Telomeres are short segments in chromosome ends, the length of which is reduced during cell lifecycles. We examined the association of mean leukocyte telomere length (LTL) and short telomere proportion (STP) with hemodynamic variables in normotensive and never-treated hypertensive volunteers . STP and mean LTL were determined using Southern blotting, and supine hemodynamics recorded using continuous tonometric pulse wave analysis and whole-body impedance cardiography. The analyses were adjusted for age, body mass index (BMI), alcohol use, smoking, plasma chemistry, and estimated glomerular filtration rate (eGFR). In univariate analyses, mean LTL and STP both correlated with age, BMI, eGFR, aortic blood pressure, augmentation index, and pulse wave velocity . Mean LTL also correlated with systemic vascular resistance (p<0.05). In linear regression analyses of all hemodynamic variables, mean LTL was only an independent explanatory factor for augmentation index , while STP was not an explanatory factor for any of the hemodynamic variables, in contrast to age, BMI and several cardiovascular risk factors. To conclude, augmentation index was predominantly related with chronological aging, but also with mean LTL, suggesting that this variable of central wave reflection is a modest marker of vascular biological aging. Telomeres have several important functions for cell homeostasis, such as preventing chromosomes from attaching to each other and helping deoxyribonucleic acid (DNA) repairing to function properly. Without telomeres, DNA repair mechanisms would misrecognize chromosomes as broken DNA, and this would lead to inappropriately connected chromosomes . TelomerReduced leukocyte telomere length (LTL) has been associated with cardiovascular risk factors, such as family history of cardiovascular disease, lower endothelial progenitor cell number, and lower high-density lipoprotein cholesterol (HDL-C) concentration . In addiShorter LTL was associated with impaired pressure-diameter relation of the carotid artery in American Indians , while mIn 163 hypertensive men treated with BP and lipid lowering medications, shorter LTL was related to the presence of carotid artery plaques . LTL wasAccording to a recent review, we do not have the final evidence whether telomere shortening is a true cause or merely a consequence of cardiovascular disease . AltogetThe study included 566 subjects, 287 men and 279 women, and their mean age was 45 years (age range 19-72 years) . In womeRadial and aortic systolic and diastolic BPs, systemic vascular resistance index (SVRI), and PWV were lower in women than in men . Heart rS=0.444), aortic diastolic BP (rS=0.314), AIx@75 (rS=0.569), and PWV (rS=0.653) , but not with heart rate, ventricular ejection duration, or stroke volume . Of note, the variables BP, PWV, systemic vascular resistance, heart rate, ventricular ejection duration, and stroke volume are all hemodynamic determinants of AIx [Age directly correlated with aortic systolic BP (rS=0.653) . Age alss of AIx –23.S=-0.333) and BMI (rS=-0.243) were inversely correlated, while eGFR (rS=0.174) was directly correlated with mean LTL (The factors that are known to influence LTL presented with expected results: age (rmean LTL .S=-0.183), aortic diastolic BP (rS=-0.130), AIx@75 (rS=-0.181), PWV (rS=-0.286) . Mean LTL also inversely correlated with the magnitude of AIx  or cardiac index , but was also inversely correlated with office systolic BP  and office diastolic BP .Mean LTL inversely correlated with aortic systolic BP (r=-0.286) , and SVRS=0.333), BMI (rS=0.151), aortic systolic BP (rS=0.073), aortic pulse pressure (rS=0.144), AIx (rS=0.164), AIx@75 (rS=0.161), and PWV (rS=0.258) directly correlated, while eGFR inversely correlated (rS=-0.141) with STP , and glucose as included variables, the significant explanatory variables for LTL were age , BMI , and moderate alcohol consumption category  . The significant explanatory variables for STP were age , male sex , and low alcohol intake category  .In addition to mean LTL or STP, the included variables in these analyses were age, sex, BMI, smoking status, categorized alcohol intake, plasma C-reactive protein (CRP), sodium, potassium, uric acid, LDL-C, HDL-C, triglycerides, glucose, and eGFR  and 5. IMean LTL was not an explanatory factor for aortic systolic BP, aortic diastolic BP, or PWV, in contrast to age, and several cardiovascular risk factors . HoweverIn this study we examined whether mean LTL or STP were associated with hemodynamic variables in 566 normotensive and never-treated hypertensive volunteers. None of the subjects used medications with direct influences on cardiovascular function. We found multiple significant correlations between mean LTL or STP and hemodynamic variables in univariate analyses. However, in the regression analyses AIx, a marker of wave reflections, was the only hemodynamic variable that was moderately but independently related with mean LTL, while none of the hemodynamic variables were independently related with STP.The most important task of telomeres is to prevent chromosome heads from attaching to each other and to protect chromosomes from inadequate DNA repair mechanisms . After tWe found that in addition to age, the explanatory variables for mean LTL and STP in regression analyses were BMI and alcohol consumption category, and in the case of STP also male sex. Benetos et al. suggested that for a given chronological age, biological aging in men is more advanced than in women . The finIn the course of aging, the amounts of elastin and smooth muscle cells decrease in arteries whereas the quantity of collagen increases . These cRecently, age- and sex-adjusted LTL, but not muscle telomere length, was found to be shorter in patients with atherosclerotic cardiovascular disease than in controls . IncreasS=0.290). In contrast, heart rate, ventricular ejection duration, and stroke volume were not associated with age in our study population.In the present study, AIx was the only hemodynamic variable with a small independent influence on LTL in the regression analyses. Therefore, our results suggest that the influences of chronological and biological aging in the vasculature are reflected in the magnitude of the AIx. The level of AIx is influenced by arterial stiffness, heart rate, ventricular ejection duration, body height, BP, systemic vascular resistance, and stroke volume , 37, 38.Aging, obesity and cardiovascular risk factors like smoking and heavy alcohol use impair cardiovascular function and are associated with telomere shortening , 7. AlthThe present study was carried out in normotensive and never-treated hypertensive subjects, and the multivariable linear regression analyses were adjusted for several factors that influence cardiovascular function. Our results may be generalized to the Finnish population, as the demographic characteristic of the study participants were similar to the results of a recent population study in our country . The stuIf we had applied two different methods for LTL determinations that would have yielded similar associations with hemodynamic variables, the conclusions of the study would be stronger. Two previous studies that compared Southern blotting and qPCR for LTL analyses found correlations exceeding 0.8 between these two methods , 45, butA significant association between short LTL and increased odds ratio for stroke and myocardial infarction was reported in a meta-analysis . Anotherclinicaltrials.gov NCT01742702). Announcements subject recruitment were distributed in Tampere University and Tampere University Hospital, and announcements were published in a newspaper. Moreover, beginners in Varala Sport Institute’s long-distance running program were informed about the opportunity to participate in this research, and occupational health care offices around Tampere were informed that their clients could participate. The subjects who were interested contacted directly the research nurse. The present study included 566 subjects , who were screened from altogether 878 subjects (480 men and 398 women) who had participated in the hemodynamic measurements.The data originates from the DYNAMIC-study on hemodynamics  or Cobas6000, module c501 . To exclude patients with renal diseases, urine dipstick analysis was made using an automated refractometer test . Cystatin C and creatinine based eGFR was calculated using the CKD-EPI formula .Hemodynamic measurements were performed by research nurses in a quiet, temperature-regulated room. The subjects were instructed not to consume caffeine or nicotine containing products or a heavy meal for at least 4 hours or alcohol for at least 24 hours before the measurements. During the measurements, the subjects lay supine on the recording table with the electrodes for impedance cardiography placed on body surface, the tonometric sensor for pulse wave analysis on radial pulsation of the left wrist, and the oscillometric brachial cuff for BP calibration on the right upper arm , 51, 57.BP and pulse wave form were continuously captured from the radial pulsation by a tonometric sensor , which was attached to the left wrist using a band. Radial BP was calibrated approximately every 2.5 minutes by a brachial BP measurement from the opposite arm. Aortic BP, aortic pulse pressure, aortic reflection time, AIx (augmented pressure/pulse pressure*100), AIx@75, and pulse pressure amplification  were determined with the SphygmoCor software  .R, JR Medical Ltd., Tallinn, Estonia) records changes in body electrical impedance during cardiac cycles. The device was used to determine heart rate, stroke volume, cardiac output, and PWV [R device by subtracting the assumed central venous pressure (3 mmHg) from mean arterial pressure and dividing it by cardiac output. Cardiac output and systemic vascular resistance were related to body surface and presented as indexes (CI and SVRI respectively). The method and electrode configuration has been previously reported [The whole-body impedance cardiography device  were measured using the Southern blot technique as previously described in detail . The intS) between LTL and proportion of short telomeres and other variables were calculated for the scatter plots. Alcohol intake was analyzed as series of discrete variables that were given a score of either 0 or 1; the cut-points for women were 0, 1-7, 8-14, and above 15 standard 12-gram doses of alcohol per week; for men 0, 1-14, 15-24, and above 25 doses of alcohol per week, according to the Finnish Guidelines [The data were analyzed by SPSS version 25.0 . Spearman correlations coefficients (ridelines . Informaidelines , smoking10-transformation for the statistics. The variables that were included in the linear regression analyses correlated with P value <0.1 in univariate analyses with the variable of interest. P-values <0.05 were considered statistically significant.Linear regression analyses with backward elimination was applied to evaluate the associations between LTL and proportion of short telomeres with age, sex, BMI, smoking status, categorized alcohol intake, plasma CRP, sodium, potassium, uric acid, LDL-C, HDL-C, triglycerides, creatinine and cystatin C based eGFR , and aorSupplementary Figure 1Supplementary Table 1


