Perioperative hemoglobin drop after noncardiac surgery is associated with acute kidney injury (AKI). However, opinion on the tolerable difference in postoperative hemoglobin drop in patients with different preoperative hemoglobin levels does not reach a consensus. This study aimed to identify hemoglobin drop thresholds for AKI after noncardiac surgery stratified by preoperative hemoglobin levels.P-value approach identified cut-off points of hemoglobin drop within postoperative 7 days for patients with or without preoperative anemia. Stratified by preoperative anemia, hemoglobin drop’s odds ratio as continuous, quintile and dichotomous variables by various cut-off points for postoperative AKI were calculated in multivariate logistic regression models before and after propensity score weighting (PSW).This was a single-center retrospective cohort study for elective noncardiac surgery from January 1, 2012, to December 31, 2018. The endpoint was the occurrence of AKI 7 days postoperatively in the hospital. The generalized additive model described the non-linear relationship between hemoglobin drop and AKI occurrence. The minimum P < .001; after PSW: 1.42 (95%CI 1.17 -1.74), P < .001) and 43 g/L (1.81 (95%CI 1.35—2.27), P < .001; after PSW: 2.88 (95%CI 1.85—4.50), P < .001) respectively. Overall thresholds and corresponding odds ratio were 43 g/L (1.82 (95%CI 1.42—2.21)), P < .001; after PSW: 3.29 (95%CI 2.00—5.40), P < .001). Sensitivity analysis showed similar results. Heterogeneity subgroup analysis showed that intraoperatively female patients undergoing intraperitoneal surgery without colloid infusion seemed to be more vulnerable to higher hemoglobin drop. Further analysis showed a possible linear relationship between preoperative hemoglobin and perioperative hemoglobin drop thresholds. Additionally, this study found that the creatinine level changed simultaneously with hemoglobin level within five postoperative days.Of the 35,631 surgery, 5.9% (2105 cases) suffered postoperative AKI. Non-linearity was found between hemoglobin drop and postoperative AKI occurrence. The thresholds and corresponding odds ratio of perioperative hemoglobin drop for patients with and without preoperative anemia were 18 g/L (1.38 (95%CI 1.14 -1.62), Heterogeneity of hemoglobin drop endurability exists after noncardiac non-kidney surgery. More care and earlier intervention should be put on patients with preoperative anemia.The online version contains supplementary material available at 10.1186/s12882-022-02834-3. Perioperative hemoglobin drop in noncardiac surgery is related to postoperative kidney injury. Preoperative hemoglobin level is a critical risk factor for postoperative AKI. There is no recognized tolerance threshold for postoperative hemoglobin reduction among different preoperative hemoglobin levels. These parameters are essential for the prevention of perioperative renal injury. We assume that hemoglobin drop within 7 days after the operation will affect perioperative AKI and that patients with different preoperative hemoglobin statuses have different tolerance thresholds. Based on this hypothesis, this retrospective observational study aimed to identify the hemoglobin drop threshold of patients with different preoperative hemoglobin levels. Moreover, trying to understand the relationship between hemoglobin reduction and blood creatinine level within 7 days after surgery.This retrospective observational cohort study was undertaken at Peking University First Hospital in China, a 1500-bed teaching hospital. The Ethics Committee approved this study.Due to the study’s retrospective nature, the lack of patient follow-up, and the absence of patient identification information, the IRB waived the necessity for written informed consent.This study extracted data from the hospital’s perioperative database . Adult  was calculated using the preoperative value minus each of the minimum HGB values after surgery; in this case, we would get 7 values of minimum hemoglobin level and hemoglobin drop. Likewise, creatinine was calculated similarly, with the name creatinine level and creatinine increment (each max postoperative creatinine minus preoperative creatinine).In this study, preoperative hemoglobin levels less than 120 g/L in females or 130 g/L in male patients were defined as preoperative anemia. The hemoglobin was tested closest to the date of surgery.The information on each patient collected in the present study included their demographic and essential characteristics ; preoperative co-existing disorders, and lab tests , and intraoperative parameters 0.10,11 The modified John Hopkins Hospital criteria (MJHSC) were used to categorize the surgical complexity .P < 0.001.An analysis of patients’ subgroups based on their characteristics showed interaction in gender, whether intraperitoneal surgery or intraoperative colloid infusion. Female patients undergoing intraperitoneal surgery with preoperative anemia were inclined to suffer AKI Fig. , S5. TheP < 0.001 , P < 0.001, respectively , This study found the timeliness between perioperative hemoglobin level and corresponding creatinine. Creatinine level changed simultaneously with hemoglobin level within five postoperative days (Supplementary figure SThe present study showed that postoperative AKI occurred in 5.9% of adult patients undergoing elective noncardiac non-kidney surgery. Multivariable adjustment before or after PSW showed that higher hemoglobin drop was strongly associated with increased AKI occurrence. The perioperative hemoglobin drop thresholds were 18 and 43 g/L for patients with and without preoperative anemia. Hemoglobin drop thresholds for multi-mini-datasets with preoperative hemoglobin (span of 3 g/L) from 90 to 160 g/L demonstrated that, with the preoperative hemoglobin level decrease, the hemoglobin drop thresholds decrease dramatically accordingly.The time window for acute kidney injury is seven days after surgery. However, previous studies have primarily focused on changes in hemoglobin levels within 24 h after surgery –43. The It is accepted that preoperative hemoglobin level is a critical risk factor for postoperative AKI. Therefore, it is crucial to minimize preoperative hemoglobin level effects to understand the relation between hemoglobin drop and AKI. This study used stratification and multi-mini-datasets to accomplish this precondition.In patients with preoperative anemia, various body reserves have already begun to mobilize or are even exhausted. Such patients are less tolerant of bleeding. More active intervention should be taken in these patients.This study also discovered a same-day corresponding relationship between postoperative blood creatinine level (creatinine increase) and hemoglobin level (hemoglobin drop) Figure S, S3. As Due to clinical work characteristics, most postoperative patients have their blood routine and blood creatinine checked once a day. Although hemoglobin and blood creatinine was not obtained in the same test operation, the blood draw time was often the same, which indicates that the patient’s hemoglobin level and blood creatinine were likely to correspond within hours. Once kidney damage occurred, the dependence of this renal function on hemoglobin began to break away, and treatment was to no avail at this moment. It suggests that more frequent hemoglobin tests and earlier interventions may benefit patients with more AKI risk factors. This research proposes interesting directions for more in-depth research later. It also provides meaningful help for future clinical practice, as in the past, we made clinical decisions mainly on the postoperative hemoglobin level, ignoring the considerable influence of preoperative hemoglobin level on bleeding tolerance.To the best of our knowledge, this is the first study focusing on the heterogeneity of hemoglobin drop thresholds for noncardiac non-kidney surgeries based on an analysis of real-world clinical data.Our research has some advantages. After stratifying our analyses by perioperative variables, we found that our results remained reliable. Sensitivity analysis suggests that the relationship between hemoglobin drop and AKI does not change significantly depending on patient characteristics and the time frame of preoperative hemoglobin. We also proved the robustness of our conclusion by PSW analysis.Although we tried our best to implement the best research methods and improve the database’s quality, various shortcomings and errors were inevitable. This dataset did not include proteinuria analysis, and preoperative chronic kidney disease and eGFR assessment were not entirely performed. The results of this study only draw associations and cannot imply causality. Thus, we cannot suggest that the management of achieving a hemoglobin drop below the thresholds will reduce AKI risk. Further randomized trials are needed. The single-center retrospective design might limit the generalizability of the present study, and external validation is warranted. Since each person’s hemoglobin level cannot be tested frequently, the lowest hemoglobin value in this study can only be equal to or higher than the patient’s actual lowest value. Therefore, the actual threshold may be higher than the threshold of this study.Heterogeneity of hemoglobin drop endurability exists after noncardiac non-kidney surgery. More care and earlier intervention should be put on female patients undergoing intraperitoneal surgery with preoperative anemia.Additional file 1:Table S1. Definitions of variables. Table S2. Postoperative events. Table S3. Improvement of Hemoglobin drop in full models for classification. Table S4. Sensitivity analyses. Multivariable logistic regression with surgery duration adjustment. Table S5. Sensitivity analyses. Multivariable logistic regression with exclusion of patients with Intraoperative hypotension. Table S6. Sensitivity analyses. Multivariable logistic regression with preoperative hemoglobin mean level within three months instead of the hemoglobin value tested closest to the date of surgery. Table S7. Patient characteristics and operative variables in cohorts by hemoglobin drop more or no more than 43 g/L after propensity score weighting.Additional file 2:Fig S1. Restricted cubic spline function curves of the unadjusted and adjusted relationship between Hemoglobin drop and AKI probability. Shaded areas represent 95% confidence intervals. Additional file 3:Fig S2. Timeliness between perioperative hemoglobin level and corresponding creatinine. The red line represented minimum hemoglobin level, with its corresponding red axis on the left. In plots A and B, the blue line represented creatinine level, with their corresponding blue axis on the right; in plots C and D, the blue line represented creatinine increment with their corresponding blue axis. Creatinine level changed simultaneously with hemoglobin level within five postoperative days. After day 5, this phenomenon disappeared.Additional file 4:Fig S3. Timeliness between perioperative hemoglobin drop and corresponding creatinine. The red line represented maximum hemoglobin drop, with its corresponding red axis on the left. In plots A and B, the blue line represented creatinine level, with their corresponding blue axis on the right; in plots C and D, the blue line represented creatinine increment with their corresponding blue axis. Additional file 5:Fig S4. Subgroup analyses stratified by patient and operative variables in patients without preoperative anemia.Additional file 6:Fig S5. Subgroup analyses stratified by patient and operative variables in patients with preoperative anemia.


