Red cell distribution width (RDW) is a parameter that indsicates the heterogeneity of red blood cell size and could be a prognostic factor in some diseases. Also, intracerebral hemorrhage (ICH) is considered a vascular event with a high mortality rate. We aimed to examine the role of RDW, neutrophil to lymphocyte ratio (NLR), and neutrophil to platelet ratio (NPR) in predicting the prognosis of patients with ICH.This is a retrospective cohort study conducted on 140 patients with ICH admitted to the neurology ward and intensive care unit (ICU) in Imam Reza Hospital, Tabriz, Iran. Demographic data, National Institutes of Health Stroke Scale (NIHSS), and complete blood count test parameters were evaluated within 24 h after hospitalization. These variables were collected and re-evaluated three months later.p = 0.05), neutrophil count (p=0.04), platelet count (p = 0.05), and NIHSS (p<0.01)  had a significant difference between the deceased patients and those who partially recovered after three months. The ROC curve showed that NIHSS (area under curve (AUC): 0.902), followed by NPR (AUC: 0.682) variables had the highest AUC.The mean age of the study population was 61.14 (± 16) years and 51% were male. The mean NLR (RDW could be a relevant prognostic factor and predictor in determining 3-months survival in ICH. Nevertheless, further large-scale prospective cohorts might be needed to evaluate the associations.The online version contains supplementary material available at 10.1186/s12883-022-02721-2. Red cell distribution width (RDW) is a parameter that represents the dispersion of erythrocyte volume. Coefficient of size changes of red blood cells is more accurate than the structure of red blood cells in peripheral blood smears , 2. The Neutrophil to lymphocyte ratio (NLR) and neutrophil to platelet ratio (NPR) are indices that can represent the activities of the inflammatory complex and inflammatory responses in the vascular bed . The NLRIn 2019, the total prevalent cases of ICH were 20.66 million : 18.02–23.42), which showed a 58.0% increase since 1990. Furthermore, ICH was accounted for 68.57 million (95% UI: 63.27–73.68) disability-adjusted life-years in 2019, which increased 25.0% since 1990 . It is aThe predictive value of some blood markers in patients with different types of strokes has been evaluated in the previous research . HoweverThe target population in the present retrospective cohort study was patients with ICH referred to Imam Reza Hospital, Tabriz, Iran, from 2014 to 2019. Using the random sampling method, a total number of 140 participants enrolled in the study. Patients over 18 years old and a definitive diagnosis of first-time cerebral hemorrhage with complete laboratory information were included in the study. Exclusion criteria were age under 18 years, history of cancer, end-stage liver disease, acute or chronic renal failure, receiving blood products in previous three months of hospitalization, ICH following trauma, and long-term duration  between ICH and hospitalization.Informed consent was obtained from all patients in the study. The study was approved by the regional ethics committee (Ethics Code: IR.TBZMED.REC.1398.797). All methods were performed in accordance with the national guidelines and regulations.Patient information, including age, gender, underlying diseases , CBC parameters including white blood cell count, lymphocyte and neutrophil count, hemoglobin concentration, hematocrit, erythrocyte count, mean corpuscular hemoglobin concentration (MCHC), RDW and platelet count, neurological function and severity of the stroke measured using the National Institutes of Health Stroke Scale (NIHSS) score were collected. Moreover, mortality at discharge, within 28 days, and three months later were collected. NLR was calculated by dividing absolute neutrophil count to the absolute lymphocyte count.The primary outcome was to determine the relationship between RDW, NLR and NPR with the 3-month prognosis of participants. The secondary outcomes were to determine the RDW, NLR and NPR mean values in patients with ICH. Also, we aimed to evaluate the short-term mortality rate and the effects of using RDW, NLR and NPR simultaneously to predict ICH prognosis.p-values less than 0.05 were considered statistically significant.Collected data were analyzed by SPSS statistical analysis software version 18 . First of all, the Smirnov-Kolmogorov test was used to assess the normal distribution of variables. Demographic variables were analyzed by descriptive statistical methods, and presented with percentage, frequency and mean ± standard deviation (SD). Analysis of quantitative variables was performed using independent sample T-test or Mann–Whitney U test. The n = 47), lobar hematoma (n = 11), thalamus (n = 24), and intraventricular (n = 31). In addition, infratentorial hematomas were located in pons (n = 15), midbrain (n = 1), and cerebellum (n = 11).The average age of 140 patients was 61.14 years with an SD of 16 and ranged from 18 to 96 years old. There were 71 males and 69 females in our sample Table . The medIn this study, the mortality of patients in a short period of 28-day hospitalization and 3 months was considered. Results of mortality study in two time periods showed that in the final result of 3 months, 11 people were added to the number of patients who died in comparison with the 28-day study period and the deceased participants increased from 33.6% to 41.4% , while the higher neutrophil count was associated with higher survival (p = 0.04)  was assessed and compared with a T-test between the two groups. Higher NIHSS scores were statistically significant with death within three months p < 0.0, while tThe receiver operating characteristic (ROC) curve was utilized to compare the predictions of deaths by variables, including RBC, NIHSS, NPR, NLR, and RDW at the end of the 3-month follow-up. We found that the NIHSS (area under curve (AUC): 0.902), followed by NPR (AUC: 0.682) variables had the highest AUC Fig. .Fig. 2ROThe findings of the present study showed that higher NIHSS score and lower neutrophil count are associated with death and NPR could be a mortality predictor in patients with ICH.RDW as an available laboratory factor, which is a marker of the variation in the volume of red blood cells , can be Of note, a wide range of diseases and even physiological conditions lead to changes in the level of RDW in the human body. For example, different types of anemia, inflammatory diseases, and cancers can cause changes in the size of red blood cells . Thus, RThe NLR is calculated as dividing the number of neutrophils to the number of lymphocytes in peripheral blood and measures the inflammatory response . An acutNumerous studies have shown that high levels of neutrophils are sensitive markers for determining mortality . JicklinWe acknowledge that our study had several limitations. First, since it was a retrospective study, restrictions in data collection, participant inclusion, and lack of a control group exist. Second, it was conducted in a single hospital. Third, the variables were only measured in two time points in 28-days, and 3-months and they were not remeasured during the period of hospitalization. Fourth, the follow-up was limited to 3 months and no long-term follow-up was conducted.The current study demonstrated that NIHSS and neutrophil count are associated with ICH mortality. According to the results of the present study, it is suggested to increase the sample size in future studies to increase the accuracy of the results, control and delete other probable variables affecting RDW in the sample, including the information about the region and volume of hemorrhage and evaluate the relationship between study variables and the prognosis of patients in different age groups.Additional file 1: Figure S1. Evaluation of mean variables by patient's final prognosis.


Kidney transplantation (KTx) is the preferred form of renal replacement therapy in chronic kidney disease (CKD) patients, owing to increased quality of life and reduced mortality when compared to chronic dialysis. Risk of cardiovascular disease is reduced after KTx; however, it is still a leading cause of death in this patient population. Thus, we aimed to investigate whether functional properties of the vasculature differed two years post-KTx (postKTx) compared to baseline (time of KTx). Using the EndoPAT device in 27 CKD patients undergoing living-donor KTx, we found that vessel stiffness significantly improved while endothelial function worsened postKTx vs. baseline. Furthermore, baseline serum indoxyl sulphate (IS), but not p-cresyl sulphate, was independently negatively associated with reactive hyperemia index, a marker of endothelial function, and independently positively associated with P-selectin postKTx. Finally, to better understand the functional effects of IS in vessels, we incubated human resistance arteries with IS overnight and performed wire myography experiments ex vivo. IS-incubated arteries showed reduced bradykinin-mediated endothelium-dependent relaxation compared to controls via reduced nitric oxide (NO) contribution. Endothelium-independent relaxation in response to NO donor sodium nitroprusside was similar between IS and control groups. Together, our data suggest that IS promotes worsened endothelial dysfunction postKTx, which may contribute to the sustained CVD risk. Over 800 million people currently live with chronic kidney disease (CKD), a leading cause of mortality worldwide . This fiEndothelial dysfunction describes the change from physiological to pathological activity in endothelial cells, characterized by prothrombotic activity, reduced vasodilation and a proinflammatory state . It is oThe effects of KTx on vascular function have been previously studied. While several studies suggest that KTx ameliorates vessel stiffness ,20, the In the present study, we hypothesized that living donor-KTx (LD-KTx) has beneficial effects on endothelial function and vessel stiffness in the microcirculation, assessed using EndoPAT—a device previously reported to identify patients with early coronary atherosclerosis and CVD ,30. TherCharacteristics of patients at baseline and postKTx are presented in p < 0.01; Firstly, we investigated the long-term effects of LD-KTx on components of EVA using EndoPAT. Reactive hyperemia index (RHI) was decreased postKTx compared to baseline in 20/27 (74%) patients (median (IQR): 2.18 (1.63–2.50) vs. 2.51 (2.17–2.91); p < 0.01; On the contrary, augmentation index (AIx) was attenuated postKTx compared to baseline in 21/27 (78%) patients (median (IQR): −6% (−17–2) vs. 4% (−7–10); vs. postKTx (median: 43.0 (37.3–56.5) ng/mL vs. 44.55 (37.3–52.3) ng/mL; p > 0.05; vs. postKTx (median: 515.1 (368.3–756.0) ng/mL vs. 479.0 (327.9–784.3) ng/mL; p > 0.05; Next, we investigated the effects of renal function restoration on two novel biomarkers of vascular function: P-selectin and matrix metalloproteinase 9 (MMP-9). No difference was observed for plasma P-selectin at baseline p < 0.05; P-selectin  after adjustment for covariates are depicted in bold.A multivariate model was calculated only for correlations for which a significant univariate correlation was found . Non-nor2, respectively; 38% of subjects were male.Finally, considering the above findings between IS and RHI/P-selectin