Diagnosing and treating hypertension plays an important role in minimising the risk of cardiovascular disease and stroke. Early and accurate diagnosis of hypertension, as well as regular monitoring, is essential to meet treatment targets. In this article, current recommendations for the screening and diagnosis of hypertension are reviewed. The evidence for treatment targets specified in contemporary guidelines is evaluated and recommendations from the USA, Canada, Europe and the UK are compared. Finally, consideration is given as to how diagnosis and management of hypertension might develop in the future. Hypertension affects around 40 % of the worldwide population aged over 25 years, and is estimated to be implicated in approximately half of the deaths from stroke or cardiovascular disease . Early aTraditionally, hypertension has been diagnosed using clinic blood pressure (BP) measurements, typically taking several readings on several occasions and then treating those whose mean BP is consistently above the diagnostic threshold –6. HowevABPM is widely regarded as the “gold standard” for BP measurement. For example, both the Dublin outcome study, involving 5,292 patients, and a meta-analysis of 7,030 individuals from the International Database of Ambulatory Blood Pressure in relation to Cardiovascular Outcome (IDACO) database, found that systolic and diastolic ABPM measurements significantly and independently predicted cardiovascular outcomes over and above clinic BP , 13. FurThere is also strong evidence for the prognostic accuracy of SMBP over clinic BP. SMBP is a significantly stronger predictor of cardiovascular outcomes , 23, 24,Very few studies have assessed SMBP, ABPM and clinic BP against each other for cardiovascular outcomes. Fagard et al. compared these three methods of BP measurement for predicting cardiovascular events over 10 years in 391 older patients . The autIn a systematic review, Hodgkinson et al. evaluated 20 studies that had made a hypertension diagnosis with clinic or home BP measurement compared to ABPM as reference standard . Using aCurrent diagnostic thresholds for out-of-office measurement are based on work by Head et al., which compared 8,575 ABPM measurements to contemporaneous clinic readings taken by trained staff . They foA strong argument for using out-of-office measures arises from the concept of masked hypertension, where patients have a normal or controlled clinic BP but an elevated out-of-office measurement. Diagnosis of this condition is important because patients can be untreated or undertreated putting them at greater risk of cardiovascular disease . BanegasThe cost-effectiveness of routine out-of-office measurement in the diagnosis of hypertension was assessed in a modelling exercise undertaken as part of the development of the National Institute for Health and Care Excellence (NICE) hypertension guideline . This shNew technologies may provide a useful interface between non-physician screening and primary care. Telemonitoring and electronic submission of readings are becoming more popular  and, witA recent randomised controlled trial (RCT) using telemonitoring in the UK found that the direct mean cost of systolic BP reduction was £25.56/mmHg per patient compared to usual care . Even thAnother barrier, particularly significant to the USA, is the need for uniform quality standards which drive reimbursement. There is a lack of acceptance that patient-reported data meets quality measures, which stipulate that controls, such as face-to-face visits and physiologic measurements, adhere to certain specifications, for example nurse-only BP checks . In theoIn addition to the method of screening for hypertension, the frequency of such screening is also important, but the evidence to underpin this is scarce. Piper et al. tried to confirm “the shortest interval in which clinically significant, diagnosed hypertension may develop” in their recent systematic review . They foWhilst primary care remains the commonest setting for hypertension screening, there is growing evidence to suggest that community screening may help to reach greater numbers of patients. A comprehensive systematic review by Fleming et al. showed that screening has been undertaken in a range of locations, with pharmacies and mobile units the most successful settings assessed, albeit with a high level of heterogeneity . HoweverNovel primary care settings may also prove successful, such as optometry . In the Recently, a group of primary care practices in the USA developed an algorithm for identifying patients at risk of hypertension from their electronic records . The innSince 2011, in the UK, guidelines from NICE have recommended that a raised clinic BP reading (≥140/90 mmHg) in an undiagnosed patient should be followed by confirmatory ABPM, unless BP ≥180/110 mmHg . Home BPIn comparison, the European Society of Hypertension (ESH) practice guidelines (2013) recommend that office BP remains the “gold standard” for screening, diagnosis and management of hypertension . HoweverThe Canadian Hypertension Education Program (CHEP) have recently updated their recommendations for the diagnosis of hypertension to include the use of ABPM and home BP monitoring . For anyAlthough it can be argued that the relationship between BP and cardiovascular risk is continuous, hypertension targets provide an essential management guide . The HypOver the last decade, work to establish accurate BP targets for treatment has been ongoing. A comprehensive meta-analysis by Law et al. reported a fall in cardiovascular disease (CVD) events by 25 %, a reduction in heart failure by about 25 % and in stroke by 33 % for every 10 mmHg drop in systolic BP and every 5 mmHg drop in diastolic BP without a lower threshold, at least to 110 mmHg systolic . A recenThe modelling work of Port et al. contradicts the epidemiological and trial evidence , 72 findRecent work examining the effectiveness of BP targets in a treated hypertension population of 398,419 has shown the presence of a J-shaped curve, where the highest rate of mortality came from lower and higher BP than the reference standard of 130–139/60–79 mmHg. The nadir for systolic and diastolic BP was 137/69 mmHg, but stratified analysis for patients with diabetes showed that the nadir was slightly lower at 131/69 mmHg, while patients ≥70 years of age had a nadir of 140/70 mmHg . This suHowever, the time taken to bring patients to the optimum systolic target can also impact on mortality outcomes. Xu et al. investigated the time to intensification of treatment and the time to follow-up for new medications . Delays Earlier this year, Zanchetti et al. carried out a meta-analysis on 68 BP lowering trials to try and answer questions about the effectiveness of current thresholds . They foNICE reviewed three systematic reviews and 27 prognostic studies to develop their current treatment threshold recommendations . The cutNICE suggests an ABPM treatment target of <135/85 mmHg for patients below 80 years of age and an ABPM target of <145/85 mmHg for those patients over 80 years . CurrentThe ESH 2013 guidelines suggest a target of <140 mmHg for all patients under 80 years of age and a diagnostic target of <90 mmHg. Diabetic patients should be treated to a diastolic target of <85 mmHg. Patients over 80 years with a systolic BP ≥160 mmHg should be treated to a target between 140 and 150 mmHg according to the evidence [The recent JNC 8 guideline recommended treating those between 18 and 60 years old to a target of 140/90 mmHg . HoweverDue to its diagnostic accuracy, ABPM seems set to assume greater prominence for the new diagnosis of hypertension – it is already in place in the NICE and arguably the ESH guidelines , 37 and Outside of primary care, other health professionals, such as pharmacists, dentists and optometrists, are starting to have more of a role in monitoring BP. There will need to be clear pathways set up between these organisations and primary care providers in order to follow-up cases of high BP readings . Self-moMeasurement of blood pressure is well captured by the guidelines, but what is less clear is how to ensure adequate population screening. Further studies should seek to establish optimum rescreening intervals, alternative ways to gain full population coverage and methods to identify those at greatest risk.Many trials have shown that controlling blood pressure is an important way of reducing heart disease and stroke , 84, 85.Overall, the mainstay of hypertension diagnosis and monitoring is likely to remain systematically identifying and then treating patients to fairly conventional targets, with use of out-of-office monitoring for both diagnosis and management. Ensuring physicians do not succumb to clinical inertia is probably as important as the actual methods and targets used .