Postoperative delirium is a challenging complication due to its adverse outcome such as long hospital stay. The aims of this study were: 1) to identify preoperative risk factors of postoperative delirium following knee arthroplasty, and 2) to develop a machine-learning prediction model.A total of 3,980 patients from two hospitals were included in this study. The model was developed and trained with 1,931 patients from one hospital and externally validated with 2,049 patients from another hospital. Twenty preoperative variables were collected using electronic hospital records. Feature selection was conducted using the sequential feature selection (SFS). Extreme Gradient Boosting algorithm (XGBoost) model as a machine-learning classifier was applied to predict delirium. A tenfold-stratified area under the curve (AUC) served as the metric for variable selection and internal validation.n = 196). The following seven key predictors of postoperative delirium were selected: age, serum albumin, number of hypnotics and sedatives drugs taken preoperatively, total number of drugs  taken preoperatively, neurologic disorders, depression, and fall-down risk . The predictive performance of our model was good for the developmental cohort . It was also good for the external validation cohort . Our model can be accessed at https://safetka.connecteve.com.The incidence rate of delirium was 4.9% (A web-based predictive model for delirium after knee arthroplasty was developed using a machine-learning algorithm featuring seven preoperative variables. This model can be used only with information that can be obtained from pre-operative electronic hospital records. Thus, this model could be used to predict delirium before surgery and may assist physician’s effort on delirium prevention.The online version contains supplementary material available at 10.1186/s12888-022-04067-y. The prevalence of elective knee arthroplasty for arthritis continues to increase, reaching 1.5% in the general population and 10.4% in those aged 80 years . A patteElectronic health records (EHRs) accumulate huge amounts of data, facilitating machine-learning and the use of artificial intelligence –12. MachThis study has the following hypotheses 1) patients might have a high-risk of delirium after knee arthroplasty and long hospital stay, and 2) postoperative delirium can be predicted through machine-learning using only preoperative features. Thus, the objectives of this study were: 1) to identify key preoperative risk factors, especially modifiable factors, for delirium development, and 2) to develop and validate a machine-learning model for predicting postoperative delirium in knee arthroplasty patients.This study included the patient who underwent primary and revision knee arthroplasty from January 2016 to Sep 2019 at two tertiary referral hospitals . The devA total of 4,029 patients were eligible . After apply the exclusion criteria, 1,931 patients from hospital A were assigned to the developmental cohort and 2,049 patients from hospital B were assigned to the validation cohort  . NaturalWhen psychiatrist’s diagnosis was absent, diagnosis of delirium should be conducted in more complicated method. To be more specific, those red flag word set contains “increased irritability, no motor response, no verbal response, aggressive behavior, delusional, inappropriate emotional response, hard to communicate, lose orientation to time, place, person, decreased attention”. Inside EHR, not only physician but nurses also record patients’ status in timely fashion. Thus, it contains pretty much comprehensive and thorough information pertaining to patients’ medical and mental condition. Therefore, records containing those words in red flag set cannot directly diagnose but can assist psychiatrist determine whether patients were delirious at that time or not. For example, when red flag words were present on some patient’s EHR record and antipsychotic drugs were prescribed on the same day, the patient was very likely to be delirious. Otherwise, when antipsychotic drugs were not prescribed, we analyzed entire EHR record of each patient and decision was made in a most conservative manner. To sum up, patients without enough evidence of delirium was classified as non-delirium and there was no missing data relating to the outcome measurement.Therefore, delirium assessment was conducted by trained staffs using DSM-5 augmented with a validated medical record review method , 19–21.p-value < 0.05 were only chosen, which made them 20. When calculating p-value, t-test and chi-square test were used in continuous and categorical variables, respectively. These 20 variables are listed in Table A total of 63 variables were initially chosen as candidate predictors based on findings of previous studies , 21, 22.Demographic data included age, sex, body mass index (BMI), current smoker, and alcohol consumption (more than 5 times/week) , 24. TheSerum laboratory results included blood urea nitrogen (BUN), creatinine, BUN/Cr ratio, eGFR , hemoglobin (Hb), hematocrit (Hct), white blood cell (WBC), c-reactive protein (CRP), erythrocyte sedimentation rate (ESR), total protein, albumin, prothrombin time (INR), ALP, AST, ALT, total bilirubin, total cholesterol, sodium, and potassium . Urine laboratory results included albumin level . The collection of preoperative laboratory values is a routine procedure in most Korean hospitals. Thus, missing values were quite rare.To explore preoperative medication status and underlying diseases, admission records were combined with in-hospital drug prescriptions . Three iHypertension, diabetes mellitus, hypoglycemia, hypercholesterolemia, acute kidney injury, end-stage renal disease, atrial fibrillation, pulmonary embolism, ischemic heart disease, neurologic disorders , depression, generalized anxiety disorder, schizoaffective disorder, obstructive sleep apnea, cerebrovascular disease, meningitis, adrenal insufficiency, peripheral arterial disease, peripheral vascular disease, malignancy, sepsis, septic arthritis, and HIV + were extracted. History of trauma and history of amputation were also extracted.https://arxiv.org/abs/1603.02754. AUROC was obtained by roc_auc_score function in scikit-learn library. It is calculated as area under the curve when FPR and TPR(true positive ratio) are plotted on XY axis with varying threshold values. Python 3.7.11 and Google Colaboratory were used to encode the machine-learning algorithm. Missing values were imputed using a built-in GBM algorithm. Two feature-selection methods were used: sequential feature selection and forward elimination. The stratified K-fold (K = 10) approach was used to select predictor variables and optimize hyperparameters.All statistical analyses were performed using SAS version 9.4 . A gradient boosting machine (GBM) was used to predict the probability of delirium, employing all predictor variables. GBM used a series of decision trees, where each tree corrected residuals of previous trees. XGboost is a machine learning based gradient boosting model. Figure N = 1351, 70%) and a test group . The 20 variables were divided into categorical variables and continuous variables. Feature selection method with stratified tenfold cross validation on training group was applied for each variable subgroup. Top three variables selected by this algorithm were included in the final model. For each variable subgroup, the 4th, 5th and 6th ranked variables presented by this algorithm were tested in conjunction with six pre-selected variables. The variable that maximized the performance of internal validation was incorporated into the final model. The final model contained a total of seven variables.The developmental cohort was divided into two subgroups: a training group (N = 1351) with seven selected variables and tested with the test group (N = 580) to calibrate the internal validation within the developmental cohort. Youden index was used to identify the optimal ROC curve threshold [n = 2,049).The final model was trained using the training group (hreshold . Externap < 0.001) than non-delirious patients. Of 20 variables, seven key predictors were selected for the model, including four continuous variables  and three categorial variables . The odds ratio of polypharmacy  patients was 2.38 : 1.55–3.30). The XGBoost importance plot is shown in Fig. https://safetka.connecteve.com. The model automatically calculates the probability of postoperative delirium and visualize the value itself along with weights and significance hierarchy of each seven variables that users enter. The model was saved as “Predict_Delirium_after_knee_arthroplasty.pkl”. Thus, clinicians could still use the model when several value of variables cannot be obtained. The detailed protocol was uploaded in github repository; https://github.com/JasonJeongMed/Postoperative_Delirium_prediction_afterKA. The AUROC curve and the confusion table of internal and external validation are shown in Fig. Of 3,980 patients, 196 4.9%) were diagnosed with delirium after knee arthroplasty. These delirious patients had longer hospital stays , CAM-ICU, and CERAD (Consortium to Establish a Registry for Alzheimer’s Disease) neuropsychological battery. Chart based retrospective decision of delirium can omit several patients with delirium when chart information is not sufficient to prove the status of the patients. This could lead to relatively low proportion of delirious patients compared to other studies that focused on delirium prediction , 30, 31.With just 7 preoperative variables, a web-based machine learning algorithm that can predict delirium after knee arthroplasty was constructed. The model is simple. It was validated to improve both short- and long-term prognoses of knee arthroplasty patients. Postoperative delirium could be a potential correlating factor of longer hospital stay. Thus surgeons should strive to avoid.Additional file 1: Supplementary Table 1. Comparison of the Delirium and non-delirium groups of the developmental cohort in 64 features.Additional file 2: Supplementary Table 2. Keywords for classification of medication.