postKTx, we investigated the ex vivo effects of IS in an isolated organ culture bioassay. Briefly, isolated resistance arteries from non-CKD individuals were cultured with 100 µM IS for 24 h before vascular function and structure were assessed using wire myography. The median (interquartile range) age and BMI of the participants were 44 (35–47) years and 25.9 (22.9–34–7) kg/mp < 0.001; p < 0.05; p > 0.05; Resistance arteries from the IS-incubated group (n = 6) showed reduced bradykinin (BK)-mediated endothelium-dependent relaxation compared to the control group  undergoing living-donor KTx at the Department of Transplantation Surgery at the Karolinska University Hospital. In this longitudinal study, all study participants were sampled immediately before KTx and two years postKTx before comparisons were made, including EndoPAT measurements, blood samples for future analysis of pre-specified markers and blood pressure readings. Basic patient characteristics are outlined in The Endo-PAT 2000 device  assessed RHI and AIx representing endothelial function and arterial stiffness, respectively. The test was performed by a trained investigator following the manufacturer’s instructions. In brief, participants were asked to refrain from talking and remain in a relaxed state for the duration of the study. While lying in a supine position, probes were inflated around the participants’ fingers and a blood pressure cuff was placed around the bicep of the test arm before both forearms were placed on arm supports. Additional foam anchor rings and tape were used to ensure the probes did not touch stray fingers or the arm supports. The examination consisted of three 5 min recordings. First, a baseline period of 5 min was recorded before blood flow in the brachial artery of the test arm was occluded for 5 min by rapidly inflating the blood pressure cuff to at least 60 mmHg above systolic blood pressure and no less than 200 mmHg. Finally, the occlusion was released by deflating the pressure cuff for a 5 min post-occlusion recording period. The EndoPAT software automatically calculated RHI and AI. RHI is quantified as a ratio of post-occlusion to pre-occlusion pressure in the test arm, divided by the ratio of post-occlusion to pre-occlusion pressure in the control arm. The AIx was calculated from the difference between the systolic peaks of the PAT waveform. The heart rate-corrected AIx (AIx@75) was used for further analysis .Blood specimens were routinely drawn at the time of KTx and postKTx (two years after). Subjects were fasted at the time of blood collection. Samples were stored for <2 h at 4 °C until centrifugation. Upon arrival at the laboratory, the blood samples were centrifuged at 2650G for 20 min, aliquoted and either processed immediately (standard techniques) or stored at −80 °C until analysis. Creatinine, albumin, calcium, phosphate, total cholesterol, triglycerides, HDL cholesterol and high-sensitivity C-reactive protein  were measured using standard methods at the Department of Laboratory Medicine, Karolinska University Hospital at Huddinge . ConcentTwo biomarkers of vascular remodeling, P-selectin and MMP-9, were analyzed in plasma or serum using enzyme-linked immunosorbent assay (ELISA) kits. Human P-selectin Quantikine ELISA kit  and Human MMP-9 Quantikine ELISA kit  were performed according to the manufacturers’ instructions.2 for 24 h [The median (interquartile range) age and BMI of the participants were 44 (35–47) and 25.9 (22.9–34–7), respectively, while 38% of participants were male. During planned operations, a piece of subcutaneous fat was removed at the incision site. Samples were immediately placed in iced physiological salt solution (PSS) and kept at 4 °C until dissection. Resistance arteries (diameter ≈ 150–400 µm) were dissected from the sample using stereomicroscopy. One or two artery segments (segment length ≈ 1.6–2.0 mm) were isolated from each participant depending on the number of arteries available in the fat biopsy. Isolated arteries were cultured in wells containing DMEM medium supplemented with 5% FBS, 1% Na Pyruvate, 2.5% penicillin/streptomycin, 1% FungiZone, 1% L-glutamine and 1% HEPES at 37 °C in a humidified atmosphere with 5% COfor 24 h , in the A total of 6 participants were included in the IS incubation group, and 8 participants were included in the control group. For each experimental condition, i.e., control and IS, only one vessel segment was used; no repetition or duplicates were performed. BK and SNP relaxation were calculated as % relaxation achieved, whereby the stable level of contraction prior to the addition of vasodilators was set at 0% and the baseline obtained before the addition of contractile stimuli as 100%. The contribution of NO and EDHF was then calculated. Since NOS and COX inhibition blocks NO and PGI2, the remaining response was considered to be EDHF-mediated dilatation. Of note, differences in dilation after COX inhibition were not observed D suggestt-test or Wilcoxon matched-pairs signed rank test was used to compare differences between continuous variables with repeated measures, while McNemar’s test was used for categorical variables. Univariate correlations were assessed using Spearman’s rank correlation. To identify independent associations between IS and markers of endothelial dysfunction or vessel stiffness, multivariate linear regression models for significant correlations in univariate analyses were used. Covariates in the multivariate models included age at study entry, sex, presence of diabetes, dialysis treatment and statin usage at baseline. In all multivariate models, non-normally distributed variables were log10 transformed. Missing values: Lipoprotein(a) = 3, AGE score = 1, HDL cholesterol = 1, IS = 1, pCS = 1, P-selectin = 1. For concentration-dependent ex vivo experiments, groups were compared using two-way ANOVA. Differences between continuous variables were assessed using Mann–Whitney U test. p-values < 0.05 were considered statistically significant.Statistical analysis was performed using GraphPad Prism v8.0.2  SPSS Statistics 29.0  and STATISTICA 7.0 . For all continuous variables, Kolmogorov–Smirnov test was used to test for normality. The paired-sample


P < .001). In the binary logistic regression model, the subjects with SUA higher than 420 μmol/L were associated with a 2-fold increase in the odds of albuminuria , as compared with those with SUA lower than 300 μmol/L. Moreover, the multinomial regression analysis revealed that the subjects with SUA higher than 420 μmol/L had about 3-fold increase in the odds of macro-albuminuria , as compared with those with SUA lower than 300 μmol/L. However, SUA was not significantly associated with the presence of micro-albuminuria. Although the SUAwas not independently risk factor for micro-albuminuria, it was closely correlated with the development of macro-albuminuria in Chinese T2DKD patients. Elevated SUA may be useful for predicting the occurrence of macro-albuminuria but not onset of micro-albuminuria at the early stage of T2DKD.Previous studies suggested that increased serum uric acid (SUA) level is an independent risk factor for albuminuria in Type 2 diabetes (T2D) patients. However, the association between SUA and onset of Type 2 DKD (T2DKD) remained to be clarified. This was a cross-sectional clinical study in which 1210 Chinese T2D patients were enrolled. According to the urine albumin-to-creatinine ratio (UACR), the cohort was divided into normal-albuminuria (UACR < 30 mg/g), micro-albuminuria (UACR 30–300 mg/g) and macro-albuminuria (UACR > 300 mg/g). The micro- and macro-albuminuria groups were combined into albuminuria category. Results showed that T2D patients with macro-albuminuria have significantly higher SUA than the other 2 groups ( Reciprocally, persistent albuminuria is an independent risk factor for DKD progression. Moreover, evidence from multiple observational studies and clinical trials in diabetes has suggested that albuminuria acts as a strong predictor of renal and cardiovascular events.,5Diabetic kidney disease (DKD) is regarded as the leading cause of chronic kidney disease (CKD) and end-stage renal disease worldwide, occurring in approximately 40% of individuals with Type 2 diabetes (T2D) and 30% of those with Type 1 diabetes (T1D).–8 Elevated SUA level might contribute to the pathogenesis of diabetes and its complications. In patients with T1D, the association between elevated SUA level and the development and progression of albuminuria has been reported by several studies.–12 However, a cross-sectional study from Steno Diabetes Center Copenhagen failed to show the significant association in Caucasian T1D patients after adjustment included sex, age, diabetes duration, body mass index, high-density, lipoprotein cholesterol, smoking, hemoglobin A1c (HbA1C), 24-hours pulse pressure, estimated glomerular filtration rate (eGFR) and treatment with RAAS blockers. The association between elevated SUA and albuminuria in patients with T2D also remained controversial. Some observational studies have shown that elevated level of SUA was associated with increased risk of the development of albuminuria,,15 whereas a large prospective cohort study based on a Japanese diabetes registry reported a significant relationship between baseline SUA level and progression from micro- to macro-albuminuria, not the onset of micro-albuminuria in patients with T2D. We conducted a cross-sectional study to examine the association of SUA levels with micro-albuminuria and macro-albuminuria in Chinese patients with T2D.Elevated serum uric acid (SUA), a final product of purine nucleotide metabolism, may reflect endothelial dysfunction, activation of renin-angiotensin-aldosterone system (RAAS), increase of oxidative stress and inflammation.The study was conducted in the Department of Endocrinology, Affiliated Hospital of the Nanjing University of Chinese Medicine. This clinical study was approved by the local ethics committee of the Affiliated Hospital of Nanjing University of Chinese Medicine (2019NL-I09-02), and registered in the Chinese Clinical Trial Registry (ChiCTR2000028949). A total of 1210 patients with Type 2 diabetes were consecutively recruited from our diabetes patient ward for medical examination and complications screening. Patients with acute diabetic complications, urinary tract infection, cancer or any other serious chronic debilitating disease were excluded.am. Urinary albumin was measured by an immunonephelometric method on an early morning spot sample and expressed as the albumin-to-creatinine ratio.Demographic parameters were collected and glucose and lipids metabolic index were measured. Data including diabetes duration, body mass index, systolic and diastolic blood pressure, medications, hyperuricemia and hypertension were also collected systematically. All biochemical indexes were measured in our clinical laboratory with ISO15189 certification. SUA and serum creatinine was measured by Beckman automatic biochemical analyzer in the fasting fresh blood samples obtained from the subjects between 8:00 and 9:00  The eGFR was calculated by the Chronic Kidney Disease Epidemiology Collaboration equation. Hyperuricemia was defined as SUA at > 420 μmol/L (7 mg/dL). Dyslipidemia was defined as TC ≥ 5.18 mmol/L, TG ≥ 1.7 mmol/L, LDL-C ≥ 3.37 mmol/L or HDL-C < 1.04 mmol/L. Target blood pressure was 130/80 mm Hg. Target of HbA1c was from < 6.5% to < 8.0% based on eGFR, macrovascular complications, comorbidities, life expectancy, hypoglycemia awareness, resources for hypoglycemia management and propensity of treatment to cause hypoglycemia. Blood biochemistry was conducted using an automatic biochemical analyzer . Urine albumin and creatinine (UACR) were measured using a Beckman Coulter AU680 . Normal- albuminuria was defined as UACR ＜30 mg/g. Micro-albuminuria was defined as UACR 30–300 mg/g. Macro-albuminuria was defined as UACR ＞300 mg/g.Type 2 diabetic kidney disease (T2DKD) was diagnosed according to the KDOQI guidelines.Continuous variables following normal distribution are presented as mean ± standard deviation, and analyzed using 1-way ANOVA, followed by Tukey post hoc analysis for pairwise comparisons. Continuous variables not following normal distribution are presented as median and interquartile range, and analyzed using Kruskal–Wallis test. Categorical variables are presented as percentage and analyzed using chi-square tests. Multivariate regression analysis was conducted to examine the risk factors for micro- and macro-albuminuria. Factors entered as candidate independent variables included demographics (age and sex) and all other factors associated with the outcome in the univariate analysis, except for variables with multicollinearity correlations.Participants were further stratified according to SUA levels: reference value, < 300 μmol/L (5 mg/dL); low, 300–360 μmol/L (6 mg/dL); moderate, 360–420 μmol/L (7 mg/dL); and high > 420 µmol/L. A sensitivity analysis was used to verify the association of SUA categories with micro- and macro-albuminuria. The results of regression analysis are reported as odds ratio (OR) and 95% confidence interval (95% CI).P < .05 (2-tailed).All statistical analyses were conducted using SPSS 26.0 . Statistical significance was as P < .001). Pairwise comparison revealed that significantly higher SUA in patients with macro-albuminuria than with no or micro-albuminuria (P < .001 for both) but no significant difference between the normal-albuminuria and micro-albuminuria groups. The prevalence of hyperuricemia was significantly higher in the macro-albuminuria group, compared with the normal-albuminuria  and micro-albuminuria  groups. In the micro-albuminuria group, hyperuricemia was significantly higher than that in the normal-albuminuria group .The analysis included a total of 1210 patients with T2D : 452 patients with no albuminuria, 450 with micro-albuminuria and 308 with macro-albuminuria (Table P < .001). Hyperuricemia was higher in subjects with (21.5%) vs. without albuminuria .We first conducted an analysis combining micro- and macro-albuminuria into an albuminuria group Table . CompareThe pairwise comparisons among the normal-, micro- and macro-albuminuria groups Table  were theP = .02).Table P = .18) and adjusted analyses  when comparing the no and micro-albuminuria groups.The multinomial logistic regression analysis Tables  and 4 shP < .001, using normal-albuminuria as the reference category, OR = 1.003, 95% CI: 1.001–1.005, P = .003, using micro-albuminuria as the reference category).Taking normal-albuminuria or micro-albuminuria as the reference category respectively, the risk factors for macro-albuminuria were demonstrated in Table Sensitivity analysis confirmed that higher SUA categories were associated with albuminuria and macro-albuminuria in T2D as accurately as SUA level did Tables  and 6. SP = .005), as compared with the subjects with SUA lower than 300 μmol/L. The subjects with SUA more than 420 μmol/L (7 mg/dL) were associated with 2 or 3-fold increase in the odds of macro-albuminuria, as compared with those SUA lower than 300 μmol/L (5 mg/dL) .The T2D patients with SUA higher than 420 μmol/L were associated with a 2-fold increase in the odds of albuminuria  increase in SUA level was accompanied by 22.7% increase in the odds of albuminuria even after the adjustment of eGFR, sex, age, diabetes duration, fasting glucose and HbA1c at baseline. In addition, a prospective study from Japan showed that SUA was an independent risk factor for the onset of albuminuria despite the association was weak. For every 1 μmol/L higher SUA at baseline, T2D patients had 1-fold increased risk of developing albuminuria during a median follow up period of 6.9 years. However, in the above several studies, this positive association of SUA and albuminuria in T2D patients has failed to be confirmed.,21 For example, another prospective cohort study based on a Japanese diabetes registry involving 2518 patients failed to observe the correlation between SUA and the onset of albuminuria after 2 years of follow-up. The associations between SUA level and the risk of micro-albuminuria with special focus on Chinese Type 2 DKD patients have not been investigated. Our present research offered evidence that SUA level was not an independent risk factor for the early onset of DKD in T2D patients.In recent years, increasing attention has been paid to the association between SUA and T2DKD. However, the role of SUA in the onset of DKD remained still controversial. Several cohort studies have demonstrated that increased SUA level is regarded as an independent risk factor for the development of albuminuria. However, our results were inconsistent with the prospective data from Kailuan cohort. The community-based study in China involving 1327 diabetic patients failed to reveal an association between high level of SUA and development of macro-albuminuria with 10 years follow-up period, though an increase trend of cumulative incidence of macro-albuminuria. The possible reason for the conflicting results might be due to a lower statistical power caused by a lower proportion of patients with hyperuricemia (5.3%) in the Kailuan study. Besides, Type 1 and Type 2 diabetes were not distinguished in the study. In addition, our finding offered the first evidence that the subjects with SUA higher than 420 μmol/L (7 mg/dL) was associated with 3-fold increase in the odds of macro-albuminuria in T2D patients, as compared with those SUA lower than 300 μmol/L (5 mg/dL). Admittedly, further studies are needed to identify an optimal range of SUA among patients with T2DKD in Chinese population.Interestingly, it was found in our study that elevated SUA was closely correlated with the development of macro-albuminuria in patients with T2DKD. This was similar to 1 cohort study in Japan in which the baseline SUA levels were demonstrated to be a significant and independent predictor for progression from micro-albuminuria to macro-albuminuria in T2D patients.,8 Normalizing SUA levels could attenuate the progression of albuminuria and renal structural damages in T2D mice model. Furthermore, the association between CKD progression and SUA has been investigated in human biopsies. It was shown that CKD patients with high levels of SUA displayed more serious segmental glomerulosclerosis and tubular atrophy/interstitial fibrosis. In addition, the renal beneficial effects  have been observed in T2D by lowering SUA therapy.–27 However, these studies are small sample size, open labeled and limited generalizability due to the enrolled populations and research conditions. It remained unclear about the important role of SUA in the pathogenesis of T2DKD till now. Further studies are needed to clarify the benefit of lowering SUA therapy to prevent and slow down the kidney damage of T2D.Although the causal relationship between SUA and DKD has not been clarified, evidence from experimental studies explored the molecular mechanism underlying the close relationship of SUA levels with progression of renal injury. Elevated SUA levels could cause activation of RAAS, endothelial dysfunction, oxidative stress and inflammation at the cellular and tissue level which was associated with glomerulosclerosis and tubulointerstitial fibrosis in kidney.,29 our study indicated that age, high glucose levels, duration of diabetes and hypertension of patients were the independent risk factors for the development of T2DKD. Most of these risk factors could be controllable by anti-diabetic or anti-hypertensive treatment and lifestyle changes. In addition, our study demonstrated intensive blood pressure control could reduce the risk of proteinuria, especially in those patients with preexisting macro-albuminuria, which was in accordance with Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study. Both the United Kingdom Prospective Diabetes study and the DCCT studies suggest that intensive blood glucose control (HbA1c ≤ 7%) could significantly reduce the risk of the onset and progression of albuminuria in patients with diabetes.,31 However, there was not a significant association between target attainment rate of glucose and the postponed development of albuminuria in our study. The previous meta-analysis showed intensive glucose control increased the number of severe hypoglycemic events but without lower the micro-vascular and macro-vascular events in patients with T2D. Due to the increased risk of hypoglycemia, the intensive glucose control failed to bring cardiovascular benefit, enhanced survival benefit and improved life expectancy to patients in the advanced stage of T2DKD (eGFR ≤ 45 mL/minute). Therefore, T2D patients in our study were stratified with individual HbA1c targets according to eGFR, macrovascular complications, comorbidities, life expectancy, hypoglycemia awareness, resources for hypoglycemia management and propensity of treatment to cause hypoglycemia. However, our study showed that glucose control with individual HbA1c targets was not likely to reduce the risk for the development of albuminuria in our cohort. Future clinical investigation is needed to search for the better strategy for glucose control and optimum HbA1c value for T2DKD patients.In consistent with the previous studies,There are several limitations in our present study. First of all, the cross-sectional study could not offer solid evidence for exploring the causal relationship between SUA level and appearance of albuminuria in T2D patients. Secondly, generalization of our results is limited because our cohort was not from multicenter but from homogeneous population at a single center. Thirdly, the usage information of some novel anti-diabetic drugs such as sodium-dependent glucose transporters 2 inhibitor and glucagon-like peptide-1 receptor agonist(s) were not recorded in our data. It was due to the usage rate of those medications was very low in the enrolled subjects.In conclusions, our study demonstrated that increased SUA level was not an independently risk factor for the onset of micro-albuminuria in the early stage of T2DKD in Chinese patients. However, it was closely correlated with macro-albuminuria and the elevated SUA level could be taken as a significant predictor for the occurrence of macro-albuminuria in the advanced T2DKD.This work was supported by the National Natural Science Foundation of China (82074359), The National Integrative Medicine Key Training Project of China（2019-44）and The Open Projects of the Discipline of Chinese Medicine of the Nanjing University of Chinese Medicine Supported by the Subject of Academic priority discipline of Jiangsu Higher Education Institutions (ZYX03KF027).