The renin–angiotensin system influences blood pressure levels and the occurrence of target organ damage (TOD). Thus, the aim of this study was to correlate the angiotensin-converting enzyme gene (ACE) insertion/deletion 155 non-diabetic hypertensive individuals on antihypertensive treatment underwent ABPM. Peripheral blood samples were drawn for biochemistry and genetic analysis of the ACE I/D polymorphism by polymerase chain reaction. ND was defined as ≥10 % differences in the mean systolic blood pressure (BP) during wakefulness and sleep.p < 0.001) in non-dippers. There was significant difference in the prevalence of left ventricular hypertrophy (LVH) between ACE genotypes  with an increased risk in carriers of the DD genotype . Carriers of the D allele had higher systolic BP during wakefulness and by ABPM (p < 0.05), higher left ventricular mass  and higher prevalence of LVH , compared to the II genotype.There were no differences in clinical or biochemical variables or TOD in respect to ND status, except for higher BP levels during sleep (The DD genotype is associated with a higher prevalence of LVH. The presence of the D allele appears to be associated with higher mean 24-h and wake systolic BP measured by ABPM in hypertensive patients under antihypertensive treatment. Hypertension (HT) is a highly prevalent disease associated with increased risk of target organ damage (TOD), including myocardial infarction, stroke and left ventricular hypertrophy (LVH). Changes in blood pressure are influenced by daily activities and interactions with neurohumoral, behavioral and environmental factors. Under physiological conditions, there is a drop in the blood pressure (BP) between wakefulness and sleep, a phenomenon known as nocturnal blood pressure dipping (ND). The absence of ND is associated with TOD and higher mortality –4.Due to the multifactorial etiology of HT, many researchers are studying the association between genetic polymorphisms and HT and its complications. This research studied the angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism, which is characterized by the presence (insertion) or absence (deletion) of an Alu repetitive sequence of 287 base pairs (bp) in intron 16 of the ACE gene . The varThe ACE I/D polymorphism is linked to risk for myocardial infarction and cardiovascular events –9, LVH –12, micrThe findings reported in the literature in respect to the relationship of this polymorphism with BP levels and TOD are controversial , 21–31. 2, creatinine clearance <30 mL/min/m2, and secondary hypertension.This project was approved by the Research Ethics Committee of the State Medical School in São José do Rio Preto (no. 169/2008). All participants were informed about the purpose of the work and gave their written informed consent before participating in the research. This was a cross-sectional study, which enrolled 155 hypertensive individuals followed-up at a university hospital outpatient clinic. The exclusion criteria were age under 40 years, history of valvular disease, systolic/diastolic dysfunction, diabetes mellitus (DM), body mass index (BMI) ≥35 kg/mAn investigative protocol was used to collect information on age, gender, medicines taken, and comorbidities. Data regarding DM, strokes, MI, and dyslipidemia (DLP) were used to assess comorbidities. Patients who had presented with two or more fasting glycemia levels ≥126 mg/dL or altered oral glucose tolerance test (≥200 mg/dL) were excluded . History2. Besides stroke and MI, TOD was also considered as the presence of microalbuminuria and left ventricular hypertrophy (LVH). Microalbuminuria was characterized as the average of two 24-h urinary albumin excretion rates ≥20 μg/min.Weight and height were measured and BMI was calculated using the formula: BMI = weight (kg)/height (m)All echocardiographic examinations were performed by the same experienced echocardiographer. M-Mode echocardiograms were performed under cross-sectional control, with the patient in partial left decubitus position, using an Philips HD15 PureWave ultrasound system and S5-2 Broadband Sector Array Transducer  with 2.5- to 3.5-MHz mechanical transducers. Left ventricular (LV) dimensions and mass were assessed from 2D-guided M-mode tracings according to American Society of Echocardiography (ASE) recommendations. M-mode measurements were averaged from three cycles. LV end-systolic, end-diastolic, and stroke volumes were calculated. Ejection fraction was calculated from derived volumes with computed based on the “cubed” or “Teichholtz” equations, but only in the absence of asynergy. 2-D method of Simpson calculated was performed in distorted ventricles . To eval2 in men and >95 g/m2 in women  with a 95 % confidence interval (95 % CI). All statistical analyses were performed using the Minitab 15.0 computer program. An alpha error greater than 5 %  was considered statistically significant.Descriptive analysis was conducted for the quantitative variables with the presentation of mean values and standard deviations. The Student 2) and microalbuminuria (58.1 %) stand out in this sample. On comparing individuals with and without ND, there were no differences between clinical, and biochemical variables or TOD except for lower BP levels during sleep (p < 0.001) in patients with ND . By logistic regression . There was no significant difference between genotypes in respect to the other TOD investigated in this study.When grouped according to the genotype of the ACE I/D polymorphism, the groups did not significantly differ in respect to mean age, gender, BMI and duration of HT. There were no statistically significant differences between the three genotypes  and mean 24-h BP by ABPM Table . Howeverp value = 0.036 and p value = 0.042, respectively) , left ventricular mass index  and, consequently, higher prevalence of LVH  than individuals with the II genotype. By logistic regression, D allele carriers had a three times higher risk of LVH than those with the II genotype  .Carriers of the D allele (ID and DD genotypes) had higher awake systolic BP and mean 24-h BP compared to those with the II genotype  blockers , 52. TheIt is known that TOD is more related to the mean 24-h BP levels than office BP levels , 2, whicIn the present study, the DD genotype was associated to higher risk of LVH compared to the II genotype, which suggests that the ACE I/D polymorphism may be more important than ND in the genesis of LVH. In favor of this hypothesis, the results of a meta-analysis found a greater risk for LVH associated with the D allele or DD genotype in untreated hypertensive patients . In addi2, which reduces greatly the possibility of sleep apnea. Finally, the lack of a control group of normotensive individuals, in our viewpoint, was the main limitation of this study. Besides, we can cite two strong points. The study population was separated in two groups, according to nocturnal dipping and the investigation of influence of the ACE I/D polymorphism on 24-h BP levels and on target organ damage.Some limitations of this study should be mentioned. First, the size of the sample was small, in part, because of the difficulty to select patients due to the exclusion criteria. Second, it was not possible to exclude patients with obstructive sleep apnea, a fact that may influence the frequency of LVH. However, we have excluded patients with BMI ≥35 kg/mTo our knowledge, this is the first study that evaluates the ACE I/D polymorphism in respect to ABPM and TOD in Brazilian hypertensive patients. The present study reports two findings: the presence of the D allele of the ACE I/D polymorphism is correlated with higher mean 24-h systolic BP and wake systolic BP, and the DD genotype is associated with higher prevalence of LVH in non-diabetic hypertensive patients on antihypertensive treatment.


Gliptins should have beneficial effects beyond glycemic control, potentially on the pathophysiology of cardiovascular (CV) diseases, with some basic studies demonstrating this possibility. However, we are yet to answer whether there are any direct CV effects in the clinical setting. We aimed to examine the beneficial effects of sitagliptin in Japanese patients with diabetes and high CV risk for 12 months.This was a prospective, multicenter, observational study of 205 patients with type 2 diabetes. All participants had more than one major CV risk factor and were treated with sitagliptin for 12 months. At 3 or 12 months, we examined the effects of treatment on glycemic control, CV function , and CV biomarkers.Patients were predominantly elderly (68.8 ± 9.9 years) and male (71.5 %) and typically had more than three CV risk factors (79.2 %). Treatment with sitagliptin significantly reduced the hemoglobin A1c (HbA1c) level from 7.09 % ± 0.81 % at baseline to 6.67 % ± 0.69 % at 3 months and 6.68 % ± 0.73 % at 12 months (both P < 0.001). The reduction in HbA1c was also in tandem with the decrease in the level of high-sensitive C-reactive protein throughout the study. Independent of the change in HbA1c, sitagliptin reduced systolic (−7.0 ± 18.9 mmHg) and diastolic blood pressure (−5.1 ± 11.7 mmHg) at 12 months, and this was associated with a decrease in urinary albumin. In contrast, there were no beneficial effects on cardiac and endothelial function or on the levels of serum B-type natriuretic peptide, high-sensitive troponin T, and urinary 8-hydroxy-2′-deoxyguanosine.In Japanese patients with diabetes and multiple CV risk factors, sitagliptin showed a decrease in blood pressure associated with an improvement in albuminuria in addition to glycemic control.Trial registration: UMIN000005663The online version of this article (doi:10.1186/s12933-016-0371-z) contains supplementary material, which is available to authorized users. Type 2 diabetes is strongly associated with coronary atherosclerosis and vascular complications, both of which are responsible for worse morbidity and mortality . AlthougSitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor (gliptin), has been shown to increase plasma incretin hormone levels, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Increases in these peptides appear to be responsible for the principle mechanism of action of sitagliptin; as the levels of GLP-1 increase, glucose concentrations decrease . SitagliDPP-4 is a widely expressed glycoprotein that exists either as a transmembrane protein or in a soluble form in plasma, and has many targets other than GLP-1 and GIP. In addition, the GLP-1 receptor is variously expressed, being located not only in pancreatic cells but also in the lungs, kidneys, intestines, peripheral and central nervous systems, and the CV system. Based on this, it has been suggested that gliptins should have beneficial effects beyond glycemic control, potentially on the pathophysiology of CVD, with some basic studies demonstrating this possibility . HoweverWe performed this prospective study to determine whether sitagliptin therapy for 12 months had any beneficial effects on glycemic control and CV function in Japanese patients with diabetes at high risk of CVD.This was a prospective, multicenter, observational study. Eligible patients with diabetes at high risk of CVD were treated with sitagliptin for 12 months from August 2011 to September 2012, at nine hospitals and clinics in Japan. The patients received sitagliptin at dosages of 25, 50, or 100 mg/day at the discretion of the attending physician, and biochemical markers, urinalysis, electrocardiography (ECG), and echocardiography (UCG) were assessed before, and at 3 and 12 months after treatment. In a sub-study at the Department of Internal Medicine, Kinki University Faculty of Medicine and the Tazuke Kofukai Medical Research Institute, Kitano Hospital, we also performed reactive hyperemia-peripheral arterial tonometry (RH-PAT) before and at 3 months after starting sitagliptin and measured CV biomarkers before and at 3 and 12 months after treatment.http://www.umin.ac.jp under UMIN000005663.The study protocol was approved by the Ethics Committee of Kinki University Faculty of Medicine and Osaka Foundation for the Prevention of Cancer and Cardiovascular Disease. Written informed consent was obtained from all patients. The trial was registered at The inclusion criteria were as follows: (1) age ≥20 years; (2) type 2 diabetes with a hemoglobin A1c (HbA1c) ≥6.2 %, a fasting glucose ≥110 mg/dL, or a postprandial glucose ≥140 mg/dL despite appropriate diet and exercise, oral antihyperglycemic agents, or insulin therapy; and (3) at least one CV risk from among hypertension, dyslipidemia, previous CV event, advanced age (≥65 years), current smoking, obesity (body mass index ≥25), and hyperuricemia. Patients were excluded if they met the following criteria: (1) history of diabetic coma and ketoacidosis within 6 months before the study, (2) serious trauma or infectious disease, (3) currently nursing or pregnant women, (4) dialysis or severe renal insufficiency (creatinine clearance <30 mL/min), and (5) known hypersensitivity to any component of the study medications.The primary endpoint was the change in HbA1c after 3 and 12 months of sitagliptin therapy. The major secondary endpoints were changes in body weight, blood pressure (BP), biochemical measures, urinary measures, ECG parameters, and UCG parameters.BP was measured during office visits at baseline and after 3 and 12 months of treatment. Cuffs were used with the bladder encircling at least 80 % of the mid-arm circumference and placed directly on the skin. All BP measurements were taken after 5 min of rest with patients sitting and with the arm resting on a table at the level of the heart.