Results of recent clinical trials have shown that in heart failure (HF) heart rate (HR) values > 70 beats/minute are associated with an increased cardiovascular risk. No information is available on whether the sympathetic nervous system is differently activated in HF patients displaying resting HR values above or below this cutoff.In 103 HF patients aged 62.7 ± 0.9 (mean ± SEM) years and in 62 heathy controls of similar age we evaluated muscle sympathetic nerve traffic  and venous plasma norepinephrine , subdividing the subjects in different groups according to their resting clinic and 24-h HR values.r = 0.92, P < 0.0001 and r = 0.81, P < 0.0001, respectively) and 24-h  HR. The behavior of sympathetic markers described in HF was specific for this clinical condition, being not observed in healthy controls.In HF progressively greater values of clinic or 24-h HR were associated with a progressive increase in both MSNA and NE. HR cutoff values adopted in large scale clinical trials for determining cardiovascular risk, i.e., 70 beats/minute, were associated with MSNA values significantly greater than the ones detected in patients with lower HR, this being the case also for NE. In HF both MSNA and NE were significantly related to clinic (Both clinic and 24-h HR values greater than 70 beats/minute are associated with an increased sympathetic activation, which parallels for magnitude the HR elevations. These findings support the relevance of using in the therapeutic approach to HF drugs exerting sympathomoderating properties. It inhibitor ivabradine Trial (SHIFT) have additionally shown that in HF the cutoff value of HR above which cardiovascular risk is increased is positioned at 70 beats/minute [If inhibitor ivabradine in patients with coronary disease and leFt ventricULar dysfunction (BEAUTIFUL) trial [Several studies have unequivocally shown that in patients with chronic heart failure (HF) an elevated resting heart rate (HR) predicts the occurrence of fatal and non-fatal cardiovascular outcomes independently from other known risk factors –9. Data s/minute , 5. Whils/minute , a lowerL) trial . Among tL) trial , 12. ThiL) trial –18. HoweThe study population consisted of 103 HF patients of both genders  with an age range between 42 and 70 years and of 62 healthy individuals  with superimposable age. For both groups the evaluation was done retrospectively and it was based on the detection of a HR value below or above 70 beats/minute at the office visit performed the day preceding the microneurographic nerve traffic recording session made in the frame of different investigations carried out between 2016 and 2021. All individuals included in the study were normotensive and in sinus rhythm and no individual had a history of myocardial infarction in the 12 months before the study or clinical or laboratory evidence of valvular heart disease, renal insufficiency, hypertension, diabetes mellitus or any other condition (except HF in the HF group) known to affect autonomic modulation of the cardiovascular system . While hMeasurements included body mass index, sphygmomanometric and beat-to-beat finger systolic and diastolic blood pressure via a validated instrument , HR (EKG), respiration rate (pneumotacograph), and oxygen saturation . They also included (1) MSNA via the microneurographic technique , 16, 18,Simultaneous MSNA, beat-to-beat HR and blood pressure recordings were digitized with a sampling frequency of 1000 Hz . MSNA was quantified over a 30-min period as bursts incidence over time (bursts/min) , 12, 22.t test for unpaired observations or by chi-square statistic to determine their differences. The Pearson correlation coefficient was used to determine the relationships between resting MSNA and other parameters, a P < 0.05 being taken as the minimal level of statistical significance. All statistical analyses were performed by SAS software version 9.4 .All participants were examined in the morning after a light breakfast and an overnight abstinence from alcohol and coffee consumption. They were asked to assume the supine position, after which 3 sphygmomanometric blood pressure and HR  values were obtained. Following the BP and HR measurements, the patients were fitted with an intravenous cannula and the devices to measure finger BP and to record an EKG. Blood samples were taken 30 min after positioning the venous cannula. A microelectrode was then inserted into a peroneal nerve to obtain MSNA, which was recorded together with finger BP and the EKG during a 30-min period. Data were collected in a semidark and quiet room kept at a constant temperature of 20 °C–22 °C. As mentioned above, the study had a retrospective nature and included data collected and already blindly analyzed for other microneurographic studies not related to the objective of the present investigation. We included in the present analysis all patients examined in previous studies who fulfilled the criteria of enrollment mentioned above. This allowed to avoid any potential bias in data analysis. Values from individual participants were averaged for each patients group (see below) and expressed as means ± SEM. The two study populations were subdivided into different groups (four for HF patients and three for controls) according to the clinic HR values displayed at rest by the subjects. Comparisons between groups were made by 2-way ANOVA, using the Student As shown in Table r = 0.35 and r = 0.24, P < 0.001 and P < 0.05, respectively).As shown in the left upper and lower panels of Fig. Table Individual and average clinic HR values assessed in the 3 groups are shown in Fig. r = 0.71, P < 0.0001) than for NE . Similar relationships were detected when 24-h HR values were taken into account. However, when correlations were sought separately in the 3 groups of healthy controls characterized by different HR values both MSNA and venous plasma NE failed to show any significant correlation with clinic or 24-h HR.Similarly to what previously described for HF patients, in the whole healthy control population we found that MSNA and venous plasma NE showed a highly significant relationship with clinic HR, the correlation being much closer for MSNA  the majority of HF patients evaluated in the present study were under treatment with a number of different compounds capable to trigger opposite sympathetic effects , therebyThe clinical implications are that the evidence that in HF patients showing resting HR greater than 70 beats/minute sympathetic activity is already markedly increased provides an important pathophysiologic background for defining patients at greater cardiovascular risk. The same HR cutoff value appears to be valid for employing in the therapeutic approach to HF drugs capable to exert sympathomoderating properties .In HF HR values greater than 70 beats/minute are associated with an increased sympathetic activation, both when assessed by direct recording of MSNA and when evaluated as plasma NE concentrations. The sympathetic overdrive parallels for magnitude the HR elevations, this being the case for both clinic and 24 h HR.


Patients with persistent nephrotic-range proteinuria have a high risk of kidney dysfunction and cardiovascular events. Recently, the maintenance of proteinuria remission has been demonstrated to reduce the risk of kidney endpoint. However, the effect of remission duration on cardiovascular outcomes remains unclear.This study enrolled 982 patients with primary nephrotic syndrome who had achieved clinical remission. Remission duration was defined as the maintenance time (months) of the first remission. Arteriosclerotic cardiovascular disease (ASCVD) and kidney dysfunction (ESKD or eGFR reduction >50%) were the endpoints. Survival curves, Cox regression models, restricted cubic spline analysis were used and the cutoff time points were determined.p = .001). The initial time point was seven months for remission to present the protective effect to ASCVD and the maximum time point was 36 months. Remission duration was also an independently protective factor to kidney dysfunction. This effect was shown from the beginning of remission and reached the maximum at 26 months.During the 38.3 months of follow-up, 161 (16.4%) patients developed ASCVD (51.3 per 1000 patient-years) and 52 (5.3%) patients developed kidney dysfunction (15.3 per 1000 patient-years). Multivariate analysis showed that remission duration was an independently protective factor to ASCVD, in which each one-year extension associated with a 15% reduction of the risk (HR, 0.854; 95% CI, 0.776 ∼ 0.940, The maintenance of proteinuria remission was crucial for the improvement of cardiovascular and kidney outcomes in nephrotic syndrome patients. Nephrotic syndrome (NS) is characterized clinically by the presence of peripheral edema, heavy proteinuria, hypoalbuminemia, and hypercholesterolemia. Most adult patients with NS have primary glomerular diseases, including membranous nephropathy (MN), minimal change disease (MCD), and focal segmental glomerulosclerosis (FSGS) ,2.Patients with persistent high-grade nephrotic-range proteinuria have a high rate of deterioration to end stage kidney disease (ESKD) . In contLittle population-based data exist about the adults with primary NS and the risks of cardiovascular outcomes. In a cohort of 907 adults with nephrologist confirmed primary NS attributed to MCD, FSGS and MN, the adjusted rates of acute coronary syndrome, heart failure, ischemic stroke, venous thromboembolism, and death were significantly higher than those in 89,593 matched adults ) was approved by the Ethics Committee of Peking University First Hospital and was in compliance with the purpose of the Declaration of Helsinki. All participants provided written informed consent before participating in the study.According to KDIGO 2021 clinical practice guideline, treatment response of NS includes CR, partial remission (PR), and relapse  or a reduction of eGFR > 50% from the baseline value at the time of enrollment. eGFR was calculated according to the Chronic Kidney Disease Epidemiology Collaboration equation [The primary kidney endpoint was the occurrence of kidney dysfunction, which was a composite of ESKD [estimated glomerular filtration rate (eGFR) < 15 mL/min/1.73mequation .t test or Mann–Whitney U test was used to compare differences between two groups for continuous variables, and chi-square test or Fisher exact test was used to compare differences between two groups for categorical variables. Univariate and multivariate linear regression analyses were performed to analyze the potential determinants of remission duration. Variables with significance in univariate analysis were included in multivariate analysis.Continuous variables with normal distribution were expressed as means ± SDs, and variables with non-normal distribution were expressed as medians and interquartile ranges (IQR). Categorical variables were expressed as frequencies and proportions. According to distributions, independent sample The incidence rate of ASCVD or kidney dysfunction was represented by the number of cases per 1000 patient-years. The maximum selection test was used to calculate the landmark time point. The survival curve was calculated by Kaplan–Meier method. Log-rank test was used to compare the incidence rates between the patients divided according to the landmark.A univariate Cox proportional hazards regression model was used to investigate the factors associated with clinical outcomes. A multivariable Cox proportional hazards regression model was used to investigate associations between remission duration and outcomes. The remission duration was included into the Cox model as a continuous variable or categorical variable. When as a categorical variable, the group with remission duration lower than the landmark was used as reference. Three models were constructed to adjust the factors associated with remission duration. 24 h urinary protein was adjusted together with other baseline factors in model 1, remission status (CR or PR) was adjusted in model 2, and relapse in model 3. HR and 95% confidence interval (CI) were reported. The curve of HR over remission duration was drawn by restrictive cubic spline analysis, and piecewise regression was carried out to determine the initial cutoff point and stable cutoff point of HR decline.p < .05 was considered statistically significant.Data were analyzed using SPSS Statistics version 24.0 (IBM) and R 4.0.5 software. A two-sided Supplementary Table 1. The mean age was 49.8 ± 16.3 years, with a gender ratio of male/female as 1.4. 302 (30.8%) patients had a history of smoking, 536 (54.6%) patients had hypertension, and 220 (22.4%) patients had diabetes mellitus.The baseline features of 982 patients were shown in 2. In terms of NS complications, 303 (30.9%) patients underwent infections, 45 (4.6%) patients had thromboembolisms, and 65 (6.6%) patients had acute kidney injury.All patients received kidney biopsy. 