Hypertension remains a public health challenge worldwide. In the Democratic Republic of Congo, its prevalence has increased in the past three decades. Higher prevalence of poor blood pressure control and an increasing number of reported cases of complications due to hypertension have also been observed. It is well established that non-adherence to antihypertensive medication contributes to poor control of blood pressure. The aim of this study is to measure non-adherence to antihypertensive medication and to identify its predictors.A cross-sectional study was conducted at Kinshasa Primary Health-care network facilities from October to November 2013. A total of 395 hypertensive patients were included in the study. A structured interview was used to collect data. Adherence to medication was assessed using the Morisky Medication Scale. Covariates were defined according to the framework of the World Health Organization. Logistic regression was used to identify predictors of non-adherence.A total of 395 patients participated in this study. The prevalence of non-adherence to antihypertensive medication and blood pressure control was 54.2 % (95 % CI 47.3–61.8) and 15.6 % (95 % CI 12.1–20.0), respectively. Poor knowledge of complications of hypertension , unavailability of antihypertensive drugs in the healthcare facilities , lack of hypertensive patients education in the healthcare facilities , prior experience of medication side effects , uncontrolled blood pressure , and taking non-prescribed medications  were associated with non-adherence to antihypertensive medication.This study identified predictors of non-adherence to antihypertensive medication. All predictors identified were modifiable. Interventional studies targeting these predictors for improving adherence are needed. Hypertension (HTN) remains a public health challenge worldwide because of its high prevalence and related complications. In 2000, 26.4 % of the World’s adult population had hypertension . In Sub-In SSA, the control of HTN is low. For example, in West African countries this control is low, less than 10 % except for Nigeria where it is approximately 30 % . In the Non-adherence to antihypertensive medication (NAM) is one of the main factors contributing to uncontrolled HTN . In factFrom October 2013 to November 2013, a cross-sectional study was carried out at Kinshasa Primary Health-care (KPHC) network facilities. This network consists of 51 facilities that allows for follow-up of patients with NCDs like hypertension and diabetes, living in Kinshasa .We included in the study hypertensive patients >18 years who have been under antihypertensive drugs for at least a month.Hypertensive pregnant women were excluded.p represents the proportion of non-adherence to antihypertensive medication (we assumed that p = 50 % because the proportion of NAM in the DRC is unknown), q (1 − p), z value of the standard normal distribution corresponding to a significance level of alpha of 0.05 (1.96) and d the precision degree that we assumed to 5 % too. The minimal size computed was 384 patients. A total of 408 patients present in the health facilities were selected but only 395 (96.8 %) were eligible and enrolled. The study protocol was approved by the institutional review boards of the Kinshasa School of Public Health, Bureau Diocésain des Oeuvres Médicales de Kinshasa, and Service Médical Armée du Salut and conducted in accordance with the Helsinki Declaration II. All study participants provided written informed consent.Only 25, out of 51 facilities, scheduled patients’ visits during the survey were therefore selected. All patients present in the facility and who met the inclusion criteria were enrolled. The sample size was computed using the following formula Patients were surveyed using a structured questionnaire, either in French or translated in Lingala, the local language. Five surveyors had been trained over 3 days and the interview instrument was pretested prior to its use. Covariates were defined according to the WHO framework. This framework was used because actually, no model of medication adherence for HTN has been published. The Health Beliefs Model has been used in several studies but it does not include all the dimensions of the NAM factors like those described by the WHO framework . The varCo-morbidity has been defined in this study as HTN associated with diabetes mellitus (DM) or organ damage targets . Patients were interviewed if identified by a health professional as having one of these conditions.Only the blood pressure measured by healthcare providers on the day of the survey and recorded in the patient medical file was considered. Three hundred ninety (390) out of three hundred ninety five (395) had the values of blood pressure recorded in their medical file (98.7 %). Uncontrolled HTN was defined, for a patient without co-morbidity, as a patient with a SBP ≥140 mmHg and a DBP ≥90 mmHg. For a patient with co-morbidity, uncontrolled HTN was defined as a patient with SBP ≥130 mmHg and for DBP ≥80 mmHg .The self-reported medication adherence was measured using the Morisky Scale, which is a validated scale with a good internal consistency. Its Cronbach’s alpha has been reported to be of 0.90 in studies of inner-city patients with hypertension , 20. Patt test. Categorical variables were reported as a frequency and percentage and groups were compared using χ2 test. The logistic regression helped to identify independent predictors of non-adherence. All variables associated with non-adherence to antihypertensive medication in the bivariate analysis were included in the final model. Odds ratio (OR) with a corresponding 95 % confidence interval was reported to quantify the strength of association. Significance was set at p-value of less than 0.05.All analyses were performed using Statistical Package for Social Sciences (SPSS) version 21.0. . Descriptive statistics were used to summarize the study population characteristics. Continuous variables were reported using mean with standard deviation. Means for age of non-adherent and adherent patients were compared using Student’s Tables Approximately half of the patients suffered from HTN for less than 5 years. The mean systolic blood pressure was 148.6 ± 22.1 and 87.8 ± 14.3 mmHg for the diastolic blood pressure. The control of HTN was present in 15.6 % (95 % CI 12.1–20.0 %) patients. Almost two-thirds of the patients (64.6 %) experienced physical symptoms due to HTN. Dizziness was the most common physical symptom reported. Co-morbidities were present in 53.9 % of participants, of which DM was the most common (52.4 %).More than half of the participants had less than 5 years of antihypertensive treatment duration. On average, the patients took 1.7 ± 1.2 pills daily. Approximately half of the patients (55.9 %) experienced medication side effects, 20.5 % declared taking non-prescribed medications. Around one in three patients reported to have forgotten to take blood pressure medicine (31.9 %) and to have skipped taking drugs when they felt well (31.4 %). Using the Morisky Scale, we found that over half of participants (54.2 %) were non-adherent to their medication.Table Table Table This study aimed to measure NAM and to identify its predictors. This study found a high prevalence of NAM and a poor control of blood pressure. Patients, therapy and health system factors were the predictors of NAM.The prevalence of non-adherence to antihypertensive medication was high and consistent with previous findings , 22, 23.This study also reported a poor control of blood pressure. These findings corroborate previous studies carried out in African populations, where the proportion of blood pressure control was very low, less than 10 % . This poThis study reports poor knowledge about risk factors related to HTN. This has also been described by a previous study carried out in Pakistan . FurtherSocial and economic factors  are described by the WHO as the NAM factors . In thisHypertension is considered as a condition without symptom, the experience of physical symptoms due to HTN influences treatment adherence significantly, patients who do not feel unwell may be less adherent. In a qualitative study carried out in Bandundu (a province of the DRC), hypertensive patients reported that they took medication only when they experienced perceived symptoms of HTN . In thisPatient education is described as a catalyst for lifestyle change and treatment adherence . This asAlso, this study found that patients who took non-prescribed medication were twice more likely to be non-adherent to treatment than other patients. We surmise that probably these patients use complementary and alternative medicine (CAM) which is defined as a “group of diverse medical and healthcare systems, practices, and products that are not presently considered to be part of conventional medicine” . PreviouUnavailability of antihypertensive medication in healthcare facilities is a barrier to health care and is described as a factor of medication non-adherence. Patients who reported the availability of antihypertensive medication in healthcare facilities were about twice more likely to be adherent. These findings are consistent with that previously reported by Ghozzi in Tunis .We acknowledge some limitations in this study. A potential selection bias may have been introduced in this study relating to the level of care facilities surveyed. Also, information bias was possible—firstly by using the self-reported questionnaire for measuring medication adherence and secondly by reporting the blood pressure measured by non standardized methods. However, these overall findings corroborate those found in previous studies. We think that the results of this study may be generalized to hypertensive patients living in Kinshasa.This is the first study in the DRC with a large sample to measure the antihypertensive non-adherence and to identify related predictors. These findings show that all predictors identified were modifiable by strengthening the capacity of healthcare providers by communication with patients. Antihypertensive medication should be made available in healthcare facilities.