−1.094 × (age)−0.287  . Heart rate (HR), rhythm, PR interval, QRS interval, QT/corrected QT (QTc) interval, and the SV1 + RV5 value were obtained . In the In the sub-study, we assessed peripheral endothelial function by RH-PAT using an EndoPAT2000 , as described previously . RH-PAT 2 test for proportions and the unpaired t test or analysis of variance (ANOVA) for continuous variables, as appropriate. The linearity of the relationship between two variables was assessed by linear regression analysis, and Pearson’s correlation coefficient was calculated. Differences between the reduction or increase in each marker and the change in HbA1c were compared using Student’s t tests. Further multiple logistic regression analysis was performed to define independent variables that might predict the change in HbA1c. Overall differences between before and after sitagliptin administration were determined using repeated measures ANOVA. All P values <0.05 were considered statistically significant. Results are expressed as the mean ± standard deviation (SD). All analyses were performed using JMP version 10.0.Categorical variables were compared using the χOf the 211 patients enrolled, 6 patients were excluded from the analysis because they discontinued sitagliptin after 3 months, citing dizziness (2 patients), mild hypoglycemia (1 patient), headache (1 patient), or general malaise (1 patient). However, no severe adverse events, including severe hypoglycemia, were reported. One patient withdrew consent. The baseline characteristics of the 205 participants are shown in Table At baseline, HbA1c and fasting blood glucose were 7.09 ± 0.81 % and 139.8 ± 33.0 mg/dL, respectively, and both parameters significantly reduced by 3 and 12 months (both P < 0.001). However, there were no changes in insulin, HOMA-IR, low-density lipoprotein cholesterol, triglyceride, or the uric acid level. Only high-density lipoprotein (HDL) cholesterol level reduced significantly. In addition, the eGFR decreased significantly during the study period, but changes in the UACR were not significant.The changes in HbA1c (ΔHbA1c) at 3 and 12 months were significantly associated with the baseline HbA1c level  at baseline to 65.0 ± 11.9 bpm at 12 months (P < 0.01). However, although the QT interval shortened significantly , the QTc interval did not change . Other parameters did not change, including the rhythm, PR interval, QRS interval, and SV1 + RV5 value.2 at baseline to 105.1 ± 31.9 g/m2 at 12 months (P = 0.027). However, the other parameters, including LV dimension, EF, E/A, Dct, e′, and E/e′, showed no changes between baseline and 12 months  and in systolic BP (ΔSBP) over 12 months were significantly associated; patients with a reduction in albuminuria n = 63) showed a greater reduction of SBP over the same period than those with an increase in albuminuria (n = 57) . The tertile of ΔSBP (n = 40 each) was negatively correlated with a decrease in albuminuria (P = 0.045). In contrast, although ΔSBP or ΔDBP was significantly associated with ΔeGFR   . In the Prolongation of the QT interval is an important risk factor for ventricular arrhythmia and sudden death. In the present study, the QT interval was significantly shortened from baseline to 12 months (P < 0.001), but there was no significant difference in the QT interval after correction for the change in HR  (P = 0.093). The basic research by Lee et al. showed that sitagliptin treatment could reverse calcium regulation in cardiomyocytes, which might contribute to its shortening effects on the QT interval in hypertensive animals . In otheGLP-1 receptors are located in cardiac myocytes, coronary vascular endothelial cells, and smooth muscle cells; and, mainly in basic studies, GLP-1 has been reported to improve cardiac function and provide cardioprotective effects . NikolaiWe showed that sitagliptin reduced SBP and DBP independent of ΔHbA1c and that this was associated with a reduction in the level of albuminuria. It might also have been associated with a reduction in the LV mass index. Relatively few studies have examined the effects of DPP-4 inhibitors on BP in patients with diabetes . PresentDPP-4 inhibition with sitagliptin increases the activity of GLP-1, which has been reported to decrease urinary salt uptake and increase urinary salt excretion . In factThe development of albuminuria is a key step in the progression of diabetic kidney disease, and worsening of albuminuria is a significant predictor of both progressive renal disease and CVD in patients with diabetes. The mechanisms underlying albuminuria are complex, and improved insulin sensitivity, weight loss, reduced blood glucose levels, lower BP, and suppressed inflammation might all contribute to a reduction in albuminuria. Several studies have reported a significant correlation between improvements of albuminuria and BP in patients with diabetes, hypertension, or nephropathy. Kawasaki et al. reported in a retrospective analysis that sitagliptin reduced albuminuria, and that this was independently associated with reductions in BP and eGFR in 247 patients with diabetes . In the First, this was an uncontrolled study and the effects of sitagliptin were only assessed by comparison of measurements at three independent time points. It might be possible that the significant changes in several measures were affected by factors other than sitagliptin treatment. However, all the patients were educated about the importance of diet and physical exercise, and most had stable medical treatment at least 1 month before the study inclusion. Second, the study assessments took place at 3 or 12 months, and may have been too short for the assessment of CV effects and outcomes. Therefore, the analysis may have been insufficient to provide conclusive evidence for long-term CV effects and outcomes associated with sitagliptin. Future studies must examine the BP lowering effects of sitagliptin and its direct influence on CV outcomes. Third, most of the participants had early-stage diabetes (69.3 % had an HbA1c <7.0 %) and higher age (73.4 % were aged >65 years), meaning that our results cannot be extrapolated to all patients with diabetes and high CV risk. Finally, our study design also led to the exclusion of some patients with severe chronic kidney disease or end-stage renal disease, which limits the applicability of the data in these settings.We conducted a prospective, multicenter, observational study of 205 patients with type 2 diabetes at high risk of CVD who were treated with sitagliptin for 12 months. The efficacy of sitagliptin for glycemic control was demonstrated by the higher baseline HbA1c level and the reduction of hs-CRP levels. Sitagliptin also showed BP lowering effects over the 12-month study period associated with the prevention of microalbuminuria progression. However, there were no beneficial effects on cardiac and endothelial function or on serum BNP, hs-TnT, and urinary 8-OHdG levels. We conclude that in Japanese patients with diabetes at high risk of CVD, sitagliptin had beneficial effects on BP and glycemic control over 12 months and it might offer long-term advantages in the management of diabetes with comorbid CVD.


The present study aimed to investigate the association between plasma brain natriuretic peptide (BNP) levels and systolic blood pressure (SBP) variability over a one-year period. Blood pressure was measured in 44 patients treated for hypertension (73±9 years old) at an outpatient clinic every one to two months over a one-year period. The standard deviation (SD) and the coefficient of variation (CV) were calculated to assess SBP variability. Mean SBP was also calculated over the year. Plasma BNP levels were measured at the end of the one-year period. BNP was found to correlate with mean SBP . However, BNP was not observed to be correlate with either the SD  or the CV  of the SBP. Multiple regression analysis revealed that only the mean values of SBP were independently associated with BNP . Thus, BNP was found to be correlated with mean SBP, but not SBP variability. In conclusion, plasma BNP levels may reflect the average SBP, but not SBP variability over the one-year period prior to the measurement of BNP in patients with hypertension. Brain natriuretic peptide (BNP), a hormone secreted by ventricular cardiomyocytes in response to pressure overload in the left ventricle , reflectSeasonal variation in blood pressure has been reported –15, withIn the present study, it was hypothesized that SBP variability over a one-year period may reflect cardiac damage and may be significantly correlated with plasma BNP levels. In order to evaluate this hypothesis, the association between SBP variability over a one-year period and plasma BNP levels was assessed in patients with hypertension. This association was then compared with the association between mean SBP and BNP levels in these patients.A total of 44 patients  who had been diagnosed with hypertension at Kagawa University Hospital , and who had visited the outpatient clinic regularly between September 2012 and August 2013, were included in the present study. Hypertension was defined as SBP ≥140 mmHg and/or diastolic blood pressure (DBP) ≥90 mmHg. Blood pressure was determined using the conventional cuff method. All patients were treated with at least one antihypertensive drug. For at least one year prior to the present study, as well as during the present study, the antihypertensive drug regimens of the patients did not change. Patients with a history of heart failure or evident heart disease were excluded and none of the study subjects had a history of atherosclerotic cardiovascular disease or stroke. Patient blood pressure was measured at an outpatient clinic every one to two months during the study year. At the end of the observation period, blood samples were taken in the morning after an 8-h overnight fast. Total cholesterol, triglycerides, high-density lipoprotein cholesterol, blood urea nitrogen, creatinine, uric acid, hemoglobin, C-reactive protein and glycosylated hemoglobin were measured using standard laboratory techniques. Patients with renal dysfunction whose creatinine levels were ≥1.4 mg/dl were excluded from the present study. The association between plasma BNP levels and various clinical parameters, including blood pressure and laboratory data, were analyzed. This protocol was approved by the Ethics Committee of Kagawa University . Informed consent was obtained from all participants.Patient SBP was measured in the morning at an outpatient clinic. Patients were not instructed as to whether to take their hypertension medication prior to or subsequent to the clinical visit. Upon arrival at the outpatient clinic, patients rested for ≥1 min and SBP was then measured. SBP was measured once, while the patient was seated, by a physician who was trained in using the automated oscillometric sphygmomanometer  and blinded to patient blood examination data. The SD and the coefficient of variation (CV) of the SBP values obtained over the one-year observation period were calculated in order to assess SBP variability. The mean SBP values over the year were also calculated to assess average blood pressure control.Plasma BNP levels were measured at the end of the observation period. In brief, samples were taken by a laboratory using an MI02 Shionogi BNP instrument . Each blood sample was collected in an EDTA-2Na-treated blood sampling tube and then centrifuged at a low temperature to separate the plasma for the assay.Data are expressed as the mean ± SD. Statistical analyses were performed using SPSS software, version 18.0 . For the comparison of monthly mean values of SBP obtained from the patients over the study period, one-way analysis of variance (ANOVA) was used. Linear regression analysis was performed to analyze the association between plasma BNP levels, blood pressure and other variables. Step-wise multiple regression analysis was performed to identify which blood pressure parameters were independently associated with plasma BNP levels. A value of P<0.05 was considered to indicate statistical significance.The clinical parameters of the study subjects are summarized in The variation in SBP over the one-year observation period in all subjects is shown in Linear regression analysis was performed to assess the correlation between parameters of SBP variability, mean SBP and plasma BNP levels at the end of the one-year observation period . Only meThe present study compared SBP variability and mean SBP over a one-year observation period in order to identify the association between these variables and plasma BNP levels in patients with hypertension. The highest levels of SBP were observed during December and March, whereas the lowest levels were observed during September. These findings suggest the following: i) SBP variability during the one-year period was not correlated with the plasma BNP levels detected at the end of the observation period; ii) mean SBP during the one-year period was correlated with the plasma BNP levels detected at the end of the observation period and iii) only the mean values of SBP were independently associated with plasma BNP levels.Seasonal variation in blood pressure is a well-established phenomenon –15, withThe present study aimed to investigate the association between cardiac damage and SBP variability and mean SBP through detecting plasma BNP levels. BNP was found to be correlated with the mean values of SBP, but not with parameters of SBP variability in treated patients with hypertension. These findings indicate that mean values of SBP rather than SBP variability may be a marker of cardiac damage in treated patients with hypertension. Visit-to-visit variability in SBP (SD of SBP) has been demonstrated to be a strong predictor of stroke, independent of mean SBP ,19. TherThe specific mechanism through which plasma BNP levels were found to be associated with mean SBP levels, but not SBP variability, is yet to be elucidated. BNP is a hormone secreted by ventricular cardiomyocytes in response to pressure overload of the left ventricle . IncreasIn conclusion, plasma BNP levels showed stronger correlation with mean values of SBP than with parameters of SBP variability during a one-year observation period. Therefore, the plasma BNP levels taken at the end of the study year may reflect average SBP control, but not the SBP variability during the study year in patients with hypertension.