746 (76.0%) patients were diagnosed as primary MN, 163 (16.6%) patients were MCD, and 53 (5.4%) patients had primary FSGS. At the time of remission, urinary protein was 2.0  g/24h, serum albumin was 34.4 ± 5.6 g/L, and eGFR was 87.1 ± 25.0 mL/min/1.73 mThe time from kidney biopsy to clinical remission was 4.4  months; 461 (46.9%) patients achieved CR and 521 (53.1%) patients got PR. During the follow-up of 38.3  months, 445 (45.3%) patients underwent relapse.Supplementary Table 2).The time of remission duration was positively associated with serum albumin, hemoglobin, eGFR, remission status (CR or PR), whereas it was negatively associated with gender, 24 h urinary protein at baseline, uric acid, immunosuppressive drugs and relapse in univariate analysis. After multivariable adjustment, remission duration remained significantly associated with 24 h urinary protein at baseline, remission status and relapse (p = .001) for each one-year extension of remission, after adjustment of baseline factors (n = 746), the duration of remission maintenance was also an independently protective factor for ASCVD, with a 12% decreased risk of ASCVD for one-year longer duration  (Supplementary Table 3). Besides remission duration, higher eGFR was an independently protective factor for ASCVD as well. Older age, diabetes mellitus, LDL-C, and thromboembolism were independently risk factors for ASCVD. The protective effect of remission duration remained statistically significant after further adjustments for the related parameters, 24 h urinary protein at baseline, remission status, and relapse  months, 161 (16.4%) patients developed ASCVD, with an incidence of 51.3 per 1000 patient-years. Cox regression analysis showed that the time of remission duration was independently associated with a 15% decreased risk of ASCVD . In the patients with remission duration < 24 months, the incidence of ASCVD was 66.4 per 1000 patient-years. While in the others the incidence was 34.1 per 1000 patient-years. The difference between the two groups was statistically significant  (p < .001) (Supplementary Table 5). The results remained statistically significant after further adjustments for 24 h urinary protein, remission status, and relapse (Supplementary Table 6).The landmark of remission duration for the endpoint of ASCVD was calculated as 24 months by the maximum selection test, and the patients were divided into two groups accordingly ( = .001) . After ap < .001) for each one-year extension of remission, after adjustment of baseline factors (n = 746), the duration of remission maintenance was also an independently protective factor for kidney outcome, with a 25% decreased risk of kidney dysfunction for one-year longer duration  (Supplementary Table 7). Besides remission duration, higher eGFR was an independently protective factor for kidney dysfunction as well. Hypertension, the time from kidney biopsy to clinical remission, and thromboembolism were independently risk factors for kidney dysfunction. The prognostic effect of remission duration remained statistically significant after further adjustments for the related parameters, 24 h urinary protein at baseline, remission status, and relapse  patients underwent kidney dysfunction, with an incidence of 15.3 per 1000 patient-years. Cox regression analysis showed that remission duration was independently associated with a 30% decreased risk of kidney dysfunction . In the patients with remission duration <36 months, the incidence of kidney dysfunction was 19.2 per 1000 patient-years, while in the counterpart group it was 7.2 per 1000 patient-years  (p < .001) (Supplementary Table 8). The results remained statistically significant after further adjustments for 24 h urinary protein at baseline, remission status, and relapse (Supplementary Table 9).The landmark of remission duration for the endpoint of kidney dysfunction was calculated as 36 months by the maximum selection test, and the patients were divided into two groups accordingly ( = .001) . After aThe curve of HR to ASCVD over remission duration was drawn by restrictive cubic spline analysis, by taking HR as the vertical coordinate and remission duration as the horizontal coordinate . The pieThe curve of HR to kidney dysfunction over remission duration was presented in In the present study, we determined the quantifying relationship between the surrogate outcome of NS as proteinuria remission and the hard outcomes of ASCVD and kidney dysfunction, using a large cohort of adult primary NS under regular longitudinal care within a tertiary hospital. The results showed that remission duration was an independently protective factor to the endpoint of CVD and CKD. For the benefits of cardiovascular outcomes, the remission duration needed to be maintained at least seven months. While for the benefits of kidney outcomes, the remission played the role once it was achieved. This is, for our best knowledge, the first study to define the specific time points for proteinuria remission to exert and to perform the stable protective effect to the endpoint of ASCVD in NS. These findings provide a reference for using the surrogate outcome of proteinuria remission in the management of NS, for the improvement of hard outcomes of cardiovascular and kidney prognosis.In the current study, we observed an incidence of 51.3 per 1000 patient-years of ASCVD in NS patients, which is remarkably higher than that in general population, 6.6 per 1000 patient-years . RecentlWe found that the risk of ASCVD could be decreased 15% by one-year extension of remission duration. This effect remained significant no matter which remission status, PR or CR, was achieved. At the initiation of proteinuria remission, no significant decrease of HR was observed, suggesting that the remission duration did not show protective effect on ASCVD. The cutoff time point for HR to fall down below 1.0 was seven months, suggesting that the remission duration should be maintained for seven months or longer, so that to reduce the risk of ASCVD. Then, the remission performed continuous and incremental protective effect to ASCVD. We found the landmark of remission duration as 24 months that the risk of ASCVD was reduced 54% in the patients achieving it. When the time of remission reached 36 months, the HR became stable, which suggests the protective effect approaching the maximum, and the extension of remission duration did not show further protective effect to ASCVD.All the above results provided strong evidence that remission duration was an independently protective factor for ASCVD in NS patients, and for the first time clarified the definite time points for the initiation, landmark, and maximum of this protective effect. Although the literature supports a benefit to ASCVD by proteinuria remission ,14–17, tThe possible mechanism underlying the relationship between proteinuria and ASCVD may be the endothelial dysfunction and inflammation . DeckertIt has been fully demonstrated that proteinuria is an important risk factor for deterioration of kidney dysfunction, and the massive proteinuria in NS significantly increase the risk of ESKD . Unlike In conclusion, this study demonstrated that remission duration was an independent protective factor for cardiovascular and kidney outcomes in the patients with NS. The time points of initiation and landmark of remission duration for the benefits of prognosis could be used as a reference time in the clinical practice for NS patients.Patients with persistent nephrotic-range proteinuria have a high risk of kidney dysfunction and cardiovascular events. However, the effect of the time of maintaining clinical remission on cardiovascular outcomes remains unclear. The results of this present study showed that remission duration was an independent protective factor for the endpoint of arteriosclerotic cardiovascular disease (ASCVD) and kidney dysfunction in primary nephrotic syndrome (NS) patients. This is, for our best knowledge, the first study to define the specific time points for clinical remission to exert and to perform the stable protective effect to the endpoint of ASCVD in primary NS patients. These findings provide a reference for maintaining remission in the clinical practice of NS, for the improvement of cardiovascular and kidney prognosis.Click here for additional data file.


Objective This study aims to describe the behavior of chromosomopathy screenings in euploid fetuses.Methods This is a prospective descriptive study with 566 patients at 11 to 14 weeks of gestation. The associations between ultrasound scans and serological variables were studied. For the quantitative variables we used the Spearman test; for the qualitative with quantitative variables the of Mann-Whitney U-test; and for qualitative variables, the X2test was applied. Significance was set atp≤ 0.05.Results We have found that gestational age has correlation with ductus venosus, nuchal translucency, free fraction of β subunit of human chorionic gonadotropin, pregnancy-associated plasma protein-A and placental growth factor; there is also a correlation between history of miscarriages and nasal bone. Furthermore, we correlated body mass index with nuchal translucency, free fraction of β subunit of human chorionic gonadotropin, and pregnancy-associated plasma protein-A. Maternal age was associated with free fraction of β subunit of human chorionic gonadotropin and pregnancy-associated plasma protein-A.Conclusion Our study demonstrates for the first time the behavior of the biochemical and ultrasonographic markers of chromosomopathy screenings during the first trimester in euploid fetuses in Colombia. Our information is consistent with international reference values. Moreover, we have shown the correlation of different variables with maternal characteristics to determine the variables that could help with development of a screening process during the first trimester with high detection rates. The chromosomopathies are an important cause of perinatal deaths and child disability. It has been described that approximately 7.9 million children had some type of congenital malformation.Diverse methods have been introduced for diagnosing chromosomal abnormalities. Invasive methods such as chorionic villus biopsy and amniotic fluid sample for doing karyotype have been done for ages and are well known for their accuracy. Nevertheless, there is an estimated risk of pregnancy loss associated with these procedures, between 0.5 and 1.5%, during all three trimesters.The combined screening at 11 to 14 weeks of gestation has appeared as a tool for effective early detection of fetal trisomies and is accessible for all patients.In Colombia, congenital malformations affect 2 to 3% of newborns and are the main cause of mortality for infants under one-year-old.This has not been previously studied in Colombia, and it is necessary to have references of the screening in our population. For that reason, the aim of this study is to describe, for the first time, the behavior of chromosomopathy screening in euploid fetuses at Bogotá, Colombia.A prospective descriptive study was performed through the analysis of pregnant women over 14-years-old, in the first trimester, between 11 and 14 weeks of gestation, who underwent prenatal care in Bogotá, Colombia. This study evaluated 566 pregnant women, between 2014 and 2018, at the Ecodiagnóstico El Bosque SAS Diagnostic Unit Centre, Clínica El Bosque and Subred Integrada de Servicios de Salud Sur Occidente ESE – Unidad de Servicios de Salud Occidente de Kennedy. Women at risk of abortion and who had not completed the screening were excluded from the study.In the first prenatal control, we collected data regarding race, socioeconomical level, mother's age, single or multiple pregnancy, personal and familiar background, mean blood pressure, cardiac heart rate, weight, height, and body mass index (BMI).As part of the screening for chromosomopathies, the following biochemical markers were measured: PAPP-A, free β-HCG and PlGF; we analyzed the ultrasonographic findings regarding theNT, absence or hypoplasia of the nasal bone, ductus venosus, and tricuspid insufficiency. These ultrasonographic data were obtained and evaluated by a certified professional. The biochemical markers were taken the same day that the ultrasound scan was performed, and they were processed by using DELFIA XPRESS . Data from the medical records were typed and validated by two of the researchers in a Microsoft Excel 2019  database (El Bosque University License).For the analytical study of the data it was used the Statistical Package for Social Sciences  software, version 22.0 (Universidad El Bosque License), in which the ultrasound scan and serological variables were compared with five maternal variables—gestational age, maternal age, family history of malformations, history of abortions, and BMI—to identify the possible association between variables. For quantitative variables, averages and standard deviation were calculated. Frequencies and percentages were determined for qualitative variables.X2was applied. Significance was set atp≤ 0.05.To establish association or not between quantitative variables, a