Non‐O blood type (BT) is a risk factor for thromboses, which has been attributed to its effects on von Willebrand factor (VWF)/factor VIII (FVIII) levels. Although high VWF/FVIII may be risk factors for portal vein thrombosis (PVT) in patients with advanced chronic liver disease (ACLD), the impact of BT on PVT is unknown. We aimed to assess (I) whether non‐O‐BT is a risk factor for PVT and (II) whether non‐O‐BT impacts VWF/factor VIII in patients with ACLD.US” including all adult liver transplantations in the US in the MELD era and (II) “Vienna” comprising patients with a hepatic venous pressure gradient (HVPG) ≥6 mmHg.Retrospective analysis comprising two cohorts: (I) “US cohort” included 84 947 patients (non‐O: 55.43%). The prevalence of PVT at the time of listing  and at liver transplantation  was similar in patients with O‐ and non‐O‐BT. (II) 411 patients were included in the “Vienna cohort” (non‐O: 64%). Mean HVPG was 18(9) mmHg and 90% had an HVPG ≥10 mmHg. Patients with non‐O‐BT had slightly increased VWF levels (318(164)% vs 309(176)%; P = .048; increase of 23.8%‐23.9% in adjusted analyses), but this difference was driven by patients with less advanced disease. However, non‐O‐BT explained only 1% of the variation in VWF and had no effect on FVIII.(I) The “Although non‐O‐BT impacts VWF in patients with early stage ACLD, its contribution to VWF variation is considerably smaller than in the general population. Moreover, non‐O‐BT had no impact on FVIII. These findings may explain the absence of an association between non‐O‐BT and PVT in patients with advanced cirrhosis. Non‐O blood type is a risk factor for thromboses in the general population.This association has been attributed to increased von Willebrand Factor (VWF)/factor VIII levels in subjects with non‐O blood type.The impact of blood type on portal vein thrombosis (PVT) in patients with advanced chronic liver disease (ACLD) is unknown.In this study, the prevalence of PVT was comparable between patients with O and non‐O blood type undergoing liver transplantation.The contribution of non‐O blood type to VWF variation was considerably smaller than in the general population and was limited to patients with early stage ACLD.Non‐O blood type had no effect on factor VIII levels in ACLD patients.These findings may explain the absence of an association between blood type and PVT in advanced cirrhosis.1As a consequence of abnormal routine coagulation tests and thrombocytopenia, cirrhosis has long been considered an acquired bleeding disorder.The multimeric glycoprotein VWF is released from endothelial cells upon activation and is cleaved by the ADAMTS13 protease into smaller, haemostatically less potent multimers.However, in patients with clinically significant portal hypertension (CSPH), VWF levels are highly elevated, most likely as a result of portal hypertensionTherefore, we aimed to analyse the impact of ABO blood type on (I) the development of PVT and (II) VWF/factor VIII levels in patients with advanced chronic liver disease (ACLD).22.1This retrospective analysis included two cohorts:US cohort” included all adult (12 years old and above) liver transplantations in the US in the model for end‐stage liver disease (MELD) era up to the end of 2017 (02/2002‐12/2017). Data were obtained through the Organ Procurement and Transplantation Network (OPTN) and the data set supplied by the United Network for Organ Sharing (UNOS). Liver re‐transplantations, transplantations for acute liver failure and entries with missing information on blood type were excluded. Moreover, patients with hepatocellular carcinoma (HCC) and/or transjugular portosystemic shunt (TIPS) were excluded from the data set for the main analyses. Finally, the analyses were repeated after re‐including these patients.(I) The “Blood type A subgroups  were referred to as blood type A in all analyses.Vienna cohort” comprised prospectively characterised patients with ACLD who underwent hepatic venous pressure gradient (HVPG) measurement at the Medical University of Vienna between 01/2006 and 02/2018 and had a HVPG ≥6 mmHg and available information on ABO blood type and plasma VWF levels. Patients with active bacterial infection or hepatocellular carcinoma (HCC) were excluded. The final cohort comprised 411 patients.(II) The “2.2US cohort,” portal vein thrombosis was evaluated at the time of listing as well as at the time of liver transplantation. The required information was independently reported to the OPTN by each transplant centre as part of the routine transplantation waiting list registry and the transplant event registry.In the “2.3Hepatic venous pressure gradient was measured in clinical routine for diagnostic or prognostic purposes or HVPG‐guided non‐selective betablocker therapy,2.4Vienna cohort” were performed using blood samples obtained at the time of HVPG measurement. VWF antigen levels were measured by a latex agglutination assay , while factor VIII activity was assessed by a one‐stage clotting assay using a fully automated CS‐5100 coagulation analyser (Sysmex). Plasma protein C and antithrombin activity were measured using chromogenic assays.Labouratory tests in the “2.5t tests/analyses of variance (ANOVA) with generalised linear modelling using the least square means technique or Mann‐Whitney U tests/Kruskal Wallis one‐way ANOVA were used to compare continuous variables. Correlations were analysed by calculating Spearman's correlation coefficients, which were further compared by Fisher transformation. Simple and multiple linear regression analyses were performed to evaluate factors independently associated with VWF/factor VIII levels. Variables showing a trend in univariate analysis (P < .1) as well as the factor of interest (non‐O blood type) were included into the multivariate models. Multicollinearity was detected by variable inflation factor (VIF). Accordingly, either decompensated cirrhosis and MELD, or Child‐Turcotte‐Pugh (CTP) score were included as covariates. A P ≤ .05 was considered statistically significant.Statistical analyses were performed using IBM SPSS Statistics 25 (IBM), GraphPad Prism 8 (GraphPad Software) and SAS 9.4 (SAS Institute). Categorical variables were reported as numbers (n) and proportions (%) of patients and continuous variables as mean ± standard deviation or median (interquartile range [IQR]), as appropriate. Differences in categorical variables were analysed for using the Chi‐squared test. Student's 2.6Vienna cohort” was conducted in accordance with the Declaration of Helsinki and approved by the institutional review board (IRB) of the Medical University of Vienna (No. 1446/2018), which waived the requirement of a written informed consent for this retrospective analysis. The University of Virginia does not require IRB approval for OPTN data set analyses and no study data related to the “Vienna cohort” were revealed to the US investigator.The sub‐study based on the “33.1US cohort”  In total, and after excluding patients undergoing re‐transplantation n = 13 784) and transplantations for acute liver failure or primary graft non‐function (n = 14 529), as well as patients with HCC and/or TIPS, 59 292 patients were included in the “3 784 andVienna cohort.”.(II) Within the study period, 1115 individual patients underwent HVPG measurement at the Vienna Hepatic Hemodynamic Lab  with a mean age of 52.55 ± 11.68 years. While 26 481 patients had blood type O, 21 902 had A, 7915 B and 2994 patients harboured blood type AB. Detailed patient characteristics of the “P < .0001), however, the differences were small and judged not to be clinically significant (maximum between group difference: 1.06%). MELD score at the time of liver transplantation was statistically significantly higher in patients with blood type O (24.24 ± 10.45), when compared to non‐O individuals . This may partially be explained by differences in waiting times for liver transplantation , since MELD at listing showed an even smaller difference between blood types . Importantly, despite being statistically significant, the differences in MELD were only modest. Moreover, patients with blood type O showed a lower prevalence of diabetes mellitus , but again, this difference was not considered clinically significant. Importantly, the proportions of overweight and obese patients as well as other baseline characteristics were well balanced between the two groups.As this study aimed to evaluate differences between O vs non‐O individuals, a comparison of baseline characteristics between these two groups is shown in Table 3.3P = .111; Table P = .5369). To assess whether the relationship between blood type and PVT prevalence is modified by the severity of liver disease, we excluded patients with HCC and/or TIPS and stratified the “US cohort” according to MELD score <15, 15‐20 and >20 points at listing. The prevalence of PVT at listing was comparable between patients with O vs non‐O blood type throughout all MELD strata: <15: 3.73% vs 3.92% (P = .517), 15‐20: 4.4% vs 4.69% (P = .384) and >20 points: 4.17% vs 4.49% (P = .208).At the time of listing for liver transplantation, 4.25% of patients without HCC and/or TIPS had a PVT and the rate of PVT was similar in individuals with O vs non‐O blood type (4.1% [1087/26 481]) vs 4.37% [1434/32 811]; Finally, we re‐included the patients with HCC and/or TIPS, which did not affect our results regarding the impact of ABO blood type on PVT Tables  and S3.3.4The majority of patients was male (70%) with a mean age of 54.1 ± 11.4 years Table . Viral hP = .048; Figure P = .882) patients.Median overall VWF level was 313 (IQR: 167)% with slightly, but statistically significantly higher levels in non‐O blood type individuals (318 [IQR: 164]%), when compared to O patients , all other baseline characteristics were well balanced between the groups.Moreover, plasma activities of protein C (information available in n = 358) and antithrombin (n = 361), as well as factor VIII/protein C ratio (n = 249) did not differ between patients with O and non‐O blood type. Except for trends towards a slightly higher HVPG and MELD score in blood type O patients (VWF levels were significantly higher in blood type non‐O patients with low MELD (<10 points) or subclinical portal hypertension (HVPG 6‐9 mmHg), while no differences were observed in patients with HVPG values of 10‐15 mmHg and profound portal hypertension (HVPG ≥ 16 mmHg), or patients with MELD scores of 10‐15 and >15 points Tables  and S5. 3.5P = .047).In unadjusted analysis, VWF levels showed a positive association with age, ALD as underlying aetiology, HVPG and factors closely related to portal hypertension  and indicators of hepatic dysfunction (MELD and CTP score) Table . In addiP = .003 for both models). Furthermore, age , decompensated cirrhosis , HVPG , MELD  and CTP score , AST; U × L−1; B: 0.12 and P = .005 for both models), GGT  and C‐reactive protein  were independently associated with VWF levels.After adjusting for potentially confounding factors in multivariate models including either hepatic decompensation and MELD, or CTP score, the absolute differences in VWF levels between patients with non‐O and O blood type ranged from 23.8% to 23.9% , indicators of hepatic dysfunction (MELD and CTP score), platelet count, indicators of liver injury  and systemic inflammation (CRP) Table . InteresP = .019/B: 0.781; P = .027), arterial hypertension , CTP score , PLT  and AST .The following factors were independently linked to factor VIII levels: age   Table . Moreove3.8US cohort,” as compared to the “Vienna cohort,” which may be related to the lower prevalence of ALD in the “US cohort” , which was considerably higher than the MELD at the time of HVPG measurement in the “Vienna cohort” .After excluding patients with HCC and/or TIPS, the male predominance was less pronounced in the “t” Table . In cont4Current European guidelines recommend extensive testing for underlying prothrombotic risk factors in patients with PVT without underlying liver disease to guide decisions on long‐term anticoagulation. In contrast, in the setting of ACLD, the relevance of thrombophilia which is not related to the severity of liver disease itself is less clear.US cohort”), the prevalence of PVT at the time of listing as well as at the time of transplantation was similar between O and non‐O individuals. Importantly, owing to the enormous sample size of the “US cohort,” we can basically rule out type II error, as we were able to assess even very small differences. For instance, a 10% decrease in the prevalence of portal vein thrombosis in patients with O blood type at the time of