Recent clinical studies have shown a relationship between abnormalities in peripheral perfusion and unfavorable outcome in patients with circulatory shock. Nitroglycerin is effective in restoring alterations in microcirculatory blood flow. The aim of this study was to investigate whether nitroglycerin could correct the parameters of abnormal peripheral circulation in resuscitated circulatory shock patients.2) during a reactive hyperemia test (RincStO2). Measurements were performed before, at the maximum dose, and after cessation of nitroglycerin infusion. Data were analyzed by using linear model for repeated measurements and are presented as mean (standard error).This interventional study recruited patients who had circulatory shock and who persisted with abnormal peripheral perfusion despite normalization of global hemodynamic parameters. Nitroglycerin started at 2 mg/hour and doubled stepwise  each 15 minutes until an improvement in peripheral perfusion was observed. Peripheral circulation parameters included capillary refill time (CRT), skin-temperature gradient (Tskin-diff), perfusion index (PI), and tissue oxygen saturation (StOP <0.05), from 3.3°C (0.7°C) to 0.7°C (0.6°C) (P <0.05), and from [log] -0.5% (0.2%) to 0.7% (0.1%) (P <0.05), respectively. Similar changes in StO2 and RincStO2 were observed: from 75% (3.4%) to 84% (2.7%) (P <0.05) and 1.9%/second (0.08%/second) to 2.8%/second (0.05%/second) (P <0.05), respectively. The magnitude of changes in StO2 was more pronounced for StO2 of less than 75%: 11% versus 4%, respectively (P <0.05).Of the 15 patients included, four patients (27%) responded with an initial nitroglycerin dose of 2 mg/hour. In all patients, nitroglycerin infusion resulted in significant changes in CRT, Tskin-diff, and PI toward normal at the maximum dose of nitroglycerin: from 9.4 (0.6) seconds to 4.8 (0.3) seconds (Dose-dependent infusion of nitroglycerin reverted abnormal peripheral perfusion and poor tissue oxygenation in patients following circulatory shock resuscitation. Individual requirements of nitroglycerin dose to improve peripheral circulation vary between patients. A simple and fast physical examination of peripheral circulation at the bedside can be used to titrate nitroglycerin infusion. In the early 1960s, the use of vasodilators in shock started with the interest in flow more than in pressure ,3. It toA real-time evaluation of peripheral microcirculatory disorders would provide bedside assessment for timely application of nitroglycerin targeting improvement in microcirculatory perfusion. In addition, recent observations have demonstrated a significant association between the persistence of abnormalities in peripheral circulation, measured in skin, muscle, or sublingual mucosa, with more severe organ dysfunction and worse prognosis when compared with traditional global variables of resuscitation -21. Alth2) [Monitoring of peripheral perfusion can be performed by using simple clinical assessment, in particular, the physical examination by touching the skin or measuring capillary refill time (CRT), body temperature gradient, and optical devices, such as pulse oximeter signal and tissue oxygen saturation (StO2) . We quesThis was an intervention study within the intensive care unit (ICU) of a university hospital. The local accredited Medical Research Ethical Committee from Erasmus MC Hospital approved the study. Written informed consent was obtained from all patients, their next of kin, or a surrogate decision maker, as appropriate. All consecutive patients admitted in the ICU for circulatory shock resuscitation were eligible for inclusion. Circulatory shock was defined as hypotension , despite adequate fluid resuscitation or the requirement for continuous norepinephrine infusion, and the presence of metabolic acidosis  in association with increased lactate levels (>2 mmol/L). Patients were eligible for inclusion if, after 6 hours of ICU admission and continuous resuscitation and stabilization, abnormal peripheral perfusion was still present despite normalization of global hemodynamic parameters. Accordingly, all patients included shared abnormalities in peripheral perfusion as baseline characteristics. Exclusion criteria were arm injury or ischemia from trauma , liver failure, and any neurological insult that could lead to increased intracranial pressure .All patients were monitored with a radial artery catheter for continuous arterial pressure monitoring. Global hemodynamic variables included heart rate, central venous pressure, and mean arterial pressure. All measurements were obtained by using standard equipment. Cardiac output was obtained if the patient was monitored with continuous pulse contour cardiac analysis .2-derived tissue oxygenation measurements to investigate the dynamic changes between tissue oxygenation and condition of peripheral perfusion. StO2-derived tissue oxygenation was monitored continuously by using an InSpectra Tissue Spectrometer Model 650  with a 15-mm probe over the thenar eminence. A vascular occlusion test was performed by arrest of forearm blood flow by using a conventional sphygmomanometer pneumatic cuff. The cuff was placed around the upper arm and was inflated to a pressure approximately 30 mm Hg greater than patient systolic pressure for 3 minutes. Upon completion of the ischemic period, the occluding cuff was rapidly deflated to 0 mm Hg. The derived StO2 parameters were divided into three components: resting StO2 values, rate of StO2 desaturation , and rate of StO2 recovery .Peripheral circulation parameters included physical examination of peripheral perfusion with CRT, forearm-to-fingertip skin-temperature gradient (Tskin-diff), and peripheral perfusion index (PI) from pulse oximeter signal. CRT was measured by applying firm pressure to the distal phalanx of the index finger for 15 seconds. A chronometer recorded the time for the return of normal color, and 5 seconds was defined as the upper limit of normality . Tskin-dPatients were considered to have abnormal peripheral circulation if the examined extremities (both hands) had an increase in CRT of greater than 5 seconds or indicated the presence of peripheral vasoconstriction . The ICU has single-patient closed rooms, and the ambient temperature in each room was individually and actively set at 22°C.To avoid significant hypotension during nitroglycerin infusion, each patient was evaluated for adequate intravascular volume as evidenced by repeated volume challenges  up to a point at which central venous pressure raised by more than 2 mm Hg or stroke volume did not increase more than 10%. After documentation of central venous pressure or stroke volume changes, a set of measurements was obtained during a control period. After baseline measurements, nitroglycerin was given as a bolus equal to the volume of the used infusion line followed by a continuous intravenous infusion initiated at 2 mg/hour (33.3 μg/minute). When peripheral circulation did not normalize within 15 minutes after the start of the nitroglycerin infusion, repeated measurements of hemodynamic and peripheral perfusion parameters were recorded and the dose was doubled. This was repeated until peripheral perfusion was normalized or a dose of 16 mg/hour was reached . During the study, infusion rates of noradrenaline or other vasoactive drugs were not changed and no additional fluids were administered.BL1 (baseline before nitroglycerin infusion), TMX (at the maximum dose of nitroglycerin), and TBL2 (30 minutes after cessation of nitroglycerin infusion). We used a Kolmogorov-Smirnov test and stratified distribution plots to verify the normality of distribution of continuous variables. Not normally distributed data underwent log transformation to achieve close to normal distribution and then qualified for longitudinal testing. We used linear model for repeated measurements (time points as independent factor) to investigate changes in the average of hemodynamic and peripheral perfusion parameters (dependent variables). The analyses of linear model are reported as mean response (standard error). Differences between groups’ means were tested by Mann-Whitney U test. A multiple regression analysis was applied to estimate the effect of nitroglycerin dose (independent variable) on parameters of peripheral perfusion (dependent variables) so that we could predict changes in CRT, Tskin-diff, peripheral PI, and StO2 for a given nitroglycerin dose. SPSS  was used for statistical analysis. A P value of less than 0.05 was considered statistically significant.Unless otherwise specified, descriptive analyses are reported as median (25th-75th). Time points of the study were defined as TMX). Cardiac index and stroke volume were measured in six patients; although both parameters showed a slight decrease, no significant differences were observed during nitroglycerin infusion.Of the 