This study aimed to investigate the risk factors of reversible posterior leukoencephalopathy syndrome (RPLS) in pregnant women with severe preeclampsia or eclampsia (SPE/E) based on a predicting model and to analyze the perinatal outcomes. n = 33) and non-RPLS group (n = 45) based on the MRI results. The general clinical data , laboratory examination, TCD results, and perinatal outcomes in the two groups were compared. The risk factors of severe preeclampsia or eclampsia complicated with RPLS were analyzed by multivariate logistic regression. The prediction model and decision curve (DCA) were established according to the clinical-imaging data.  From January 2015 to March 2020, 78 pregnant women data diagnosed with severe preeclampsia or eclampsia with cranial magnetic resonance imaging (MRI) and transcranial Doppler (TCD) screening in Xiangyang No. 1 People's Hospital and Jiangsu Province Hospital of Chinese Medicine were analyzed retrospectively. They were divided into the RPLS group (P < 0.05). The multivariate logistic regression analysis showed that hypertensive emergency, headache, WBC, PLT, ALT, and average flow velocity of the basilar artery (BAAFV) were the risk factors in the RPLS group. The aforementioned clinical-imaging data modeling  showed that the combined model predicted RPLS better. DCA also confirmed that the net benefit of the combined model was higher. In addition, the incidence of postpartum hemorrhage, stillbirth, and preterm infants was higher in the RPLS group than in the non-RPLS group .  The univariate analysis showed that poor placental perfusion, hypertension emergency, use of two or more oral antihypertensive drugs, headache, white blood cell (WBC) count, platelet (PLT) count, lactate dehydrogenase (LDH), alanine aminotransferase (ALT), uric acid (UA), serum albumin (ALB), average flow velocity, and resistance index of the posterior cerebral and basilar arteries were significantly different in the RPLS group compared with the non-RPLS group (all  More postpartum complications were detected in pregnant women with severe preeclampsia or eclampsia complicated with RPLS. Hypertensive emergency, headache, WBC, PLT, ALT, and BAAFV were the important risk factors for RPLS. The combined model had a better effect in predicting RPLS. Reversible posterior leukoencephalopathy syndrome (RPLS) is a clinical neuroimaging syndrome. Hinkey et al. first reported and proposed it in 1996. The occurrence of RPLS mainly depends on capillary filtration pressure and integrity of the blood-brain barrier. The clinical symptoms of RPLS mainly include neurological impairment, such as headache, epileptic attack, blurred vision, and mental or consciousness disorders . At presn = 33) and non-RPLS group (n = 45) based on cranial MRI results.Pregnant women with SPE/E delivered in Xiangyang No. 1 People's Hospital and Jiangsu Province Hospital of Chinese Medicine from January 2015 to March 2020 were retrospectively enrolled and followed up until September 5, 2021. Their blood pressure and symptoms at admission, laboratory test results, and so on were recorded. The inclusion criterion was pregnant women diagnosed with SPE/E undergoing cranial MRI and TCD screening during hospitalization. The exclusion criterion was pregnant women with previous serious neurological or internal diseases affecting or shortening life expectancy. A total of 78 pregnant women with SPE/E were included in the study. They were divided into RPLS group (Eclampsia: Defined as convulsions occurring in pregnant women with preeclampsia that cannot be explained by other reasons.Severe preeclampsia: Defined as any of the following adverse conditions: systolic blood pressure ≥160 mm Hg (1 mm Hg = 0.133 kPa) or diastolic blood pressure ≥110 mm Hg; 24-h urinary protein ≥5 g or random urinary protein ≥ (+++); abnormal renal function; persistent headache or visual impairment or other neurological symptoms; pulmonary edema and heart failure; upper abdominal or right upper abdominal pain; hypoproteinemia with effusion; impaired liver function; abnormality of blood and blood-forming tissues; fetal growth restriction, and so forth.Classification of hypertension: The blood pressure collected in this study was the average blood pressure of pregnant women in the hospital  to avoid the influence of antihypertensive drugs. (1) Grade 1 hypertension was defined as systolic blood pressure of 140–159 mm Hg and/or diastolic blood pressure of 90–99 mm Hg; (2) Grade 2 hypertension was defined as systolic blood pressure of 160–179 mm Hg and/or diastolic blood pressure of 100–109 mm Hg; (3) Grade 3 hypertension was defined as systolic blood pressure of ≥180 mm Hg and/or diastolic blood pressure of ≥110 mm Hg.If an acute attack lasted more than 15 min, it was persistent severe hypertension, which was an emergency of hypertension. Those who used two or more kinds of antihypertensive drugs referred to those who could not achieve the target blood pressure with single antihypertensive drug treatment and needed two or more kinds of oral antihypertensive drugs or even intravenous or intravenous-equivalent drugs. Fetal growth restriction meant that the estimated fetal weight (EFW) was less than the 10th percentile of the corresponding gestational age weight , 9, 10.MRI: Participants had a baseline or above the MRI brain examination in 2015–2020 and returned for a repeat MRI examination after 3–6, 6–12, and 12–18 months. MRI screening routinely included conventional MRI sequence T1-weighted imaging (T1WI) + T2-weighted imaging (T2WI) + fluid-attenuated inversion recovery sequence (FLAIR). For patients with headaches and other special symptoms, MRI screening included diffusion-weighted imaging (DWI) + MR venography (MRV) sequence, or other sequences were added based on the personal condition so as to distinguish them from pregnancy-related encephalopathy such as cerebral venous sinus thrombosis. The imaging diagnosis results were summarized and confirmed by two imaging physicians after reading the films. In case of disagreement, the third senior imaging physician was invited to make a joint and key diagnosis. A 3.0 T MRI scanner  and a 1.5-T MRI scanner  were used for MRI examination. The technical parameters were as follows: (1) T1WI: repetition time (TR) 2000 ms, echo time (TE) 20 ms, and number of signal averaged (NSA) = 2; T2WI:TR 2139 ms, TE 80 ms, and NSA = 3; (2) FLAIR: TR 7000 ms, TE 157 ms, NSA = 2, time reversal (TI) 2200 ms, FOV 240 × 240 mm, layer thickness 6 mm, and spacing 1 mm. (3) DWI: TR 2308 ms, TE 88 ms, number of layers = 18, layer thickness 6 mm, and NSA = 2; (4) MRV: TR 18 ms, TE 88 ms, flip angle 10°, FOV 230 × 120 × 178 mm, number of layers = 150, matrix 232 × 137, and NSA = I [TCD: The desktop transcranial Doppler ultrasound diagnostic instrument of DWL Company in Germany was adopted, and the probe frequency range was 2–2.5 MHz. The probe detected anterior circulation and posterior circulation from the temporal window, occipital window, and eye window. The detection indexes of anterior circulation included middle cerebral artery (MCA), anterior cerebral artery (ACA), and terminal end of the internal carotid artery (TICA) and posterior cerebral artery (PCA). The detection indexes of posterior circulation included the basilar artery (BA) and vertebral artery (VA).R software  were used for statistical analysis. The measurement data are expressed mean ± SD. The independent sample t-test is used for the comparison between the data groups that conform to the normal distribution, whereas the rank sum test is used for those that do not conform to the normal distribution. Counting data were expressed by frequency or percentage, and X2 test or corrected x2 test was used for intergroup comparison. The OR value and 95% CI of risk factors were calculated by multivariate logistic regression analysis. The difference was statistically significant (P < 0.05). Then, the receiver operating characteristic (ROC) curve was generated, and the area under the curve (AUC) was used to evaluate the accuracy of general data model, laboratory examination model, TCD model, and combined model in predicting RPLS. The higher the AUC and P value < 0.05 (two tailed), the higher the prediction accuracy, which shows statistical significance, and then conduct decision curve analysis (DCA). The clinical usefulness was determined by quantifying the net benefits under different threshold probabilities in the model [Spss 22.0 software  and he model .P > 0.05). The univariate analysis showed that poor placental perfusion, hypertension emergency, use of two or more kinds of oral antihypertensive drugs, and headache were significantly different in pregnant women with RPLS compared with those without RPLS (P < 0.05)  and 20 cases (eclampsia) underwent MRI and TCD, respectively. Eight patients with incomplete data or lost to follow-up were excluded. Furthermore, 85 patients, comprising 33 patients with RPLS, 2 patients with intracranial venous sinus thrombosis, 3 patients with subarachnoid hemorrhage, 2 patients with intracerebral hemorrhage, and 45 normal patients, were included. No significant difference was found between the two groups in terms of age, gestational weeks, assisted reproduction, multiple pregnancies, immune system diseases, and history of chronic hypertension ( < 0.05) .P > 0.05). The WBC count; PLT count; and levels of LDH, ALT, UA, and serum albumin were compared between the two groups, and the differences were statistically significant  (No significant difference was found in red blood cell (RBC) count, hemoglobin (HB), activated partial thromboplastin time (APTT), 24-h urinary protein quantification, aspartate aminotransferase (AST), serum total cholesterol (TC), urea nitrogen, and creatinine levels between pregnant women with RPLS and those without RPLS (All  < 0.05) .P < 0.05). No significant difference was observed in blood flow parameters of ACA, MCA, carotid artery, and vertebral artery between the two groups   .The aforementioned risk factors were analyzed by binary logistic regression. Hypertensive emergency, headache, WBC, PLT, ALT, and BAAFV were independent risk factors for severe preeclampsia or eclampsia complicated with RPLS. Four RPLS risk factor models  were established. The prediction value of the combined model was found to be high, and the combined model was the best decision to maximize the net benefit compared with the other three models Figures .Among 33 pregnant women with RPLS, 31 completed telephone follow-ups. The follow-up rate was 93.93%, and the median follow-up time was 8 months (3–18 months). All follow-up patients survived without residual neurological sequelae, such as behavior, movement, and vision and language disorders. Eight cases still complained of intermittent headaches, especially when the blood pressure was poorly controlled. During the follow-up, five patients were transferred to neurology consultation and treatment, including short-term antiepileptic, anticoagulant, nerve nutrition, and other treatment measures. In 30 patients with RPLS, the cerebral cortical edema was alleviated or disappeared after 6–12 weeks postpartum.At present, the mechanism of cerebrovascular injury in preeclampsia is unknown. Mostly, cerebrovascular injury is related to the increase in blood-brain barrier permeability caused by the dysfunction of vascular endothelial cells and the abnormal ability of cerebrovascular self-regulation. Brain hyperperfusion and vasospasm are the most crucial research mechanisms. The common imaging manifestations of nervous system injury related to preeclampsia are stroke and RPLS , 13.P < 0.05) was independent risk factors for RPLS, but the blurred vision is also a potential factor that cannot be ignored . Therefore, pregnant women should be vigilant once they have the aforementioned symptoms. The convulsive symptoms were nonspecific. No significant difference was noted between the two groups in this study (P > 0.05).Acute or subacute neurological symptoms  are the most intuitive manifestations of preeclampsia complicated with neurological injury, which need to be evaluated by MRI actively. In preeclampsia cases with neurological symptoms, the incidence of abnormal cranial MRI was 55.3%. Headache is a high-risk factor for RPLS and a precursor of eclampsia. Cortical blindness is also a unique manifestation of RPLS , 14, 15.In the course of SPE/E, hypertension emergency and use of two or more antihypertensive drugs can increase the risk of RPLS. Cerebral