listing  would have been detected with a statistical power of more than 99%. Finally, the OPTN/UNOS data have been used in a series of studies reporting information on PVT,In the general population, the impact of ABO blood type on VTE is well established. In a study assessing 1.5 million blood donors, for instance, the risk of VTE was increased by 80% in patients with non‐O blood type.The well‐documented prothrombotic state observed in liver‐healthy non‐O subjects is attributed to the impact of ABO blood type on VWF, and consequently, factor VIII levels.Accordingly, with a mean age of 54.1 ± 11.4, we would have expected a profound impact of ABO blood type in our second cohort (“Vienna cohort”). In adjusted analysis, the non‐O blood type‐related increase in VWF antigen levels was about 24%, which, in absolute terms, was comparable to the differences reported in the general population.High VWF levels indicate endothelial dysfunction and liver sinusoidal endothelial cells (LSEC) likely contribute to the increased VWF levels in these patients.r2 = .01), which is substantially less as compared to the general population (15.4%r2 = .155) or CTP score (r2 = .181).In our study, VWF levels were independently and positively associated with decompensated disease, severity of portal hypertension (HVPG), indicators of hepatic dysfunction, liver injury/hepatic inflammation (AST/GGT) and systemic inflammation (CRP). This supports the above‐mentioned considerations about the interplay between hemodynamic changes  and hepatic/systemic inflammation leading to elevated VWF levels in patients with ACLD. Moreover, similar to the general population, age and non‐O blood type increased VWF levels, independently of the other factors. Obesity as well as the analyzed components of the MetS did not affect VWF levels in univariate analyses, and thus, were not included in multivariate models. This finding is in contrast to studies not focusing on chronic liver disease (CLD)Importantly, we also investigated parameters associated with factor VIII levels: VWF and factor VIII levels showed a correlation of moderate strength, which seemed to be comparable throughout groups/strata of hepatic dysfunction/portal hypertension severity. However, as a result of the limited sample size in some of the groups/strata, we cannot entirely rule out that liver disease severity modulates the correlation between VWF and factor VIII levels. Besides age, arterial hypertension, hyperlipidaemia, hepatic dysfunction, platelet count and AST were independently linked with factor VIII levels. Although factor VIII levels were not affected by BMI, overweight, or obesity, they showed an association with arterial hypertension and hyperlipidaemia , which is in line with observations in non‐CLD cohorts.Portal vein thrombosis development in patients with ACLD has to be considered a multifactorial event not only driven by changes in coagulation, but also by reduced portal flow velocityUS cohort” did not include information on VWF/factor VIII, while in the “Vienna cohort,” screening for PVT was not standardised. However, the demographic characteristics of the two cohorts were comparable and both cohorts included patients with ACLD, although patients in the “Vienna cohort” had considerably less advanced disease. Importantly, this approach allowed to combine the strengths of the “US cohort” (very large sample size) and the “Vienna cohort” (in depth characterisation). However, the relationship between ABO blood type and PVT was evaluated in a sicker cohort than the association of ABO blood type and VWF/factor VIII levels, which is an important limitation of our study. Stratification by severity of hepatic dysfunction/portal hypertension revealed, that the impact of ABO blood type on VWF  levels seemed to be limited to ACLD patients with less advanced disease . As patients with these characteristics usually aren't listed for liver transplantation, they were not included in the “US cohort,” and thus, our findings should not be extrapolated to these patient populations. Of note, these patients with less advanced disease are per se at low risk for PVT.We have to acknowledge that the two main analyses included in this study were performed in different cohorts, since the “In conclusion, while ABO blood type contributes to the variation in VWF levels in patients with early stage ACLD, its overall impact is considerably smaller than in the general population, and may vanish in patients with advanced cirrhosis. Moreover, ABO blood type had no impact on factor VIII levels. These findings may explain the absence of an association between ABO blood type and PVT, even in a large data set of patients with advanced cirrhosis.The authors have nothing to disclose regarding the work under consideration for publication. However, the authors disclose the following financial activities outside the submitted work: BS received travel support from AbbVie and Gilead. PQ has served as a speaker and/or consultant and/or advisory board member for Roche and Takeda. CA received honoraria for lectures and advisory boards from Bayer, Boehringer‐Ingelheim, Bristol‐Myers Squibb, Daiichi Sankyo and Pfizer. MT has served as a speaker and/or consultant and/or advisory board member for Albireo, Bristol‐Myers Squibb, Dr Falk Pharma, Gilead, Intercept, MSD, Novartis, Phenex Pharmaceuticals and Regulus, and has received research funding from Albireo, Dr Falk Pharma, Gilead, Intercept, MSD and Takeda. MT is listed as a co‐inventor on patents on the medical use of nor‐ursodeoxycholic acid. TR has served as a speaker and/or consultant and/or advisory board member for AbbVie, Bayer, Boehringer Ingelheim, Gilead, W. L. Gore & Associates and MSD and has received research funding from AbbVie, Boehringer Ingelheim, Gilead, Phenex Pharmaceuticals and Philips. MM has served as a speaker and/or consultant and/or advisory board member for AbbVie, Bristol‐Myers Squibb, Gilead, W. L. Gore & Associates and Janssen. PGN, AG, GS, GL, JT and TL have nothing to disclose.All authors contributed either to research design , and/or the acquisition , analysis  or interpretation  of data. BS and MM drafted the manuscript, which was critically revised by all other authors.TableS1‐S7Click here for additional data file.


In subgroup analysis, a vegan diet demonstrated a greater reduction in systolic BP  as compared with a lacto-ovo-vegetarian diet . The vegan diet has showed a similar trend in terms of diastolic blood pressure reduction  but those with a lacto-ovo-vegetarian diet showed no changes in diastolic BP reduction , p = 0.432). In conclusion, vegetarian diets are associated with significant reductions in BP compared with omnivorous diets, suggesting that they may play a key role in the primary prevention and overall management of hypertension.The beneficial effects of a vegetarian diet on blood pressure (BP) control have been reported in previous systematic reviews; however, so far, their relative effectiveness is not well established. Here, we performed a systematic review together with trial sequential analysis to determine the effect of a vegetarian diet on the reduction of blood pressure. We searched the randomized controlled trial (RCT) through Medline, PubMed and Cochrane Central Register. Fifteen eligible RCTs with 856 subjects were entered into the analysis. The pooled results demonstrated that vegetarian diet consumption significantly lowered the systolic blood pressure (weighted mean difference (WMD), −2.66 mmHg  = −3.76, −1.55,  It is estimated that about 26% of the world’s population (957–987 million) were affected with hypertension in 2000, with 333 million from developed countries and 639 million from developing countries . It is aHigh blood pressure or hypertension is defined as systolic blood pressure of 140 mmHg or higher, and diastolic blood pressure of 90 mmHg or higher . It is aVegetarian diets are defined as dietary patterns that are determined by the level of animal food intake, and can be classified into several subtypes. Firstly, the vegan diet is defined as plant-based diet only; secondly, the lacto-ovo-vegetarian diet refers to diet that is without meat but may include eggs and/or dairy products; thirdly, the pescovegetarian diet may contain fish, but with other meats only taken < once/month; and the semivegetarian diet contains meats besides fish occasionally, but these are only taken < once/week . VegetarHowever, to date, previous studies have offered conflicting results regarding this topic ,25, and,The protocol was registered in the Medical Research and Ethics Committee, Ministry of Health Malaysia (registration number: NMRR-20-250-53210) on 25 February 2020. The reporting followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines .We searched three major citation databases  and included all relevant citations regardless of data of publication from inception to 6 January 2020. We also used forward and backward citation from the included studies to search for relevant studies. The search strategy is shown in The intervention group was defined as participants who were on a lacto-ovo-vegetarian diet  or a vegan diet  for at least two weeks. The control group was defined as participants who were on an omnivorous diet .We included randomized controlled trials of two weeks’ follow-up duration comparing the effect of vegetarian diets (which included vegan to lacto-ovo-vegetarian) with non-vegetarian diets on systolic and diastolic blood pressure as a primary or secondary outcomes. The included studies had to be published in English or have an English translation. Studies were excluded if there was no vegetarian intervention, no nonvegetarian control, or no suitable outcome data.Two investigators (KWL and HCL) independently reviewed and extracted relevant data from each of the included studies. A standardized form was used to extract data on the following variables: first author, publication year, country, baseline characteristics of the study population, baseline and follow-up blood pressure levels, and changes of blood pressure in mean ± standard deviation. All discrepancies and disagreements were resolved through consensus.p value of <0.05, which was considered as statistically significant. Meta-analyses were conducted using Open Meta Analyst software [Mean differences in systolic and diastolic blood pressure between patients assigned to receive the vegetarian and comparators diets were calculated using a meta-analysis with random-effects model and trial sequential analysis. Estimates of net changes in blood pressure associated with the consumption of vegetarian diets were combined using a random effects model and the result was reported with a 95% confidence interval with a two-sided software . We perfsoftware . Meta-ansoftware . TSA is software . Therefosoftware .We used mean ± standard deviation (SD) to express our outcomes. If the mean difference and SD were not provided, the mean was calculated by subtracting the mean of baseline measurement from the corresponding mean of post intervention measurement; SD was imputed from the end point measurement. If the mean difference was provided, but the SD was not, the latter was imputed either from the end point measurement or calculated using the confidence intervals with the formulas “SQRT (sample size) × / × 2)” proposed by ; this fuIncluded trials were independently assessed by two investigators (KWL and HCL) for risk of bias using the Cochrane Risk of Bias Tool ,33. Asse2 > 75%, p value < 0.05) [The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to assess the certainty of the evidence ,36,37,38 < 0.05) , indirec < 0.05) , impreci < 0.05) , and/or  < 0.05) .The literature search and selection process is shown in Characteristics of the 15 included studies are shown in The effect of vegetarian diets on lowering systolic blood pressure and subgroup analysis by diet subgroup, diabetes status, and country are