normality test was applied. For the comparison between the quantitative variables, it was used the test of Spearman, for the qualitative with quantitative variable it was used the test U of Mann Whitney and for the comparison between qualitative and qualitative variables, the testThis project has the approval of the Ethical Committee of the Universidad El Bosque. The ethical principles for human research from the Helsinki DeclarationWritten informed consent was obtained from the pregnant women who participated in this study, which allowed the group to use patients' information, while their privacy was respected throughout the study.A selection bias was present because the patients in this study correspond to a specific population that can't represent all the population of Bogotá. However, the bias was minimized by clearly describing our participants' characteristics and establishing that the results of this study are representative only for the population study.n = 551) of the women were mixed race (mestizo), while the remaining 3.67% (n = 21) identified as either white or African-American. The medium and low socioeconomic levels grouped 96% (n = 579) of the study participants (n = 48), followed by hypothyroidism, 6.12% (n = 35) and hypertension, 2.45% (n = 14) . The mean maternal age was 27 years . We found that 96.3% (cipants . The mo = 14) .n = 47) of the mothers had direct exposure to tobacco and only 0.87% (n = 5) had previous exposure to x-rays. Regarding the gynecologic and obstetric history, 63.96% (n = 362) of the maternal patients were multigravidas, while 25.27% (n = 143) were primigravidas. Furthermore, 37.8% (n = 214) had history of abortions; 24.2% (n = 137) had a history of one abortion, and 1.94% (n = 77) of two or more abortions. Compared with the biomarkers studied, it was found that PAPP-A had an average value of 3.19 mUl/ml (SD = 18.30). The average free β-HCG value was 36.43 mUl / ml (SD = 27.90). The mean value of PlGF concentration among the 554 participants with this information available was 31.26 pg / mL (SD = 18.30). Regarding ultrasound variables, the mean fetal heart rate of the 572 fetuses studied was 157.7 beats per minute (SD = 10.05). Regarding the cephalocaudal length, the average found was 66.35 mm (SD = 9.33). The NT had a mean of 1.60 mm (SD = 0.56). The ductus venosus presented an average pulsatility index (PI) of 0.98 (SD = 0.46) (n = 571) and the absence of this marker was found in only one fetus. Finally, tricuspid insufficiency did not occur in any if the patients of this study population. This is the first study of chromosomopathies developed in the Colombian population; therefore, it is important to determine what are the values obtained for each variable in a healthy population  . The naulation .p = 0.0000) and history of miscarriages (p = 0.013). Additionally, we found a relation between the ductus venosus and BMI but it was not significant. It was not found any case of tricuspid insufficiency; therefore, it was not possible to analyze this variable. The NT had a direct significative correlation with the gestational age and BMI. It was not found other correlations. The absence or hypoplasia of the nasal bone was associated with the family history of malformations . In relation to the biochemicalmarkers  of the genetic screening in relation with maternal characteristics in a healthy group of pregnant women in Bogotá, Colombia, to determine the importance and correlation of each test.The average results found for each variable are not far from what the literature describes, as shown inAmong the ultrasonographic variables, the ductus venosus (DV) showed an inverse relation with the gestational age, which means that the longer the pregnancy, the lower is the ductus venosus PI. Maiz et al.The absence or hypoplasia of the nasal bone in this study was significantly associated with family history of malformations, but it was only found in one patient. There were no further associations with the other variables. There are few studies which describe the role of the nasal bone and in the literature it has been described that it doesn't influence over the other variables of the screening. However, when it is used in combination with maternal age, NT, free β-HCG, and PAPP-A, it rises the DR of this screening up to 90%, with a false positive rate of 0.5%.On the other hand, the NT is proportionally associated with gestational age and BMI. This association has been described in other study populations, studies from the United Kingdom described a statistically significant correlation between the measure of NT, maternal BMI, smoking status, and Afro-Caribbean ethnicity.Of the biochemical markers, free β-HCG and PAPP-A are well now for the genetic screening during the first trimester. In this study, we found a direct relation of free β-HCG with gestational age, maternal age, and maternal BMI, while PAPP-A was inversely associated with maternal age and maternal BMI, and directly related to gestational age. A similar result for PAPP-A was obtained in Australia, where it was found an inverse relation between maternal BMI and the values of free β-HCG and PAPP-A.Finally, chromosomopathy studies began analyzing PlGF along with the other variables; studies from the United Kingdom describe that PlGF has a statistically significant direct relation with the gestational age, and inverse relation with the maternal BMI.There is no available information about the behavior of the tests used in the screening for chromosomopathies in the Colombian population. Therefore, this study could be useful for understanding the correlations of the different variables with maternal characteristics, to determine the most helpful variables for developing the first trimester screening in this population. Moreover, this article provides information on the distribution of the biochemical and ultrasonographic markers in euploid fetuses, which could be the first approach to reference values in Colombian pregnant women, agreeing with the international values of reference. We suggest that the studies in this domain should continue to develop the best way to asses an early diagnosis of chromosomopathies, with the aim of doing appropriate, timely interventions and defining the course of the pregnancy and fetus's prognosis.


Can neprilysin inhibition improve markers of cardiovascular structure and function in patients with pre–heart failure with preserved ejection fraction?In this randomized clinical trial of 250 asymptomatic patients, sacubitril/valsartan vs valsartan was associated with a reduction in blood pressure, pulse pressure, and N-terminal pro-b-type natriuretic peptide; an increase in maximal left atrial volume index measured by cardiac magnetic resonance imaging despite lower filling pressures; less decline in kidney function; and fewer serious adverse cardiovascular events.These findings could reflect improved cardiac and vascular compliance or adverse cardiac remodeling, and more work is required to understand the long-term implications. This randomized clinical trial evaluates the efficacy of sacubitril/valsartan vs valsartan in the treatment of left ventricular diastolic function in patients with pre–heart failure with preserved ejection fraction. Pre–heart failure with preserved ejection fraction (pre-HFpEF) is common and has no specific therapy aside from cardiovascular risk factor management.To investigate the hypothesis that sacubitril/valsartan vs valsartan would reduce left atrial volume index using volumetric cardiac magnetic resonance imaging in patients with pre-HFpEF.2, and preserved ejection fraction greater than 50% were included.The Personalized Prospective Comparison of ARNI [angiotensin receptor/neprilysin inhibitor] With ARB [angiotensin-receptor blocker] in Patients With Natriuretic Peptide Elevation (PARABLE) trial was a prospective, double-blind, double-dummy, randomized clinical trial carried out over 18 months between April 2015 and June 2021. The study was conducted at a single outpatient cardiology center in Dublin, Ireland. Of 1460 patients in the STOP-HF program or outpatient cardiology clinics, 461 met initial criteria and were approached for inclusion. Of these, 323 were screened and 250 asymptomatic patients 40 years and older with hypertension or diabetes, elevated B-type natriuretic peptide (BNP) greater than 20 pg/mL or N-terminal pro-b-type natriuretic peptide greater than 100 pg/mL, left atrial volume index greater than 28 mL/mPatients were randomized to angiotensin receptor neprilysin inhibitor sacubitril/valsartan titrated to 200 mg twice daily or matching angiotensin receptor blocker valsartan titrated to 160 mg twice daily.Maximal left atrial volume index and left ventricular end diastolic volume index, ambulatory pulse pressure, N-terminal pro-BNP, and adverse cardiovascular events.2; 95% CI, 0.0 to 13.7) vs valsartan  despite reduced markers of filling pressure in both groups. Changes in pulse pressure and N-terminal pro-BNP were lower in the sacubitril/valsartan group  than the valsartan group . Major adverse cardiovascular events occurred in 6 patients (4.9%) assigned to sacubitril/valsartan and 17 (13.3%) assigned to receive valsartan .Among the 250 participants in this study, the median (IQR) age was 72.0 (68.0-77.0) years; 154 participants (61.6%) were men and 96 (38.4%) were women. Most (n = 245 [98.0%]) had hypertension and 60 (24.0%) had type 2 diabetes. Maximal left atrial volume index was increased in patients assigned to receive sacubitril/valsartan (6.9 mL/mIn this trial of patients with pre-HFpEF, sacubitril/valsartan treatment was associated with a greater increase in left atrial volume index and improved markers of cardiovascular risk compared to valsartan. More work is needed to understand the observed increased cardiac volumes and long-term effects of sacubitril/valsartan in patients with pre-HFpEF.NCT04687111ClinicalTrials.gov Identifier:  However, the STOP-HF trial2 lacked a specific pharmacological therapy, and the intervention was directed at a general population with cardiovascular risk factors. Studies of other pharmacological therapies in patients with cardiovascular and metabolic risk factors in whom pre-HF was present have shown reduced incident heart failure and cardiovascular events.9 In patients with pre-HF with reduced left ventricular ejection fraction, angiotensin-converting enzyme inhibitor therapy has been associated with a reduction in incident heart failure.10 However, the high prevalence of pre-HFpEF in community populations, an estimated 30% to 63% of older adults with hypertension or diabetes,13 underlines a need for more studies targeting this cohort.The 2022 American Heart Association/American College of Cardiology (AHA/ACC) guidelines for management of heart failure highlight the importance of community identification of pre–heart failure  because of its association with increased heart failure and cardiovascular risk.1 Aging, long-standing hypertension, diabetes, obesity, and chronic inflammatory comorbidities predispose individuals to abnormalities in cardiac chamber and vascular compliance leading to tissue stiffness, increased filling pressures, hypertrophy, reduced stroke volume, and reactive myocardial fibrosis.22 The release of natriuretic peptides, predominantly in the myocardium, is an endogenous protective response, helping to preserve compliance and function by enhancing cardiac and vascular smooth muscle cyclic guanosine monophosphate.25 Sacubitril/valsartan is a first-in-class angiotensin neprilysin receptor inhibitor that reduces degradation of a range of vasoactive substances including natriuretic peptide. Along with other therapies,28 it has been investigated in symptomatic HFpEF.30 Yet, to our knowledge, no study to date has evaluated sacubitril/valsartan in a prespecified cohort with pre-HFpEF.The pre-HFpEF diagnosis requires the absence of symptoms of heart failure, which is highly subjective. Nonetheless, the 2022 AHA/ACC guidelines say it can be diagnosed in asymptomatic patients with preserved ejection fraction by the presence of at least 1 of the following: structural heart disease, including elevated left atrial size; increased filling pressures; cardiovascular risk factors with increased natriuretic peptides; or persistently elevated cardiac troponins, in the absence of competing diagnoses.The Personalized Prospective Comparison of ARNI [angiotensin receptor/neprilysin inhibitor] with ARB [angiotensin-receptor blocker] in Patients With Natriuretic Peptide Elevation (PARABLE) randomized, double-blind, double-dummy, active comparator trial was conducted from April 2015 to June 2021 at a single outpatient cardiology center in Dublin, Ireland. The trial was designed to investigate the hypothesis that sacubitril/valsartan vs valsartan would reduce left atrial volume index over 18 months using volumetric cardiac magnetic resonance imaging in patients with pre-HFpEF. Ethical approval was obtained by the St Vincent’s University Hospital Ethics Committee and competent