Objectives: To evaluate hemodynamic changes of blood pressure and heart rate on hypertensive patients undergoing tooth extraction using various types of local anesthesia (LA).Study Design: A prospective randomized clinical trial was conducted on 45 hypertensive patients who were divided equally into 3 parallel groups according to LA received. Group 1: Lidociane 2% with epinephrine 1: 80,000. Group 2: Prilocaine 3% with Felypressin 0.03 IU/ml. Group 3: Mepivacaine 3% plain. Inclusion criteria: hypertensive patients, under medical management with blood pressure ≤ 159/99. Exclusion criteria: Blood pressure ≥160 /100 and patients receiving β blockers. Negative aspiration was mandatory before the injection of 2 cartridges of LA. Blood pressure and heart rate were evaluated by Electronic Sphygmomanometer and Pulse Oximeters in 3 different time-points; 3 minutes before LA, three minutes after LA and three minutes after extraction.Results: The mean of systolic blood pressure (SBP) had increased after LA injection, and then decreased after extraction in the 3 groups of patients. Increase of SBP after extraction with (Mepivacaine plain) was higher than (Lidociane with Epinephrine) and the difference was statistically significant using ANOVA (p=0.037). The differences in the mean heart rates and mean diastolic blood pressures in the 3 groups were not significant.Conclusions: The increase of blood pressure with Epinephrine and Felypressin is negligible. Therefore, it is safe to use 2 cartridges of Lidociane 2% with Epinephrine 1:80,000 or Prilocaine 3% with Felypressin 0.03 IU/ml for hypertensive patients whose blood pressure ≤ 159/99 provided negative aspiration is verified before injection. Key words:Local anesthesia, tooth extraction, hypertensive patients, vasoconstrictors, epinephrine, Felypressin. Hypertension is defined as a systolic blood pressure [SBP] higher than 140 mHg or a diastolic blood pressure [DBP] higher than 90 mmHg. The diagnosis is based on the average of two or more readings taken at each of two or more visits after an initial screening (Hypertension is one of the most common diseases seen in patients visiting dental clinics due to its high prevalence worldwide ,3. In SaOne major concern of dental treatment for Hypertensive patients is the sudden and dramatic increase in blood pressure that could lead to life-threatening complications . These cet al. (Epinephrine is the main vasoconstrictor used in dental practice today ,6. Corbeet al.  in 2005 Epinephrine acts on both α and β receptors but predominate on β. The vasoconstriction action of epinephrine depends on stimulating α1 receptors in peripheral blood vessels . StimulaFelypressin which is a synthetic analogue of vasopressin [antidiuretic hormone] has been suggested as an alternative vasoconstrictor for epinephrine to decrease the systemic adverse reactions. It was found that local anesthetics with Felypressin increase systolic and diastolic blood pressure without any significant change in heart rate. Felypressin is considered to have no direct effect on the myocardium. Therefore, the blood pressure increase by Felypressin is considered to be the result of an increase in peripheral resistance. The clinically safe dosage of Felypressin in patients with essential hypertension is approximately 0.18 IU. This corresponds to 6 ml of local anesthetics with 0.03 IU of Felypressin, which is commercially available as a local anesthetic for dental use ,12.The aim of the this study is to evaluate the hemodynamic changes of blood pressure and heart rate on hypertensive patients receiving three different types of local anesthetic cartridges; Lidociane 2% with epinephrine 1:80,000, Prilocaine 3% with Felypressin 0.03 IU/ml and Mepivacaine 3% plain.This prospective randomized clinical trial was carried out from October, 2012 to April, 2013 on forty-five hypertensive patients underwent single tooth extraction. The procedures were performed by dental interns or dental students under supervision of surgery instructors in the Colleges Clinics. Sample size was estimated depending on power calculation. At level of significance α = 0.05 and power = 0.85 with maximum difference 1.5 and  assumed from previous studies as 1.2, the sample size for each group should be at least 15 patients per group.Inclusion criteria included patients who were already diagnosed with essential hypertension, under medical management and his/ her blood pressure ≤ 159/99. However, patients with systolic pressure ≥160 or diastolic blood pressure ≥100, patients were receiving β blockers as treatments of hypertension and patients who had cardiac diseases or uncontrolled systemic diseases were excluded. Exclusion criteria also included Epinephrine and Felypressin contraindications, pregnancy, breastfeeding, and allergy to local anesthetics material used in the study.All patients were informed about the aims of the study and informed consents were signed. The study followed the World Medical Association Declaration of Helsinki and it was ethically approved by the ethics committee of the institution. Registration number of this study in the Institute Research Center was [IRP/2012/031].All required information was documented in the questionnaire paper about name, age, gender, mobile number, file number and Hypertensive medications. Patients were divided randomly into three parallel groups; each of them contained fifteen patients. Random distribution was performed by choice of one card out of forty-five. These cards were divided into equal three groups in which the group numbers were written on its back.Group 1: receive 2 cartridges [3.6 ml] of Lidociane 2% with Epinephrine 1:80,000. Group 2: receive 2 cartridges [3.6 ml] of Prilocaine 3% with Felypressin 0.03 IU/ml. Group 3: receive 2 cartridges [3.6 ml] of Mepivacaine 3% plain.While the patient was in the dental chair, Pulse Oximeter was applied to the left index finger and heart rate was documented. Blood pressure was evaluated by using an electronic sphygmomanometer [OMRON® Automatic Blood Pressure Monitor]. Three minutes later, aspiration was done before injection of 2 cartridges of local anesthesia selected according to the group. The goal of aspiration was to avoid intravascular injection. Aspiration must be negative; otherwise, if blood aspiration occurred, the clinician had to withdraw the needle, replace the cartridge, and repeat the aspiration then do the injection. Three minutes after anesthesia, blood pressure and heart rate were measured again. The last measurements of blood pressure and heart rate were taken three minutes after extraction. Data analyses were performed using the statistical software SPSS version 18.0 for Windows. Descriptive/Univariate statistics were used which included mean and standard deviation in addition to Multivariate statistics which included analysis of variance [ANOVA].Forty-five patients included in this study, thirty-one male and fourteen female. Every group contained 15 patients. The mean age of the patients was 55.66 years. The mean age of group1 [Epinephrine] was 60.4 years. The mean age of group2 [Felypressin] was 53.4 years while the mean age of group3 [Mepivacaine plain] was 53.2 years. The mean hemodynamic changes of systolic blood pressure, diastolic blood pressure and heart rate are available in p=0.037].The mean of systolic blood pressure increased after local anesthetics injection [SBP2] then decreased after extraction [SBP3] in the three groups of patients Fig. . It was The mean diastolic blood pressure of both Epinephrine and Felypressin groups of patients decreased after injection DBP2] and after extraction [DBP3]. In contrast, mean diastolic blood pressure of Mepivacaine plain group of patient increased after injection then decreased after extraction but still higher than pre-injection measurement (Fig.  and afteThe mean heart rate increased after injection [HR2] and after extraction HR3] for the all groups of patients (Fig.  for the In this study, systolic and diastolic blood pressure and Heart rate were evaluated with three minutes intervals because epinephrine exerts its maximum action three minutes after injection . Additioet al. (Reviewing literature reveals some studies performed to estimate the effect of local anesthetics on blood pressure. A study was performed in 2001 by Silvestre et al.  on threeIn 2003, Gungormus M and Buyukkurt MC (et al. (et al. (In the present study, increasing of the systolic blood pressure after extraction with [Mepivacaine plain] was significantly higher than [Lidociane with epinephrine]. This result harmonizes with the study of Ogunlewe MO et al.  and Silv (et al. . It coulet al. (Ogunlewe MO et al.  made a set al. (Chaudhry SF et al.  found thet al. in 2011 (Silvestre  in 2011  performeet al. (As well, in our study, the changes of diastolic blood pressure were not found to be significant. However, the mean diastolic blood pressure of Mepivacaine plain group increased after injection and decreased after extraction but still higher than pre-injection measurement. In contrast, the mean diastolic blood pressure of both Epinephrine and Felypressin groups decreased after injection and after extraction. The decrease of diastolic blood pressure of Epinephrine group matches with the result of Chaudhry SF et al.  who founet al. (et al. (We found insignificant increasing in heart rate after injection and after extraction for the all groups of patients, likewise the study of Chaudhry SF et al. . On the  (et al.  noticed According to the results of this study, it is safe to use two cartridges of Lidociane 2% with epinephrine 1: 80,000 or Prilocaine 3% with Felypressin 0.03 IU/ml for hypertensive patients whose blood pressure less than 160/100 provided negative aspiration is verified prior to injection. Disadvantages attributed to the use of epinephrine or Felypressin in hypertensive patients are negligible as compared to their benefits.The limitation of this study is its small sample size. Nevertheless; the new in this study is comparing the effect of three different types of local anesthetic cartridges on hypertensive patients whose blood pressure less than 160/100. We recommend a further study to concentrate on the effect of these three different local anesthetics on stage I and stage II hypertensive patients with large number of cases.