shown in According to TSA, the cumulative Z-curve (blue curve) shown in The effect of vegetarian diets on diastolic blood pressure lowering and its subgroup analysis by diet subgroup, diabetes status, and country are shown in According to TSA, the cumulative Z-curve (blue curve) shown in Risk of bias  was asseIn the aspect of bias in outcomes measurement, the majority of the trials are at low risk of bias, except for one trial , which h2 value, which indicated there are considerable proportions of variations due to interstudy differences.A summary of the GRADE assessments of the overall certainty of the evidence for the effect of vegetarian diets on blood pressure lowering is demonstrated in From the 15 RCT that are included in our study, we noticed that the composition of interventional diet in each study shows slight differences. For the Bernard study in 2009, the vegan diet with vitamin B12 supplementation consisted of vegetables, fruit, grains, and legumes, and was high in fiber and low in fat while the quantity, energy, and carbohydrate intake were unrestricted . The stuThis meta-analysis revealed that a vegetarian dietary pattern significantly reduced systolic and diastolic blood pressure by WMD −2.655 and WMD −1.687, respectively. In general, this study yielded a similar finding to a previous meta-analysis of seven randomized controlled trials and thirty-two observational studies, which showed that the WMD in consumption of vegetarian diets versus omnivorous diet was systolic blood pressure of −4.8 mmHg in controlled trials and −6.9 mmHg in observational studies , while fAmong the various vegetarian diets, there was a difference result between the vegan and lacto-ovo-vegetarian diets. Greater reduction of BP was observed in the vegan diet. There was a greater BP reduction for the vegan diet  as well as greater reduction in systolic blood pressure in the lacto-ovo-vegetarian diet  compared with the omnivorous diet. This can be explained by the fact that regular consumption of meat, especially red meat, also increases the risk of falling ill because the processed derivatives in meat products are an associated factor for hypertension ,69,70. BThis finding suggested that dietary patterns based solely on plant sources are more effective in reducing blood pressure than other types of vegetarian diet which still include animal products or byproducts, such as eggs and dairy products, for example, in the lacto-ovo-vegetarian diet. This result is supported by previous studies in which high consumption of fruit and vegetables are associated with reduction of blood pressure when compared with those with a higher intake of dairy products ,74,75. OEven though vegetarian diets significantly improved both systolic and diastolic blood pressure, higher systolic blood pressure reduction was observed among subjects without diabetes  compared to those with diabetes . An opposite trend was observed with diastolic blood pressure in which higher diastolic blood pressure reduction was observed among subjects with diabetes  compared to those without diabetes . It could be because the mean age of the diabetic group (54.9 years old) was much older than the nondiabetic group (40.9 years old), and thus the diastolic BP reduction was not much observed among the younger nondiabetic group.Therefore, vegetarian diets have the potential to be recommended to those with underlying disease as well as the general population, in the hope that, through this nonpharmacological diet method, uncontrolled hypertension could be reduced, which would result in a meaningful decrease in the risk of developing cardiovascular diseases as well as other morbidities and mortality and lessen the excessive demand on healthcare.We also performed the meta-analysis with trial sequential analysis to estimate the effect vegetarian diet had on BP reduction. To provide insight into the power of sample size to conclude the findings, the number of patients included in trial sequential analysis did not exceed the required information size . Similar findings are applied to both systolic and diastolic blood pressure as the number of patients included in trial sequential analysis also similarly did not exceed the required information size . This indicated the cumulative evidence on whether vegetarian diets can reduce systolic and diastolic blood pressure remains inconclusive based on these 884 participants.The current meta-analysis has several limitations. Firstly, there was high heterogeneity among the controlled trials included in the analysis. The heterogeneities across studies could be due to participant characteristics, such as some of the trials involved participants with lifestyle restriction practices including limiting alcohol, salt, fatty food, caffeine intake, and/or cigarette smoking while others did not. These are confounding factors to blood pressure control, thus, it may affect the findings of the study.Secondly, this study only includes dietary patterns, instead of isolated nutrients. There was a lack of information on the nutrition value of various diet regiments consumed by participants in those trials in both the interventional and control arms. Hence, it may cause a plausible application of the results to both general and clinical populations. Only with the availability of the nutritional value of these diets, could we then give recommendations regarding the specific quantities of these foods that should be consumed for the best positive effect. It is important to know energy intake could be an important factor influencing body weight and blood pressure reduction; however, there was also a lack of information on comparisons of changes from baseline to final values for energy intake and body weight between vegetarian diets compared with control diets. Therefore, we could not entangle energy intake on blood pressure lowering in the current study.Thirdly, the included studies were mainly conducted in the USA and other Western countries . Hence, it cannot be generalized to other populations. Additionally, heavy metals can be found both in animal-derived food or plant-based food. However, sometimes it may be higher in the latter one as they can be easily contaminated with heavy metals such as arsenic, cadmium and lead, from the water, air, and soil as they grow ,78,79,80Fourthly, as mentioned previously, the sample size gathered from all clinical trials done in the past has not yet reached the required sample size for drawing a conclusive statement. Therefore, we suggest that, in future, larger randomized clinical trials aimed at examining the effect of the vegetarian diet on blood pressure be conducted, paying attention to publication bias. Furthermore, the number of studies is small and any derived conclusions should be made with caution.Notwithstanding these limitations, this study suggests that, evidence from clinical trials has shown that vegetarian diets, especially vegan diets, reduce blood pressure when compared with omnivorous diets, suggesting that they may be crucial in the primary prevention and overall management of hypertension.


Only a few reports have examined vascular endothelial function before and after educational hospitalization and the factors that affect it in patients with type 2 diabetes mellitus (T2DM). The aim of this study was to assess vascular endothelial function before and after educational hospitalization and identify factors that affect it. In 65 patients with T2DM who underwent peripheral arterial tonometry (EndoPAT) before and after hospitalization, vascular endothelial function (reactive hyperemia index [RHI]), glucose metabolism, lipid metabolism, and blood pressure were assessed before and after hospitalization. The primary endpoint was hospitalization-induced changes in vascular endothelial function. Educational hospitalization significantly improved the natural logarithmically scaled RHI (L_RHI) from 0.555 ± 0.212 to 0.625 ± 0.245 (p = 0.012). Multivariable logistic regression analysis identified hypoglycemia during hospitalization as the single factor that significantly altered vascular endothelial function (p = 0.019). The odds of achieving normal vascular endothelial function were 0.08 times lower  for each episode of hypoglycemia. Furthermore, multivariable analysis identified hypoglycemia during hospitalization as the single factor that worsened L_RHI. Our study showed that educational hospitalization of patients with T2DM improved vascular endothelial function, and that the development of hypoglycemic episodes had a significant negative impact on normalization of vascular endothelial function. Vascular endothelial dysfunction is related to the occurrence and reoccurrence of cardiovascular events; therefore, assessment of vascular endothelial function is useful in the evaluation of arteriosclerosis and risk assessment of cardiovascular disease3. Several factors are thought to contribute to vascular endothelial dysfunction in T2DM, including hyperglycemia, hyperinsulinemia with insulin resistance, and hypoglycemia. We have assessed the relevance of vascular endothelial function and hypoglycemia in T2DM10. In particular, oxidative stress induced by postprandial hyperglycemia and fluctuations in blood glucose levels is associated with vascular endothelial dysfunction9.Type 2 diabetes mellitus (T2DM) is associated with vascular endothelial dysfunction even at the early stage, and atherosclerosis plays a major role in the development of macrovascular disease. For example, the risk of cerebral infarction, ischemic heart disease, and myocardial infarction is 2–6 times higher in patients with T2DM11 reported that treatment of impaired glucose tolerance with acarbose is associated with reduced risk of cardiovascular events. Furthermore, management of dyslipidemia, quitting smoking, exercise, and use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) may improve vascular endothelial function and prevent cardiovascular diseases3.The STOP-NIDDM (Study TO Prevent Non Insulin Dependent Diabetes Mellitus) Trial research group12, and the combination of diet and exercise also improve lipid metabolism and blood pressure. Although improvement of various metabolic abnormalities may subsequently improve vascular endothelial function; little is known about the outcome of in-patient diabetes education, especially with regard to vascular endothelial dysfunction. Moreover, it is not clear which factor(s) related to vascular endothelial function are affected by such programs. The present study was designed to document the changes in endothelial function in T2DM patients after receiving in-patient diabetes education and the variables associated with these changes.In-patient diabetes education programs improve blood glucose controlAmong patients with T2DM admitted to the Hospital of the University of Occupational and Environmental Health and Wakamatsu Hospital of the University of Occupational and Environmental Health between September 2010 and May 2017, 65 were selected for this study. Their selection was based on fulfillment of the following inclusion criteria: (1) peripheral arterial tonometry (EndoPAT) was performed as part of the routine clinical care and patient education, before and after hospitalization, (2) age > 20 years, (3) no diabetic ketosis or nonketotic hyperosmolar coma during hospitalization, and (4) no infection or other acute diseases during hospitalization.This study was conducted according to the tenets of the Helsinki Declaration and current ethical codes. The study protocol was approved by the ethical committee of the University of Occupational and Environmental Health , and an opt-out method of informed consent was approved by the committee.13. An episode of hypoglycemia on SMBG was defined as a blood glucose level < 70 mg/dL. Lipid metabolism was assessed by measurement of triglycerides (TGs), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C).This was a