein (A1AG). Commercially available enzyme-linked immunosorbent assay (ELISA) kits were used to measure A1AG. The plasma and serum were centrifuged and frozen at -70 °C until further laboratory analysis.The participants were dialyzed with a polysulfone dialyzer for 4 h, twice a week, in controlled ultrafiltration HD machines. Dialysate and blood flux were prescribed to reach a Kt/V target of 1.4. Anticoagulation was performed by heparin bolus during the HD procedure. The blood pressure monitoring was measured before dialysis and was considered the mean of measures immediately before each ten dialysis sections. Pre-HD and post-HD weights were recorded. 2D echocardiography (M mode) was done the next day after HD (in a relative euvolemic state) according to a previously standardized technique using an MyLab™Seven device  attached to a multi frequential 2.5 MHz to 3.5 MHz transducers. The coefficient of variation of the echocardiographic measurements in our laboratory was 2.5%. The following data were recorded; diameters of the left ventricular (LV) cavity at systole and diastole, the thickness of the posterior wall and the septum (both at diastole and systole), and left atrium at systole. Such data were used to calculate the relative thickness of the LV, the LV mass, and the LV mass index. After the tricuspid regurgitation was identified with a continuous-wave Doppler, systolic pulmonary arterial pressure (SPAP) was calculated using the following equation , 8:SPAP = 4 × (tricuspid systolic jet) 2 + 10 mmHg . In the absence of tricuspid regurgitation, pulmonary artery pressure was calculated using acceleration time across the right ventricular outflow tract (ATRVOT) as per the formula :SPAP = 90 - 0.6 × ATRVOT in mmHg.Pulmonary hypertension was defined as SPAP ≥35 mmHg . The sevStatistical analysisBaseline characteristics were assessed with standard descriptive statistics. The estimated glomerular filtration rate (eGFR) was calculated using the Cockcroft Gault formula. The normality of data was tested by the Kolmogorov-Smirnov test. If the data was not found to be continuous then the non-parametric test was used. Continuous variables were presented as mean ± standard deviation and median with Interquartile Range (IQR) (as applicable). Quantitative variables were compared using independent t-test , z-test  and Mann-Whitney test (for non-parametric data) between two groups. For quantifying association, odds ratio with 95% confidence interval was used and significance of odds ratio was calculated by Fisher’s-Exact Probability statistic. The data were entered in Mocrosoft Excel  spreadsheet, and analysis was done using an advanced statistical tool of Microsoft Excel 2010. p<0.05 was considered statistically significant.In the present study, a total of 82 cases (71.9% men and 28.1% women) were enrolled. The mean age was 43.48±14.65 years. Out of 82 patients, 15 (18.3%) were diabetic and 50 (60.9%) were hypertensive. The majority of the patients in this study had chronic glomerulonephritis (30%), while others had diabetic kidney disease (18%), chronic interstitial nephritis (15%), or of unknown etiology (37%). In this study, PH was found in 21 (25.6%) cases with a men-to-women ratio of 2:1. Out of 21 cases of PH, mild PH was found in 7 (33.3%) cases, moderate in 14 (66.7%) and cases with severe PH were none. Non-PH group and PH group did not differ significantly when compared for mean age (p=0.39), sex (p=0.53), body mass index (p=0.74), duration of HD (p=0.55) or interdialytic weight gain (p=0.14) and the type of vascular access used for HD (p=0.11)  and pro- BNP  while not with ejection fraction . On multiple regression, SPAP was significantly associated with A1AG (p=0.04) and with pro-BNP with a p-value of 0.05. Other parameters like diabetes, hypertension, duration of HD, body mass index, hemoglobin, eGFR, ejection fraction, high sensitivity CRP and albumin did not significantly affect SPAP, which were determinants for PH  fistula causes shunting of blood from systemic arteries to systemic veins, leading to an increased venous return to the heart, which in turn leads to increased pulmonary blood flow. Thus, AV fistula can contribute to the development of PH. Pulmonary hypertension has been shown to be associated with AV fistula by some authors ,19 but oAmong echocardiographic parameters, ejection fraction was found to be significantly lower in patients of PH (p=0.005) indicating that LV systolic dysfunction, which also results in overloading of pulmonary vessels is associated with PH. High levels of pro-BNP are strongly associated with LV hypertrophy and dilatation and systolic dysfunction in patients with CKD . These eThe present study showed higher levels of inflammatory markers A1AG and pro-BNP while lower levels of ejection fraction in patients undergoing HD indicating a significant association with PH. The incidence of PH can be prevented to some extent with effective management of fluid load in these patients. This will also reduce the micro-inflammatory state in patients undergoing HD which itself is an independent risk factor for the development of PH and other cardiovascular complications in these patients.