authority approval was obtained from the Health Protection Regulatory Authority in Ireland . The protocol is available in 2 obtained using echocardiography).22 As detailed in the protocol, we reduced the entry BNP and LAVI thresholds early in the study from 35 pg/mL and 34 mL/m2 respectively to include a low-risk population, based on the observation that almost 3 in 10 major adverse cardiovascular events in the original STOP-HF trial2 occurred in patients with baseline BNP in the range of 20 to 49 pg/mL. Detailed inclusion and exclusion criteria are provided in eTable 1 in Patients gave written informed consent to participate in the study before any study-related assessments were performed. Patients 40 years and older with systemic hypertension (medicated for more than 1 month) and/or type 2 diabetes were included and had the following at screening or within 6 months prior to screening: elevated blood B-type natriuretic peptide  or N-terminal pro b-type natriuretic peptide ; and enlarged transthoracic left atrial volume index  or on low or no dose of angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker at the baseline visit. Full details of the medication manufacture, randomization, blinding, allocation concealment, and titration protocol are in eMethods 2 and eTable 2 in Full details of the study assessments and schedule are included in eMethods 3 and eTable 3 in 31The primary end point was the adjusted change in maximal LAVI measured by volumetric cardiac MRI, indexed to body surface area using the DuBois formula. Secondary outcomes were changes in NTproBNP, pulse pressure (PP), cardiac MRI measurements of structure  and function , indirect assessment of left ventricular filling pressure using Doppler echocardiography, average ratio of early transmitral flow velocity to early diastolic mitral annular tissue velocity (E/e′), and time to first major adverse cardiovascular event over the course of the study. Major adverse cardiovascular event was defined as cardiovascular death or a serious adverse cardiovascular event due to arrythmia , transient ischemic attack, stroke, valvular heart disease, myocardial infarction, deep vein thrombosis or pulmonary embolus, or heart failure requiring hospital admission. Serious adverse events related to the cardiac or vascular system were defined using European Medicines Agency guidelines as events that cause death, are life threatening, require inpatient hospitalization or prolongation of existing hospitalization, or result in serious disability/incapacity.29 and the use of a more precise imaging technique (volumetric cardiac MRI) for the primary end point, the expected effect size (2.0/5.0 = 0.40) required 96 patients in each group, using a 2-tailed α value of 5% and β of 20%. The study also had at least 80% power with a 2-tailed α of 5% to detect a 6 g/m2–difference in left ventricular mass index change by cardiac MRI and a 2-unit difference in E/e′ or e′ using tissue Doppler measurements. Primary and secondary outcome measures were analyzed with adjustment for the following variables, unless otherwise specified: age, sex, diabetes, hypertension, obesity, and vascular disease and for baseline measures of the outcome of interest. Categorical end points  were analyzed through hazard ratios by deploying Cox proportional hazards modeling. COVID-19–related procedures are outlined in eMethods 3 in Details on sample size calculations and statistical methods are presented in eMethods 4 in 2 or outpatient cardiology clinics, 461 (31.6%) had BNP greater than 20 pg/mL, ejection fraction greater than 50%, and LAVI greater than 28 mL/m2. Of these, 323 were willing to participate in screening for eligibility and inclusion in the PARABLE trial. After exclusions, 250 were randomly assigned to double-blind, double-dummy treatment with sacubitril/valsartan (n = 122) or valsartan (n = 128). In total, 245 of these patients (98%) had at least 1 feature of pre-HFpEF according to the 2022 AHA/ACC guidelines. The CONSORT diagram, including a breakdown of these data, is presented in From April 5, 2015, to December 12, 2018, among 1460 patients with available BNP and Doppler echocardiography attending the St Vincent’s University Healthcare Group STOP-HF program2. Population blood pressure control, dyslipidemia management, glucose control, and kidney function was generally good. Almost all participants (n = 245 [98.0%]) had hypertension and 60 (24.0%) had type 2 diabetes. Median (IQR) blood levels of BNP and echocardiographic LAVI at baseline were 57 (33-100) pg/mL and 33.2 (30.7-38.0) mL/m2, respectively. Tricuspid regurgitation velocity was measurable in less than half of the population. Similar numbers of patients with sacubitril/valsartan (n = 33) and valsartan (n = 28) had abnormal  pulmonary artery systolic pressure and 34 patients total (13.6%) had high-risk H2FPEF scores (≥6) (Baseline characteristics by treatment group are given in res (≥6) . More deres (≥6) . The tri2; 95% CI, 0.0 to 13.7) vs valsartan   vs the valsartan group  (Detailed Doppler echocardiography and cardiac MRI imaging data are presented in  < .001) A. SimilaP = .02) B.P = .002) as well as SBP . The LVEDV standardized to a filling pressure of 30 mm Hg (EDV30) was increased by a median (IQR) 13.8 mL (0.36 to 30.0) in the sacubitril/valsartan group vs 3.85 (−12.76 to 12.3); 30.0 in those treated with valsartan (P < .001). Left ventricular mass index was reduced in both groups without between-group differences. An analysis of the primary end point including only those patients who completed the study cardiac MRI per-protocol in the same institution prior to onset of COVID-19 restrictions showed the same result as the primary analysis . More detail on biochemistry measures at baseline and follow-up are presented in eTables 6 and 7 in 2) was significantly greater than in those assigned to sacubitril/valsartan .Ambulatory blood pressure data over 24 hours showed significant reductions in SBP, diastolic blood pressure, and PP in patients treated with sacubitril/valsartan vs those treated with valsartan . Using rP < .001) over the study period. BNP levels were maintained at baseline levels throughout the study.There was a significant reduction in NTproBNP over time observed in the sacubitril/valsartan vs valsartan group, which was sustained throughout the study . Using r2 vs valsartan 1.90 [0.21] m2; P = .04), median (IQR) Doppler echocardiographic E/e′  and mean (SD) cardiac MRI measured LAVI max .In post hoc analyses, small but significant differences between the 2 groups at baseline were noted in the mean (SD) body surface area among those who attended for cardiac MRI .Overall, both treatments appeared to be well tolerated  had high H2FpEF scores, and we did not carry out formal functional assessments, such as the Kansas City Cardiology Questionnaire or 6-minute walk test, nor did we carry out cardiac MRI assessments of patients at an interim 9-month period. Accordingly, we cannot comment on the time course of the observations reported. PARABLE is not designed or powered to provide definitive evidence on the cardiovascular outcomes over longer follow-up. Moreover, the generalizability of the PARABLE study maybe limited by the exclusion criteria adopted and the homogenous ancestry of the participating population.The results of the PARABLE trial showed that sacubitril/valsartan can increase left atrial volume index in the setting of reduced markers of filling pressure in hypertension or diabetes in patients with pre-HFpEF. This may reflect improved vascular compliance and reduced cardiac chamber stiffness mediated pharmacologically by natriuretic peptide modulating therapy. However, more work is required to exclude adverse effects of increased chamber volumes and to understand the long-term benefits and risks of sacubitril/valsartan in treating pre-HFpEF.


Enhanced de-novo collagen type VI (COL VI) formation has been associated with kidney and cardiovascular fibrosis. We hypothesized that endotrophin (ETP), a product specifically generated during collagen type VI formation, may be prognostic for heart failure (HF), cardiovascular death (CVD), kidney endpoints, and all-cause mortality in patients with type 2 diabetes.We measured ETP in plasma (P-ETP) and urine (U-ETP) samples collected at baseline and follow-up (year 3) from the randomized controlled trial, CANagliflozin cardioVascular Assessment Study (CANVAS), by use of the PRO-C6 ELISA measuring COL VI formation and ETP. At baseline, plasma and urine samples were available for 3531 and 3423 patients, respectively. At year 3, plasma and urine samples were available for 2178 (61.7%) and 2070 (60.5%) patients, respectively Patients were followed for a median of 6.1 years, and endpoints included: incident HF, CVD, three kidney composite endpoints, and all-cause mortality. Backward selection was used to identify variables to be included in the analyses. Robustness of the association with outcome was assessed by bootstrap analyses.In univariable analysis, P-ETP predicted all investigated outcomes , remained independently associated with all outcomes after adjustment for conventional risk factors , and increased C-statistics of the models for the outcomes HF, CVD, HFCVD, all-cause mortality, and kidney composite 2 (ΔC ≥ 0.002). In bootstrap analysis, P-ETP was retained with a frequency ranging from 41.0 to 98.4% for all outcomes. Levels of U-ETP were associated with outcomes in univariable analysis, but associations with most outcomes were lost after adjustment for conventional risk factors. The increase in P-ETP over time was greater with increasing albuminuria stage (p < 0.0001) and was independently associated with the kidney endpoints (p < 0.03). In the placebo arm, the increase in P-ETP was prognostic for all-cause mortality . Whereas levels of P-ETP were not impacted by treatment, levels of U-ETP significantly increased with canagliflozin treatment.P-ETP generated during COL VI formation predicts cardiovascular, kidney and mortality outcomes in patients with type 2 diabetes. As ETP identifies patients at increased risk of experiencing relevant outcomes, it may be used for patient enrichment in future clinical trials.Trial Registry Number : NCT01032629The online version contains supplementary material available at 10.1186/s12933-022-01666-7. What is already known about this subject? (maximum of 3 bullet points)Patients with type 2 diabetes are at increased risk of experiencing cardiovascular and kidney outcomes, and mortalityCanagliflozin has been suggested to have anti-inflammatory and anti-fibrotic effectsEndotrophin (ETP) has been shown to be prognostic for outcomes in a small observational study of patients with type 2 diabetesWhat is the key question? Is ETP associated with increased risk of experiencing clinically relevant outcomes in a clinical trial population?What are the new findings? (maximum of 3 bullet points)ETP is a robust, independent prognostic marker for predicting outcome in a clinical trial population of patients with type 2 diabetesETP is not affected by canagliflozin treatment in patients with type 2 diabetesAn increase in ETP is associated with increased risk of all-cause mortalityHow might this impact on clinical practice in the foreseeable future? (one bullet point only)ETP levels may be used to enrich clinical trials for patients at risk of outcome. In line with this, the FDA has issued a Letter of Support for the prognostic marker PRO-C6 (ETP) in the setting of heart failure.Type 2 diabetes is the most common etiology in patients with chronic kidney disease (CKD). Diabetic patients are prone to develop moderately increased albuminuria which is associated with an accelerated deterioration of kidney function . Sodium There are limited data on the effects of SGLT2 inhibitors on the ECM. Previous studies in patients with both type 1 and 2 diabetes have revealed that ETP is able to predict kidney and cardiovascular outcome , 21. In This post hoc, exploratory analysis was conducted using a subset of stored plasma samples from the CANVAS trial , which was a randomized, multicenter, double-blind, parallel, PBO-controlled study that evaluated the efficacy and safety of CANA 100 and 300 mg . The inclusion and exclusion criteria have been described in previous publications . In shorBaseline plasma samples from 3531 patients and urine from 3423 patients were available for this study. At year 3, plasma and urine samples were available for 2178 (61.7%) and 2070 (60.5%), respectively. ETP was measured in plasma (P-ETP) and urine (U-ETP) using a previously described competitive enzyme-linked immunosorbent assay, namely PRO-C6, developed by Nordic Bioscience, Denmark . Figure 2. Association of U-ETP with outcome. Patients were stratified based on baseline U-ETP into tertiles and Kaplan-Meier curves were plotted for each tertile. Risk was assessed with reference to tertile 1 for A) heart failure (HF), B) CV death, C) the composite of HF and CV death, D) all-cause mortality, E) the kidney composite endpoint 1 , F) -2 , and G) -3 .