retrospective study based on data available in the medical records of patients admitted to the hospital. Patients with T2DM underwent blood tests  and EndoPAT  at the time of both admission and discharge for inpatient diabetes education. Vascular endothelial function was evaluated using peripheral arterial tonometry . Glucose metabolism was assessed by calculating the average blood glucose and M-values of blood glucose level from data recorded by the self-monitoring blood glucose (SMBG) technique at the following time points: before breakfast, before lunch, before dinner, and 120 min after dinnerThe primary endpoint was a change in vascular endothelial function between at discharge relative to that at admission. The secondary endpoints were factors associated with improvement of vascular endothelial function.Both facilities provided diabetes education following similar programs. All patients received a 2-week education program including lectures from doctors, pharmacists, and nurses using brochures, slides, and videos. As part of diet therapy, salt intake was limited to 6 g and energy intake was set at 25 to 30 kcal/kg of the ideal body weight . The patients individually received at least one session of nutrition education from a dietitian during their hospitalization. Exercise therapy was performed for roughly 15 to 30 min after a meal, two to three times a day. A calorie counter was used and the target was set at 8,000 to 10,000 steps per day. Pharmacotherapy was selected in consideration of body type, insulin secretory ability, complications, and adherence, and physicians, pharmacists, and nurses explained the drugs to be used to the patients. In addition, education regarding diabetic complications, hypoglycemia, and target blood glucose level was also provided. Improvement in body weight and various metabolic abnormalities due to the education program and diet and exercise therapies can be expected to lead to behavioral changes after discharge.14. Briefly, after a 30-min acclimatization period in a room controlled for temperature and light with the patient in the fasting state, the baseline pulse amplitude was recorded during a 5-min period before the induction of local ischemia. Ischemia was induced by placing the blood pressure cuff on the upper arm, while the opposite arm served as a control. The peripheral arterial tonometry probes were placed on one finger of each hand. After 5 min, the blood pressure cuff was inflated to 60 mmHg above the systolic pressure or to 200 mmHg for 5 min and then deflated to induce reactive hyperemia. As a measure of reactive hyperemia, RHI was calculated as the ratio of the average amplitude of the peripheral arterial tonometry signal over 1 min beginning 1.5 min after cuff deflation  divided by the average amplitude of the peripheral arterial tonometry signal over the 2.5-min time period before cuff inflation (baseline) . Thus, RHI = (C/D)/(A/B) × baseline correction. Because RHI has a heteroscedastic error structure, we used the natural logarithm transformation in all analyses.The method used for the digital measurement of vascular function was based on peripheral arterial tonometry as described in detail previously17. We categorized patients with L_RHI ≥ 0.51 at the time of discharge into the normal vascular endothelial function group, whereas the others were classified into the low vascular endothelial function group. The odds ratios (ORs) for the normal vascular endothelial function at the time of discharge were estimated using univariate and multivariate logistic regression. The model included sex, age, body mass index (BMI), duration of diabetes mellitus, use of ACE inhibitors/ARBs/statins, current smoking, glucose metabolism, blood pressure, and lipid metabolism to investigate the relationship between L_RHI and hypoglycemia. We selected a similar indicator from which multicollinearity may occur for each factor, and statin use was excluded as it produced multicollinearity in the preliminary analysis. We used univariable and multivariable linear regression analyses to estimate regression coefficients for the change in vascular endothelial function (ΔL_RHI). The model was fed with data of sex, age, BMI, duration of diabetes mellitus, change in blood glucose metabolism, change in blood pressure, and change in lipid metabolism. We selected a similar indicator from which multicollinearity may occur for each factor and examined it with two models because the Δaverage and ΔM-value were found to be multicollinear in the preliminary analysis. All statistical tests were performed with SPSS Statistical Software 25.0 , and the results were considered significant when the p value was < 0.05.Data are expressed as mean ± standard deviation. The Wilcoxon signed-rank test was used to assess differences in the natural logarithmically scaled RHI (L_RHI), blood glucose, lipid, and blood pressure between admission and discharge. The cutoff value of vascular endothelial disorder was set as L_RHI < 0.51 according to previous studies2. The mean duration of diabetes mellitus was 8.7 ± 11.1 years . Of the patients, 28 (43%) were smokers and 3 (5%) had history of cardiovascular diseases. The mean systolic blood pressure was 129.7 ± 17.5 mmHg , and the mean diastolic blood pressure was 76.5 ± 12.5 mmHg . The mean fasting plasma glucose level was 158.2 ± 49.6 mg/dL , and the HbA1c value was 9.5% ± 2.3% . A comparison of patients with normal vascular endothelial function  and those with vascular endothelial dysfunction  on admission is presented in Supplemental Table Table In this study, 50 of the 65 patients used oral hypoglycemic drugs. Specifically, the number of patients using sulfonylurea (SU) decreased, whereas the number of patients using pioglitazone, metformin (MET), α-glucosidase inhibitor (αGI), dipeptidyl peptidase-4 inhibitor, glucagon-like peptide-1 (GLP-1) analogue, insulin, and sodium glucose cotransporter 2 inhibitor (SGLT2-I) increased from admission to discharge  developed hypoglycemia, and their antidiabetic therapy were as follows: SU + MET + DPP4-I + SGLT2-I in 4 patients, SU + DPP4-I + SGLT2-I in 2 patients, SU + MET + SGLT2-I in 1 patient, SU + αGI + DPP4-I + SGLT2-I in 1 patient, MET + DPP4-I in 1 patient, MET + insulin in 1 patient, MET + DPP4-I + SGLT2-I in 1 patient, MET + αGI + DPP4-I in 1 patient, pioglitazone + insulin in 1 patient, MET alone in 1 patient, and SGLT2-I alone in 1 patient. Both systolic and diastolic blood pressure levels were significantly lower at discharge .16. Accordingly, we divided the patients into two groups: the normal vascular endothelial function group  and the low vascular endothelial function group  at discharge. The high L_RHI group included 63% (41 patients), whereas the low L_RHI group included 37% (24 patients).Vascular endothelial function was evaluated after admission on mean day 4.2 ± 2.1 of admission and on mean day 18.8 ± 3.0 at discharge. The natural logarithmically scaled RHI (L_RHI) significantly increased from 0.555 ± 0.212 at admission to 0.625 ± 0.245 after discharge (p = 0.012)  the consistently normal group (N group), 2) the abnormal RHI during admission to normal at discharge group (A → N group), 3) the persistently abnormal group (A group), and 4) the normal RHI during admission to abnormal at discharge group (N → A group). The incidence of hypoglycemia showed significant differences between the four groups (P = 0.017). The highest incidence noted was 0.5 in the N → A group  hospitalization of patients for education about T2DM, including fine tuning medications and provision of diabetes-related educational program, improved glucose metabolism, lipid metabolism, blood pressure, and vascular endothelial function, and that (ii) hypoglycemia was associated with vascular endothelial dysfunction. Educational programs for patients with T2DM are known to correct lifestyle and enhance treatment mainly based on blood glucose control20 reported that improvement in postprandial hyperglycemia contributes to improved vascular endothelial function. Another report indicated that physical exercise increases the production of nitric oxide (NO) and improves vascular endothelial function through increased physiological activation of NO21. Furthermore, with regard to the association between glucose metabolism and vascular endothelial function, a study using the glucose clamp technique reported that fluctuations in blood glucose levels are associated with vascular endothelial dysfunction22. Our group has also reported that fluctuations in blood glucose levels, postprandial hyperglycemia, and hypoglycemia are associated with vascular endothelial dysfunction in diabetic patients4.In the present study, diet and exercise  therapies were initiated on admission, and oral hypoglycemic drugs were selected based on clinical conditions and glucose dynamics. These measures resulted in improvement in glucose dynamics. With respect to the effects of dietary changes on vascular endothelial function, Kondo et al.23. The average daily sodium intake in Japanese people, as estimated from urine sodium excretion, is reportedly 12.1 g in men and 10.2 g in women24. It is possible that during the hospitalization, the consumption of sodium-restricted diet (6 g sodium) leads to correction of excessive sodium intake-induced hypertension, which in turn, improves vascular endothelial function. In patients with dyslipidemia, the decrease in the production and release of endothelium-derived relaxing factors causes vascular endothelial dysfunction. Experimental studies have shown that LDL inhibits endothelium-dependent relaxation25, and it seems that hypercholesterolemic state appears to have a similar effect26. As described above, blood glucose, blood pressure, and lipids have separate effects on vascular endothelial function; therefore, a comprehensive treatment is important in maintaining vascular endothelial function. Because these conditions can be treated during educational admission to the hospital, in-patient diabetes education seems to improve vascular endothelial function.In the present study, the application of strict diet and exercise therapies improved both lipid metabolism and blood pressure. In patients with hypertension, vascular endothelial dysfunction is associated with increase in blood pressure, probably resulting from NO deactivation (which promotes vasodilation), which is caused by overproduction of reactive oxygen species; with subsequent decrease in bioavailable NO due to decreased production and release of NO; and with the increase in vasodilatory substances, such as reactive oxygen species and arachidonate metabolites27, which is an independent risk factor for cardiovascular events28. Hypoglycemia is considered to cause vascular endothelial dysfunction due to the associated increases in reactive oxygen species, catecholamines29, and proinflammatory cytokines30. We have assessed the relevance of hypoglycemia and glycemic variability in T2DM34. In particular, we reported the association between hypoglycemia and vascular endothelial function in a cross-sectional study of actual clinical cases4, the present study on changes before and after hospitalization therapy showed that the prevention of hypoglycemia is important for treatment that aims to achieve favorable vascular endothelial function. In our previous study using continuous glucose monitoring (CGM), we reported that the risk of hypoglycemia is higher with a lower mean blood glucose level and bigger fluctuations in blood glucose levels33. The present study also revealed that the mean blood glucose level was lower in patients with hypoglycemia. It seems necessary to set a higher target for blood glucose control in patients at a risk of developing hypoglycemia. In addition, the risk of hypoglycemia is known to be higher with bigger fluctuations in blood glucose levels33 and fluctuations in blood glucose levels have been reported to be associated