Diabetes mellitus is a global health issue and main cause of chronic kidney disease. Both diseases are also linked through high cardiovascular morbidity and mortality. Diabetic kidney disease (DKD) is present in up to 40% of diabetic patients; therefore, prevention and treatment of DKD are of utmost importance. Much research has been dedicated to the optimization of DKD treatment. In the last few years, mineralocorticoid receptor antagonists (MRA) have experienced a renaissance in this field with the development of non-steroidal MRA. Steroidal MRA have known cardiorenal benefits, but their use is limited by side effects, especially hyperkalemia. Non-steroidal MRA still block the damaging effects of mineralocorticoid receptor overactivation , but with fewer side effects  than steroidal MRA. This review article summarizes the current knowledge and newer research conducted on MRA in DKD. Diabetes mellitus (DM) is a worldwide health issue and it is estimated that it affected 463 million adults in 2019 ,6,7. Pat2) and/or presence of albuminuria  ≥ 30 mg/g) in a patient with DM. Albuminuria is also an important risk marker; it is associated with kidney disease progression, risk of end-stage kidney disease, cardiovascular morbidity and mortality methanesulfonamide) is a benzoxazinone derivative [Apararenone -1-(2-hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide) is a selective and highly potent MRA [2) and mild or moderate hepatic impairment (Child-Pugh A or B) do not alter esaxerenone’s pharmacokinetics in a clinically significant way. However, the effect of severe cases of renal or hepatic impairment on pharmacokinetics is still unknown [Esaxerenone  in comparison to placebo. The most common adverse event was hyperkalemia, which was dose-proportional. Another phase 3 trial in Japanese type 2 DM patients with albuminuria (Esaxerenone in Diabetic Nephropathy (ESAX-DN) study) followed [A study in Japanese patients with arterial hypertension, type 2 DM and albuminuria (UACR 30–999 mg/g) was performed by Itoh et al. . Fifty-ofollowed . In totaS)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide) is a potent, highly selective, full antagonist of the MR [Finerenone  and secondary outcome events  in comparison to placebo. Hyperkalemia was more common in the finerenone group, but discontinuation of the trial due to it was uncommon (2.3%). An additional subgroup analysis of these data showed that finerenone lowered the incidence of the composite cardiovascular outcome independent of preexisting cardiovascular diseases [2 and UACR 30–5000 mg/g to therapy with finerenone or placebo. The primary endpoint was the composite of time to cardiovascular death or non-fatal cardiovascular event . A main secondary endpoint was the composite of time to kidney failure, a sustained reduction of eGFR of ≥40% or renal death. Other secondary endpoints were time to all-cause mortality, all-cause hospitalization, UACR change from baseline to month 4 and a composite endpoint of time to first occurrence of kidney failure or sustained decrease of eGFR ≥57% from baseline over at least 4 weeks or renal death. The trial was completed, but the results are not yet published. In May 2021, only a special press release announced that the primary endpoint of the study was reached [The minerAlocorticoid Receptor antagonist Tolerability Study-Diabetic Nephropathy (ARTS-DN) was a randomized, double-blind, placebo-controlled, phase 2b study on 823 type 2 DM patients with albuminuria (UACR ≥ 30 mg/g), an eGFR higher than 30 mL/min/1.73 m8 mmol/L . They re8 mmol/L . Since t8 mmol/L . This wadiseases . Anotherdiseases ,134. It  reached . The latest meta-analysis, including randomized, controlled trials on the addition of MRA to RAS inhibitors in DKD, was published in 2019 . The autMRA have a role in DKD in lowering albuminuria. Hard outcomes such as kidney disease progression, cardiovascular events and mortality data are missing for all MRA except finerenone. The use of steroidal MRA in DKD has been limited by its side effects, especially hyperkalemia. Perhaps with sufficient attention to diet, ACE inhibitor/ARB use, potassium binder use, kidney function, regular serum potassium controls and thorough dose adjustment their use could be more widespread. With the advent of non-steroidal MRA that cause less hyperkalemia, their use in DKD might even become everyday clinical practice.