15 patients included in the study, 12 had septic shock and three had non-septic shock. Patients’ demographic data are summarized in Table 2 nor RdecStO2 is reported for these patients. Improvement in peripheral perfusion was reached in all patients. All 15 patients responded with more than 50% of CRT and PI of greater than 1.4% at the maximum dose of nitroglycerin, and nine patients responded additionally with Tskin-diff of less than -2. Twelve patients required a low dose of nitroglycerin (of less than 8 mg/hour) to normalize the peripheral perfusion parameters. We did not find differences in CRT, PI, and Tskin-diff at baseline between patients requiring low doses and patients requiring high doses. Therefore, all patients included shared abnormalities in peripheral perfusion before nitroglycerin infusion. Figure BL1, TMX, and TBL2. Nitroglycerin infusion resulted in significant changes in CRT, Tskin-diff, and peripheral PI toward normal compared with baseline values: 51% (50% to 44%), 85% (30% to 112%), and 178% (105% to 295%), respectively. Similarly, we observed a significant increase in StO2 and RincStO2 values but not in RdecStO2 at TMX. All parameters returned to baseline values after cessation of nitroglycerin infusion.Baseline parameters of peripheral perfusion and the effects of nitroglycerin on these parameters are shown in Table 2 for a given nitroglycerin dose. The effect of changes in nitroglycerin dose had a significant effect on CRT, Tskin-diff, and peripheral PI but not on StO2. When StO2 baseline values before nitroglycerin infusion were taken into account, the effect of changes in nitroglycerin dose becomes clearly significant. The magnitude of changes in StO2 was more prominent at lower StO2 values  versus 7% (4.7% to 10.5%) (P <0.05).Table We have demonstrated that intravenous infusion of nitroglycerin improves peripheral perfusion and oxygenation in shock patients with persisting abnormal peripheral circulation following initial resuscitation to global hemodynamic endpoints. Although nitroglycerin is generally used for its cardio-circulatory effects, its precise application in septic or non-septic circulatory shock continues to be debated and investigated. The use of vasodilators in shock was introduced into the clinic in the early 1960s as an additional therapeutic option for circulatory shock with or without cardiac dysfunction to counteract peripheral vasoconstriction ,28. HoweThe persistent abnormalities in peripheral circulation have been shown to predict a poor outcome in critically ill patients in terms of mortality and multiple organ dysfunction ,18,20,33Nitroglycerin has some attributes that favor its use to recruit the microcirculation in critically ill patients. First, nitroglycerin has a quick onset of action (2 to 5 minutes) with a half-life elimination of 1 to 3 minutes. Second, nitroglycerin has specific hemodynamic effects in the venous capacitance vessels resulting in pressure gradient increase in the microvasculature and thus in microvascular blood flow. In this study, improvements in the clinical parameters of peripheral circulation were obtained in all patients. CRT improved in parallel with changes in Tskin-diff and peripheral PI, suggesting that the improvement in cutaneous circulation was likely the result of an increase in cutaneous blood flow. As the major role of cutaneous circulation is thermoregulation, blood flow to the skin typically exceeds metabolic requirements. Therefore, the high blood flow relative to its oxygen demand makes the skin an appropriate organ to detect variations in peripheral blood flow.2 was more pronounced in patients who had lower StO2 values (less than 75%). This finding may be explained by the shift of blood volume from arterial to venous compartment because of predominant venous dilation with a subsequent increase in the oxyhemoglobin levels within the volume of the vascular bed in the catchment area of the near infrared spectroscopy (NIRS) probe. Significant gain in StO2 is, therefore, observed in conditions in which the functional microcirculatory reserve is poor, such as those seen in abnormal peripheral circulation. In these conditions, a low initial StO2 value yields a greater percentage change. Alternatively, we found parallel changes in StO2 reoxygenation rate but not in the StO2 deoxygenation rate. Unlike the StO2 deoxygenation rate during arterial occlusion in which venous outflow and arterial inflow are blocked, StO2 recovery after the vascular occlusion reflects the sudden increase of arterial inflow during the hyperemic response. Infusing a vasodilator will result in a larger flow-mediated dilation following reactive hyperemia and therefore in a higher rate of reoxygenation. This pattern of changes in tissue oxygenation parameters is consistent with previous reports, including some of our own group, showing that StO2-derived parameters are influenced by peripheral vasoregulation [2 deoxygenation rate in our patients, any increase in flow would result in an increase in microcirculatory hemoglobin saturation levels. Thereby, the noticeable changes in StO2 and StO2 recovery rate in our patients provide evidence that nitroglycerin markedly improves tissue oxygenation.Another interesting finding in our study was that nitroglycerin infusion led to a significant improvement in peripheral tissue oxygenation. In addition, the magnitude of changes in StOgulation -40. GiveAlthough this study makes novel observations, a limitation to our study is the small number of patients. Despite this sample size, our patients shared the same baseline common abnormality in peripheral perfusion, and our study was designed to allow every patient to serve as his or her own control, thereby minimizing bias. Hence, the evident significant improvement and worsening in the clinical parameters of peripheral circulation in all patients during and after nitroglycerin infusion strengthen our findings. Another important point to mention is that the effect of nitroglycerin on skin and muscle perfusion as measured in our patients cannot be extrapolated to other organs, such as gastrointestinal tract, liver, or kidneys. However, the accumulating evidence from the literature supports the efficacy of vasodilator therapy in improving microcirculatory perfusion in these different vascular beds. We speculate, therefore, that nitroglycerin infusion in our patients had the same beneficial effect as seen in the peripheral tissues. Finally, our study supports the hypothesis that nitroglycerin dose should be individualized and shows that non-invasive and rapidly available measures of peripheral circulation at the bedside are available to predict its response and monitor the effect to reach an effective dose Table . HoweverWe demonstrated with this study that stepwise dose of intravenous infusion of nitroglycerin reverses clinical abnormalities of peripheral circulation in patients with circulatory shock. In addition, we showed that the easy and reliable clinical parameters of peripheral perfusion can be an effective monitoring approach at the bedside to titrate the beneficial effects of nitroglycerin on peripheral circulation in individual patients with circulatory shock following initial resuscitation.• Stepwise dose of intravenous infusion of nitroglycerin reverses clinical abnormalities of peripheral circulation in patients with circulatory shock.• Nitroglycerin infusion response in some patients was observed with the dose higher than the conventional dose of 2 mg/hour.• The easy and reliable clinical parameters of peripheral perfusion can be an effective monitoring approach at the bedside to titrate the beneficial effects of nitroglycerin on microcirculation in individual patients with circulatory shock following initial resuscitation.2: rate of tissue oxygen saturation deoxygenation during arterial occlusion; RincStO2: rate of tissue oxygen saturation increase after arterial occlusion; StO2: tissue oxygen saturation; TBL1: time point at baseline before nitroglycerin infusion; TBL2: time point at 30 minutes after cessation of nitroglycerin infusion; TMX: time point at the maximum dose of nitroglycerin; Tskin-diff: forearm-to-fingertip skin-temperature gradient.CRT: capillary refill time; ICU: intensive care unit; PI: perfusion index; RdecStOThe authors declare that they have no competing interests.AL was involved with the conception and design of the work; acquisition, analysis, and interpretation of data; and drafting and revising the work critically for important intellectual content. JB was involved with the conception and design of the work; analysis and interpretation of data; and revising the work for important intellectual content. MEvG carried out the experiments and the data acquisition. EK and TJ helped to carry out the experiments. JvB participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.