with vascular endothelial function4. To determine the effects of fluctuations in blood glucose levels due to hypoglycemia on vascular endothelial function, detailed assessment of glucose dynamics using CGM is necessary. This issue needs to be investigated in the future.Our results suggest that the absence of hypoglycemic episodes contributes to normalization of vascular endothelial function. Previous studies demonstrated that strict blood glucose control increases the likelihood of development of hypoglycemic episodes35 and JDOIT336 studies that used cardiovascular events as the outcome of treatment of T2DM showed that comprehensive management of blood pressure, lipids, and blood glucose may result in the prevention of cardiovascular events. However, another large-scale study; the ACCORD Study37 showed that a similar comprehensive management strategy failed to prevent cardiovascular events and that serious hypoglycemia increased the risk of death in diabetic patients38. In our study, we showed for the first time that improvement in vascular endothelial function could be hindered by hypoglycemia even after in-hospital education program. Hence, while it is important to control hyperglycemia in diabetics through medications, it is equally important to prevent hypoglycemia as a consequence of use of such medications.Previous studies showed that correction of individual metabolic abnormalities improves vascular endothelial function. However, our study is the first to show that vascular endothelial function is improved by comprehensive management through in-hospital education program and that the extent of such improvement is attenuated in patients with hypoglycemia. In this regard, the Steno 239. In fact, it has been reported that RHI is lower with a higher BMI in patients with concurrent obesity/metabolic syndrome40. Furthermore, a previous study reported that ACE inhibitors and ARBs improve vascular endothelial function by decreasing C-reactive protein levels41. The present study also revealed that BMI and the use of ACE inhibitors or ARBs were associated with vascular endothelial function, as indicated in previous reports.The present study identified BMI and the use of ACE inhibitors or ARBs as factors affecting normal vascular endothelial function on admission. In obesity, vascular endothelial dysfunction is reported to be associated with decreased NO production due to uncoupling of the endothelial nitric oxide synthase and enhanced NO degradation which in turn is attributable to increased nicotinamide adenine dinucleotide phosphate oxidase42 have indicated that changes in vascular endothelial function can be observed within a few hours to a few days after therapeutic interventions. In the present study, the post-treatment assessment was performed at average 18.8 days after the therapeutic interventions. This period appears to be appropriate for examining changes in vascular endothelial function. Fourth, ambulatory blood pressure monitoring (ABPM) was not performed in the present study. Because vascular endothelial function has already been reported to be associated with fluctuations in blood pressure as measured using 24-h ABPM43, assessment of data from ABPM was necessary to assess the effects of blood pressure on vascular endothelial function. In addition, the present study identified high systolic blood pressure on admission as a factor contributing to normal vascular endothelial function. This may be because the present study included patients with well-controlled blood pressure, as demonstrated by a mean blood pressure of 130 mmHg, and many patients with hypertension used ACE inhibitors or ARBs. The effects of these factors may not have been excluded.The present study has several limitations. First, it was a retrospective study conducted on a small population of patients admitted to two clinical facilities. Consequently, it was difficult to perform detailed subgroup analyses based on oral hypoglycemic drugs, lipid metabolism, blood pressure, and other factors. In the present study, the effects of blood pressure, blood glucose levels, and age, among other factors, on vascular endothelial function could not be assessed and confounding factors including drugs could not be controlled for. A large-scale multicenter study needs to be conducted in the future to evaluate the separate effect of each individual metabolic abnormality on the observed improvement in vascular endothelial function induced by in-hospital education program. Second, glucose dynamics were assessed using blood glucose levels measured at four time points. Because vascular endothelial function is associated with fluctuations in blood glucose levels and postprandial hyperglycemia as measured by continuous glucose monitoring (CGM), studies involving detailed assessment of glucose dynamics using CGM may be needed in the future. Third, because vascular endothelial function was assessed only at two time points of admission and discharge in the present study, it is unclear whether vascular endothelial function was assessed at appropriate time points. However, previous reportsThe present study showed that educational hospitalization of patients with T2DM improves vascular endothelial function, and that prevention of hypoglycemic episodes enhances the normalization of endothelial function. To our knowledge, this is the first study that has dissected the effects of educational hospitalization on T2DM-related vascular endothelial function. Our results indicate that educational hospitalization improves vascular endothelial function by correcting various metabolic abnormalities and that hypoglycemia hinders improvement in vascular endothelial function.Supplementary information.


X2 = 5.538, P = 0.019). In the old-age-onset hypertension group, the proportion of MCIp without diabetes mellitus was higher than those with diabetes mellitus  and those with increased pulse pressure was higher than those without increased pulse pressure . However, the cox proportional hazard showed that older age was the only risk factor for MCIp . These results suggest that individuals with later-onset hypertension may have greater cognition decline, even with blood pressure maintained at 130/80 mmHg with antihypertensive management.To investigate the correlation between hypertension development and the progression of mild cognitive impairment (MCI) to dementia in middle-aged and elderly people. A population-based longitudinal cognition survey of people aged 55+ was conducted. The hypertension onset age was estimated by self-reported information and medical insurance card records. To study the effect of later-onset hypertension on dementia, the incidence of dementia was compared between the two groups. Of 277 hypertensive MCI participants without dementia, 56 (20.22%) progressed to dementia (MCIp) over the 6-year follow-up. The proportion of MCIp participants in the old-age-onset hypertension group (≥65 years) was higher than that in the middle-age-onset hypertension group (27.0 vs. 15.4%, respectively;  With increases in population aging, the number of individuals with dementia continues to rise, with ~47 million people worldwide in 2015, which is expected to triple by 2050 . Mild coHypertension is another disease that compromises the activites of daily living in the elderly population , 7. In tThe incidence of dementia has been related to the age of onset of hypertension. Numerous studies have shown that hypertension in middle-aged individuals is associated with increased dementia 20 or 30 years later, but the relationship to later-onset hypertension (≥65 years) is uncertain , 12. ForOur previous epidemiological investigation found that MCI in individuals with new-onset hypertension (≥60 years old) had a higher rate of dementia . We propThe research project was examined and approved by the Ethics Committee of the Mental Health Center of Pudong New Area, Shanghai (2017005). The guardians of all the dementia individuals provided ethical consent for their participation.The current research was carried out in Pudong district in Shanghai. We analyzed elderly individuals with MCI (age ≥ 55 years old) who had participated in a survey from June 2011 to June 2012 (No. PKJ2010-Y26) and were successfully contacted for a subsequent survey in 2017. All participants signed informed consent forms. Only those sufficiently educated with adequate audiovisual skills that were needed to complete the necessary examinations were included.Based on the age of onset of hypertension, the participants were divided into the old-aged group (onset age ≥ 65 years) and the middle-aged group (onset age <65 years).MCI was diagnosed using the revised Mayo Clinic criteria: (1) elderly individuals consciously exhibited memory loss, especially those with memory impairment for more than 3 months; (2) overall cognitive function was normal through the Mini-Mental State Examination ; (3) clinical dementia rating (CDR) score reached a level of 0.5; (4) Montreal Cognitive Assessment Scale (MoCA) scores were ≤ 26; (5) the patient had normal function in daily life; and (6) the patient did not meet the diagnostic criteria for dementia , 26.The criteria for dementia were as follows. (1) MMSE test scores were ≤ 17 for illiterate subjects, ≤ 20 points for subjects with primary school education, and ≤ 24 points for subjects with middle school education or above ; (2) theSubjects received cognitive and other neuropsychological assessments using the following scales where possible: (1) Mini-Mental State Examination (MMSE) scale , (2) Monn = 91) patients take calcium channel blocker, 11.6% (n = 31) patients take angiotensin receptor blockers, and 7.1% (n = 19) patients take other medicines, whereas 41% (n = 110) patients unregularly take medicines; 6.3% (n = 17) patients take no medicines.The diagnosis, duration, age of onset, stage, and treatment of hypertension were collected based on self-reports from the elderly individuals and examination of their medical insurance card records. The treatment of hypertension was as follows, 34.0% , heart disease, and depression. Heart disease included any of the following diseases or surgeries: coronary artery disease, myocardial infarction, atrial fibrillation or other arrhythmias, heart valve disease, congestive heart failure, coronary artery bypass, or pacemaker placement. The highest level of education attained, marital status, and occupation were also recorded.t-tests for normal data and Mann-Whitney U-tests for non-normal data. Categorical data were analyzed by the chi-square-test. Cox proportional hazard was conducted to identify the determinants of the MCIp outcome. A P-value of < 0.05 was considered statistically significant.Data were analyzed using the Statistical Package for Social Sciences . Continuous variables were tested for normality by the one-sample Kolmogorov-Smirnov-test. Continuous variables are expressed as the mean ± SD or median (range) as per distribution type, and categorical data are expressed as frequency and percentages. Statistical analyses were performed using independent samples p < 0.01). In addition, the MCIp individuals were more likely to be single . However, this may have been because the old-age-onset group were older than the middle-age-onset group . For those without DM, the old-age-onset hypertension group showed a higher proportion of MCIp outcomes than the middle-age-onset group  . Here, increased pulse pressure refers to the value of systolic pressure minus diastolic pressure being higher than 60 mmHg. This result implied that in those individuals with a later onset of hypertension, increased pulse pressure was associated with the progression of cognitive impairment.There were 56 individuals (20.22%) who progressed to dementia (MCIp), while 221 (79.78%) remained stable (MCIs). In comparison with the MCIs individuals, the MCIp individuals demonstrated significantly worse performance on the CDR and ADL