BH4) would recouple endothelial nitric oxide synthase and thus improve endothelial function and consequently reduce aortic stiffness.Rheumatoid arthritis is a systemic inflammatory condition associated with increased cardiovascular risk that may be due to underlying endothelial dysfunction and subsequent aortic stiffening. We hypothesized that supplementation with tetrahydrobiopterin (BH4 400 mg versus placebo (n=18), and a short‐term regimen, composed of a 1‐week treatment with BH4 400 mg once daily versus placebo (n=15). Flow‐mediated dilatation and aortic pulse wave velocity were studied 4 times, before and after each treatment phase. Acute BH4 supplementation led to an improvement of flow‐mediated dilatation, whereas placebo had no effect . Similarly, 1‐week treatment with BH4 improved endothelial function, but there was no change with placebo . There was no change in aortic pulse wave velocity following acute or short‐term BH4 supplementation or placebo .We conducted 2 randomized, double‐blinded, placebo‐controlled crossover studies examining 2 separate regimens: an acute regimen, with a single dose of BH4 improved endothelial function but not aortic stiffness. This result suggests that BH4 supplementation may be beneficial for patients with rheumatoid arthritis by improving endothelial dysfunction and potentially reducing risk of cardiovascular disease. There appears to be no causal relationship between endothelial function and aortic stiffness, suggesting that they occur in parallel, although they may share common risk factors such as inflammation.Both acute and short‐term supplementation with oral  Rheumatoid arthritis (RA) and other chronic inflammatory diseases are associated with increased premature mortality, mostly due to an excess of cardiovascular disease (CVD).BH4) availability or stability4 to eNOS,4 deficiency is thought to lead to eNOS uncoupling, in which electrons flowing from the reductase domain to the oxygenase domain are diverted to molecular oxygen rather than l‐arginine, leading to production of superoxide (O2−) rather than NO.4 to inactive BH2.4 bioavailability, which may in part mediate the endothelial dysfunction present in RA; therefore, supplementation with BH4 may be a reasonable therapeutic option to restore normal eNOS function and thus endothelial function in RA. Previous studies have demonstrated that intra‐arterial administration of BH4 improves endothelium‐dependent dilation in patients with hypercholesterolemia,4 supplementation improves endothelial function in elderly participants,4 in patients with RA. Moreover, it is unclear if improvement of endothelial function would lead to a reduction of aortic stiffness or if other mechanisms are responsible for increased aortic stiffness.The mechanism of endothelial dysfunction in RA is incompletely understood, but reduced tetrahydrobiopterin  that an improvement of endothelial function would lead to subsequent amelioration of aortic stiffening, providing evidence about the causal relationship between endothelial function and aortic stiffness; BH4 is thought to have little direct effect on inflammation per se.Our aim was to test the hypotheses (1) that oral BHOverall, 33 patients with active RA (disease activity score [DAS28] >3.5) who met the 1987 American Rheumatism Association criteria were recruited from the rheumatology clinics at Addenbrooke's Hospital, Cambridge, United Kingdom. Patients with manifest CVD, untreated hypertension (blood pressure ≥140/90 mm Hg), diabetes, hypercholesterolemia , or renal disease and current smokers were excluded because these conditions are associated with endothelial dysfunction and arterial stiffening.4 400 mg would improve endothelial function. We found that flow‐mediated dilatation (FMD) response increased , and there was a significant change in the baseline diameter ; however, there was no change in mean arterial pressure (P=0.1) or aPWV (P=0.2). Data are presented as mean±SD, and significance was determined using the paired Student t test. Based on these pilot data, the 400 mg once‐daily dose was deemed sufficient for the main study in RA patients and was similar to doses used previously in other conditions.We conducted a small pilot study in 5 healthy nonsmoking control participants (mean age 27±6 years) to test whether a single dose of BH4 supplementation.The present study was conducted in a randomized, double‐blind, crossover manner. To determine whether acute changes were sustained, patients were allocated to 1 of 2 groups: acute or short‐term BH4 400 mg or placebo (random assignment). At 3 hours after the administration of BH4 or placebo, the hemodynamic measurements were repeated. A 3‐hour time point was chosen based on published pharmacokinetic data.4 or placebo.In the acute study, participants made two 6‐hour visits to the vascular laboratory Figure A. On day4 400 mg once daily or placebo (random order), each for 1 week, with 1‐week washout between treatments . 6R‐BH4 is the synthetic form of naturally occurring BH4  and is approved for treatment of BH4‐responsive phenylketonuria.BHAll studies were conducted in a quiet, temperature‐controlled room. Blood pressure was recorded in the brachial artery using a validated oscillometric technique . Radial artery waveforms were obtained with a high‐fidelity micromanometer  from the wrist, and a corresponding central waveform was generated using a validated transfer function . Augmentation index (AIx), a composite measure of wave reflection, mean arterial pressure and heart rate were determined using the integrated software. Aortic and brachial pulse wave velocities were measured, as previously described.Endothelial function was assessed in the brachial artery using the FMD technique.Fasting lipid profile, high‐sensitivity C‐reactive protein (CRP), and erythrocyte sedimentation rate (ESR) were determined using standard methodology at the Biochemistry Laboratory at Addenbrooke's Hospital.DAS28 is a validated composite disease activity score. The components of DAS28 include the number of swollen and tender joints from 28 assessed joints, ESR, and patient‐assessed visual analog score of overall well‐being . DAS28 was calculated as described previously.4 and placebo treatments. Secondary outcomes were differences in aPWV between treatments, the relationship between changes in aPWV and FMD, and the relationship between CRP and disease activity and change in FMD and aPWV.The primary outcome of the study was the difference in FMD response between BH4 supplementation, we calculated that a total of 15 patients (per study) were needed to enter the 2‐treatment crossover study to provide >80% power at P<0.05 to detect a 4.0‐U difference in FMD response between treatments with an SD of 5.0. Data were analyzed using SPSS software . Two‐way repeated‐measures ANOVA was used to investigate the effect of the treatment. Custom hypothesis testing (simple) of within‐participant contrasts was performed for comparison of BH4 versus placebo, in which treatment order was entered as a between‐participant factor to investigate whether the order in which BH4 and placebo were received influenced the outcome. In post hoc tests, the effect of individual treatments was determined using paired Student t tests with Bonferroni adjustment for 2 comparisons. In addition, in post hoc tests, the use of methotrexate (MTX) was entered as a between‐participant factor to establish whether dyhydrofolate reductase inhibitor use influenced the BH4 response. For the skewed variables (CRP and ESR), log‐transformed values were used for the analyses. Differences between the RA and control groups were determined using the unpaired Student t test. A probability of <0.05 was considered significant. Data are given as mean±SD.Based on our pilot data and published data on BHThe authors had full access to the data and take full responsibility for its integrity. All authors have read and agreed to the manuscript as written.4 and placebo. The mean age of the participants was 57±12 years, and 27 were female. Overall, 18 and 15 participants concluded the acute and short‐term supplementation studies, respectively. There were no differences in age, BMI, DAS28, CRP, ESR, or blood pressure between groups; however, total cholesterol was slightly higher in the participants allocated to the short‐term treatment group . Baseline characteristics are detailed by group in Table Thirty‐three patients with active RA (mean DAS28 4.21±1.06) were studied before and after oral BH4 supplementation on hemodynamics and vascular function are detailed in Table 4, there was a significant increase in the FMD response, whereas placebo had no effect  . Baseline diameter of brachial artery or response to sublingual glyceryl trinitrate did not change following the treatment. There were no significant differences between the changes in blood pressure, heart rate, AIx, brachial pulse wave velocity, or aPWV  . Again, there was no change in blood pressure or aPWV  for the drug×visit×MTX interaction. If anything, there was a nonsignificant trend demonstrating that those on MTX had greater improvement of FMD following BH4 in comparison to those not on MTX . This was despite no difference in baseline FMD (P=0.9) or brachial artery diameter (P=0.98).Seventeen of the 33 RA patients were receiving MTX, a dyhydrofolate reductase inhibitor, at the time of the study. Post hoc testing demonstrated that MTX had no impact on the effect of BH4 and placebo, there were no changes in CRP , ESR , or DAS28  ; however, the change in FMD after BH4 correlated negatively with age . Baseline aPWV was significantly (P<0.05) correlated with mean arterial pressure (R=0.52), age (R=0.52), CRP (R=0.39), and ESR (R=0.66).There was no correlation between the change in FMD and change in aPWV following BHP=0.001). After treatment with BH4, the FMD response was no longer different between RA patients and controls . Baseline aPWV was higher in the RA group compared with controls , whereas blood pressure did not differ between the groups  have been shown to improve endothelial function in RA patients.4 levels are regulated by de novo synthesis of BH4 from guanosine triphosphate and through recycling of BH2 to BH4 via dyhydrofolate reductase,4 in the endothelium. Nevertheless, we found no difference in the effect of BH4 supplementation on endothelial function between those RA patients on MTX and those not receiving MTX. A trend suggested that those patients on MTX had a greater increase in FMD following BH4 supplementation, perhaps because of reduced levels of inflammation. Notably, our study was not powered to look at this difference.Previous studies have demonstrated that intra‐arterial administration of BH4 led to a change in aPWV, brachial pulse wave velocity, AIx, or blood pressure in comparison to placebo. Park et al recently demonstrated in patients with chronic kidney disease that 6R‐BH4 significantly improved AIx4 400 mg in hypertensive patients, but this study was not placebo controlled.4 was shown to reduce carotid artery compliance, but there was a confounding fall in systolic blood pressure.4 without change in mean arterial pressure.We and others have demonstrated that patients with RA have increased aortic stiffening in comparison to healthy participants,Our study also provided evidence about causality for endothelial function and aortic stiffness. We demonstrated previously that under resting conditions, local NO production modulates distensibility of muscular iliac artery in humans and that exogenous NO increases arterial distensibility4 and BH2 levels in our study; however, numerous studies have demonstrated that supplementation with 6R‐BH4 leads to increase in serum BH4 levels.4 levels were still 4–5 times the basal values.4 supplementation in patients with RA nor predict whether it may have beneficial effects on future cardiovascular events.We did not assess serum BH4 improves endothelial function as measured by a response to reactive hyperemia. These findings suggest that recoupling of eNOS using cofactor BH4 may provide a rational therapeutic approach to prevent CVD in patients with chronic inflammatory diseases. BH4 supplementation did not appear to reduce aortic stiffness, suggesting that endothelial dysfunction is not a pathophysiology behind aortic stiffening in RA and that these conditions may just exist in parallel, both influenced by common risk factors such as inflammation and increased reactive oxygen species production.This study shows for the first time in patients with RA that oral BHMäki‐Petäjä and Wilkinson were funded by British Heart Foundation. Wilkinson, Cheriyan and Shenker received funding from the Comprehensive Local Research Network and Wilkinson and Cheriyan from the National Institute for Health Research: Cambridge Biomedical Research Centre.None.