blood vessels are early target organs affected by hypertension. In the case of sustained hypertension emergency, the risk of serious adverse events such as hypertensive encephalopathy, intracerebral hemorrhage, cerebral infarction, and RPLS increases, and long-term high blood pressure levels lead to cerebral arteriosclerosis and hypoxic changes in brain tissue, which is related to the decline in cognitive function and the occurrence of dementia after many years , 11, 16.Soma Pillay et al. found that patients with preeclampsia who needed to use an antihypertensive drug had a significantly increased risk of white matter lesions during pregnancy and 6-month postpartum. Kurosaki et al. found that the diastolic blood pressure of patients with preeclampsia negatively correlated with the function of cognitive nerve units in the brain. These results suggested that hypertension had an important impact on cerebrovascular injury. Active antihypertensive treatment can avoid stroke and other complications caused by severe hypertension and alleviate the development course of white matter lesions. However, antihypertensive treatment did not significantly reduce cerebral perfusion volume in patients with preeclampsia. As a risk factor for RPLS, the use of two or more antihypertensive drugs also objectively confirmed the impact of uncontrollable hypertension on cerebrovascular injury. In other words, although the combined use of antihypertensive drugs reduced the incidence of stroke, RPLS did not improve –20.Endothelial dysfunction caused by abnormal placental vascular perfusion in eclampsia may be related to abnormal cerebrovascular function. The same results were also observed in the placental blood flow perfusion in patients with RPLS using prenatal ultrasound 3D-flow function analysis, and the postpartum placental vascular cast was confirmed . SimilarWhen eclampsia is complicated with RPLS, pregnant women with increased cerebral blood flow, hyperperfusion, and increased blood-brain barrier permeability need to undergo MRI. However, we cannot force all pregnant women with eclampsia to undergo MRI due to its high cost and claustrophobic symptoms. Therefore, a more convenient TCD was chosen for cerebral blood flow assessment, and good benefits were achieved. This study found that the blood flow resistance of posterior cerebral artery and basilar artery decreased and the average flow velocity increased in pregnant women with RPLS, showing the sign of “low resistance and high output.” This novel important finding provides an opportunity for the universal screening of RPLS in the future.Uric acid and lactate dehydrogenase levels are one of the indicators reflecting the severity of endothelial dysfunction, which have a high correlation with RPLS. This study found that both significantly increased in the RPLS group, suggesting that endothelial inflammatory injury might play an important role in the process of brain edema of RPLS, which could be used as a predictor of the degree of brain edema of RPLS –24.This study found that the ALT level in the RPLS group was higher than that in the non-RPLS group, and the AST and ALT levels in the two groups were significantly higher than the normal value, indicating varying degrees of damage to the liver function of pregnant women with pregnancy-induced hypertension or SPE/E combined with RPLS, but this was not a specific index . The coaAlbumin and 24-h urinary protein quantification are good indicators for observing preeclampsia, which are related to the risk of brain edema and ascites. The serum albumin levels in the RPLS group is lower than that in the non-RPLS group, which also showed that serum albumin levels could be used as a predictor of the degree of brain edema of RPLS. Although the involvement of 24-h urinary protein in the prediction and evaluation of RPLS has decreased, some studies suggested that Hb and 24-h urinary protein levels had significant changes in pregnant women with preeclampsia . In thisIn this study, the WBC count of pregnant women in the RPLS group was significantly higher than that in the non-RPLS group, which might be related to the relatively serious condition and enhanced inflammation or stress response of pregnant women in the RPLS group.It is reported that the main factor directly related to perinatal outcome is gestational age. However, this study found that the incidence of postpartum hemorrhage, preterm infants, and stillbirths was slightly higher in the combined RPLS group than in the non-RPLS group. No significant difference was found in placental abruption, neonatal asphyxia, hypoxic-ischemic encephalopathy (HIE), and neonatal respiratory distress syndrome (RDS) between the two groups. It was suggested that eclampsia combined with RPLS had a certain impact on maternal complications and perinatal infants , 4, 24 .In this study, no significant difference was found in age, gestational weeks of delivery, assisted reproduction, multiple pregnancies, immune system diseases, history of chronic hypertension, RBC count, HB, APTT, and 24-h urinary protein, AST, TC, urea nitrogen, and creatinine levels between the RPLS and non-RPLS groups. It was suggested that the aforementioned factors were not risk factors for severe preeclampsia or eclampsia complicated with RPLS.In addition, four RPLS prediction models  were established in this study based on the aforementioned risk factors. The results suggested that the prediction value of the combined model was high. DCA also confirmed that the net benefit of the combined model was high. The nomogram tool based on the risk factors of the combined model simplified the prediction method of RPLS and has been applied in clinical practice . Our proThis study included only the data of 93 pregnant women with SPE/E who underwent cranial MRI and TCD, accounting for 54.07% (93/172) in this group, of which about 35.48% (33/93) had RPLS. Considering that in clinical practice, only patients with severe preeclampsia have improved clinical systemic evaluation and imaging examination, the data of this study ignored most mild preeclampsia cases, which is biased and needs to be confirmed by further prospective multiinstitutional studies in the later stage. The difference in RPLS between eclampsia and severe preeclampsia could not be compared due to insufficient data, and hence, training and test sets could not be set up. Probably, the results slightly varied as per the diversity characteristics of the participants, but it was insignificant. Also, only the high-risk factors for RPLS were reported to help clinicians select the target population undergoing MRI examination. However, the impact of these MRI signs on pregnant women's long-term cognition and health status needs to be studied in the future.In conclusion, Hypertensive emergency, headache, WBC, PLT, ALT, and BAAFV, and so forth are independent high-risk factors for RPLS. A clinical-imaging data-based combined model for predicting RPLS is promising and may achieve more clinical benefits.


Hypertension is a common risk factor for cardiovascular disease and mortality worldwide. Proper nutrition and diet are known to play an indispensable role in the treatment and management of hypertension. Bioactive compounds that occur in small quantities in foods such as onions, fish and red wine are being intensively studied to uncover their vasoprotective, antioxidant, anti-proliferative and anti-inflammatory effects which are beneficial to attenuate chronic disease and protect human health. In this article, the anti-hypertensive, and cardio-protective effects of five food-derived bioactive compounds: resveratrol, quercetin, coenzyme Q10, DHA and EPA and their proposed mechanisms of action are reviewed in detail. High blood pressure, also known as hypertension, is a chronic condition affecting over 1.28 billion people globally and results in nearly 9.4 million deaths every year due to the associated complications .In this context, over the years, several food-derived bioactive constituents including angiotensin-converting enzyme (ACE) inhibitory peptides, vitamins C and E, flavonoids, flavanols, cathecins, anthocyanins, phenolic acids, polyphenols, tannins, resveratrol, polysaccharides, fibre, saponin, and sterols have been evaluated for their anti-hypertensive efficacy in various experimental settings . AlthougIn this review, we provide a detailed insight into the current research developments on bioactive compounds for the management and treatment of hypertension. By providing a brief overview of the pathogenesis of hypertension, we aim to review the anti-hypertensive effects of five selected food-derived bio-actives, resveratrol, quercetin, coenzyme Q10, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), which have been shown efficacy in randomized human feeding studies and try to elucidate the modes of action . We furtThe literature search was conducted with the use of the scientific databases and search engines Pubmed, Google Scholar and Scopus. The search terms “resveratrol”, “docosahexaenoic acid”, “DHA”, “eicosapentaenoic acid”, “EPA”, “quercetin” and “coenzyme Q10” were used in combination with any of the following terms: “hypertension”, “blood pressure” “spontaneously hypertensive rat”, “SHR”, “renovascular hypertension” “2K1C”, “pulmonary hypertension”, “salt sensitive hypertension”, “Dahl salt sensitive rat”, “clinical trial”. There were no limitations placed on the literature search pertaining to the publication date of the studies. Case reports, commentaries and editorials were excluded from the literature search. For the preclinical trials, the studies were only considered if the animal model fell under the following categories: pulmonary hypertension, spontaneously hypertensive rats, renovascular hypertension and salt sensitive hypertension. Normotensive animal models were excluded from the literature search. For the clinical trials, any studies evaluating the select bioactive compounds in combination with other treatments were excluded. Studies pertaining to metabolites or analogues of the compounds were also excluded. Furthermore, only clinical trials containing hypertensive subjects were considered.Hypertension or high blood pressure is among the most prevalent and important modifiable risk factors for cardiovascular disease and premature mortality . As of 2The 2017 American Heart Associate guidelines define hypertension or systemic arterial hypertension as a chronic increase in systolic blood pressure (SBP) above 130 mm Hg and/or diastolic blood pressure (DBP) above 80 mm Hg measured in a relaxed sitting posture . In addiRegulation of blood pressure is a complex integrated response involving a variety of organ systems, including the central nervous system, cardiovascular system, kidneys, and adrenal glands. Uncontrolled hypertension can damage these organs, and it is a major contributor to the development of congestive heart failure, end-stage renal disease, and stroke . HyperteThe established anti-hypertensive drug classes available for treating hypertension/heart failure include diuretics, β-adrenergic receptor blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone antagonists . HoweverHypertension is classified as either idiopathic/essential (primary) or non-essential (secondary) hypertension ,21,22. EBlood pressure regulation is defined as the control of blood supply to a particular organ to match its metabolic needs . The maiAn increase in the activity of the sympathetic nervous system (SNS) is associated with higher cardiac output, tachycardia, higher norepinephrine levels, and peripheral vasoconstriction in hypertensive young adults . The SNSThe renin-angiotensin-aldosterone system (RAAS) is a hormonal system that plays a fundamental role in blood pressure regulation by controlling vasoconstriction and sodium and fluid homeostasis, and it is an important mediator of essential hypertension . The mosThe endothelium plays a crucial role in the control of blood pressure by regulating blood vessel tone through nitric oxide production . In response to blood flow-induced shear stress, nitric oxide is synthesized by endothelial cells from L-arginine by the action of nitric oxide synthase. Nitric oxide induces vasodilatation by stimulating guanylyl cyclase to produce cyclic guanosine monophosphate, which mediates vascular smooth muscle relaxation. Studies have demonstrated that hypertensive patients have lower levels of nitric oxide compared with their normotensive counterparts . FurtherSeveral prospective cohort studies have revealed that high blood pressure increases the risk of premature mortality and cardiovascular complications . Hyperte−2 for men and ˃100 g·m−2 for women. The risk of developing LVH in normotensive subjects has been estimated to be 1.3%–1.6%, whereas the risk increases in subjects with mild and severe hypertension to 2.7%–5.6% and 75.6–82.6%, respectively [Left ventricular hypertrophy (LVH) is defined as the enlargement and thickening of the left ventricle of the myocardium. Based on echocardiographic measurements, LVH is diagnosed when left ventricular weight indexed to body surface area is ˃131 g·mectively . LVH is ectively ,27. LVH ectively . VentricSeveral etiological factors have been implicated in the pathogenesis of LVH in hypertension, including pressure overload with an increase in total peripheral resistance, as well as neurogenic and hormonal factors .The main determinants of pressure overload of the left ventricle in the context of hypertension are aortic stenosis and increased arterial blood pressure. Both increased intraventricular pressure and aortic stenosis result in cardiomyocyte hypertrophy and enhanced peri-myocytic extracellular matrix deposition .Different hypertrophic factors, including the components of the RAAS, such as angiotensin-II and aldosterone have an important role in the development of hypertensive heart disease by inducing cardiac hypertrophy . ExperimBesides its blood pressure-elevating effects, such as enhancing sodium retention, and stimulating the SNS, aldosterone has been reported to induce cardiac fibrosis and potentiate the fibrotic effects of angiotensin-II in hypertension. Therefore, aldosterone has a critical role in the pathogenesis of hypertension-associated LVH; it has also been suggested that the effects of aldosterone with regards to the pathogenesis of hypertensive heart disease and heart failure are independent of renin and angiotensin-II because the administration of an aldosterone receptor antagonist, Aldactone, in combination with other standard heart failure medications markedly improved the outcomes in individuals with severe heart failure .Activation of the SNS in hypertension may contribute to the development of LVH. The role of SNS in stimulating LVH is evidenced by the presence of LVH and heart failure in subjects with pheochromocytoma, a catecholamine-secreting tumor of the medulla of the adrenal gland .Another important factor that can affect left ventricular mass in hypertension is high dietary sodium consumption. In spontaneously hypertensive rats the development of LVH was potentiated by a high-sodium diet. Furthermore, high-sodium intake caused an increase in the myocardial weight in Wistar Kyoto Rats independently of blood pressure ,29. SaltRenovascular hypertension is defined as high blood pressure as a result of the narrowing of the arteries in the kidneys; it is a major form of secondary hypertension that involves decreased blood flow to the kidneys and increased activation of the RAAS ; it accoPulmonary arterial hypertension (PAH) is a progressive disease associated with increased construction and remodeling of pulmonary arteries causing increased pulmonary vascular resistance, right ventricular hypertrophy and dysfunction and heart failure  It is chProper nutrition is imperative in the prevention and management of hypertension. Poor dietary habits, such as the consumption of high amounts of sodium and saturated and trans fats and low amounts of fibre, are considered important risk factors for hypertension. One important strategy is the use of functional foods and nutraceuticals; these are foods that offer health-related benefits and are considered advantageous for the treatment and prevention of disease . This reQuercetin is a bitter tasting flavonoid known for its potent antiviral, anti-carcinogenic, antioxidant, anti-inflammatory and disease-prevention abilities ,42,43,44V currents and the overexpression of 5-HT2A and inducible nitric oxide synthase (NOS) induced by MCT in PASMCs while also reducing AKT and S6 phosphorylation [Quercetin has been reported to exert protective effects against PAH such as decreased mPAP, prevention of right ventricular hypertrophy and remodeling of pulmonary arteries in various PAH animal studies ,46,47. Irylation . Quercetrylation .The two-kidney, one-clip Goldblatt hypertension animal model (2K1C) is commonly used to study renovascular hypertension, as decreased perfusion to the kidneys through partial obstruction of the renal artery will persistently increase blood pressure . QuercetThe spontaneously hypertensive rat (SHR) model is an animal model used to study primary hypertension; it is the most studied model of hypertension to date. In SHRs, hypertension develops around 5–6 weeks of age. In the adult phase, systolic blood pressure can reach 180–200 mmHg . SHRs evSeveral studies have evaluated the cardioprotective effects of quercetin in an SHR model. Quercetin and its metabolites effectively reduce an increase in blood pressure and heart rate ,64,65,66Quercetin possesses potent antioxidative properties that allow it to effectively attenuate oxidative stress in this model. It is reported that dietary quercetin improves oxidation status in many ways; it attenuates lipid peroxidation by reducing both plasma and hepatic malondialdehyde (MDA) levels ,60,62,64Quercetin is most popular for its blood pressure-lowering and antioxidant properties. However, there is evidence that quercetin also ameliorates structural and functional properties in the heart. The following studies evaluate the effects of quercetin against cardiac hypertrophy in an SHR model. In addition to lower blood pressure and LV-body weight ratio in SHR, Yan et al. reported that quercetin treatment significantly attenuated Ang II-induced H9C2 myoblast cell hypertrophy in vitro. In addition, it suppressed the activation of transcription factors c-fos and s-jun, which are components of activator protein 1 (AP-1), as well as the downstream hypertrophy gene. In addition, the treatment significantly increased peroxisome proliferator-activated receptor γ (PPAR-γ) activity. AP-1 is known to play a significant role in cardiomyocyte hypertrophy. PPAR-γ is a transcription factor that regulates gene expression in the AP-1 pathway and many others. The PPAR-γ dependent pathway has been shown to play a critical role in the inhibition of cardiac hypertrophy . Further+ channel (ENaC) mRNA expression in the kidney, but not in the colon, which is significantly increased by a high-salt diet. ENaC is important for the regulation of blood pressure, as it contributes to the reabsorption of Na+ in renal tubules [The Dahl salt-sensitive rat model has been extensively used to study salt-sensitive hypertension and chronic kidney disease, as the kidney plays a critical role in the long-term regulation of blood pressure through the regulation of the body’s fluid and electrolyte balance . In this tubules . In addi tubules . TherefoIn other salt-induced models of hypertension, quercetin has proved to possess anti-hypertensive effects. In respective comparative studies, quercetin has been reported to be more effective than nifedipine and verapamil, which are calcium channel blockers, in improving hemodynamic and metabolic abnormalities associated with a high salt diet in sodium chloride-induced hypertensive rat and deoxycorticosterone acetate (DOCA)-salt hypertensive rat models ,78. In a2. The results of the study determined that quercetin treatment significantly reduced SBP and DBP in the hypertensive group.One double-blind, placebo-controlled, crossover design study administered a high dose of quercetin aglycone (1095 mg) to 17 overweight, normotensive, and hypertensive men . Partici2 with an SBP of 138.4 ± 2.3 mm Hg and a DBP of 84.4 ± 1.3 mm Hg. There were two groups: APOE3/3 and APOE4. The men received 150 mg/d of quercetin, while the others received the placebo treatment for 8 weeks; those who received the quercetin treatment had their SBP significantly lowered; this beneficial effect was associated with decreased triacylglycerol and increased HDL-C levels.Another double-blind, randomized, crossover, placebo-controlled trial studied the effects of quercetin in 49 men aged 48 to 68 years . Partici2. For 6 weeks, participants either consumed 150 mg/d of quercetin or a placebo. The results indicated that the APOE3/3 group that consumed quercetin had their significantly SBP lowered. Participants in the APOE4 group had no significant effects on blood pressure. The authors suggested that ineffective treatment for the APOE4 group can be attributed to the fact that carriers of the APOE4 allele may not be responsive to quercetin. The beneficial effect was associated with a decrease in oxidized LDL and TNF-𝜶 in overweight-obese carriers of the apo ε3/ε3 genotype [Egert et al. did a study on how quercetin impacts overweight/obese patients. There were 42 men and 51 women aged 25 to 65 years included in this double-blinded, placebo-controlled, crossover trial. SBP was 130.3 ± 16.4 mm Hg, and DBP was 81.6 ± 9.3 mm Hg, with a BMI of 30.6 ± 3.2 kg/mgenotype .2. For stage 1 hypertensives, SBP was 148 ± 2 mm Hg and DBP were 96 ± 1 mm Hg with a BMI of 29.3 ± 1.3 kg/m2. This randomized, double-blind, placebo-controlled, crossover study had a total of 41 participants who either consumed 730 mg/d of quercetin or a placebo for 12 weeks. For those with stage 1 hypertension, SBP and DBP were significantly lowered. The SBP and DBP of prehypertensive participants were not affected by the quercetin treatment. According to the authors, quercetin’s ability to lower blood pressure may be dependent on the severity of hypertension. Data from preclinical trials support this statement, as decreases in blood pressure due to quercetin supplementation were observed in hypertensive but not normotensive rats [A similar study looked at how quercetin affects men and women with prehypertension or stage 1 hypertension . For preive rats ,86.2. This randomized, double-blinded, placebo-controlled, cross-over trial had participants consuming 500 mg of quercetin or a placebo daily for 4 weeks. Quercetin significantly lowered DBP, although there were no changes to SBP [Shi and Williamson looked at the effects of quercetin in 22 pre-hyperuricemic men aged 19 to 60 years. Participants had an SBP of 123.2 ± 7.2 mm Hg, and a DBP of 73.8 ± 9.2 mm Hg. The BMI ranged from 18.5 to 29.9 kg/ms to SBP .2. For the quercetin group, participants had an SBP of 126.25 (19.41) mm Hg, and a DBP of 10.06 (81.95) mm Hg. For 8 weeks, participants consumed 500 mg/day of quercetin or a placebo. There were no significant changes to SBP or DBP. The authors suggest that this may be due to the anti-hypertensive drugs that these post-MI patients were taking to control hypertension. Therefore, the efficacy of quercetin to lower blood pressure may decrease when the blood pressure is already in a managed state [In another double-blind, placebo-controlled, randomized clinical trial, researchers studied how quercetin will affect patients with post-myocardial infarction . There wed state .2. SBP was 130.3 ± 16.4 mm Hg, and DBP was 81.6 ± 9.3 mm Hg. Participants received 150 mg/d of quercetin or a placebo for 6 weeks. SBP decreased significantly for participants in the quercetin group, with no changes to DBP. The lowering of SBP was associated with the reduction of oxidized LDL levels [One double-blinded, randomized, placebo-controlled cross-over trial observed the effects of quercetin in 93 overweight men and women with high-cardiovascular disease risk phenotype . ParticiL levels .2 and 31.1 ± 3.9 kg/m2 respectively. The main group participants had an SBP of 137.1 ± 7.9 mm Hg, and a DBP of 84.4 ± 5.5 mm Hg. Comparative group participants had an SBP of 138.8 ± 6.4 mm Hg and a DBP of 84.4 ± 9.7 mm Hg. Participants received 1000 mg of quercetin twice a day for 6 months. Then, the dose was lowered to 500 mg twice a day for another 6 months. The results determined that SBP and DBP decreased significantly. Treatment also lowered uric acid levels and normalized kidney and diastolic heart function in these participants [The last study looked at the effects of quercetin in patients with gout and essential hypertension . This 12icipants .Overall, the majority of the randomized controlled trials (RCT) outcomes show a significant effect of quercetin supplementation in the lowering of BP, which suggests that this bioactive has the potential