NAFLD was diagnosed based on ultrasound examination, Hepatic Steatosis Index (HSI) and Fatty Liver Index. Baseline anthropometric, blood pressure and biochemical parameters were collected. The serum irisin level was determined using an ELISA test. We observed that NAFLD was associated with an increased concentration of irisin. Moreover, Spearman correlations and linear regression analysis revealed that irisin level correlates with some anthropometric and biochemical parameters such as body mass index, glycated hemoglobin, aspartic aminotransferase, creatinine and urea. Logistic regression analysis depicted that odds for NAFLD increase 1.17 times for each 1 μg/mL rise of irisin concentration. Finally, ROC analysis showed that the concentration of irisin possesses a discriminate capacity for NAFLD and optimal cut points concentration could be designed. The risk of NAFLD in the subgroup with irisin concentration above 3.235 μg/mL was 4.57 times higher than in patients with the lower concentration of irisin. To conclude, the obtained results suggest that irisin concentration is associated with some anthropometric and biochemical parameters and should be further investigated toward its usage as a diagnostic biomarker of NAFLD.Irisin is a cytokine involved in many metabolic pathways occurring, among others, in muscles, adipose tissue and liver. Thus, fluctuations in irisin levels are suggested to be related to metabolic diseases. Therefore, the purpose of our study was to evaluate whether irisin may be associated with non-alcoholic fatty liver disease (NAFLD). A total of 138 patients  were enrolled in the study. The patients were assigned to the NAFLD group ( Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver pathologies and is the main reason for patients reporting to hepatologists . The disThe presence of NAFLD is associated with the risk of health consequences. They result from both the natural progression of liver disease  and an increased risk of developing other pathologies, such as cardiovascular complications  and non-HCC malignant neoplasms  ,6. RecenNAFLD diagnostics raise much controversy. To date, liver biopsy remains the gold standard procedure for the diagnosis of NASH and the staging of NAFLD. The usefulness of this diagnostic tool in daily medical practice raises much controversy, especially in view of the fairly good prognosis for most NAFLD patients, the lack of a definitively established form of therapy and the risks and costs associated with performing this test. Regardless of the non-invasive NAFLD diagnostic tool used, other secondary causes of fatty infiltration of the liver should be ruled out first, including alcohol abuse, certain medications, genetic and chronic diseases, and environmental factors . To asseIrisin is a hormone involved in metabolic pathways; namely, it increases the uptake of glucose and fatty acids by muscles, reduces gluconeogenesis and stimulates glycogenesis in the liver, as well as converts white adipose tissue (WAT) into brown adipose tissue. Irisin was also demonstrated to diminish the severity of inflammation as well as to affect the function of kidneys, neurons, bones, endothelial cells and beta cells of the pan-creas ,16. ManyTherefore, the aim of this study was to determine whether irisin may be related to NAFLD. To achieve this goal, we assessed the correlation between the irisin levels determined by ELISA test and the prespecified anthropometric and metabolic parameters in groups of patients with and without NAFLD diagnosis due to ultrasound examination, HSI and FLI.In total, 138 adult patients aged 65.61 ± 10.44 years on average (including 68 women and 77 patients with T2DM) hospitalized between January 2016 and April 2016 for various internal medicine diseases at the Department of Internal Medicine, Diabetology and Clinical Pharmacology at the Medical University of Lodz were included in the study. The study was approved by the Bioethics Committee of the Medical University of Lodz. Prior to enrollment, each participant provided written consent to participate in the study. Exclusion criteria included the presence of secondary causes of excessive fatty liver infiltration , Amanita phalloides mushrooms, phosphorous poisoning, petrochemicals and Bacillus cereus toxin), prediabetes and type 1 diabetes mellitus, gestational or other than T2DM, diseases that may affect muscle metabolism such as glycogen metabolism disorders, lipid metabolism disorders and mitochondrial myopathies, severe kidney or liver dysfunction (including those who had had an organ transplant), musculoskeletal damage, or a surgery undergone during the last 6 months, pregnancy and severe infections. The enrolled patients had a medical history and underwent a physical examination. The necessary diagnostic tests for glucose metabolism abnormalities (according to ADA) or the presence of secondary causes of fatty livers were performed. Blood pressure  and anthropometric measurements  and hip circumference (HC)) were measured and used to calculate the body mass index (BMI) and waist-hip ratio (WHR). Next, blood samples were taken to determine fasting plasma glucose (FPG), glycated hemoglobin level (HbA1c), total cholesterol (T-CH), LDL cholesterol (LDL-CH), HDL cholesterol (HDL-CH), triglycerides (TG), total bilirubin, uric acid, urea, creatinine concentrations, liver enzymes, including alanine aminotransferase (ALT), asparagine (AST) and gamma-glutamyltransferase (GGTP) activity. Postprandial plasma glucose (PPG) was measured two hours after standardized breakfast . These markers were measured using standard laboratory methods. The estimated glomerular filtration rate (eGFR) was calculated based on the Modification of Diet in Renal Disease (MDRD) equations. An ultrasound examination (US) was also performed by an experienced radiologist to assess the presence of hepatic steatosis. Hepatic steatosis was assessed based on observations including (1) increased liver echogenicity compared to the renal cortex; (2) decreased conspicuity of hepatic vasculature; (3) presence of focal fat sparing; and (4) decreased ability to visualize the diaphragm and deeper liver parenchyma. We also calculated the HSI and FLI to confirm the presence of fatty liver by ultrasound examination. 2). HSI values of 36 and above indicate that the presence of NAFLD is highly likely. Values below 30 indicate that NAFLD can be ruled out [The HSI was calculated using the following index equation:uled out . The FLI was calculated from the formula:FLI scores of 60 and above indicate that NAFLD is present, between 30 and 60 remain inconclusive and below 30 indicate that NAFLD should be ruled out .n = 72, including 46 patients with T2DM) and patients without NAFLD . The patients were assigned to the following groups: patients with concomitant NAFLD , the diagnosis of NAFLD seemed questionable and the patient was not enrolled in the study.After blood sampling, the serum was separated and frozen at a temperature of −80 °C. Serum concentration of irisin was determined using an ELISA Kit  according to the manufacturer’s protocol. The inter-assay variability and intra-assay variability were <7% and <8%, respectively.p < 0.05 was considered statistically significant.The anthropometric and biochemical characteristics as well as irisin concentration of the groups were expressed as medians with lower and upper quartiles. As the distribution of variables was not in accordance with normality determined by the Shapiro–Wilk test, the differences between 2 groups were assessed by the Mann–Whitney U test. A Chi square test was performed for sex ratio and T2DM ratio comparisons in the groups. The relationship between irisin concentration and anthropometric and biochemical parameters was evaluated using a Spearman (non-parametric) correlation coefficient. The most significant irisin-related variables were determined using the stepwise forward multiple regression method. Logistic regression analysis was conducted to assess the relationship between the risk of NAFLD and irisin concentration. The non-parametric variables included in the linear regression analysis were logarithmically transformed. Receiver Operating Characteristic (ROC) analysis with an area under the curve (AUC) as a quality index was carried out to determine the potential of irisin concentration as a diagnostic tool. The optimal cut-point was determined by means of the Younden index method (cut-point 3.235 μg/mL). The patients were divided into two subgroups according to the cut point of irisin concentration. The difference in frequency of NAFLD between the subgroups was tested by Chi square test with Yates correction. All analyses were performed using GraphPad Prism 8.0 software  and STATISTICA 13.0 software . The comparison of the studied groups (+NAFLD and −NAFLD) in terms of age, sex, T2DM occurrence, anthropometric parameters and blood pressure is presented in p < 0.01).As depicted in p = 0.0023). The optimal cut-point was determined by means of the Younden index method (cut-point 3.235 μg/mL). The patients were divided into two subgroups according to the cut-point of irisin concentration. The difference in frequency of NAFLD between the subgroups was tested by the Chi square test with Yates correction (p = 0.0009). The risk of NAFLD in the subgroup with a higher irisin concentration was found to be above 4 times higher than that in the subgroup with a low concentration of irisin .To explore the potential of irisin concentration as a diagnostic tool for NAFLD risk, ROC analysis was conducted  . HoweverIrisin is a peptide produced from proteolytic cleavage, glycosylation and probably dimerization of processing of Fibronectin type III domain-containing protein 5 (FNDC5) . The expWe found that NAFLD patients had elevated irisin levels. To determine the potential of irisin concentration as a diagnostic tool for NAFLD risk, we conducted multiple statistical analyses, including logistic regression and ROC analysis. Our results have shown that the risk of NAFLD is above 4 times higher if irisin concentrations are higher than 3.235 μg/mL. Additionally, we found that NAFLD increases 1.17 times for each 1 μg/mL rise of irisin concentration. Data on irisin concentrations in NAFLD patients are inconsistent and leave a lot of confusion. Most studies indicate a decreased concentration in this group of patients ,35,36. HIn studies assessing the concentration of irisin, imaging tests  or liver biopsies are the main methods for diagnosing fatty liver infiltration ,37,38,39FNDC5 and irisin have been detected mainly by 3 antibody-dependent methods: Western blot , enzyme-linked immunosorbent assays  and protein liquid chip assay . Among all the methods, mass spectrometry  with quantification peptides is considered the “gold standard” for the measurement of protein concentrations. However, the credibility of this method raises a lot of controversy because high methodological variability, preparation of plasma or serum samples for MS requires removal of highly abundant albumins and immunoglobulins and subsequent concentration, which leads to varying amounts of retained proteins for analysis and the very low MS values question the validity of a large proportion of all reported irisin levels measured with ELISA . In our The study population, which differs in age, sex, obesity or overweight, presence of dyslipidemia, T2DM/prediabetes, physical activity or other comorbidities, may have a significant impact on irisin concentration. It should be noted that when other causes of fatty liver were excluded, different amounts of alcohol were considered ,35,37,39In our study, patients with NAFLD had statistically higher body weight, WC, HC, BMI, WHR, ALT, AST, GGTP and TG than patients without NAFLD. Interestingly, the number of patients suffering from T2DM was statistically significantly greater in the +NAFLD group than in the −NAFLD group. There were no statistically significant differences between the groups in age, sex, height, blood pressure, markers of carbohydrate metabolism , kidney function , total bilirubin, T-CH, LDL-CH, HDL-CH and uric acids. In Polyzos’s study, NAFLD patients did not differ in age, BMI, WC, HDL-CH, uric acids and glucose concentration, but had higher AST, ALT, GGTP and TG values than patients without NAFLD. In linear regression analysis, irisin was independently inversely associated after adjustment for BMI or WC, gender and age in the NAFLD group . AnotherConsidering the results we obtained, it is also worth mentioning the previously suggested relationship between a higher concentration of irisin and the progression of NAFLD related to the increase in fat content in the liver, the onset of inflammation and the process of fibrosis. It has been shown that the level of this myokine may indicate a more aggressive liver disease phenotype associated with increased intrahepatic fat content, fibrogenesis and more severe liver damage ,48. ThisAs mentioned, some NAFLD patients develop disease progression and development of NASH, liver fibrosis and cirrhosis. It has been shown that polymorphism in the FNDC5 gene (rs3480) is associated with NAFLD progression to NASH and liver fibrosis. It should be highlighted that this effect is independent but additive to the patatin-like phospholipase domain-containing 3 (PNPLA3) and the transmembrane 6 superfamily member 2 (TM6SF2)—two major inherited determinants of hepatic fat accumulation, based on genome-wide association studies . AdditioThe following limitations of our study should also be recognized. Our study is biased by its design, namely a cross-sectional observational study, although the participants were randomly selected. The study included a relatively low number of patients. In our study, we also did not include information about physical activity before inclusion in the study, which might have affected the concentration of irisin. Some studies have suggested that aerobic exercise training promotes irisin secretion . HoweverThe obtained results suggest that irisin may be used as a diagnostic biomarker of NAFLD since it correlates with anthropometric and biochemical parameters associated with liver function. The obtained results suggest that irisin may be used as a diagnostic biomarker of NAFLD since it correlates with anthropometric and biochemical parameters associated with liver function.