scales (= 0.003) , and theP = 0.000, HR = 0.618) and BMI  were the independent determinant of MCI outcome at follow-up and that patients with a age <80 and higher BMI were more likely to maintain cognitive function (P > 0.05).The cox proportional hazard model was fitted to analyze the determinants of the MCI outcome at follow-up . Demographic data and variables such as hypertension, age at onset of hypertension, blood pressure grouping, and pulse pressure were taken as independent variables in the model. The variable assignment for the cox proportional hazard analysis is listed in function . Other fIn this prospective study of 277 MCI participants aged 73.48 ± 7.47 years having a late onset of hypertension (≥65 years) was related to a higher dementia risk compared with those with an onset of hypertension in middle age. This increased risk was limited to participants who reported a mean SBP of 130/80 mmHg. In addition, the differences disappeared after stratification according to age and BMI, SBP, and DBP levels. To our knowledge, our study is the first to report blood pressure levels and to include hypertension by age of onset.n = 2,800) showed that incidences of MCI and dementia decreased by 15% with intensive control of blood pressure (SBP < 120 mmHg) compared with the standard control group (SB < 140 mmHg)  (Some researchers have found that an increased risk of dementia was related to the increase in SBP in the group under 75 years old . The ris = 0.02) ; moreove = 0.02) .n = 1,440; 8-year follow-up) where the risk of dementia increased by 2.4 times when blood pressure was <140/90 mmHg in middle- to old-aged individuals with hypertension.The results of this study are not consistent with some previously published results. The reasons may be as follows: First, the average age of the participants in this study was 73 years with a mean SBP of 130/80 mmHg, 57% of them were <75 years old, 8 patients 2.89%) had SBP < 120 mmHg and 8 (2.89%) had SBP ≥ 160 mmHg. Our sample size was relatively small. Second, through medication management with a goal in the normal range (130/80 mmHg), the proportion of MCIp was different between the two groups, suggesting that aggressively lowering SBP may not be beneficial in elderly individuals (.89% had n = 559), Corrada et al. . The results suggested that the relationship between hypertension and dementia in the elderly cohort was different from that in the middle-aged cohort. Hypertension may be a result of compensatory responses of the body. That is, the etiology of hypertension is similar to that of dementia, but the clinical symptoms occur at different times.Furthermore, some studies have found that the relationship between the risk of dementia and the increase in SBP was not yet clear for those older than 85 years . After 1a et al.  reportedIn addition, the cognitive impacts of middle-aged hypertension can only be followed up and analyzed after excluding cerebrovascular accidents ; that isHowever, the results of the cox proportional hazard analysis failed to identify age of hypertension onset, blood pressure and increased pulse pressure as risk factors for MCI deterioration, and only older age was identified as a risk factor. This is consistent with the results of other studies confirming that old age is the main risk factor for dementia . We founn = 2,367) revealed that cerebrovascular risk factors such as white matter degeneration, hypertension, diabetes, and smoking were associated with aging and contributed to dementia, although the age range of this survey was 20–90 years  was significantly reduced compared with younger age groups . That is90 years . It shouWe noticed that the incidence of MCIp was higher in the groups of patients that had higher pulse pressure. Pulse pressure is a sign of arterial stiffness. It was previously shown that pulse pressure was associated not with hypertension and apolipoprotein E4 but with the deposition of beta-amyloid plaques in the brain . In otheJefferson et al.  used pulRegarding the prevention of dementia by antihypertensive therapy, some studies have suggested that the risk of dementia was increased by the potential hypotension induced by antihypertensive therapy due to impaired vascular regulation mechanism in elderly individuals –40. A 16Besides, the result suggested that participants with higher BMI were more likely to maintain cognitive function. However, it is still early to tell the parameter can be protective factors, we cannot distinguish the actual BMI and the BMI decrease due to osteoporosis and malnutrition, which can confound the treatment of hypertension and DM.These results suggest that individuals with later-onset hypertension may have greater cognition decline, even in patients with blood pressure maintained at 130/80 mmHg with antihypertensive management.First, 277 elderly people with hypertension in the MCI community were followed up prospectively. The sample size was small, and the age distribution was uneven. The follow-up time was 6 years. There might have been sample bias that affected the proportion of MCIp to some extent.Second, the survey of occupational mental activity, post-retirement economic life, lifestyle, and other factors in the MCI population with hypertension was not detailed enough, and the influence of an insufficient sample size also had some influence on the results of the study.Third, the diagnosis of dementia in this study sample did not combine detection with imaging and cerebral spinal fluid (CSF) biochemical indicators without classification by Alzheimer's disease, Lewy bodies dementia, Dementia associated with parkinsonism, etc. And the mental state assessed without a “comprehensive” neuropsychological battery. The history and examination of hypertension were mainly provided by the community elderly individuals and medical record cards. There was no 24-h ambulatory blood pressure monitoring, which may have introduced some bias and had a certain impact on the objectivity of the results. So there were several confounders not considered in the analysis .First, the results of the current investigation showed that MCI patients with hypertension with an average age of ~73 years old were prone to develop dementia, which suggests that the administration of antihypertensive drugs for hypertension in this population (≥65 years old) should be comprehensively considered. Because of the different mechanisms underlying hypertension, maintaining blood pressure at 130/80 mmHg may not have a positive effect regarding the protection of cognitive function. Second, this study showed that pulse pressure had a negative effect regarding the protection of cognitive function. In the group with increased pulse pressure, the proportion of the elderly patients progressing to dementia was higher than that of the middle-aged patients. This suggests that the pathogenesis of hypertension in older patients may be different than in middle-aged patients and that the effect of increased pulse pressure on cerebrovascular function also increased with age. Therefore, increased pulse pressure may be one of the risk factors for dementia. In the future, it is necessary to expand the research sample size and improve the experimental methods for further confirmation.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Ethics Committee of the Mental Health Center of Pudong New Area, Shanghai (2017005). The patients/participants provided their written informed consent to participate in this study.HQ and CH guided the implementation of the research, collated, and analyzed the data. XZ and BZ were the leaders. BZ gave essential points for the analysis of data. XZ was responsible for the quality control. All authors have read and approved the manuscript and ensure that this is the case.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The aim of this case–control study was to look for an association between hypertension and acne keloidalis nuchae (AKN) in black subjects.2 or more  and having systolic hypertension  were associated with AKN.We recruited 303 consenting subjects comprising 101 patients with AKN and 202 controls, case-matched by age (± 5 years). The mean patients age was 34.9 ± 10.7 years versus 35.6 ± 11.2 years for controls. The average duration of AKN progression in cases prior to consultation was 1831 days (5 years). The most frequently observed AKN lesions were papules , fibrous scars  and folliculitis/pustules . In terms of quality of life, the mean score of dermatology life quality index was 8.3 ± 5.2 (extremes: 0 to 22). In multivariate analysis, having a BMI of 25 kg/m Acne keloidalis nuchae (AKN) is a chronic scarring folliculitis observed mainly in men of African descent , 2. ContWe conducted a case–control study from January to December 2018 in three dermatology departments  in Lomé, Togo. Cases were male patients, over 18 years of age, seen in dermatology for AKN located at the neck and/or extending to other parts of the scalp. For the controls, any lesion suggestive of AKN  of the neck was a non-inclusion criteria. Each case was matched with two controls per age (± 5 years). Cases were recruited at outpatients dermatological clinics and controls recruited at outpatients dermatological clinics and then in other hospital departments. The recruitment was consecutive and comprehensive. The questionnaire used for general and dermatological examination was developped for this study . Comparisons of means were made using the Student's test for matched samples and qualitative variables with the McNemar test. These tests made it possible to study the existence of statistical links between the factors considered and the AKN. Conditional logistic regression was used to identify the factors associated with AKN. Factors with a value of p < 0.20 in univariate analysis were taken into account for the multivariate model with a significance level of 5%. All analyses were performed using RWe recruited 303 consenting subjects comprising 101 patients with AKN and 202 controls. The mean patients age was 34.9 ± 10.7 years versus 35.6 ± 11.2 years for controls. The average duration of AKN progression in cases prior to consultation was 1831 days (5 years). The most frequently observed AKN lesions were papules , fibrous scars  and folliculitis/pustules  (Table 2 and above was associated with the risk of AKN (p < 0.001). Systolic hypertension (≥ 140 mmHg) was present in 23.8% of cases versus 7.9% of controls (p = 0.009). Diastolic hypertension (≥ 90 mmHg) was present in 33.7% of cases versus 29.2% of controls (p = 0.461)  and having systolic hypertension  were associated with AKN . Although high BMI is thought to be a mechanical risk factor for AKN , it is a risk factor for high blood pressure. Our study therefore confirms that there is an association between AKN and systolic hypertension, as previously suggested by other authors [In our study, not only were mean systolic p < 0.001) and diastolic (p = 0.001) arterial pressures higher in cases than controls, the calculation of the odds ratio shows an association between systolic hypertension and the presence of AKN. Furthermore, the risk of AKN increases with BMI, as shown by the OR, which was 4.91 in overweight or obese subjects (BMI ≥ 25 kg/m and dias authors . With re authors , 11. Pat authors . There i authors . In addi authors , 15. The authors . This ro authors , 18. HowThe main limitation of this study is that, we have not evaluate the association between, AKN severity and hypertension, because of the number of patients. Ideally, the link between the severity of AKN and hypertension should be assessed. A multicentre study to have a larger number of cases will be necessary to look for this link between AKN severity and hypertension. Secondly, we did not assess the quality of life in the controls to make a comparative study on this point.Additional file 1. Questionnaire used for general and dermatological examination in this study.