to be considered as an add-on to anti-hypertensive therapy. Further well-designed trials are needed to optimize the effective dosage and to investigate the possible drug interactions between quercetin and existing anti-hypertensive medications.Resveratrol is a polyphenol that naturally occurs in a variety of food sources such as grapes, peanuts, apples, plums, blueberries, and soy, with the highest concentrations of resveratrol found in red wine and Itadori tea ,92; it hSeveral studies have evaluated the anti-proliferative, antioxidant and anti-inflammatory effects of resveratrol in models of pulmonary hypertension. Resveratrol has been reported to normalize right ventricular systolic pressure and prevent RV hypertrophy, and oxidative stress as well as reduce the expression of inflammatory markers such as IL-6, IL-1, TNF-α, platelet-derived growth factor-α/β, TGF-β, monocyte chemoattractant protein-1 ,100,101.Using a hypoxic pulmonary hypertension (HPH) rat model, Xu et al. reported that resveratrol treatment reduced ROS production and inflammatory markers in PASMCs induced by hypoxic conditions. Resveratrol inhibited the expression of HIF-1α, the main transcriptional regulator of cellular response to hypoxia, by suppression of the MAPK/ERK1 and PI3K/AKT pathways . Resvera+/K+-ATPase, lactate dehydrogenase and catalase were markedly improved [A handful of studies have used the 2k1C rat model to determine the anti-hypertensive and cardioprotective effects of resveratrol in the case of renovascular hypertension. In all studies in this category, a consistent finding was significantly reduced systolic blood pressure in 2K1C rats ,111,112.improved ; these rA large body of research has analyzed the efficacy of resveratrol in improving cardiac and metabolic parameters in an SHR model. Many studies have observed attenuation of high blood pressure in this model following resveratrol treatment ,116,117,2O2 [Many studies have observed the antioxidant effects of resveratrol in this model. In vitro studies following resveratrol treatment have shown attenuation of an array of oxidative stress markers such as superoxide anion , H2O2 [12O2 ,119,126,2O2 ,117, 8-i2O2 ,116, pro2O2  and TBAR2O2 ,121,122.2O2 ,113,117,2O2  and cata2O2 . Moreove2O2 .In terms of cardiac function, resveratrol has proven to be effective in preventing the development of hypertrophy and cardiac dysfunction. Grujic-Milanovic et al. reported resveratrol treatment provided protective effects against hypertrophy by preserving the lamina elastica interna and elastic fibers in the aortic endothelium of female SHR and blunting the expression of TGF-β, which mediates the promotion of vessel structure alterations . Thandap−/− DOCA mice. The results of the study determined that the loss of AMPKα2 function reversed the vasodilatory effects of resveratrol, suggesting that resveratrol’s anti-hypertensive effects rely heavily on its activation of AMPK [Few studies have evaluated the effects of resveratrol in salt-sensitive models. Using a Dahl salt-sensitive hypertensive rat model, Rimbaud et al. observed a significant improvement in fraction shortening and systolic, diastolic, and aortic endothelial functions were preserved without any changes in blood pressure following resveratrol treatment . In a DO of AMPK . In anot of AMPK . Though 2. A total of 192 men and women aged 40 years or older were included in this 6-month study with SBP between 131.8 and 134.1 mm Hg, and DBP between 80.9 and 81.4 mm Hg. There were three groups for this study: the first group received 500 mg of resveratrol a day, while the second group received 40 mg of resveratrol per day, and the last group received the placebo. There were no significant changes to blood pressure in either of the three groups. The authors speculate that this might be due to the study’s limited sample size, which might have prevented resveratrol from having its full potential [Resveratrol can control blood pressure, oxidative stress, cell adhesion, oxidative stress, and endothelial function . Numerouotential .2. Participants received 250 mg of resveratrol per day with oral hypoglycemic agents, while the control group received only oral hypoglycemic agents for 3 months, respectively. The results showed that there were significant reductions in SBP and DBP in the individuals who consumed resveratrol daily. This favorable effect was linked to a reduction in LDL-C and an improvement in glycemic index [In the second study, a prospective, open label, randomized, controlled trial was done on 62 men and women aged between 30 to 70 years with type 2 diabetes . Particiic index .2. SBP ranged between 131.61 ± 17.97 mm Hg, and DBP ranged between 85.30 ± 13.70 mm Hg. Individuals in the placebo group received corn starch capsules, while participants in the intervention group received 600 mg of resveratrol daily for 12 weeks. There were no significant results on SBP or DBP. The authors state that the number of clinical disturbances before the administration of resveratrol may have affected the blood pressure results [Another randomized, double-blind, placebo-controlled clinical study observed how resveratrol affects the blood pressure of individuals who are overweight/obese and have non-alcoholic fatty liver disease . The stu results .2 and received 500 mg of trans-resveratrol per day. The results proved that there were no significant effects on SBP or DBP of the participants. According to the authors, this may be attributed to the study’s short duration or the baseline characteristics of those who participated in this trial [A randomized, double-blinded, placebo-controlled, parallel-group trial was conducted to observe the effects of resveratrol in 24 obese men ages 18 to 70 years for 4 weeks . Individis trial .2. SBP ranged between 139 ± 2 and 142 ± 2 mm Hg, and DBP was 87 ± 2 mm Hg. Patients in the intervention group received 300 mg/day. According to the results, there were no changes to SBP and DBP in the intervention group, which may be due to the small sample size they used in this study [In a similar study, Marques et al. evaluated the effects that acute trans-resveratrol had on individuals with endothelial dysfunction in a randomized, cross-over, double-blind, placebo-controlled trial . There wis study .2. For 30 days, individuals in the intervention group consumed 150 mg of resveratrol per day, while the others received the placebo treatment. There were significant reductions in SBP for those who consumed the resveratrol capsules. Reduced glucose levels, triglyceride levels, and inflammation markers were linked to this positive effect [The effect of resveratrol in 11 obese men aged 52.5 ± 2.1 years were observed in a randomized double-blind crossover study . SBP rane effect .2. For 16 weeks, participants either received a high dose of resveratrol (1000 mg/day), a low dose of resveratrol (150 mg/day), or a placebo treatment. There were no significant changes to SBP or DBP in either group. The study’s design, including the dosages administered, the duration of the study, and the criteria for participants to be included in this study, lead the authors to speculate that there was no effect on blood pressure [Kjær et al., studied how resveratrol affects patients with metabolic syndrome in a randomized, placebo-controlled, double-blind, parallel-group clinical trial . There wpressure .2. SBP ranged between 132 ± 2.2 and 135 ± 3.5 mm Hg and DBP ranged between 83 ± 1.7 and 88 ± 2.2 mm Hg. For six months, individuals consumed 150 mg/d of resveratrol, or the placebo treatment. There were no significant effects on SBP or DBP. According to the authors, there are no known mechanisms linking resveratrol to changes in blood pressure [Another study observed the effects of resveratrol in 41 overweight/obese men and women in a parallel-group, double-blind clinical trial . Participressure .There are conflicting findings in the human studies that examined how resveratrol affects hypertensive patients. Despite the fact that some trials had no impact on blood pressure, many of them showed a reduction in SBP and DBP. The anti-hypertensive effects that this bioactive provides are anticipated to have more favorable results with further human trials that have wider inclusion criteria and populations, as well as higher doses of resveratrol when conducting the study.10) is a 1,4-benzoquinone, also known as ubiquinone [10 is also essential for the production of cellular energy and is known to play a role in immune function [Coenzyme Q10 , abundantly found in fish oil . AdditioEicosapentaenoic acid is also long chain n-3 PUFA ; it mainThe protective effects of DHA and EPA have been evaluated in different models of pulmonary hypertension. In MCT-induced PAH rat models, DHA decreased mPAP and reduced pulmonary vascular remodeling and RV hypertrophy; it also improved lung inflammation and suppressed the accumulation of macrophages and T lymphocytes in lung and pulmonary arteries. Additionally, DHA may provide anti-proliferative effects by arresting the cell cycle of PASMCs through the inhibition nuclear factor of activated T cells-1 . In anot2 [2+ influx through L-type calcium channels [In MCT-induced PAH rats, EPA is reported to lower systolic pulmonary arterial pressure, provide anti-inflammatory effects by improving pulmonary GPR120 mRNA expression and inhibit PASMC proliferation stimulated with TGF-β or FGF2 . In addi2 . EPA tre2 . In sheechannels .A handful of studies have assessed the anti-hypertensive and cardio-protective effects of DHA supplementation  in an SHR model. DHA supplementation alone can effectively prevent a rise in blood pressure in SHR ,174,175.+-induced contracted SHR aortic rings but not improve aortic contractile or relaxant responses to acetylcholine or nitroprusside, which suggests that the vasorelaxant effects of DHA are associated with intracellular Ca2+ release and modulation of L-type Ca2+ channels in VSMC and are independent of endothelium-derived nitric oxide [In addition, it has been reported to reduce vascular wall thicknesses in the coronary, thoracic, and abdominal aorta. DHA was able to induce relaxant effects in both norepinephrine and high-Kic oxide ,176. A cic oxide ,174 In aic oxide ,177,178Past studies have shown that EPA supplementation can provide anti-hypertensive effects in SHR. A couple of studies found EPA treatment reduced systolic blood pressure in this model ,180, whi2. For five weeks, men in the DHA group consumed 2 g of DHA per day, while the placebo group received 1 g of olive oil per day. The outcomes showed significant reductions in the SBP and DBP of the participants in the DHA intervention group when compared to the placebo group. The beneficial effect of DHA could be associated with a lowering of LDL-C and an increase in HDL-C [There has been sufficient evidence to suggest that DHA contributes to many functions of the body, particularly cardiovascular function. Currently, there are only three studies that have assessed the effects of DHA on blood pressure in hypertensive individuals. In a study by Sagara et al., 156 Scottish men aged 45 to 59 who were overweight, hypertensive, and hypercholesteremic were included . Particiin HDL-C .2. SBP ranged between 115 to 180 mm Hg, and DBP was less than 110 mm Hg. There were three groups: the placebo group, the DHA group, and the EPA group. Each participant consumed 4 g per day in their respective group for 6 weeks. The findings revealed that neither DHA nor EPA had any significant effects on blood pressure. The authors have suggested a number of potential explanations for why there were no changes in blood pressure, including the use of other pharmaceutical treatments, adequacy of glycemic control, higher variability in blood pressure in diabetes patients, insufficient statistical power, and the use of olive oil as a placebo [The second study was a double-blind, placebo-controlled trial of parallel design done on 39 participants, which included men and postmenopausal women ages 40 to 75 years . This st placebo .2 [The last study looked at how DHA and EPA impacted the blood pressure in 59 mildly hyperlipidemic, overweight men. Participants were ages 20 to 65 years old with a BMI between 25 to 30 kg/m2 . SBP was2 .Overall, the number of human studies that have assessed the direct effects of DHA on hypertension is very limited. Two out of the three human trials show that DHA independently lowers SBP and DBP. More human trials need to be conducted in order to affirm these