Supplemental Digital Content is available in the text This study was designed to assess the effect of the addition of low-dose spironolactone on blood pressure (BP) in patients with resistant arterial hypertension.Patients with office systolic blood pressure (SBP) >140 mm Hg or diastolic blood pressure (DBP) >90 mm Hg despite treatment with at least 3 antihypertensive drugs, including a diuretic, were enrolled in this double-blind, placebo-controlled, multicentre trial. One hundred sixty-one patients in outpatient internal medicine departments of 6 hospitals in the Czech Republic were randomly assigned to receive 25 mg of spironolactone (N = 81) or a placebo (N = 80) once daily as an add-on to their antihypertensive medication, using simple randomization. This study was registered with ClinicalTrials.gov, number NCT00524615.P < 0.001 for all) in daytime, nighttime, and 24-hour ambulatory BP monitoring and in the office. The respective DBP differences were −3.2, −6.4, −3.5, and −3.0 mm Hg . Adverse events in both groups were comparable. The office SBP goal <140 mm Hg at 8 weeks was reached in 73% of patients using spironolactone and 41% using placebo (P = 0.001).Analyses were done with 150 patients who finished the follow-up (74 in the spironolactone and 76 in the placebo group). At 8 weeks, BP values were decreased more by spironolactone, with differences in mean fall of SBP of −9.8, −13.0, −10.5, and −9.9 mm Hg (Spironolactone in patients with resistant arterial hypertension leads to a significant decrease of both SBP and DBP and markedly improves BP control. It is defined as blood pressure (BP) that remains above goal in spite of the concurrent use of 3 antihypertensive agents of different classes prescribed at optimal dosages; 1 of the 3 agents used should be a diuretic.4 If no secondary cause of hypertension is found, multidrug treatment regimens including 3, 4, or more antihypertensive drugs are usually necessary to lower BP and, thus, lower the risk of future cardiovascular events.The prevalence of resistant hypertension has varied from 9.5% to 12.8% in recent reports.11 The BP lowering effect of spironolactone was shown to be markedly larger than that of other antihypertensive drugs,7 doxazosin12 or dual blockade of the renin-angiotensin-aldosterone system.13 However, various confounding factors could have significantly influenced the results of the previous trials with spironolactone and with the absence of a control group, the cause and effect relationship, as well as safety, could not be established.14Spironolactone is a mineralocorticoid receptor antagonist. In low doses (median 25 mg daily), it has been shown to substantially lower BP in several uncontrolled trials in resistant arterial hypertension, leading to a significant reduction of systolic blood pressure (SBP) between 14 and 36 mm Hg and diastolic between 7 and 12.5 mm Hg.15 we designed and performed a prospective randomized trial  to evaluate the effect of adding 25 mg spironolactone in patients with resistant arterial hypertension.17 We decided to administer a low dose of spironolactone 25 mg/day in the trial, as the effect of this dose seemed to be substantial according to data from previous trials, and we wanted to avoid possible adverse effects.Because evidence from randomized trials was necessary to provide proof for the efficacy of spironolactone as an add-on treatment in resistant hypertension,17 After several discussions with other experts, we decided to perform an extension of this trial (ASPIRANT-EXT) by continuing the enrollment with the same inclusion and exclusion criteria to include the total number of participants that had been planned at the beginning of the trial.After being stopped prematurely after the first interim analysis with 117 enrolled patients, the ASPIRANT trial showed a significant decrease of systolic, but not diastolic blood pressure (DBP) with spironolactone treatment.17 We enrolled patients >18 years with resistant arterial hypertension. Resistant hypertension was defined as office SBP >140 or DBP >90 mm Hg despite being treated with at least 3 antihypertensive drugs, including a diuretic. Patients with diabetes or chronic kidney disease (defined as serum creatinine >133 μmol/L or proteinuria >300 mg/day) were enrolled if the office BP was >130/80 mm Hg.ASPIRANT-EXT was an investigator-led, prospective, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial. The design of the trial has been described previously.The study was done in accordance with the principles of the Helsinki declaration. The study protocol was approved by the ethical review committees at all 6 participating secondary or tertiary care centers and by the State Institute for Drug Control of the Czech Republic. Written informed consent was obtained from all patients before enrollment. This study was registered at clinicaltrials.gov as NCT00524615 and the EudraCT number of the trial was 2007-003558-27.18 hyperkalemia >5.4 mmol/L, hyponatremia <130 mmol/L, porphyria, pregnant or lactating women, or women of fertile age not using effective contraception, patients with known prior hypersensitivity to the drug Verospiron  or currently using any aldosterone antagonist . Patients were not enrolled if a secondary cause of hypertension was found before randomization.For safety reasons we excluded all patients with severe hypertension (SBP >180 or DBP >110 mm Hg) who needed an immediate adjustment of treatment, renal insufficiency with serum creatinine >180 μmol/L or glomerular filtration rate <40 mL/minute calculated by the Modification of Diet in Renal Disease formula,Patients were randomly assigned in a 1 : 1 ratio to receive either spironolactone at a dose of 25 mg once daily or a placebo once daily in the morning, as an add-on to their current antihypertensive therapy, using simple randomization without stratification. Patients received blinded study medication in phials marked with different colors in a random manner. The Olomouc University Hospital Pharmacy Department prepared the study medication containing spironolactone or placebo as identical looking gelatinous capsules, placed into glass containers similar in weight and appearance. This department also held the randomization codes, which were disclosed after the study. The individual who prepared the blinded color-marked containers of drugs was not otherwise connected to the study, and all the investigators and patients were blinded to patient assignment and medication during the whole study period. All the study investigators deemed the blinding to be adequate and sufficient throughout the study.19 Average daytime BP was calculated from values measured between 09:00 and 21:00 hour, average nighttime BP from values measured between 01:00 and 06:00 hour, and average 24-hour BP was calculated from all the values recorded by ABPM.20After randomization, visits were scheduled at 4 and 8 weeks. In patients with diabetes, patients >75 years and with serum creatinine >133 μmol/L, an additional safety visit was performed 2 weeks after randomization. During every visit, office BP was recorded by a calibrated mercury sphygmomanometer in seated patients with their arm supported. The value was recorded as the average of the second and third measurements with a minimum delay of 3 minutes between the measurements. At baseline and 8 weeks, 24-hour ambulatory blood pressure monitoring (ABPM) was performed with validated devices with BP measurements programmed every 20 to 30 minute.21 Antihypertensive medications and all other medications were recorded at baseline and patients did not change doses or the number of their antihypertensive medications throughout the trial. At every visit, patients were asked about the occurrence of any adverse effects of the medication. Compliance of patients was assessed by the calculation of returned tablets.Serum sodium, potassium, chloride, urea and creatinine, body weight, and pulse were measured during every visit. Plasma renin activity (PRA), plasma aldosterone and aldosterone/renin ratio (ARR), albuminuria, and proteinuria in a 24-hour urine sample were measured at baseline and at 8 weeks. The blood samples for PRA and aldosterone were collected in the morning, after the patients had been seated for 5 to 15 minute, without discontinuation of the medications.According to study protocol, the administration of randomized medication was to be terminated at any time in case of symptomatic hypotension <100/60 mm Hg, increase of serum potassium >6.0 mmol/L, increase of serum creatinine >25% compared with baseline and exceeding the upper reference limit of 104 μmol/L, if the patient did not tolerate the study medication because of adverse effects or any other reason, or if the patient withdrew informed consent.Our primary end-point was the comparison of the fall of daytime systolic and diastolic pressure on ABPM between the spironolactone and placebo groups after 8 weeks of treatment. The secondary end-points were the comparison of the fall of 24-hour and nighttime systolic and DBP and office BP between the spironolactone and placebo groups after 8 weeks of treatment. Further secondary end-points were to compare the changes of serum levels of sodium, potassium and creatinine, and body weight between treatment groups and to evaluate the response to spironolactone treatment based on the baseline potassium, PRA, aldosterone level and baseline ARR.U test for continuous variables and the Fisher exact test for categorical variables. Change in BP between the groups was calculated by the Mann–Whitney U test of the difference from baseline. Statistical analysis was computed using SPSS 18.0.2 .Standard descriptive statistics were applied in the analysis. Continuous variables were described using mean and standard deviation (SD) when the prerequisite of normality was fulfilled and the median and 5th and 95th percentile range in the case of nonnormal distribution. Categorical variables were described by the number of cases and the percentages of categories. The statistical significance of differences between study groups was analyzed by the Mann–Whitney 9 We needed a total of 102 patients to have 90% power for SBP and 146 patients for DBP at P < 0.05. We expected about 90% of the randomized patients to complete the trial and, therefore, planned to recruit 160 patients.16Power calculations were based on an expected average difference of SBP fall between spironolactone and the placebo 10 mm Hg (SD 18.0 mm Hg) and DBP fall difference 5 mm Hg (SD 10.7 mm Hg).The study sponsors only provided financial support; they were not involved in the study design, had no role in the collection, analysis, or interpretation of the data and were not involved in decisions about its publication. The corresponding author had full access to all data and had final responsibility for the decision to submit the study for publication.The trial profile is shown in Figure Baseline characteristics were well matched between the treatment groups in baseline demographic characteristics, mean baseline BPs, baseline serum and urinary laboratory characteristics, and antihypertensive medication, with the exception of higher baseline glycemia and higher diabetes mellitus prevalence in the placebo group Table .2. Mean office BP was 154/92 mm Hg, daytime ABPM BP was 143/84 mm Hg, 24-hour ABPM BP was 143/82 mm Hg. Isolated systolic hypertension (office SBP >140 mm Hg and DBP <90 mm Hg) was present in 35% of patients in the spironolactone group and 38% of patients in the placebo group. Patients were using a mean of 4.5 antihypertensive drugs (median 4.0) in both the spironolactone and placebo groups. Most patients used either hydrochlorothiazide or indapamide. A