Hypertension, a risk factor for cardiovascular disease (CVD), is frequently associated with other CVD risk factors. Despite recent improvement in blood pressure (BP) control in Europe, a substantial proportion of patients fail to achieve BP targets.This retrospective cohort study used longitudinal patient databases (LPDs) in France and Italy to examine CVD risk profiles, treatment patterns, and BP goal attainment in hypertensive patients treated in real-world clinical practice between 2007 and 2008. Overall, 147,964 and 140,189 eligible patients from LPDs in France and Italy, respectively, were prescribed an antihypertensive medication in 2007.p < 0.001) higher in patients with hypertension without other risk factors vs patients with hypertension with other risk factors . The odds of BP control were significantly lower for patients with vs patients without an associated CVD risk factor .Among patients with hypertension with other risk factors , the most prevalent risk factors were being elderly , followed by hypertension combined with dyslipidemia  and isolated systolic hypertension . The odds ratios for target BP attainment were significantly  contains supplementary material, which is available to authorized users. The majority of hypertensive patients have concomitant cardiovascular disease (CVD) risk factors , 2, and Despite overall improvement in blood pressure treatment and control over the past decades in Europe and the USA , 10, a sTo help better understand the remaining unmet needs in blood pressure treatment, we examined CVD risk profiles, treatment patterns, and blood pressure goal attainment in hypertensive patients treated in actual clinical practices in France and Italy. The specific study objectives were (1) to identify demographic characteristics and CVD risk profiles of adult hypertensive patients, (2) to examine and document antihypertension treatment patterns in segments of patient populations with and without hypertension with other risk factors, and (3) to assess blood pressure goal attainment rates in these patient segments.This was a retrospective, observational, longitudinal, single-cohort database study conducted in primary health care practices in France and Italy. The study period was 1 January 2005 to 31 December 2008.Primary care data were extracted from Cegedim Strategic Data’s (CSD’s) proprietary, longitudinal patient databases (LPDs) in Italy and France. CSD’s LPDs hold anonymized electronic patient records collected from 700 participating general practices (GPs) in Italy who use the Millewin patient management software. CSD’s LPD in France holds similar data from 1200 participating GPs who use the Doc’Ware patient management software. The panels of volunteering participants are selected to be nationally representative according to geographical area, age, and gender. CSD’s LPDs contain patient-level prescriptions, diagnoses, demographics, and other medical data entered at the time of consultation by participating GPs and include routinely collected electronic health records for more than 800,000 patients in Italy and 1,600,000 patients in France. Information on diagnoses is encoded at the time of information collection, the codes being mapped on the tenth revision of the International Classification of Disease (ICD-10). Prescription data contain the dispensed drug name, the Anatomical Therapeutic Chemical (ATC) classification category, dose regimen, and prescription duration.The study population was defined as those aged 18 years or older at index date who fulfilled the following criteria during the index period , and serum creatinine). Index medication was defined as the last prescription of antihypertensive medication(s) prior to or on the index date. Medical history data were extracted during the baseline period according to ICD-10 classification. These data were used to stratify the study population into non-mutually exclusive patient groups based on specific CVD risk profiles  were also collected during the follow-up period and were stratified into monotherapies, fixed-dose combination medications, and free-dose combination therapies. The following medications were defined as categories of monotherapy: centrally acting agents, diuretics, beta blockers, calcium-channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs), or angiotensin II receptor blockers (ARBs). Fixed-dose combination medications were defined as diuretic + beta blocker, beta blocker + CCB, ACEI + diuretic, ACEI + CCB, ARB + diuretic, or ARB + CCB. Free-dose combinations were those combination therapies that were not fixed-dose.The study population was stratified into two treatment groups: treatment-naive and previously treated. The treatment-naive patient group had no antihypertensive medication prescribed during the baseline period, and the index prescription was regarded as the first-line therapy. Those in the previously treated group were prescribed at least one antihypertensive medication during the baseline period.p values were less than 0.05. A stepwise multivariate logistic regression was performed to keep only the variables significant at the 0.05 level, and adjusted ORs with 95 % CI were then calculated.Descriptive statistics were employed using SAS 9.2 software to assess patient characteristics, clinical profile, treatment pattern, and blood pressure control. No sample size calculation was necessary; data collection was exhaustive given the defined criteria. Categorical data were summarized by sample size and/or percentage (compared to the size of completed data). Mean, median, standard deviation, and range were reported for continuous variables. Univariate binary logistic regressions were performed to predict the achievement of blood pressure goal with selected predictors or covariates in the survey. Estimated odds ratios (OR) were presented with 95 % confidence intervals in order to assess the relationship between the achievement of blood pressure goal and the presence of the factor, one by one. Next, 11 predictor variables were selected for France and 8 predictor variables for Italy in the multivariate model when The last blood pressure measurement within the follow-up period was used to identify the blood pressure control rates based on levels defined in the 2007 ESH/ESC treatment guidelines in each defined patient segment  in France; 1.38  in Italy). The odds of BP control were significantly lower for patients with vs patients without an associated CVD risk factor .Based on the univariate logistic regression analysis, the odds ratios for target BP attainment were significantly , prescrDue to the period of study, the renin inhibitor drug class was not considered in this study and, consequently, no assessment can be made with regard to this drug class. Furthermore, these study results are subject to the quality and availability of the EMR data collected by the participating physicians. Only one BP measurement closest to the end of the follow-up period was used, which may have created some challenges in determining BP control. However, most patients would have been treated for an extended period of time at the end of follow-up, and BP control should have been established. An additional limitation of this study was that a relatively imbalanced proportion of patients were lost to follow-up in the two populations , and it is difficult to tell if the data were randomly or systematically lost. However, this is a reflection of the real-world environment in which the study was conducted and indicates a greater need for adherence to guidelines, better quality of control and recording of patient data regardless of outcome, and greater follow-up with patients. Given the limitations of the clinical settings where these data were collected, generalization of these findings to the wider population should be made with caution.This study confirms that the majority of treated hypertensive patients in France and Italy have at least one associated additional CVD risk factor. Despite many treatment options available, attainment of blood pressure targets was substantially less optimal in patients with at least one associated CVD risk factor compared with patients without any associated CVD risk factors. The findings from this study can be used by health care providers to help identify gaps in quality of care for patients being treated for hypertension and to review appropriate interventions and follow-up patterns.


Transcatheter embolisation is widely used to close pulmonary arteriovenous malformations (PAVMs) in patients with hereditary haemorrhagic telangiectasia (HHT). Data on the direct cardiovascular haemodynamic changes induced by this treatment are scarce.We investigated the direct haemodynamic effects of transcatheter embolisation of PAVMs, using non-invasive finger pressure measurements.t-test.During the procedure, blood pressure, heart rate (HR), stroke volume (SV), cardiac output (CO), total peripheral resistance (TPR) and delta pressure/delta time (dP/dt) were continuously monitored using a Finometer®. Potential changes in these haemodynamic parameters were calculated from the pressure registrations using Modelflow® methodology. Absolute and relative changes were calculated and compared using the paired sample p = 0.01) and −9.5 % (p = 0.01) respectively, without a significant change in HR (1.8 %). Mean arterial blood pressure increased by 4.1 % (p = 0.02), while the TPR and dP/dt did not increase significantly .The present study includes 29 HHT patients  who underwent transcatheter embolotherapy of PAVMs. The total number of embolisations was 72 (mean per patient 2.5). Directly after PAVM closure, SV and CO decreased significantly by −11.9 % (Significant haemodynamic changes occur directly after transcatheter embolisation of PAVMs, amongst which a decrease in stroke volume and cardiac output are most important. Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant inherited disease characterised by vascular malformations, ranging from small telangiectases in skin and mucosal membranes to large visceral arteriovenous malformations (AVMs) predominantly localised in the lungs, brain and liver –3. PulmoBetween 2008 and 2010, we included 29 patients who underwent transcatheter embolisation of PAVMs in the St. Antonius Hospital Nieuwegein, which is a national HHT referral centre in the Netherlands. All patients provided informed consent.A PAVM was defined as a direct communication between a pulmonary artery and a pulmonary vein, bypassing the pulmonary capillary filter , and wasDuring the transcatheter embolisation of PAVMs, arterial pressure was measured on a finger of the left hand using a Finometer® device . The Finometer® measures blood pressure by a combination of the volume clamp method of Penaz and the ‘Physiocal’ criteria developed by Wesseling –10. The During the PAVM embolisation, finger pressure measurements with the associated event marks were monitored and digitally stored. Review of these data was performed using BeatScope® software. Five minute averages of systolic (SBP), diastolic (DBP) and mean blood pressure (MBP), heart rate (HR), stroke volume (SV), cardiac output (CO), total peripheral resistance (TPR) and delta pressure/delta time (dP/dt) were calculated after an electronic calibration procedure. SV and CO (CO is the product of SV and HR) were calculated from the finger pressure wave using the Modelflow® methodology . The carReturn-to-flow calibration, using the arm cuff, was used for calibration of the blood pressure. There was no calibration with invasive determinations for the CO, SV and TPR. Both absolute values and absolute and relative changes (delta absolute and delta percent) are presented.t-tests. A significance level of p < 0.05 was considered significant.The statistics were performed using SPSS version 17.0 for Windows . Descriptive statistics were used to describe patient characteristics. Continuous variables with normal distribution were presented as mean ± SD. Differences within groups were analysed performing paired samples A total of 29 HHT patients  were included, in which 72 PAVMs were embolised (mean per patient 2.5). An Amplatzer® plug was used in 54 cases and a detachable coil in the remaining 18 cases. The baseline characteristics are presented in Tables p = 0.01) and −0.4 ± 0.8 l/min . As expected, the CI decreased as well . DBP and MBP increased significantly by 5.2 ± 10.3 mmHg  for DBP and 5.7 ± 12.1 mmHg  for MBP, respectively. There was no significant change in SBP . The dP/dt did not change significantly: 2.1 ± 290.0 mmHg/s . There was a correlation between the delta dP/dt and the SBP . HR and TPR increased, but this appeared to be non-significant: 1.6 ± 7.4 beats/min  and 0.1 ± 0.5 Woods units . These data are summarised in Table Directly after PAVM embolisation the SV and CO decreased significantly: −6.4 ± 13.0 ml  . This se2). The amount of microscopic PAVMs under the detection limit of chest CT may further influence the shunt percentage and different haemodynamic responses in HHT patients.The haemodynamic responses after PAVM embolisation may differ between HHT patients, which can be related to difference in number and size of PAVMs at baseline . In the r = 0.6  was reported for the correlation between the delta blood pressure and the delta dP/dt [r = 0.73, r2 = 0.53, p < 0.0001) and demonstrates that the dP/dt is responsible for more than 50 % of variance in the blood pressure. Because of the significant increase in MBP and decrease in CO, we also expected a significant increase in TPR. A possible explanation might be an increase in central venous pressure due to the embolisation. Unfortunately, no measurements of the right atrium pressure were performed during the embolisation procedure.Due to the decrease in pulmonary right-to-left shunt from 14 to 5 % after PAVM embolisation, a consequent decrease in preload and SV can be expected (mean change −12 % in the current study). As there was no change in HR, the CO decreased as well (−9.5 %). The MBP increased by 4 % after PAVM embolisation, which is probably due to the non-significant increase in TPR (6 %), as the MBP is a product of TPR and CO. As blood pressure is inversely related to indoor temperature , the falta dP/dt . This isA potential clinical implication of our findings might be associated with the presence of pulmonary hypertension (PH) in HHT , 19. PH First, our study is limited by its small sample, which may have influenced the results. Second, the Modelflow® model does not seem to be accurate in measuring absolute values of SV, CO and TPR. The differences between the uncalibrated model and invasive determinations (measured with the thermodilution method) in individual patients are usually small, but can be substantial and unreliable in some , 20. HowThe present study shows that significant haemodynamic changes occur directly after embolisation of pulmonary arteriovenous malformations, amongst which a decrease in stroke volume and cardiac output are most important. This may especially provide additional insights into the haemodynamic responses after PAVM embolisation in HHT patients prone to PH.