effects in hypertensive patients.2. SBP was 141.2 ± 11.1 mm Hg, and DBP was 86.8 ± 6.4 mm Hg. For 3 months, patients either received 1800 mg/d of EPA or 10 mg/d of pravastatin. SBP and DBP significantly decreased in the EPA group; this beneficial effect was associated with a reduction of total cholesterol [EPA has often been a recommended source to prevent cardiovascular disease, and all complications related to the cardiovascular system . There alesterol .Another study looked at how EPA affects the blood pressure of mild to moderate essential hypertensive patients . There w2. Individuals consumed 4g of EPA, DHA, or a placebo for 6 weeks. There were no significant changes to the SBP or DBP of the participants. The use of supplemental drugs for treatment, adequate glycemic control, the higher changes in blood pressure in diabetes patients, using olive oil as a placebo and a lack of statistical power are possible explanations put forth by the authors as to why there were no changes in blood pressure [In a similar study, a double-blind, placebo-controlled trial of parallel design was done on 39 postmenopausal women and men to study the effect of EPA and DHA on blood pressure . Participressure .Overall, the studies so far show mixed results about the role that EPA plays in lowering blood pressure for hypertensive patients. More robust studies with increased sample sizes, higher EPA doses, and broader population criteria are needed to validate the clinical benefits of EPA.Purified quercetin is available as a dietary supplement in doses of up to 1000 mg/day . AccordiResveratrol is generally well-tolerated; however, gastrointestinal, and nephrotoxic adverse effects have been documented in humans ,192,193.Data from clinical trials indicate that coenzyme Q10 has a very good safety profile; it does not accumulate in plasma or tissues after the termination of supplementation . In healn = 12,750 participants) compared with the control group . Treatment with omega-3 fatty acids was associated with dygeusia, gastrointestinal disorders, and skin abnormalities . In addition, some adverse effects such as gastrointestinal disturbance and low-density lipoprotein cholesterol elevation were more pronounced with EPA/DHA combination products [The safety and tolerability of prescription omega-3 fatty acid products (EPA and DHA) was evaluated in a meta-analysis of 21 randomized controlled trials . There wproducts .In summary, all the bioactive compounds discussed in this review have shown strong evidence of blood pressure-lowering effects in animal and human studies. The perceived anti-hypertensive effects can range from antioxidant effects to modifying signal transduction in vascular physiology. Nevertheless, certain limitations of the current review need to be considered as these studies show some level of heterogeneity, making it difficult to draw concrete conclusions in relation to types of subjects, dosage, form of analyzed product or interactions with other disease conditions. Future studies must try to avoid the risk of potential bias associated with other confounding factors such as other dietary or lifestyle factors.The knowledge of the anti-hypertensive effects, bio-availability and the most effective dosage of these compounds may be useful information for (1) Plant breeders to create new cultivars with high levels of these compounds using conventional breeding in conjunction with emerging molecular biology techniques (2) primary processors to develop pre and post harvesting strategies to optimize the levels of these compounds (3) Food technologists to enhance the levels of these compounds through processing technologies to deliver required quantities in appropriate servings. The information provided in this review is a step towards the goal of finding a dietary solution for preventing or managing hypertension and its complicationsFuture clinical studies should focus on the study design to eliminate the risk of bias related to potential confounding variables such as other underlying conditions or lifestyle factors. Moreover, the dosages, source, length of intervention and frequency of consumption should be considered. In order to take these molecules into mainstream clinical usage, it is necessary to carry out better quality RCTs  with advanced and accurate outcome measures (such as ambulatory blood pressure monitoring). Further interventional trials are necessary to determine the clinical value of supplementation and to identify possible drug interactions between these bioactive molecules and standard anti-hypertensive medications. For instance, there have been studies showing that quercetin can be metabolized by the cytochrome P450 system .Overall evidence from a large body of preclinical and human studies suggests that the bioactive compounds discussed in this review  could have important and clinically relevant anti-hypertensive effects. However, well-designed clinical trials are still required to o widen our understanding towards the underlying mechanisms of action and to narrow the knowledge gap between preclinical findings and human trial data.


Measurement of the hepatic venous pressure gradient (HVPG) is the gold standard to evaluate the presence and severity of portal hypertension. The procedure is generally safe and well tolerated, but nevertheless, some patients demand for sedation. However, it is unknown whether propofol sedation would impair the accuracy of portal pressure measurements.This is a prospective observational cohort study including cirrhotic patients with suspected portal hypertension undergoing invasive measurement of HVPG. Measurements of HVPG were performed in awake condition as well as under sedation with propofol infusion.p = 0.34), wedged hepatic vein pressure values (WHVP) decreased in an average by  2.05 mmHg  which was proportional to the magnitude of HVPG. In 31 out of 37 patients (83.8%), portal hypertension with HVPG ≥ 12 mmHg was found. Under sedation with propofol, two patients (5.4%) with borderline values would have been incorrectly classified as < 12 mmHg. After adjustment for the average difference of − 10%, all patients were correctly classified. Intraclass correlation coefficient between HVPG measurement in awake condition and under propofol sedation was 0.927 (95% CI 0.594–0.975).In total, 37 patients were included. Mean HVPG in awake condition was 15.9 mmHg (IQR 13–19) and during sedation 14.1 mmHg (IQR 12–17). While measures of free hepatic vein pressure (FHVP) were not altered after propofol sedation (Propofol sedation during HVPG measurements is generally safe, however it may lead to relevant alterations of HVPG readings.The online version contains supplementary material available at 10.1007/s12072-021-10261-z. Liver cirrhosis is a continuum, ranging from a compensated to a decompensated stage, as defined by the occurrence of decompensating events such as variceal haemorrhage, ascites, or hepatic encephalopathy . Since dAside from systemic inflammation, mitochondrial dysfunction, oxidative stress and metabolic changes, portal hypertension has been described as one of the main determinants for the development of decompensated cirrhosis. The magnitude of portal hypertension can be ascertained via measurement of hepatic venous pressure gradient (HVPG) –4. ComplSeveral non-invasive techniques have been proposed as surrogate markers, yet none of them has accomplished to replace the invasive HVPG measurement which still is the gold standard for evaluation of portal hypertension , 10. DesAdult patients (age > 18 years) with cirrhosis and suspected portal hypertension undergoing HVPG measurement between 01/2007 and 12/2009 were prospectively included in this study. Patients with inability to obtain a reliable HVPG measurement due to vein-to-vein collaterals, portal-vein thrombosis, or known allergy to propofol were excluded from the trial. All patients provided written informed consent. The study was approved by the Ethics Committee of the University Hospital of Basel (EKNZ) and performed in accordance with the ethical guidelines of the Declaration of Helsinki .The HVPG measurements were performed by experienced hepatologists following a standard operating procedure . In brieAfter the first measurement in awake condition, all patients underwent a second measurement with sedation using intravenous application of propofol. Infusion rates of propofol were titrated to achieve and maintain a moderate level of sedation that allowed the patient to tolerate the procedure with minimal to mild pain while maintaining adequate cardiorespiratory function. The moderate level of sedation was defined as a Richmond Agitation-Sedation Scale score of − 3 points . During In some cases, after completing both measurements of the HVPG, transjugular liver biopsy was performed via the same catheter introducer sheath placed in the right internal jugular vein.The primary aim was to assess the diagnostic accuracy of HVPG measurements with and without propofol sedation. Proportions of correctly or wrongly classified patients were compared between both assessment strategies. Secondary aims included assessment of the diagnostic accuracy after error adjustment.Unless stated otherwise, categorical variables are expressed as number (percentage) and continuous variables were reported as mean ± standard deviation (SD).r). Paired Student’s t test was applied for comparisons of normally distributed continuous data. A Bland–Altman Plot was created for agreement analysis. Measurement differences outside of the 95% CI limits of the Bland–Altman Plot were analyzed to identify potential predisposing factors for mismatch. All p values are two sided. All statistical analyses were performed using STATA, version 15.1 (StataCorp LLC).Estimates of the effect sizes and corresponding 95% confidence intervals (CI) were determined using linear regression. Receiver operating characteristic (ROC) analyses were performed to analyse the discriminative power to identify patients with CSPH (10 mmHg) or a threshold of ≥ 12 mmHg. CSPH prognosticates the formation of esophageal or gastric varices and is per se associated with a worse prognosis . Correla2, and the majority were male (62%). Main causes of cirrhosis included alcoholic liver disease (54%) and chronic hepatitis C infection (22%). Around half of the patients were classified as CHILD–Pugh class A or B, respectively, with only one patient classified as C. Patients had a median MELD-score of 7 pts. (IQR 5–10). Most of the patients were classified as ASA class III (70%) and the median dose of propofol infusion was 130 mg (IQR 100–200).Demographic and baseline clinical characteristics of the 37 patients included in the study are presented in Table p < 0.001) and diastolic blood pressure by 5.78 mmHg  . While measures of free hepatic vein pressure (FHVP) were not altered after propofol sedation (p = 0.34), wedged hepatic vein pressure values (WHVP) decreased by 2.05 mmHg . There was a strong correlation between HVPG results with and without propofol   when compared to measurements without sedation . There was no difference in the effect of propofol when patients were stratified according to CHILD category or etiology of cirrhosis . There was no dose relationship of propofol with the relative change in HVPG .While patients had normal blood pressure and pulse without sedation, application of propofol led to significant declines in both systolic blood pressure by 12.65 mmHg .In total, 33 (89.2%) of 37 patients had CSPH with a HVPG of 10 mmHg or higher. Under sedation with propofol, one patient (2.7%) was incorrectly classified due to a decrease of HVPG from 10 mmHg without propofol to 8 mmHg with propofol  out of 37 patients. Under sedation with propofol, two patients 5.4%) were incorrectly classified due to a decrease of HVPG in both patients from 12 mmHg without propofol to 11 mmHg with propofol . Nevertheless, respiratory oscillations might be of high relevance in patients with known obstructive sleep apnea who have a higher risk of hypoxemia and strained respiration during propofol sedation . TherefoIn recent years, several non-invasive techniques have been proposed for the determination of portal hypertension: liver stiffness measured by transient elastography , 25, colIn an older study, HVPG measurements have been investigated with the use of different doses of the short-acting benzodiazepine midazolam . At a doSupplementary file1 (DOCX 25 KB)Below is the link to the electronic supplementary material.