small number of patients used a combination of more diuretics, such as hydrochlorothiazide with amiloride, hydrochlorothiazide with furosemide, or indapamide with furosemide.The mean age of patients was approximately 60 years, heart rate was 68 beats per minute and body mass index was 32.3 kg/mP < 0.001) for systolic and −3.2 mm Hg  for DBP. The APBM nighttime systolic, 24-hour ABPM systolic, and office SBP values were significantly decreased by spironolactone, as were the respective DBP values . The respective office DBP goal <90 mm Hg was reached in 54 (73%) patients using spironolactone and 48 patients using the placebo (63%) (P = 0.223).The office SBP goal <140 mm Hg at 8 weeks was reached in 54 (73%) patients using spironolactone and in 31 (41%) patients using the placebo .In 40 patients (27%), a secondary cause of hypertension was found during subsequent evaluation after trial completion with comparable distribution in both study arms: primary aldosteronism (8 in the spironolactone and 12 in the placebo group), renovascular hypertension , obstructive sleep apnea  and nephrogenic hypertension . The overall results of the trial were consistent when patients with secondary hypertension were removed from analyses . Serious adverse events leading to study medication discontinuation occurred in 4 patients using spironolactone and 1 patient using the placebo (P = 0.367). The total number of adverse events was 30 in the spironolactone group and 31 in the placebo group .The frequency of adverse events was comparable in both study arms  and, therefore, the placebo-corrected spironolactone BP lowering effect was less than reported in previous uncontrolled trials. In another randomized trial with patients with diabetes, the addition of 25 to 50 mg (average 35 mg) spironolactone led to a similar mean placebo-corrected daytime ambulatory BP decrease of 8.9/3.7 mm Hg after 16 weeks.23To our knowledge, this is the largest randomized placebo controlled trial to assess the antihypertensive effects of low-dose spironolactone in patients with truly drug-resistant hypertension. Previous uncontrolled observational trials showed a substantial office BP reduction after the addition of spironolactone, ranging from 14 to 32.2 mm Hg systolic and 7 to 12.5 mm Hg diastolic.24 and could explain the significant reduction of pulse pressure and larger reduction of SBP in our trial.A numerically lesser, although statistically significant, effect of spironolactone on DBP in our trial may be explained by the relatively low baseline DBP with a significant proportion of patients (37%) having isolated systolic hypertension. Besides the diuretic effect of spironolactone, its reduction of vascular stiffness probably plays an important role in patients with resistant hypertension25 and we postulate that its marked reduction by spironolactone might provide a prognostic benefit in patients with resistant hypertension. Furthermore, the observed reduction of proteinuria and albuminuria with spironolactone is a sign of possible end-organ protection.The strongest effect of spironolactone in the ASPIRANT–EXT trial was observed on nighttime BP (decrease of −13.0/−6.4 mm Hg), which was not affected by placebo at all. Nighttime BP is a very strong predictor of future cardiovascular events9 There may be a dose–response effect with spironolactone up to 50 mg/day in patients with essential hypertension and higher doses >50 mg/day do not produce further reductions in BP.26 In patients with primary aldosteronism, increasing the dose of spironolactone (up to 75–225 mg/day) may have a greater antihypertensive effect.27 It is possible that the increase of spironolactone dose to 50 mg/day or more could have led to a more substantial decrease of BP, but would be likely to also cause a higher occurrence of adverse events.The dose of 25 mg spironolactone daily, chosen to be administered in our trial, seems optimal to us for use in resistant hypertension, as it offers good antihypertensive efficacy and a low number of adverse effects, comparable to placebo in the short-term. With the 25 mg dose, the long-term occurrence of adverse events is low, about 13%, leading to the discontinuation of spironolactone only in 6% of patients.28 we are convinced that the 8-week study duration was sufficient for the full effect of spironolactone to be shown, and no further BP reduction would be observed if the trial had had a longer duration. However, the hormone-related adverse effects of spironolactone (such as gynecomastia) usually take a longer time to develop and would likely become more frequent with a longer study duration.9A possible limitation of our study is the relatively short duration of 8 weeks. As the maximal hypotensive effect of spironolactone is reached after 7 weeks of treatment in patients with resistant hypertension,29 Therefore, eplerenone seems to be an appropriate alternative if spironolactone is not tolerated because of sexual adverse effects.Eplerenone has also been shown to provide significant add-on BP lowering effect when treating resistant hypertension. The BP reductions achieved by 50 to 100 mg eplerenone daily in an observational trial were very similar to BP reductions achieved by 25 mg spironolactone in this trial: clinic BP was reduced by eplerenone by 17.6/7.9 mm Hg and 24-hour ambulatory BP by 12.2/6.0 mm Hg.30The mild increase of serum potassium and creatinine with spironolactone was expected. It needs to be stressed, that the majority of recruited patients had normal renal function with only 18.7% of patients exceeding the baseline creatinine upper reference limit of 104 μmol/L. The risk of hyperkalemia and worsening of renal function would be higher if spironolactone was used in patients with chronic kidney disease, especially with a glomerular filtration rate <45 mL/minute and serum potassium >4.5 mmol/L.31 In our trial, larger BP reduction was observed in patients with higher baseline ARR >17 and lower baseline potassium ≤4.1 mmol/L. This could possibly help identify the patients for which treatment with spironolactone is most effective.Previous trials reported conflicting data about whether the BP response to spironolactone can be predicted by baseline aldosterone, ARR, or baseline potassium.21 which might have affected the measured values of ARR and may be another limitation of this study, but we believe that this approach is easier to adopt in everyday practice.Antihypertensive drugs were not discontinued before blood sampling in accordance with current guidelines,2. Indeed, patients enrolled in a majority of recent trials in resistant hypertension were also obese or at least borderline overweight, regardless of whether the trials used spironolactone30 or other measures34 as treatment intervention. Obesity has recently been found to be closely connected with resistant hypertension,4 and in fact it appears to be a cause of treatment-resistant hypertension.35 We are convinced that the results of our trial can be generalized to the vast majority of resistant hypertension patients encountered in everyday clinical practice.Patients enrolled in our trial were obese with mean body mass index >32 kg/m36 and its antihypertensive efficacy seemed to be higher in elderly patients age >62 years37. The current analysis confirmed that the presence of more than one-fourth of patients with subsequently found secondary forms of hypertension did not change the overall trial results. However, secondary causes of hypertension should be intensively looked for in patients with resistant hypertension and treated causally whenever possible.According to the World Health Organization, the global prevalence of hypertension is currently about 1.5 billion people and the prevalence of drug resistant hypertension is about 12%. Based on these statistics, we estimate that there are about 180 million patients with resistant hypertension worldwide. Keeping this in mind, we decided not to insist on complete exclusion of secondary hypertension before enrollment into the trial, as these measures would not be possible in certain developing countries. In our previous analyses, we showed that spironolactone treatment is effective to a similar extent both in patients with and without a secondary cause of hypertension,38 Thus, at present spironolactone appears to be the most effective measure to control BP in resistant hypertension. Whether the positive effect of spironolactone on BP leads to a decreased number of cardiovascular events and decreased mortality needs to be explored in further studies.A recent randomized sham-controlled trial  did not find the catheter-based renal denervation to be more effective than the sham procedure in lowering BP in resistant hypertension.In conclusion, the ASPIRANT-EXT trial confirms that spironolactone is an effective drug to lower both SBP and DBP in patients with resistant arterial hypertension with excellent safety over a short period. These results warrant more widespread use of spironolactone globally, considering its low cost and wide availability.


Spinal cord injury patients may develop proteinuria as a result of glomerulosclerosis due to urosepsis, hydronephrosis, vesicoureteric reflux, and renal calculi. Proteinuria in turn contributes to progression of kidney disease. We report one paraplegic and two tetraplegic patients, who developed recurrent urine infections, urinary calculi, and hydronephrosis. These patients required several urological procedures . These patients had not received antimuscarinic drugs nor had they undergone video-urodynamics. Proteinuria was detected only at a late stage, as testing for proteinuria was not performed during follow-up visits. Urine electrophoresis showed no monoclonal bands in any; Serum glomerular basement membrane antibody screen was negative. Serum neutrophil cytoplasmic antibodies screen by fluorescence was negative. All patients were prescribed Ramipril 2.5 mg daily and there was no further deterioration of renal function.Spinal cord injury patients, who did not receive antimuscarinic drugs to reduce intravesical pressure, are at high risk for developing reflux nephropathy. When such patients develop glomerulosclerosis due to recurrent urosepsis, renal calculi, or hydronephrosis, risk of proteinuria is increased further. Take home message: (1) Screening for proteinuria should be performed regularly in the ‘at-risk’ patients. (2) In the absence of other renal diseases causing proteinuria, spinal cord injury patients with significant proteinuria may be prescribed angiotensin-converting enzyme inhibitor or angiotensin-II receptor antagonist to slow progression of chronic renal disease and reduce the risk of cardiovascular mortality. A cross-sectional analyses of Veterans with spinal cord injury and disorders across all VA facilities of USA in 2006.revealed that 1 in 3 Veterans with had chronic kidney disease [Wall and associates  found foProteinuria is likely in spinal cord injury patients, who did not receive antimuscarinic drugs to reduce intravesical pressures and therefore, are at high risk for developing reflux nephropathy and consequently proteinuria . When spAn 18-year-old, British male, while attending a party, was held by the neck and thrown out in 1981. He fell on his face and found that he could not move his limbs. This patient had sustained C-5 tetraplegia. X-ray of cervical spine revealed C-6/C-7 dislocation. During rehabilitation, this patient had indwelling urethral catheter drainage. He developed several episodes of urine infection and received multiple courses of Ampicillin, Gentamicin, and Amikacin. Cystogram revealed right vesicoureteric reflux. In 1982, division of external urethral sphincter was performed. He