A low T50 value is an independent determinant of cardiovascular morbidity and mortality in various populations. Aim was to investigate the T50 and its relationship to type 2 diabetes mellitus.Serum calcification propensity is emerging as an independent predictor for cardiovascular outcomes in high-risk populations. Calcification propensity can be monitored by the maturation time of calciprotein particles in serum  with a median age of 66 (62–75) years, diabetes duration of 6.5 (3.0–10.2) years and hemoglobin A1c (HbA1c) of 49 (44–54) mmol/mol.Using nephelometry, serum T50 was normally distributed with a mean value of 261±66 min. In linear regression, serum T50 was lower in women and current smokers. A lower T50 value was found in patients with a higher HbA1c or higher systolic blood pressure, insulin users and patients with a longer history of diabetes. The association with HbA1c was independent of other determinants in multivariable analysis. There was no association between T50 and previous macrovascular events or the presence of microvascular disease.Serum T50, and prospective studies will have to be performed to address this hypothesis.Serum calcification propensity is independently associated with glycemic control, suggesting that a lower HbA1c may be associated with better cardiovascular outcomes. Retrospective analysis could not establish an association between a history of macrovascular events and TNCT01570140. Diabetes mellitus (DM) is accompanied by increased vascular calcifications and an excess cardiovascular morbidity.50 score is a novel functional blood test that quantifies serum calcification propensity.The T50 with parameters of type 2 DM.This is the first study to determine associations of T50, suggesting that that better glycemic control may correlate with a less pronounced development of vascular calcification.In this large cohort of primary care treated persons with type 2 DM, hemoglobin A1c was significantly associated with T50 value has predictive value for cardiovascular disease in the type 2 DM population.Although promising, it has to be determined if the TDespite intensive glycemic control and adequate management of cardiovascular risk factors, type 2 diabetes mellitus (T2DM) is accompanied by microvascular disease, including retinopathy, nephropathy and neuropathy, and macrovascular disease. Individuals with T2DM are prone to developing vascular calcifications, which considered playing a causal role in the etiology of diabetic complications.1Previously, vascular calcifications were considered a result from passive precipitation of calcium and phosphate. Nowadays, the process of calcification is considered a consequence of a disequilibrium of a between calcification stimulating and inhibiting factors.50 serum calcification propensity test has been developed to allow for quantification of the serum anticalcification buffer capacity.50 test measures in vitro how rapidly CPP2 are formed in a patient blood sample. In other words, the result of the T50 test reflects the velocity of calcium phosphate crystallization in blood with lower T50 values indicating increased calcification propensity. Results of the T50 test have been determined to be an independent mortality predictor in both chronic kidney disease (CKD)20 21This increased formation and maturation and defective clearance of CPP may be an important novel cardiovascular risk factor .50 test with parameters of T2DM management in a large cohort of stable patients.Because any serum test that can be used reliably to assess vascular calcification would be considered an asset in assessing cardiovascular risk in patients, we aimed to assess the association of the Twww.hzd.nu). Fifty-two out of the 110 general practices of the Care Group Drenthe agreed to participate; in these practices, approximately 8300 patients with T2DM were treated.This is a cross-sectional study. Baseline data and blood samples were obtained from the e-VitaDM study and Zwolle Outpatient Diabetes project Integrating Available Care (ZODIAC) study. The e-VitaDM study was designed to assess the feasibility of using an online platform in routine primary healthcare for subjects with T2DM. This study was conducted in general practices that are connected to the Care Group Drenthe in the Drenthe region of the Netherlands .The primary aim of the present study was to investigate the cross-sectional association between T50. Consequently, the final study sample consisted of 932 patients.Patients were recruited during a regular check-up by their (diabetes) practice nurse. Patients were included from May 2012 to September 2014. Patients with T2DM, aged ≥18 years and the general practitioner as main care provider for T2DM were eligible for participation. For the e-VitaDM study, there were no exclusion criteria. A total of 1710 out of 3988 patients, who were asked to participate in the eVita-DM study, gave written informed consent. Of these patients, 730 had no blood samples or were not included in the ZODIAC study and in 48 there was insufficient blood available to measure TBaseline demographic data included sex, age, duration of diabetes, BMI, alcohol use and smoking habits. Information concerning alcohol use and smoking habits was derived from questionnaires at baseline. Additional medical data were extracted from the diabetes-specific database at the Isala Diabetes Centre. This centre gathers data of primary care treated patients with T2DM in a large part of the Netherlands on a yearly basis to provide benchmark information to general practitioners. This database includes data on physical examination, use of medication, and laboratory blood and urine tests. The following data were extracted: date of diabetes diagnosis, height, weight, diastolic and systolic blood pressure, cholesterol, HbA1c, serum creatinine, urine creatinine, urine albumin, urine creatinine:albumin ratio, the presence of macrovascular complications and microvascular complications.Macrovascular complications included (a history of) angina pectoris, myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass grafting, cerebrovascular accident or transient ischemic attack. Microvascular complications included diabetic retinopathy, albuminuria and diabetic peripheral neuropathy. Microalbuminuria was defined as an albumin:creatinine ratio between 2.5–25 mg/mmol in men and 3.5–35 mg/mmol in women. Macroalbuminuria was defined as a ratio higher than 25 mg/mmol and 35 mg/mmol for men and women, respectively.50 was measured as described previously.At baseline, aliquots of blood samples were stored at −80°C (without thawing) until measurement. Serum T2 test or Fisher’s exact test. Normality of variables was assessed using frequency distribution histograms and QQ plots. Univariable linear regression analysis was used to investigate associations between variables that showed a normal distribution of the residuals. Multivariable linear regression analysis was used to investigate associations between a dependent variable and multiple independent covariates, for which a backward regression model was established. Regression models were checked for linearity, homoscedasticity, absence of multicollinearity, independence and normality of errors. A p value <0.05 was considered statistically significant. Univariable logistic regression analysis was used to assess the relationship between a binary outcome dependent variable and an independent covariable. All statistical analyses were performed using SPSS V.24 .Normally distributed data are presented as mean±SD, and non-normally distributed data are presented as median (IQR). Means or medians were compared between groups using Student’s t-test or analysis of variance, or the Mann-Whitney U test or Kruskal-Wallis test, as appropriate. Categorical variables were compared using the χ50 tertile with the middle tertile ranging from 235 to 293 min. In brief, the population had a median age of 65.8 years (62–75), 54.7% was male, mean diabetes duration was 6.5 (3.0–10.2) years, baseline HbA1c was 49 (44–54) mmol/mol and median (estimated) renal function in this study was 74 (61–86) mL/min/1.73 m2. A total of 234 patients (25.1%) had a history of a macrovascular event. A total of 205 patients (30.8%) had a documented microvascular complication. Treatment of diabetes consisted strictly of dietary interventions for 19.5% of patients, whereas 67.5% took oral blood glucose lowering drugs and 13.0% used insulin therapy.Patient baseline characteristics are shown in 50 is depicted in 50 values (p<0.001). Similarly, a lower T50 value was associated with the status of current smoker, while a higher T50 value was associated with using alcohol. Furthermore, the tertile with the lowest T50 values had the highest Hb1Ac (p<0.001) and more often a history of retinopathy (p=0.016).The distribution of serum T50, with females having a mean T50 of 249±65 min, compared with 271±64 min for males .Backward regression was used with all variables to investigate which variables would be significantly associated with T50 test) and indices of T2DM management, in particular HbA1c, in a large population of outpatients. Interestingly, we found that several factors reflecting an unfavorably disease status, namely a higher HbA1c, insulin dependence, and a longer history of diabetes, were all associated with lower T50 values. In multivariable analysis, only HbA1c remained significantly associated with T50.In the present, study we explored the association between calcification propensity , in a hemodialysis population. It is possible that the differences between these studies can be explained by the outsize cardiovascular risk, possibly partially CPP mediated, that is conferred by end-stage renal disease, which outweighs the effects of traditional cardiovascular risk factors, which may be more relevant in our non-CKD population and in a prehemodialysis population. On the other hand, Keyzer et al50 and gender in a renal transplantation cohort, most of whom had undergone dialysis for over 5 years but who had higher T50 values after transplantation than our cohort of patients with diabetes. More studies will be required to elucidate whether associations between gender and calcification propensity, and between serum lipid levels and calcification propensity are disease specific.Female sex and lower LDL cholesterol levels were associated with lower T50 will start to decrease. Given the pathophysiology of CPPs as a mechanism to buffer calcium and phosphate overload and the relevance of the kidney in regulating phosphate excretion through fibroblast growth factor 23 and Klotho, it is possible that the early disturbances in these factors that occur already during subtle renal injury can rapidly result in an increased serum calcification propensity.Interestingly, serum calcification propensity was not associated with estimated glomerular filtration rate in the present T2DM population but was associated with the albumin/creatinine ratio. This indicates a window between the occurrence of incipient renal damage and the impairment of renal function in which serum T50 and a history of macrovascular disease or the presence of microvascular disease. The only exception was the presence of diabetic retinopathy, but it had such a low prevalence in our cohort that independent validation in larger or more tailored cohorts will be required to provide reliable answers. It should be noted that macrovascular disease was not assessed prospectively and that a T50 measurement at baseline may be a better predictor for future events, rather than reflect past events.We did not detect an association between serum T50 measurement in the vascular burden in diabetes and cardiovascular outcomes.In summary, in this cohort of patients with T2DM, we found that serum calcification propensity was negatively and independently associated with HbA1c, which suggests that better glycemic control may correlate with a less pronounced development of vascular calcification, which ultimately might lead to better cardiovascular outcomes. We were, however, unable to establish an association with the past occurrence of macrovascular disease or with the presence of microvascular disease . Prospective studies will be required to elucidate the role of serum calcification propensity and the T