Objective: The frontal QRS-T angle (fQRS-T) is linked to myocardial ischemia and ventricular arrhythmias. On the other hand, non-dipper hypertension is a risk factor for cardiac adverse events. The objective of this research was to determine whether the fQRS-T, a marker of ventricular heterogeneity, could be used to predict non-dipper hypertensive individuals in the lack of left ventricular hypertrophy.Methods: The observational study was carried out retrospectively. Patients diagnosed with hypertension were included in this study. Blood tests were routinely conducted for all patients. Electrocardiography (ECG) was conducted for each patient and echocardiography was performed. Blood pressure (BP) values were collected from the ambulatory Holter records. According to ambulatory Holter monitoring, the individuals were separated into two groups. The association between fQRS-T and hypertension was investigated.Results: The research involved 123 patients, with an average age of 51.85±8.22 years, comprising 76 women (61.8%) and 47 males (38.2%). According to ambulatory Holter monitoring, patients were separated into dippers (n=65) and non-dippers (n=58). There were no statistically significant in the laboratory and echocardiographic variables (p>0.05). QT dispersion (QTd) and fQRS-T were substantially greater in the non-dipper group than in the dipper group . Independent determinants of non-dipper status were determined by univariate and multivariate logistic regression analyses. fQRS-T was found to be the only independent indicator of non-dipper status .Conclusion: The fQRS-T may be a useful marker for estimating non-dipper hypertensive individuals in the lack of left ventricular hypertrophy. Hypertension is a serious cardiovascular disorder that affects a high number of people and causes severe morbidity due to organ dysfunction. Hypertension can cause cerebral hemorrhage or stroke, loss of vision in the eye, heart failure, heart attack, and kidney failure . High blBlood pressure (BP) fluctuates during the day. BP is maximum in the morning, gradually declines over the day, and remains minimum at night. According to ambulatory BP monitoring, dipper hypertension is diagnosed when nighttime BP drops by almost 10% compared to daytime levels, whereas non-dipper hypertension is diagnosed when the reduction is less than 10% . HypertePrevious research has indicated that the QT interval, QT dispersion (QTd), and corrected QT dispersion (cQTd) were longer in non-dipper hypertensive individuals than in dipper individuals . BecauseThe goal of this study is to examine whether the fQRS-T, a predictor of ventricular heterogeneity, could be used to predict non-dipper hypertensive individuals in the lack of left ventricular hypertrophy.Study design and subjectThe study was conducted at a single center between 2020 and 2022. The study population was established through a retrospective, observational study. Patients with arterial hypertension diagnosed by ambulatory Holter monitoring were included in the research. A total of 123 patients with arterial hypertension were enrolled in this research. Patients with coronary artery disorders, active cancer, hyperthyroidism, mild or severe valve disease, heart failure, chronic renal failure, left ventricular hypertrophy, chronic obstructive pulmonary disease, or congenital heart disease were excluded. Patients whose data were inaccessible and whose analysis was unsuccessful were excluded from this study. The local ethics committee  approved the study protocol (No: 2022-251) dated December 9, 2022. It adhered to the Declaration of Helsinki's ethical guidelines for human experimentation (2013).Study protocolAll patients routinely underwent blood tests containing hemoglobin, creatinine, sodium (Na), potassium (K), fasting plasma glucose, aspartate and alanine aminotransferase, high/low-density lipoprotein, triglycerides, and thyroid-stimulating hormone. A 12-lead ECG was performed with an electrocardiograph  at a rate of 25 mm/s and 10 mm/mV amplitude for each patient. Echocardiography examinations were performed with a phased array transducer (S4-2) using an ultrasonography device . BP measurements were obtained from the ambulatory Holter  records.DefinitionsECGs were evaluated and analyzed by two specialists who were blinded to the study. The fQRS-T is the angle formed by the difference between the QRS and T axes Figure .When the angle surpassed 180 degrees, it was changed to the lowest possible angle (360 degrees). The fQRS-T was generated from automatically obtained ECG device data.The ambulatory BP Holter recorder device was worn by qualified and experienced personnel. Systolic BP ≥140 mm Hg and/or diastolic BP ≥ 90 mm Hg, history of hypertension, or use of antihypertensive medications were defined as hypertension. Between 07:00 and 23:00, blood samples were collected every 15 minutes, and between 23:00 and 07:00, every 20 minutes. Utilizing brief temporal intervals, the period from 10:00 to 22:00 was deemed daytime, whilst the period from 24:00 to 6:00 was deemed nighttime. Non-dipper hypertension was described as systolic and diastolic BP values that decreased by less than 10% or remained stable. When the mean systolic and diastolic blood pressure values decreased by more than 10%, it was categorized as dipper hypertension.StatisticsFor the analysis, IBM SPSS Statistics for Windows, Version 24.0  was used. Initial continuous variables are shown as mean standard deviation or median (interquartile range). Applying Kolmogorov-Smirnov, and Shapiro-Wilk tests, the normality distribution of the variables was determined. Categorical variables were represented with frequencies and percentages. Chi-square or Fisher's exact test is utilized for categorical variables. To compare continuous variables, a Student's t-test or Mann-Whitney U-test was used. If the p-value was less than 0.05, tests were judged statistically meaningful.The research involved 123 patients, with an average age of 51.85±8.22 years, comprising 76 women (61.8%) and 47 males (38.2%). The patients' clinical characteristics were summarized in Table According to ambulatory Holter monitoring, patients were separated into dippers (n=65) and non-dippers (n=58). There were no statistically significant in the laboratory and echocardiographic variables, as shown in Table Patients' electrocardiographic parameters were analyzed and evaluated Table .QTd and fQRS-T were substantially greater in the non-dipper group than in the dipper group . Independent determinants of non-dipper status were established by univariate and multivariate logistic regression analyses. fQRS-T was found to be the only independent indicator of non-dipper status   curve revealed that an elevated fQRS-T >30.5 degrees predicted non-dipper hypertension with 78.3% sensitivity and 83.4% specificity  (Figure This research revealed that the QTd and fQRS-T were higher in non-dipper hypertensive patients. An Independent association was found between fQRS-T and non-dipper hypertension.Nighttime BP is a substantial risk factor and a potential treatment focus for cardiovascular disease and mortality in both hypertensive and healthy individuals . Almost Ventricular repolarization parameters such as QT duration, QTd, and cQTd were found prolonged in hypertensive individuals . AccordiIn clinical practice, discovering novel ECG characteristics like fQRS-T may be valuable for predicting the onset of non-dipper hypertension. The fQRS-T, an indication of heterogeneity in ventricular activation and conduction, is the angle between ventricular depolarization and repolarization . There aOne research showed that the fQRS-T is a predictor for newly diagnosed hypertension individuals . Zehir eLimitationsThe study population was small. Individuals were not systematically monitored for comparing arrhythmia episodes to fQRS-T. Lastly, the results did not apply to all hypertension individuals since dysrhythmia and ventricular hypertrophy patients were excluded.This study showed that the FQRS-T angle calculated greater than 30.5 degrees on the superficial ECG may be a useful indicator for detecting non-dipper hypertension in hypertensive patients without left ventricular hypertrophy. In clinical follow-ups, the non-invasive and straightforward fQRS-T method may be used and non-dipper hypertensive patients could be treated effectively. With this strategy, early diagnosis may avert adverse events. More multicenter studies are needed for routine clinical usage.