was prescribed Phenoxybenzamine 10 mg three times a day. Despite this, he had high residual urine volume and he developed urine infections. Cystogram revealed persistence of right vesicoureteric reflux. In 1983, bladder neck resection was performed. He was prescribed Distigmine and penile sheath drainage was tried. In hindsight, Distigmine could have predisposed high pressure voiding and reflux nephropathy. This patient developed recurrent urine infections and repeated attacks of orchitis. In 2001, stones in right renal pelvis were treated by extracorporeal shock wave lithotripsy. Subsequently, this patient felt unwell and had rigors. Ultrasound examination revealed left hydronephrosis and a calculus at the ureteropelvic junction. Left ureteric stenting was done followed by extracorporeal shock wave lithotripsy of left renal calculus. Later, this patient developed stone in left ureter; ureteric stenting was done in another hospital. Computed tomography revealed that the stone was lying outside left ureter, anterior to left psoas muscle. The ureteric wall was thickened and ureteric lumen was narrow. Extracorporeal shockwave lithotripsy of left renal calculus was performed. Subsequently, the ureteric stent could not be removed because of encrustations over the proximal coil. Extracorporeal shock wave lithotripsy of encrustations over proximal coil of ureteric stent was performed. The ureteric stent was then removed. A month later, this patient developed temperature and shivering. Ultrasound revealed moderate left sided hydronephrosis with mildly reflective urine in the collecting system, suspicious of infection. Left ureteric stenting was done and the patient received Gentamicin. During follow-up, the stent was removed, but a new stent could not be inserted. He developed temperature and rigors. Left nephrostomy was performed in 2009. Nephrostomy tube was being changed every 6–8 weeks. In 2012 this patient became unwell. Ultrasound revealed hydronephrotic right kidney with stone in pelviureteric junction. Right nephrostomy was performed. Extracorporeal shock wave lithotripsy of right renal calculus was carried out. Computed tomography revealed residual stone fragments and cortical scarring . In 2005, this patient developed fever with rigors he developed multi-organ failure requiring ventilation and noradrenaline infusion. Ultrasound scan revealed bilateral hydronephrosis with multiple stones in left kidney. Bilateral percutaneous nephrostomy were carried out. X-ray of chest revealed generalized infiltration of both lung fields. Tracheostomy was performed. With Tazocin therapy, he improved. Extracorporeal shock wave lithotripsy of left renal calculi was carried out. In 2006, balloon dilatation of right pelviureteric junction was performed. Left ureteric catheterization was not possible; Terumo guide wire could be passed through left ureteric orifice for one cm only. A stent was introduced antegrade in left ureter and nephrostomy was removed. In 2007, Right nephrostomy and left ureteric stent were replaced at regular intervals. In 2011, ultrasound examination revealed the right kidney measuring 9.4 cm with diffuse cortical scarring; cortical thinning was noted. Left kidney was grossly hydronephrotic with diffuse cortical thinning. MAG-3 renogram, performed in 2011, revealed relative function of 24% by left kidney compared with 76% for the right kidney. Uptake and drainage of left kidney had deteriorated from the earlier study with a persistent obstructive pattern. Drainage of right kidney was impaired. The findings were consistent with deterioration in cortical function of the left kidney. In 2012, this patient developed sepsis following blockage of right nephrostomy. Right nephrostomy was changed; about 200 ml of thick purulent fluid was drained. Left nephrostomy was performed two weeks later. Subsequently, left ureteric stent was removed. In 2013, computed tomography revealed tiny calculi in mid and lower pole of right kidney; 10 mm calculus at the lower pole of left kidney; cysts in left kidney; cortical scarring in both kidneys  those, who have not been taking anticholinergic drugs and at risk for developing vesicoureteric reflux and reflux nephropathy. (2) Patients, in whom vesicoureteric reflux has been demonstrated in video-urodynamics. (3) Patients with recurrent urine infection, hydronephrosis, renal scarring detected during imaging studies. (4) Patients with chronic infection – e.g. pressure sores, chronic osteomyelitis. (5) Longstanding spinal cord injury, although it is difficult to define a cutoff point, whether we should screen for proteinuria after ten years or twenty years. (6) Older patients. (7) Patients with co-morbidities like diabetes mellitus, hypertension.In spinal cord injury patients, serum creatinine level may be low because of reduced muscle mass; estimated glomerular filtration rate may be misleadingly high. Serum creatinine level is not sensitive in detecting early deterioration of renal function in patients with spinal cord injury . Kaji anAlshayeb and associates  carried Spinal cord injury patients with proteinuria had more impaired renal function and increased mortality compared with spinal cord injury patients without proteinuria. Vaziri and associates  observedIndependent of the underlying causes, chronic proteinuric glomerulopathies have in common a sustained or permanent loss of selectivity of the glomerular barrier to protein filtration. Glomerular sclerosis is the progressive lesion beginning at the glomerular capillary wall, the site of abnormal filtration of plasma proteins. Injury is transmitted to the interstitium favoring the self-destruction of nephrons and eventually of the kidney. The results of experimental and clinical studies show that proteinuria may accelerate kidney disease progression to end-stage renal failure. Evidence indicates that this process occurs through multiple pathways, including induction of tubular chemokine expression and complement activation that lead to inflammatory cell infiltration in the interstitium and sustained fibrogenesis. Macrophages are prominent in the interstitial inflammatory infiltrate. This cell type mediates progression of renal injury to the extent that macrophage numbers in renal biopsy predict renal survival in patients with chronic renal .Proteinuria is associated with a faster progression of kidney disease. In general, reduction in proteinuria correlates with slowing the progression of kidney disease. In controlled trials in Chronic Kidney Disease, Angiotensin Converting Enzyme (ACE) inhibitors and Angiotensin Receptor Blockers (ARB) reduce protein excretion by approximately 35% to 40%. In experimental animals, enhanced glomerular capillary pressure causes impaired glomerular permeability to proteins and permits excessive proteinuria. Reabsorption of filtered proteins can injure the tubular cells and interstitium of the kidney by activating intracellular events and the release of vasoactive and inflammatory mediators. Both ACE inhibitors and ARBs reduce the intraglomerular pressure and thereby, reduce the glomerular permeability barrier to proteins and limit proteinuria and filtered protein-dependent inflammatory signals .National Institute for Health and Clinical Excellence  in EnglaIf a patient does not have diabetes mellitus, but has hypertension and albumin: creatinine ratio < 30 mg/mmol, antihypertensive treatment should be instituted. In patients with hypertension and albumin: creatinine ratio ≥ 30 mg/mmol, Angiotensin Converting Enzyme inhibitors or Angiotensin Receptor Blockers should be prescribed .In patients with albumin: creatinine ratio ≥ 70 mg/mmol with or without hypertension or cardiovascular disease, Angiotensin Converting Enzyme inhibitors or Angiotensin Receptor Blockers should be prescribed .Therapeutic targets for ACE inhibitors and ARBs in chronic kidney disease are as follows : (1) BloSpinal injury patients with bladder involvement are well known to be at risk of high bladder residual volumes, urinary infections and stone formation. Over time these combined insults do take their toll on kidney function. While renal excretory function is often monitored by blood tests that measure urea and creatinine levels, proteinuria is not actively looked for. Proteinuria can occur when the blood tests are relatively normal, and should be acted upon as a sign of renal disease. Chronic kidney disease thus identified via blood or urine tests requires the same intensity of intervention as any other cause such as diabetes. In addition to the usual measures of correction of electrolyte and acid base imbalances, tight blood pressure control and cardiovascular risk reduction, spinal patients require added focus on prevention and early treatment of infections, and decompression of high pressure urinary systems. In those with more severe kidney damage, decisions should be made in advance with the patient on treatment ceilings and in those who are appropriate for dialysis, preparation for the same made in a planned manner so that their transition to renal replacement is smooth. Our paper highlights the need to detect proteinuria as marker for renal damage and the treatment of proteinuria as a means to defend renal function or at the very least, retard progression of renal disease.We had been focusing on the urological care of these three patients; prescribing antibiotics for urine infection; providing drainage to obstructed kidneys; breaking urinary calculi by extracorporeal shockwave lithotripsy, percutaneous nephrolithotripsy, and ureteroscopic lithotripsy We did not routinely investigate these patients for proteinuria and co-existing renal disease until recently. We missed the opportunity for early detection of proteinuria and we failed to prescribe ACE inhibitors to slow the progression of kidney damage at an earlier stage.(1) Spinal cord injury patients, who have not undergone video-urodynamics and not been taking antimuscarinic drugs are at risk for developing reflux nephropathy and proteinuria. (2) Patients who develop pressure sores, recurrent urosepsis, renal calculi, and hydronephrosis may develop proteinuria due to glomerulosclerosis. These patients should be tested for proteinuria during follow-up. (3) In the absence of other renal diseases causing proteinuria, spinal cord injury patients with significant proteinuria may be prescribed angiotensin-converting enzyme inhibitor or angiotensin-II receptor antagonist to slow progression of chronic renal disease and reduce the risk of cardiovascular mortality. (4) These spinal cord injury patients require careful monitoring of blood pressure and renal function while taking angiotensin-converting enzyme inhibitor or angiotensin-II receptor antagonist, as tetraplegic patients are likely to have low blood pressure, and some patients may have reduced glomerular filtration rate as well.The leading author wrote to three patients explaining the educational value of this case presentation and requested their permission to present their cases in the open access journal; the authors are most grateful to the patients for allowing us to include their case histories in this publication.The authors declare that they have no competing interests.SV managed all cases, conceived the idea for this manuscript, collected the data, and wrote the draft. AA was the Consultant in Renal Medicine and provided expert advice. GS was the Consultant Urological Surgeon; BMS was Consultant in charge of three cases; PLH carried out radiological examinations. All authors have been involved in drafting the manuscript, revising it critically for important intellectual content, and have given final approval of the version to be published.