Background: The existence of membranous cytoplasmic bodies in biopsied kidney tissues is one of the important findings when considering Fabry disease as the first choice diagnosis. However, there are possible acquired lysosomal diseases associated with pharmacological toxicity, although less attention has been paid to them.Case Presentation: We experienced 3 male patients presenting with proteinuria and specific pathological changes strongly suggesting Fabry disease. We sought detailed clinical and biochemical information to avoid a wrong diagnosis. The patients were examined clinically and pathologically, and plasma α-galactosidase A (GLA) activity and the globotriaosylsphingosine (lyso-Gb3) concentrations were measured. Electron microscopic examination revealed numerous membranous inclusion bodies in podocytes, and biochemical analysis revealed normal GLA activity and a normal lyso-Gb3 level in plasma, showing that they did not have Fabry disease. They suffered from hyperlipidemia, myeloma, or lupus nephritis. They had received pitavastatin calcium, clarithromycin, loxoprofen and/or prednisolone, and there was no medication history of cationic amphiphilic drugs.Conclusions: In this case series, the etiology of the inclusions was not clarified. However, these cases indicate that careful attention should be paid on diagnosis of patients exhibiting inclusion bodies in kidney cells, and it is important to confirm their past and present illnesses, and medication history as well as to measure the GLA activity and lyso-Gb3 level. Three male patients are described in this case series, presenting with proteinuria and membranous cytoplasmic bodies (MCBs) in podocytes in kidney biopsies. MCBs in kidney cells are known to be the most important pathological finding for Fabry disease. But the results of assaying of α-galactosidase A (GLA) activity and measurement of the globotriaosylsphingosine concentration in plasma revealed that our patients did not have Fabry disease. Although the etiology of the MCBs has not been clarified yet, we should pay attention on diagnosis in cases exhibiting MCBs in kidney cells, and biochemical confirmation is necessary to avoid a pitfall in diagnosis of Fabry disease. Fabry disease MIM 301500) is an X-linked genetic sphingolipidosis caused by a deficiency of α-galactosidase A  500 is an. AlthougHowever, less attention has been paid to the concept that there may be acquired lysosomal storage diseases presenting with inclusion bodies, ie, drug-induced lysosomal disease . CationiA summary of the patients examined in this study  is presented in GLA activity in plasma was measured fluorometrically with 4-methylumbelliferyl α-D-galactopyranoside  as a substrate in the presence of N-acetyl-D-galactosamine  to specifically inhibit N-acetylgalactosaminidase in samples, as described previously . Plasma The research followed the tenets of the Declaration of Helsinki. Written informed consent for kidney biopsies followed by analysis for diagnosis were obtained from all the patients, although those for genetic analysis could not be obtained. The biochemical studies involving human samples were approved by the Ethics Committee of Meiji Pharmaceutical University.To determine the normal range of plasma GLA activity, the mean value and the standard deviation (SD) were calculated using Excel 2013  on the basis of data from 30 healthy subjects, and it was determined to be mean±2SD. The GLA activity levels of the patients were examined whether they were out of the normal range or not.A 48-year-old male. When he was 10 years old, he presented with proteinuria and was diagnosed as having nephritis. In childhood, he suffered from left hemiplegia of unknown etiology. At 45 years, he developed arrhythmia and electrocardiographic examination revealed a complete right bundle branch block. At 47 years, hyperlipidemia, proteinuria, and microhematuria were found. His serum creatinine, total protein, and albumin levels were normal. He was treated with pitavastatin calcium and prednisolone, and underwent kidney biopsies. A light microscopic examination revealed segmental glomerular sclerosis and moderately increased mesangial cells. No apparent vacuolation was found in the kidney cells. Electron microscopic examination revealed numerous lamellar inclusion bodies in podocytes. But they were not detected in other kidney cells.A 72-year-old male. There was a past history of pancytopenia, proteinuria, and prostatic cancer. At age 68, due to recurrent fever, he was treated with clarithromycin and loxoprofen. Thereafter his renal function rapidly decreased over 2 months and the first renal biopsy was performed. Pathological examination revealed minor glomerular abnormalities, suggesting interstitial nephritis. Although urinary Bence-Jones protein (kappa) and monoclonal protein (IgG-kappa) were detected in this patient, drug-induced interstitial nephritis was also suspected because the drug lymphocyte stimulation tests were positive for both clarithromycin and loxoprofen. Bone marrow aspiration did not reveal any increase in plasma cells. He was treated with prednisolone and his renal functions improved. However, thereafter his proteinuria got worse and the serum creatinine level increased again, and a second renal biopsy was performed. Light microscopic examination revealed cytoplasmic vacuoles in podocytes but not in other kidney cells. No increase in mesangial cells and development of mesangium was found. There was no glomerulosclerotic change, although mild lymphocyte infiltration was found. Electron microscopic examination revealed numerous myeloid bodies in podocytes but not in other kidney cells.A 33-year-old male. At age 19 years, he suffered from idiopathic thrombocytopenic purpura and thus was treated with prednisolone. At age 23 years, he developed osteonecrosis of the femoral head and thus artificial joint replacement was performed. Due to persistent pain, he has taken loxoprofen until present. When he was 32 years old, proteinuria was found and a renal biopsy was performed. Antinuclear, anti-double stranded DNA, and anti-single stranded DNA antibodies were all positive. The serum C3 and C4 levels, and serum complement activity (CH50) were all within normal range. From the data, he was thought to have lupus nephritis. A renal biopsy was conducted, and light microscopic examination revealed moderate glomerulosclerosis and increased mesangial cells. Electron microscopic examination revealed numerous myeloid bodies in podocytes but not in other kidney cells. Immunofluorescence microscopy disclosed strong staining for IgG (subclass: IgG1>IgG4) and C3, and moderate staining for IgA and C1q in the area of the basement membrane and mesangium.From the pathological findings for renal biopsies , the patThe plasma lyso-Gb3 level, which is known to be a good biomarker of Fabry disease, was also measured. The results revealed that their lyso-Gb3 levels were within normal levels (<2 nmol/L) , which sSince high-risk screening studies have revealed many Fabry patients exhibiting manifestations of CKD -31, and As regards to cases 1 to 3, there is no history of cationic amphiphilic drugs  having been prescribed for them. Unfortunately, samples for analyzing the substrates accumulated in lysosomes were not available, and the etiology of the inclusion bodies in these cases has not been elucidated yet. Cases 1, 2, and 3 suffered from hyperlipidemia, myeloma, and lupus nephritis, respectively, and case 1 had a medication history of pitavastatin calcium and prednisolone, case 2 also took clarithromycin, loxoprofen and prednisolone, and case 3 took loxoprofen and prednisolone too. There has been a report that electron dense deposits were found in the subintimal area of an arteriole in a patient with lupus nephritis . We coulIn summary, the existence of inclusion bodies is an important sign when considering Fabry disease but great care should be taken not to make the wrong diagnosis, and it is important to examine the past and present illnesses, and the medication history, as well as to measure the GLA activity and lyso-Gb3 level.There are limitations to this study. We could not elucidate the cause of the intracellular inclusion bodies found in the biopsied kidney tissues from the patients. It will be necessary to biochemically analyze the substrates accumulated in kidney tissues when such cases are found in the future. Identification of the accumulated substrates will provide us with a lot of information to solve the problem.HS designed and managed the research, and wrote the paper. TaTs, ToTa, and TaTo performed the biochemical analysis, and NT, DM, SW and YA performed the clinical analysis of the 3 male patients examined here and the Fabry patient.The authors declare no conflict of interests.This work was supported by the Program for the Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation ; and the Program for Research on Intractable Disease of Health and Labor Science Research (HS).