Background: High blood pressure is a common condition in hemodialysis patients. Uric acid, which is high in these patients due to decreased clearance, had been shown to positively correlate with blood pressure in animal studies.Objectives: The goal of this investigation was to evaluate the impact of high uric acid level on blood pressure in these patients.Patients and Methods: Ninety-one patients, on three times weekly hemodialysis, were studied. Uric acid levels were measured just before and after hemodialysis along with blood pressures before, during and after each session. Data were analyzed by SPSS 15. A P value less than 0.05 was considered significant.Results: 40 (44%) of patients had serum uric acid ≥6 mg/dl. Before dialysis 51 (61%) and 19 (21%) had high systolic blood and diastolic blood pressures respectively. Also, 50 (55%) were with wide pulse pressure and 63 (69%) had high mean arterial pressure (MAP). Additionally 62 (68%) developed inter-dialysis hypotension. After measuring odds ratio for hyperuricemia in each group, we observed low risk of hypruricemia in the group with high systolic pressure , the high MAP group  and wide pulse pressure group . There was no association between high uric acid level and diastolic pressure (P = 0.11) and inter-dialysis hypotension (P = 0.33). No relationship was found between serum uric acid and KT/V (P = 0.2), normalized protein catabolic rate (nPCR) (P = 0.07) and body mass index (BMI) (P = 0.4).Conclusions: This study showed paradoxical association between high uric acid level and high systolic pressure, high MAP and wide pulse pressure and these effects were independent of dialysis duration, dialysis efficacy and nutrition, assuming that these relationships could be due to reverse epidemiology in dialysis patients. Blood pressure variation is very important in hemodialysis patients. As uric acid is a proven factor in blood pressure in animals and humans, finding its association with hypertension in hemodialysis patients can be a promising therapeutic gold. Numerous studies during last decades showed strong relationship between uric acid and hypertension -4. Uric Kidneys excrete approximately 60% to 70% of total uric acid from body . Uric acHypertension is a common finding in hemodialysis patients, occurring in 75% of them and it is a significant factor in cardiovascular disease, stroke and renal failure ,22. WideThe aim of this study was to investigate the relationship between serum uric acid levels and blood pressure both as modifiable risk factors in morbidity and mortality in adult hemodialysis patients.Patients (19 to 79 years old) including in this cross-sectional study were males and females above 18 years old on 4 hours hemodialysis, 3 times per week for at least 3 consecutive months in 3 hemodialysis centers in Shiraz, Iran. No drugs that could alter blood pressure were administered during dialysis. Patients receiving medications with impact on uric acid level  were excluded. One patient had in remission malignancy (multiple myeloma) and one patient had inactive rheumatologic disease (Sjogren syndrome). No one had liver or infectious disease.Blood pressures were measured by 1 automatic sphygmomanometer in hemodialysis center by a nurse just before and after dialysis and every 1 hour during dialysis in 3 consecutive sessions. According to KDOQI guideline, hypertension was defined as systolic pressure ≥140 mm Hg and diastolic pressure ≥90 mm Hg, high mean arterial pressure (MAP) as pressure ≥97 mm Hg, interdialysis hypotension as a decrease of SBP>20 mm Hg from basal value associated with signs and symptoms. Also wide pulse pressure was recorded as ≥60 mm Hg difference between systolic and diastolic pressure before dialysis.Weights were measured before and after dialysis and KT/V was calculated for each patient.Blood samples were taken from patients just before dialysis from arterial line for blood urea nitrogen (BUN), uric acid, albumin before dialysis. BUN and uric acid after dialysis were measured too.As nutrition can effect level of uric acid, nutrition status was assessed by normalized protein catabolic rate (nPCR). Generally the nPCR shows the amount of protein taken by patient and uric acid is a product of protein. Also body mass index (BMI) was calculated for each patient.Of all patients, 52% were took antihypertensive medication (except for diuretics).1) The research followed the tenets of the Declaration of Helsinki; 2) informed consents was obtained; and 3) the research was approved by ethical committee of Shiraz University of Medical Science.P value <0.05 was considered significant.All data were analyzed by SPSS 15 . Values were shown as the mean±standard deviation (SD) or as percent frequency. Correlation analysis between 2 values was performed by Pearson correlation test. Association between uric acid and blood pressures was calculated by odds ratio using multiple regression analysis. A This study included 60 (65.9%) males and 31 (34.1%) females. The average age was 50.8±16.7 years. Data are shown in The average predialysis and postdialysis uric acid level was 5.7±1.02 mg/dl and 3.2±0.99 mg/dl, respectively. In this study, 40.91 (44%) had predialysis serum uric acid ≥6 mg/dl. Only 1 patient had serum uric acid ≥6 mg/dl after dialysis; thus association between postdialysis uric acid and other variables was not possible.P = 0.212).There was no relationship between uric acid and Kt/V (P = 0.402).No association was found between uric acid and BMI (P = 0.071).No relationship was observed between uric acid and nPCR (P = 0.273).There was no relationship between uric acid and duration of dialysis  had high systolic blood pressure. Also 19 (20.9%) had high diastolic pressure. Likewise 63 (69.2%) had high MAP, and 50 (54.9%) had high wide pulse pressure too. Additionally 62 (68.1%) developed interdialysis hypotension.P = 0.01); for high MAP was 0.382 ; for wide pulse pressure was 0.416 ; for predialysis diastolic hypertension was 0.407 ; and for interdialysis hypotension was 0.648 . Therefore, there is lower risk for systolic hypertension, high MAP and wide pulse pressure in the group with high uric acid level Associations are summarized in Odds ratio for high uric acid level in the group with predialysis systolic hypertension was 0.352  and only 1 patient had this level after dialysis. Another important observation was paradoxical relationship between high uric acid and high systolic blood pressure, high MAP and wide pulse pressure. These associations were independent of dialysis duration. Dialysis efficacy, BMI and albumin confirmed that nutrition and protein breakdown did not affect uric acid level.These findings were contrary to previous studies in literature in animals and humans. The most significant of these studies were 3 trials that induced hyperuricemia in rats can cause hypertension after 3 weeks in mazzali experiment. Mechanism of hypertension in these rats were included renal artery vasoconstriction, arteriolopathy, decreased nitric oxide and increased oxidants and angiotensin in kidney. Lowering uric acid with drugs like allopurinol or using radical scavengers, to reverse intrarenal oxidative stress induced by uric acid,blood pressures were returned to normal. ,27,28. IDespite these observations, lowering uric acid level was not effective in lowering mortality and CKD progression , to the The present study can be another example of reverse epidemiology as described previously that high BMI is a survival factor in maintenance hemodialysis patients or by Liu et al that high cholesterol level is inversely related to dialysis mortality ,34. The We showed that high uric acid levels can be a marker of protection against high systolic blood pressure, high MAP and wide pulse pressure, all of which can increase mortality in hemodialysis patients.Our study has some pitfalls. Firstly, we did not investigate the effect of lowering uric acid with drug on blood pressure. Secondly, larger group could be better for conducting this study and also patients under peritoneal dialysis can be included. In fact, we could only consider 91 patients which most of them had low uric acid level. Larger group in a longer period of time may be needed to study this aspect of dialysis. Additionally, we did not find any association between uric acid and markers of nutrition as they affect uric acid level and we also did not consider the effect of residual renal function on uric acid and blood pressure.This work was extracted from thesis of Elaheh Vafaie at the internal medicine department of Shiraz University of Medical Sciences .Collecting data: EV. Statistical analysis: MMS and EV. Drafting manuscript: EV and MMS. Study supervision: JR and MS.The authors declared no competing interests.The Research Council of Shiraz University of Medical Sciences financially supported this project (grant No. 90-01-01-3037).


Secondary outcomes demonstrated in both groups that CF intake decreased pulse wave velocity and lowered total peripheral resistance, and increased arteriolar and microvascular vasodilator capacity, red cell deformability, and diastolic blood pressure, while cardiac output remained affected. In the elderly, baseline systolic blood pressure was elevated, driven by an arterial-stiffness-related augmentation. CF intake decreased aortic augmentation index (−9 %) and thus systolic blood pressure . CF intake reverses age-related burden of cardiovascular risk in healthy elderly, highlighting the potential of dietary flavanols to maintain cardiovascular health.Increased vascular stiffness, endothelial dysfunction, and isolated systolic hypertension are hallmarks of vascular aging. Regular cocoa flavanol (CF) intake can improve vascular function in healthy young and elderly at-risk individuals. However, the mechanisms underlying CF bioactivity remain largely unknown. We investigated the effects of CF intake on cardiovascular function in healthy young and elderly individuals without history, signs, or symptoms of cardiovascular disease by applying particular focus on functional endpoints relevant to cardiovascular aging. In a randomized, controlled, double-masked, parallel-group dietary intervention trial, 22 young (<35 years) and 20 elderly (50–80 year) healthy, male non-smokers consumed either a CF-containing drink (450 mg CF) or nutrient-matched, CF-free control drink bi-daily for 14 days. The primary endpoint was endothelial function as measured by flow-mediated vasodilation (FMD). Secondary endpoints included cardiac output, vascular stiffness, conductance of conduit and resistance arteries, and perfusion in the microcirculation. Following 2 weeks of CF intake, FMD improved in young (6.1 ± 0.7 vs. 7.6 ± 0.7 %,  The mechanisms underlying vascular aging are largely unknown but involve all segments of the arterial vascular system. Hallmarks of vascular aging are not entirely identical to those of atherosclerosis, but increasing age is associated with endothelial dysfunction and vascular stiffening, as well as isolated systolic hypertension, and a substantial excess of cardiovascular mortality  and ELDERLY (50–80 year) healthy male Caucasian adult subjects without history, signs, or symptoms indicative of cardiovascular disease, including previous myocardial infarction, stroke, and peripheral artery disease or current or previous medication Fig. . ParticiMeasurements were taken fasted before (baseline) and 1 h after the first drink on day 1 and day 14. Endothelial function (primary end point) was measured as flow-mediated vasodilation (FMD). Secondary endpoints included measures of cardiac output, the physicomechanical properties of the large conduit arteries, the dilatory capacity and tone of resistance arteries, and perfusion in the microcirculation , standardized and matched in composition. All beverage mixes were agglomerated powders, utilizing a maltodextrin base into which flavoring and sweeteners were incorporated. The beverage mixes were provided in sachets  labeled with an alphanumeric identifier to enable a double-masked study design.A high flavanol cocoa extract  was the source of flavanols in the CF-containing drink. The CF-containing drink (FLAVANOL) provided 450 mg of total cocoa flavanols per serving . Given the natural presence of theobromine and caffeine in cocoa extract, both theobromine and caffeine were added to the control beverage mix in order to match the composition of alkaloids in the CF-containing test product. Coloring was also added so that the 0 mg CF drink was also indistinguishable in appearance. Compositional details for the 0 mg (CONTROL) and 450 mg CF (FLAVANOL) test drinks are provided in Table Cardiac function was determined by heart rate (HR), cardiac output (CO), stroke volume (SV), and total peripheral resistance (TPR); the function of major conduit arteries, elastic aorta and muscular brachial artery, was characterized based on their physicomechanical properties and capacity to dilate Fig. . PhysicoBrachial artery FMD and nitroglycerin-mediated vasodilation (NMD) were measured by ultrasound  in combination with an automated analysis system  as described  was used for continuous beat-to-beat assessment of cardiovascular variables, including stroke volume, BP, heart rate, and total peripheral resistance by impedance cardiography, which included ECG, phonocardiography, Finapres , and BP monitoring system .Office blood pressure was measured three times after 10 min of rest using an automated clinical digital sphygmomanometer  with appropriately sized cuff placed around the upper arm at heart level. Furthermore, we determined 24-h ambulatory BP measurements on the day before day 1 of the study and during the last 24 h of the study on day 13 until the clinical visit on day 14. Values are expressed as day, night, and total average. Furthermore, we determined BP at the fingertip using a tonometric device . Values were taken over 5 min and results represent average of measurements taken. Central BP was derived from peripheral pulse wave analysis obtained with applanation tonometry using a proprietary transfer function .Central blood pressure parameters including augmentation index (AIX) were measured by applanation tonometry using the SphygmoCor® system. Via a transfer function, the pressure waveform of the ascending aorta was synthesized. PWV was determined from measurements taken at the carotid and femoral artery as described  was measured by mercury-in-rubber strain gauge plethysmography  according to standard techniques at rest and during reactive hyperemia secondary to 3 min of forearm ischemia.2 on the volar site of the forearm. Microvascular reactivity was assessed during postocclusive reactive hyperemia. Following the baseline perfusion , a blood pressure cuff located at the proximal forearm was inflated to suprasystolic pressure. After the cuff release, the microvascular response on reactive hyperemia was recorded. Data acquisition and analysis were performed by LDPIWin Software . Maximum perfusion, amplitude of perfusion (maximum perfusion − baseline perfusion), ratio (maximum perfusion / baseline perfusion), percentage increase ((maximum perfusion − baseline perfusion) / baseline perfusion × 100), time to peak response, and area under curve were evaluated without subtracting biological zero from the data  as described  according to the manufacturers’ instructions as described  containing 3′-O-ethyl-(−)-epicatechin (500 nM) as a recovery standard. Samples were centrifuged at 17,000×g for 15 min at 4 °C, and the supernatant was collected. The pellet was extracted again with 2 ml of acidified ice-cold methanol  containing 3′-O-ethyl-(−)-epicatechin (500 nM), and then with 1 ml of 50 % methanol acidified with 0.5 % acetic acid and containing 3′-O-ethyl-(−)-epicatechin (500 nM). Combined supernatants underwent concentration (to approximately 50 μl) using a Speedvac system  and were mixed with resorcinol (300 pmol) and catechol (300 pmol) prior to analysis by HPLC. Flavanol monomers and O-methylated metabolites were analyzed using a Hewlett-Packard 1200 series HPLC  equipped with diode array and fluorescent detection. Samples (50 μl) were injected onto a reversed-phase Phenomenex Luna C18(2) column (4.6 × 150 mm) with 3-μm particle size. The mobile phase consisted of (A) HPLC grade water, (B) 200 mM sodium acetate, pH 4.4/Methanol (84/16), and (C) acetonitrile, and the following gradient protocol was run: 0 min, 75 % A, 25 % B; 5 min, 75 % A, 25 % B; 20 min, 65 % A, 25 % B; 28 min, 63 % A, 25 % B; 34 min, 55 % A; 25 % B; 41 min, 45 % A, 25 % B; 45 min, 25 % B, 75 % C; 55 min, 25 % B, 75 % C; 56.1 min 75 % A, 25 % B; and 60 min, 75 % A, 25 % B. The flow rate was 0.8 ml/min. Detection of flavanols and their metabolites was performed using a fluorescent detector with excitation wavelength of 276 nm and emission wavelength of 316 nm. The concentration of each compound was determined using an external calibration curve produced with the use of authentic standards.(−)-Epicatechin and its related metabolites where analyzed in plasma by HPLC-FLD/UV and electrochemical detection using authentic standards provided by Mars Inc., as previously described . Baseline data represent data of first visit . The primary test for an effect was a three-way repeated mixed model measurements ANOVA  and intervention (CONTROL/FLAVANOL). ANOVA and confidence intervals for pairwise comparisons were computed with SPSS 20 (IBM). Correlations were Pearson’s n = 4) and cholesterol , this was tenably driven by a significantly lower stroke volume in the ELDERY . Peripheral SBP  and DBP  as assessed by standard office measurement, as well as total peripheral resistance (TPR), were significantly greater in ELDERLY. Similarly, greater values were observed in 24-h ambulatory Holter monitoring (continuous measurement over 5 min at the fingertip), and central BP. ELDERLY participants exhibited stiffer arteries with significantly greater pulse wave velocity  and aortic augmentation index  as compared to YOUNG. Endothelium-dependent and endothelium-independent conduit artery vasodilator function, as measured by FMD  and nitroglycerin-mediated , respectively, was lower in the ELDERLY. The baseline diameter of the brachial artery was greater in ELDERLY subjects . As detailed in Table At baseline on day 1, resting cardiac output was significantly lower in ELDERLY as compared to YOUNG  and ELDERLY  as compared to that on study day 1 (0 h). Additional acute ingestion of FLAVANOL did not further increase endothelial function assessed at 1 h on day 14. Despite differences in baseline FMD, it is noteworthy that each individual exhibited positive responses following FLAVANOL intake. The mean changes in FMD following FLAVANOL were 1.3 ± 0.6 % in the young and 1.0 ± 0.6 % in the elderly at 1 h and 1.6 ± 0.8 % in the young and 1.4 ± 0.7 % in the elderly at 14 days. To evaluate determinants of inter-individual response, we correlated the change in FMD at 1 h and 14 days with baseline epidemiological parameters . This analysis showed that none of these parameters correlated with changes in FMD. The baseline diameter of the brachial artery and NMD remained unaffected by either FLAVANOL or CONTROL.The FLAVANOL intervention led to an acute increase in brachial artery FMD at 1 h after CF ingestion in both YOUNG  and YOUNG  and that PWV remained decreased at 0 h on day 14  and did not further decrease at 1 h after FLAVANOL drink at day 14. Importantly, FLAVANOL only decreased office peripheral SBP  and AIX  in ELDERLY, and this was detectable at all time points investigated as compared to day 1, 0 h. Notably, this decrease in SBP was confirmed by 24-h ambulatory monitoring and central blood pressure measurements. We found a significant correlation between the changes in SBP and AIX after FLAVANOL . It is known that part of the PWV can be modulated by endothelial function. It is noteworthy that the changes in PWV showed a close correlation with improvements in FMD at day 14 , thereby corroborating a mechanistic link between increases in endothelial function and a decrease in SBP in ELDERLY subjects.As depicted in Table r = −0.6, p = 0.01). This suggests that the FLAVANOL intervention acted primarily on the vascular and not the cardiac component of systemic hemodynamics.As detailed in Table r = 0.6, p = 0.01).RBC deformability increased after FLAVANOL intervention in both YOUNG and ELDERLY. This was paralleled by significantly increased maximal perfusion of the cutaneous capillaries as measured by laser Doppler during reactive hyperemia. Significant univariate correlation existed between the increase in maximal perfusion and RBC deformability . After 14 days of two-times-daily CF consumption and following overnight fasting, baseline levels remained significantly higher as compared to those on day 1. Additional acute ingestion of FLAVANOL led to flavanol plasma levels of 745 ± 21 and 857 ± 50 nM (p < 0.0001 vs. baseline day 14) in YOUNG and ELDERLY, respectively, but these levels were not significantly different from values observed after acute ingestion on day 1.At the baseline visit, only low levels of total plasma flavanols were detected . At 1 h (day 1) after acute consumption of FLAVANOL, but not CONTROL, both, YOUNG and ELDERLY, showed significantly increased levels of plasma flavanols  have been shown to elicit a small, but significant DBP-reducing effect of −2.2 mmHg in a meta analysis of a heterogeneous study population including patients with and without CVD  in FMD in this study population. Consequently, it can be argued tenably that despite of limitations with regard to study duration, our data are relevant in furthering understanding of pharmacodynamics aspects of CF-mediated changes in endothelial function, cardiac output, conductance of conduit and resistance arteries, and perfusion in the microcirculation. An additional limitation regarding the design of this study is the exclusion of female participants. The rationale for doing so was based on complexities related to the influence on FMD and other cardiovascular readouts of hormonal changes that occur in women during the menstrual cycle and during peri-menopause and menopause. To assess detailed mechanistic aspects of CF-intake-related changes in cardiovascular function over the background of menstrual-cycle-dependent modulations, it will require a specific and comprehensive study design, which was beyond the scope of this investigation. Finally, the elderly subjects in our study presented with significantly lower cardiac output as compared to the young subjects that was not significantly changed by the flavanol intervention. It has been appreciated for a long time that besides stiffening of the arteries, stiffening of the heart occurs with advancing age (Tresch and McGough A CF-based dietary intervention in elderly individuals decreases systolic blood pressure and improves vascular stiffness. These beneficial effects are associated with improved endothelial function in large arteries and enhanced vasodilator function in resistance arteries, as well as with improved microcirculatory perfusion that can already be observed in young healthy participants. Our findings provide clear evidence and novel insights that scientifically underpin the potential of dietary CF to reverse, or at least to attenuate, features of circulatory dysfunction associated with vascular aging in healthy men, a major contributor to atherogenic risk independent of numeric age.