The recently suggested distinct pathogenic pathways for myeloperoxidase (MPO) and proteinase 3 (PR3) anti-neutrophilic cytoplasmic antibodies (ANCA) associated vasculitis could result in different modes of presentation and outcome. Moreover, kidney outcome was related to a new histopathologic classification of pauci-immune glomerulonephritis. As reports were not always concordant, possible because differences in severity of organ lesions and ethnicity, we evaluated the outcome of a cohort of Central-East European patients with crescentic glomerulonephritis in relation with ANCA specificity and histopathological classification.Seventy-five patients were consecutively diagnosed by kidney biopsy  and followed for a median period of 3.2 years. Study end-points were response to therapy, end stage renal disease (ESRD) and death.p = 0.006) times higher than in those who did not. The rate of response to therapy (without signs of active vasculitis and stable or declining serum creatinine) was 60 % and was associated with dialysis independency, older age and higher platelet number at presentation. The probabilities to survival 1 and 5 years for kidney and patient were 93 and 64 %, and respectively 88 and 67 %. Kidney survival was predicted by response to therapy and dialysis independency at presentation. Patients with BVAS < 15 and responding to induction therapy had better chances of survival. Neither response to therapy nor outcome was influenced by ANCA specificity or by the histopathological class.PR3-ANCA patients were younger, in higher proportion male and had higher Birmingham Vasculitis Activity Scores (BVAS). The kidney disease was severe at presentation  and worst in PR3-ANCA positive patients . The lung was the second most affected organ (31 % severe lung hemorrhage). Lung and kidney damage were related; the odds of hemorrhagic alveolitis in patients needing dialysis at presentation were 4 (95 % CI 1–13; When kidney damage is severe in ANCA vasculitis, the need of dialysis at presentation and the response to induction therapy overcome the prognostic utility of both ANCA specificity and histopathological class. ANCA-associated vasculitis is a rare, but severe autoimmune disease –3. KidneThe histological features of kidney biopsy could have a certain relationship to the outcome. Older studies have suggested that the proportion of normal glomeruli was a predictor of a good renal outcome , while tWe aimed to evaluate ANCA phenotypes, kidney and patient outcome in a cohort of Central-East European patients with severe crescentic glomerulonephritis admitted in a tertiary Nephrology center in relation with ANCA specificity and histopathological classification.This is a retrospective cohort study on all adult patients consecutively diagnosed by kidney biopsy with pauci-immune crescentic glomerulonephritis and followed in a single Nephrology center serving a population of about 4.85 million. From January 2000 till January 2014, pauci-immune crescentic glomerulonephritis were diagnosed in 104 patients. Thirteen patients were excluded because they were ANCA negative, 4 because of incomplete data and 12 were lost to follow-up.The final cohort comprised 75 patients with ANCA positive pauci-immune crescentic glomerulonephritis who were followed over a median period of 3.2  years.All subjects signed an informed consent form authorising us to use their demographic and medical data in this study.The study was performed in accordance with Helsinky Declaration and it was approved by the local Ethics Committee of the “Dr. Carol Davila” Teaching Hospital of Nephrology.The criteria for pauci-immune crescentic glomerulonephritis diagnosis were crescents (cellular and/or fibrous) in at least 50 % of examined glomeruli by light microscopy and a direct immunofluorescence assay of 0 to 1+ on a scale from 0 to 4+ . For thiANCAs were assessed by capture PR3-ANCA and MPO –ANCA ELISA  or by indirect immunofluorescence .Markers of kidney damage were proteinuria measured in 24 h urine collection, hematuria , serum creatinine and the histopathologic classes.Hemorrhagic alveolitis was diagnosed based on chest radiographs and acute anemia without evidence of another external bleeding, and was classified as severe when oxygen partial pressure in arterial blood decreased under 60 mmHg. Severe anemia was defined as hemoglobin level less than 7 g/dL.Inflammation was assessed using erythrocyte sedimentation rate (ESR), serum fibrinogen, serum albumin, platelet count and white blood cells count.The measurements were performed by standard laboratory methods on an Olympus AU 400 chemistry auto-analyzer, and a MINDRAY BC 3000 hematology auto-analyzer.The severity of vasculitis was evaluated using Birmingham Vasculitis Activity Score ver. 3 (BVAS) .The follow-up protocol included monthly visits with clinical (BVAS) and laboratory evaluation, until remission and every 3 months thereafter.Response to therapy was defined as disappearance of hematuria, stable or improving serum creatinine and no signs of activity in other organs .Dialysis therapy was considered temporary when needed for less than 3 months.Study end-points were response to therapy, end stage renal disease (ESRD) and death.2, two pulses in the first month, then one pulse monthly for the next five months in the majority of patients (the mean cumulative cyclophosphamide dose was 4.6 g). Maintenance therapy consisted in prednisone (10 mg daily in the first year and 7.5 mg daily afterwards) and azathioprine 1.5–2 mg/kg per day for at least 2 years. Plasmapheresis was only occasionally performed (5 patients), usually in case of severe hemorrhagic alveolitis, because this therapy is not reimbursed by the health insurance authority.Induction therapy was done with steroids  associated with cyclophosphamide 0.5 g/mCategorical variables are presented as percentages and comparison tests were performed using Pearson χ2 test. Continuous variables are displayed as mean with 95 % confidence interval (95 % CI) or median and quartiles , according to their distribution. Comparisons were done with ANOVA, Mann-Whitney and Kruskal-Wallis tests, as appropriate.Survival analyses were conducted with the Kaplan-Meier method and Mantel-Cox log-rank test for comparisons. Models of binomial or multinomial logistic regression were built to estimate differences between groups at presentation. Multivariate Cox proportional hazard ratios (PHR) models were used to evaluate parameters associated with various outcomes.p ≤ 0.05 was considered statistically significant.A Statistical analyses were performed with SPSS  and Analyse-it™  packages.p = 0.006) times higher than in those who did not.Table Most patients (76 %) were MPO-ANCA positive. PR3-ANCA patients were younger, in higher proportion male, had higher BVAS, resulting from more frequent upper respiratory tract and eye symptoms and more severe kidney damage Table , Fig. 1.Most of the patients (52 %) were in the crescentic histopathologic class. PR3-ANCA and MPO-ANCA specificities had a similar distribution in the histopathologic classes Table .When evaluated by logistic regression, in patients with creatinine ≥5 mg/dL, PR3-ANCA was associated with male gender and dialysis at presentation Table .Table 2DForty-five patients (60 %) responded to the induction therapy in 4  months. Neither the histopathologic class nor the ANCA specificity influenced the rate of response.In multivariate Cox regression analysis, although older patients and those with higher platelets number responded better, the need for dialysis at presentation was the most powerful predictor of response: the hazard ratio of response was two and a half times higher in patients not needing dialysis at presentation Table .Table 3POf the 51 patients alive at the end of the observation period, 38 (51 % of the whole cohort) were dialysis-free.As compared to dialysis dependent-patients, those dialysis-free were older females and had less severe kidney disease at presentation . The kidney survival was not influenced by the vasculitis severity, ANCA serology or the histopathological class Table .Table 4Pp < 0.001), while those not needing dialysis at presentation had a 84 % lower risk of kidney death .The unadjusted probability of kidney survival 1 and 5 years was 93 % and 64 %. The median ESRD-free survival time was longer in responders to induction therapy and in those who did not need dialysis at presentation Fig. . In a Con = 9; 38 % of deaths).Fifty one (68 %) patients survived. The main cause of death was pulmonary hemorrhage (Surviving patients had less severe vasculitis (lower BVAS), less severe kidney disease  and higher serum albumin levels. They responded in higher proportion to induction therapy. ANCA specificity and the histopathological class did not influence the patient outcome Table .Table 5Pp = 0.05) - and the response to induction therapy - non-responders had five times less chances of survival  . As in other series of vasculitis with severe kidney involvement , 30, theThe rate of complete remission was 60 %, lower than that reported in controlled trials 75–85 %) –37, wher5 % –37, In spite of severe kidney disease at presentation, 51 % of our patients were alive and dialysis free at the end of the observation period, which is similar to reports from studies enrolling vasculitis patients with severe kidney dysfunction (56–64 %) , 40. MorWhile kidney survival was associated with the initial organ damage, patient’s survival depended on vasculitis activity at presentation as reflected by BVAS. Several studies reported associations between BVAS and long term outcome , 42. We The other independent predictor of death was the response to induction therapy; the responders had five times more chances of survival than non-responders. As induction therapy was conducted according to current guidelines, including dose adjustment to renal function and age, this further underlines the limits of the existing therapeutic regimens.Other studies reported differences in long term survival related to ANCA specificities , 28 whilA histopathological classification of ANCA-associated glomerulonephritis was recently proposed by Berden et al. , aiming There are some limits of our study. The number of participants was low and the period of observation rather short, both limiting the statistical power. The single center design could be a limit for extrapolation of the results to other population, but data on Central East European population are scarce and on the other hand, this design increases the accuracy of data collection. ANCA were assessed by indirect immunofluorescence and/or by ELISA, and discrepancies between results obtained by these methods were described.In ANCA positive pauci-immune crescentic glomerulonephritis, the kidney and patient outcomes are related to the severity of kidney damage at presentation and to the response to therapy, but not to ANCA specificity or to the histopathological class. Thus, “the blast” - the acute injury inducing severe organ damage - results in a peculiar distribution in histopathological classes, reduced responsiveness to therapy and poorer outcome, and could hide the prognostic influence of both “the trigger” - i.e. ANCA specificity - and of the histopathology lesions.


The efficacy of montelukast in the treatment of asthma has been demonstrated in numerous controlled clinical trials. The aim of this study was to assess the real-life effectiveness of montelukast administered as monotherapy or in combination with current ICS in children with uncontrolled asthma.Twelve-week open-label, phase IV, multicenter, prospective cohort study. Eligible patients included children aged 2-14 years diagnosed with asthma for =6 months who were: (i) uncontrolled as per the Canadian Asthma Consensus Guidelines, and; (ii) either untreated, using a short-acting ß2–agonist as-needed or using any dose ICS. In this analysis, patients with Asthma Control Questionnaire (ACQ) score >0.75 were included. Patients 6-14 and 2-5.9 years old were treated once-daily with montelukast 5mg and 4mg, respectively. Primary outcome measure was the proportion achieving asthma control (ACQ=0.75). Secondary outcomes were the absolute change in ACQ and in the Pediatric Asthma Caregiver’s Quality of Life Questionnaire (PACQLQ) over time.Among the 328 patients included, 76 (23.2%) were treated with montelukast monotherapy and 252 (76.8%) with montelukast combined with ICS. By 4 weeks of treatment 61.3% and 52.9% of patients in the monotherapy and combination group, respectively, achieved asthma control. These proportions increased to 75.0% and 70.9%, respectively, at week-12. Clinically and statistically (P<0.001) significant improvements were observed in ACQ (monotherapy: mean (SD) of 1.67 (0.69) at baseline and 0.50 (0.52) at week-12; combination therapy: 2.02 (0.83) and 0.64 (0.86), respectively) and PACQLQ (monotherapy: mean (SD) of 5.34 (1.14) at baseline and 6.51 (0.85) at week-12; combination therapy: 4.42 (1.35) and 6.21 (1.03), respectively) in both patient subgroups. After a 12-week montelukast add-on therapy, 22.6% of patients reduced their ICS dosage.Montelukast as monotherapy or in combination with ICS represents an effective treatment strategy for achieving asthma control in pediatric patients and improving caregivers’ quality of life.3 investigators.On behalf of the ACTIONClinicaltrials.gov: 00832455.